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WO2007034909A1 - Process for production of (3r,5r)-7-amino-3,5-dihydroxyheptanoic acid derivative - Google Patents

Process for production of (3r,5r)-7-amino-3,5-dihydroxyheptanoic acid derivative Download PDF

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WO2007034909A1
WO2007034909A1 PCT/JP2006/318834 JP2006318834W WO2007034909A1 WO 2007034909 A1 WO2007034909 A1 WO 2007034909A1 JP 2006318834 W JP2006318834 W JP 2006318834W WO 2007034909 A1 WO2007034909 A1 WO 2007034909A1
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group
acid derivative
formula
substituted
acid
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Tetsuji Hayano
Akira Nishiyama
Nobuo Nagashima
Noriyuki Kizaki
Yoshihiko Yasohara
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Kaneka Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method for producing a (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative useful as a pharmaceutical intermediate, particularly an HMG-CoA reductase inhibitor intermediate.
  • Patent Document 1 3 ⁇ 42004- 533479
  • Patent Document 2 Special Table 2004— 533481
  • Patent Document 3 Japanese Patent Laid-Open No. 08-198832
  • Patent Document 4 Special Table 2000—515882
  • Non-Patent Document 1 Synthetic Communications, 2003, 33 (13), 2275.
  • the present invention is a cheap and easily available raw material power that can be easily and efficiently implemented on a commercial scale.
  • R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted carbon. It represents any of the aralkyl groups of formulas 7 to 12.
  • R 3 and R 4 are hydrogen or a hydroxyl protecting group, and R 3 and R 4 may be taken together to form a bridging hydroxyl protecting group.
  • X 1 represents a halogen atom.) (3R, 5S) — 7-Noro 3,5-dihydroxyheptanoic acid derivative is aminated with ammonia, and is represented by the following formula (I );
  • the present invention relates to a method for producing a (S) -5-halo 3-hydroxypentanoic acid derivative represented by the formula (wherein R 2 and X 1 are the same as above).
  • the present invention has five process powers (1) to (5).
  • the carbon number means a number that does not include the carbon number of the substituent.
  • substituents examples include a hydroxyl group, an alkoxy group, a nitro group, an amino group, an acyl group, a carboxyl group, and a halogen atom.
  • the method for producing the compound (IV) from the compound (II) is not particularly limited !, but for example, acid chloride (II) and the following formula (III);
  • a method of decomposing alcohol can be used.
  • the acid chloride ( ⁇ ) and acetic acid enolate (III) are reacted with each other, or the acid chloride (II) and malonate ( ⁇ ) are reacted and then decarboxylated.
  • X 1 represents a halogen atom, specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a chlorine atom or a bromine atom. . More preferably, it is a chlorine atom.
  • R 2 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, specifically, a methyl group, an ethyl group, isopropyl Group, tert-butyl group, n-octyl group, etc., preferably methyl group or ethyl group. More preferred is an ethyl group.
  • acetic acid enolate (III) is prepared by reacting an acetic acid ester with a base, by reacting a haloacetic acid ester with a zero-valent metal, or by reacting an acetic acid ester with a metal salt and a tertiary amine. Any of the methods of preparing them may be used.
  • Acetic acid esters and haloacetic acid esters are not particularly limited, and include methyl acetate, ethyl acetate, tert-butyl acetate, methyl acetate, ethyl acetate, and methyl bromoacetate.
  • acetic acid enolate (III) by reacting an acetic ester and a base
  • specific examples of the base include magnesium amides, lithium amides, and Grignard.
  • examples include reagents, sodium amides, potassium amides, alkyllithiums, metal alkoxides, and metal hydrides.
  • magnesium amides include the following formula (XIV):
  • R 9 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or Represents! / Of a silyl group having 3 to 12 carbon atoms, specifically, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclohexyl group, an n-octyl group, or a phenyl group.
  • X 3 represents a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom.
  • the magnesium amides can be prepared by known methods (for example, JP-A-8-523420) from secondary amines that are inexpensive and readily available and Grignard reagents. Alternatively, a known method (for example, J. Org. Chem., 199) from lithium amide and magnesium halide. 1, 56, 5978-5980).
  • lithium amides include the following formula (XV);
  • R 7 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or This represents any deviation of the silyl group having 3 to 12 carbon atoms, specifically, the same as R 8 and R 9 described above. An isopropyl group is preferred.
  • Grignard reagents include the following formula (X):
  • methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, n-octyl group, phenyl group, naphthyl group, p-methoxyphenyl group, p —-Trobenzyl group and the like are preferable, and a methyl group, an ethyl group, an isopropyl group, an n-butyl group, and a tert-butyl group are preferable, and a tert-butyl group is more preferable.
  • X 4 represents a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom, and more preferably a chlorine atom.
  • Examples of the sodium amides include sodium amide and sodium diisopropylamide.
  • Examples of the potassium amides include potassium amide, potassium diisopropylamide, potassium dicyclohexylamide, potassium hexamethyldisilazide and the like.
  • Examples of the alkyl lithium include methyl lithium, n-butyl lithium, tert-butyl lithium and the like.
  • Examples of the metal alkoxides include sodium methoxide, sodium methoxide, magnesium ethoxide, potassium tert-butoxide and the like.
  • Money Examples of genus hydrides include lithium hydride, sodium hydride, potassium hydride, and hydrogenation power.
  • the base is preferably lithium amides or magnesium amides, specifically lithium diisopropylamide, lithium dicyclohexylamide, or lithium hexamethylzide, and more preferably lithium diisopropylamide.
  • the amount of the base used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount of the above-mentioned acetate ester. Further, in the method of preparing enoacetate (III) by reacting a haloacetic acid ester with a zero-valent metal, chloroacetic acid ester, bromoacetic acid ester, or odoacetic acid ester is more preferable as haloacetic acid ester.
  • the zero-valent metal is preferably zinc, magnesium, tin or the like, and more preferably zinc or magnesium.
  • the amount of the zerovalent metal used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the haloacetic acid ester.
  • the metal salt is preferably tetrachloride-titanium, tetrachloride-zirconium, or tin tetrachloride, and more preferably tetrachloride-titanium.
  • the amount of the metal salt used is preferably 1 to: LO times the molar amount, more preferably 1 to 3 times the molar amount with respect to the acetate ester.
  • the tertiary amine is preferably pyridine, imidazole, methylimidazole, N-methylmorpholine, N-methylpyrrolidine, diisopropylethylamine, triethylamine, or tri-n-butylamine, and more preferably. Is diisopropylethylamine, triethylamine, or tri-n-butylamine.
  • the amount of the tertiary amine used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the acetate ester.
  • the amount of the enolate acetate (III) thus prepared is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the acid chloride (II).
  • Examples of the solvent that can be used in this step include aprotic organic solvents.
  • examples of non-protonic organic solvents include benzene, toluene, n-hexane, and cyclohexane.
  • Hydrocarbon solvents such as methylcyclohexane; jetyl ether, tetrahydrofuran,
  • Amide solvents such as dimethyl sulfoxide; urea solvents such as dimethylpropylene urea; phosphonic triamide solvents such as hexamethylphosphoric triamide.
  • the above solvents may be used alone or in combination of two or more. Of the above solvents, tetrahydrofuran and ether solvents are preferable, and tetrahydrofuran is more preferable.
  • the reaction temperature is preferably ⁇ 100 to 30 ° C., more preferably ⁇ 80 to 10 ° C.
  • the mixing order of the reagent and acid chloride ( ⁇ ) for preparing enolate acetate ( ⁇ ) is arbitrary, but preferably enolate acetate (III) is prepared, and acid chloride (II) is added thereto. It is better to react.
  • a general process may be performed in order to obtain a reaction fluid force after completion of the reaction.
  • a general inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate or the like is mixed in the reaction solution after completion of the reaction, and a general extraction solvent such as ethyl acetate, jetyl ether, chloride or the like is mixed.
  • the desired product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure.
  • the target product obtained in this way is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography or the like.
  • the malonate (XIII) can be prepared by reacting a malonic acid monoester alkali metal salt, an alkaline earth metal halide and a tertiary amine.
  • the malonic acid monoester alkali metal salt is preferably malonic acid monoester alkali metal salt.
  • examples thereof include a sodium salt, a malonic acid monoester sodium salt, a malonic acid monoester potassium salt, or a malonic acid monoester cesium salt, preferably a malonic acid monoester sodium salt or a malonic acid monoester potassium salt.
  • Malonic acid monoester potassium salt is preferred.
  • the amount of the malonic acid monoester alkali metal salt used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
  • the alkaline earth metal halide is preferably calcium chloride, magnesium chloride, magnesium bromide, magnesium iodide or the like, and more preferably salt magnesium.
  • the amount of the alkaline earth metal halide used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
  • Examples of the tertiary amine include diisopropylethylamine, diisopropylmethylamine, triethylamine, N, N-dimethylaniline, N-methylmorpholine, 1,4-diazabicyclo [2,2,2] octane. 1,8-diazabicyclo [5,4,0] undek 7-en, N, N, ⁇ ', ⁇ '-tetramethylethylenediamine, quinoline, pyridine and the like.
  • Preferred are diisopropylethylamine, triethylamine and the like, and more preferred is triethylamine.
  • the amount of the tertiary amine used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
  • Examples of the solvent that can be used in this step include an aprotic organic solvent. Specific examples are those mentioned above.
  • the above solvents may be used alone or in combination of two or more.
  • ester solvents or ether solvents are preferable, and ethyl acetate or tetrahydrofuran is particularly preferable.
  • the reaction temperature is preferably 0 to 100 ° C, more preferably 10 to 40 ° C.
  • the mixing order of the reaction reagents is arbitrary.
  • malonic acid monoester alkali metal salt, alkaline earth metal halide and tertiary amine are mixed first, and acid chloride (II) is finally added. It is better to carry out the reaction.
  • an acid such as hydrochloric acid or hydrobromic acid is added to the obtained reaction solution and stirred, decarboxylation proceeds to obtain the desired compound (IV).
  • a general process may be performed in order to obtain a reaction fluid force after completion of the reaction.
  • a general inorganic acid or organic acid in the reaction solution after completion of the reaction For example, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, and the like are mixed, and the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like.
  • the target product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure.
  • the target product obtained in this way is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography or the like.
  • the (S) -5-halo 3-hydroxypentanoic acid derivative represented by the formula (V) is a novel compound unknown in the literature that is useful as a pharmaceutical intermediate.
  • X 1 and R 2 are the same as described above, and preferably X 1 is a chlorine atom, and is an R 2 force methyl group or an ethyl group. More preferably, R 2 is an ethyl group.
  • the reaction solution obtained in the step (1) may be used as it is, or an isolated and purified product may be used.
  • the asymmetric reduction method in this step is not particularly limited as long as it can selectively reduce the carbonyl group of the compound (IV), and a hydride modified with an optically active compound.
  • a method of hydrogenation in the presence of an asymmetric transition metal catalyst is preferred.
  • a method for hydrogenation in the presence of an asymmetric transition metal catalyst will be described.
  • the asymmetric transition metal catalyst include ruthenium, rhodium, iridium, and platinum. Ruthenium complexes are more preferred from the viewpoints of stability, availability, and economics of complexes where group VIII metal complexes are preferred.
  • the asymmetric ligand in the metal complex is preferably a bidentate ligand as a phosphine ligand preferred by a phosphine ligand.
  • Bidentate ligands include BINAP (2, 2'-bisdiphenylphosphino-1,1,1-binaphthyl); Tol- BINAP (2,2,1-bis (di-p-tolylphosphino-one) 1,1,1, binaphthyl) and other BINAP derivatives; BDPP (2,4-bis (diphenylphosphino) pentane); DIOP (4,5-bis (diphenylphosphinomethyl) -1,2,2-dimethyl-1, 3—dioxane; BPP FA (1— [1,2,2-bis (diphenylphosphino) ferroceyl] ethylamine); CHIRAP HOS (2,3-bis (diphenylphosphino) butane); DEGPHOS (l—substituted one 3, 4-bis (diphenylphosphino) pyrrolidine); DuPHOS (l, 2-bis (2,5-substituted
  • the amount of the metal catalyst to be used is preferably 0.1 times or less by mole, more preferably 0.05 to 0.0001 times by mole, relative to the compound (IV).
  • a hydrogen pressure preferably L ⁇ 100kgZcm 2, more preferably from l ⁇ 30kgZcm 2.
  • reaction solvent examples include water; alcohol solvents such as methanol, ethanol and isopropanol; aprotic organic solvents and the like. Specific examples of the aprotic organic solvent include those mentioned above. These may be used alone or in combination of two or more. Preferred is water or an alcohol solvent, and more preferred is a mixed solvent of methanol and water or ethanol and water.
  • the mixing ratio of the methanol / water or ethanol / water mixed solvent can be selected arbitrarily.
  • the volume ratio of methanol Z water or ethanol Z water is preferably 100 Zl to lZl, more preferably 20 Zl to 4 Zl.
  • the amount of the solvent to be used is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (IV).
  • the reaction temperature is preferably -20 to 100 ° C, more preferably 0 to 60 ° C.
  • a general process may be performed. For example, after removing the transition metal catalyst from the reaction solution after completion of the reaction by decompression or pressure filtration, the reaction solvent is distilled away by an operation such as heating under reduced pressure to obtain the desired product.
  • the target product thus obtained may be further purified by a general purification technique such as power crystallization, fractional distillation, column chromatography, etc., having sufficient purity that can be used in subsequent steps. .
  • An enolate is prepared by reacting an acetate derivative represented by formula (I) with a base or a zero-valent metal, and (S) -5-halo-3-hydroxy represented by the formula (V).
  • a pentanoic acid derivative is reacted to form the following formula (VII):
  • R 1 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted group Alternatively, it is an unsubstituted aralkyl group having 7 to 12 carbon atoms, and specific examples thereof are the same as those given for hydrogen and R 5 .
  • R 1 is preferably a tert butyl group.
  • X 2 represents a hydrogen atom or a halogen atom, and specifically includes a hydrogen atom, a chlorine atom, an iodine atom, or an iodine atom, preferably a hydrogen atom or a bromine atom.
  • reaction solution obtained in step (2) may be used as it is, or an isolated and purified product may be used. good. It can also be synthesized separately by methods other than (2)! /.
  • the use amount of the acetate derivative (VI) is 1 to: LO times molar amount, preferably 1 to 5 times molar amount with respect to the compound (V).
  • Bases used in the preparation of the enolate include the same magnesium amides, lithium amides, Grignard reagents, sodium amides, potassium amides, alkyllithiums as exemplified in step (1), Examples thereof include metal alkoxides and metal hydrides.
  • Preferred bases are magnesium amides, lithium amides or Grignard reagents. Of these, lithium diisopropylamide is preferably tert-butylmagnesium chloride. These bases may be used alone or in combination. For example, the lithium amides are effective when used in combination with the Grignard reagents.
  • the amount of the base used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount relative to the acetate derivative (VI).
  • the zero-valent metal that can be used in preparing the enolate in this step is zinc, magnesium, tin or the like, preferably zinc or magnesium.
  • the amount of the zero-valent metal used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount relative to the ester acetate derivative (VI).
  • reaction solvent in this step examples include aprotic organic solvents. Specific examples are those mentioned above.
  • the solvents may be used alone or in combination of two or more.
  • a hydrocarbon solvent or an ether solvent is preferable. Particularly preferred is tetrahydrofuran.
  • the reaction temperature in this step is preferably -30 to 100 ° C, more preferably -10 to 60 ° C.
  • the mixing order of the reactants is arbitrary.
  • the base is mixed with the mixed solution of 5-halo-3-hydroxypentanoic acid derivative (V) and acetate derivative (VI). Or you can add a zero-valent metal and react it! / ⁇ .
  • X 2 of the acetic acid ester derivative (VI) is hydrogen
  • the odorous methylmagnesium is previously added to the mixed solution of the 5-halo 3-hydroxypentanoic acid derivative (V) and the acetic acid ester derivative (VI).
  • Grignard reagents such as isopropyl magnesium chloride, tert butyl magnesium chloride,
  • magnesium amides such as magnesium iodide diisopropylamide, magnesium chloride dicyclohexylamide, etc.
  • the reaction is performed by dropping a solution of lithium amides or magnesium amides.
  • a general process may be performed in order to obtain a reaction fluid force after completion of the reaction.
  • the reaction solution after completion of the reaction is mixed with a general inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, etc., and a general extraction solvent such as ethyl acetate, jetyl ether, chloride, etc.
  • Extraction is performed using methylene, toluene, hexane or the like.
  • the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained.
  • the target product obtained in this way is almost pure, but it may be further purified by a general method such as crystallization purification, fractional distillation, column chromatography or the like.
  • R 4 is a hydrogen atom or a hydroxyl-protecting group, and R 4 may be taken together to form a bridging hydroxyl-protecting group.
  • the protective group is not particularly limited as long as it is used as a protective group for a hydroxyl group, but the protective 'Groups' in 'Organic Synthesis' 3rd edition (Protective Groups in Organic Synthesis, 3rd Ed.), Theodora W. Protecting groups described in pages 17-200 of 1999, published by JOHN WILEY & SONS by Theodora W. Green.
  • Examples of the protecting group for the hydroxyl group for crosslinking when R 3 and R 4 are combined include the crosslinking protecting groups described on pages 201 to 245 of the above-mentioned literature. Specific examples include an isopropylidene group, a methylene group, an ethylidene group, a tert-butylmethylidene group, and a 1-phenylethylidene group.
  • a hydrogen atom or a protecting group for a hydroxyl group of a bridge is preferred, and a hydrogen atom or an isopropylidene group is more preferred.
  • X 1 is a chlorine atom, R 3 and R 4 are both hydrogen atoms, and R 1 is a tert butyl group represented by the following formula (XI);
  • the reaction solution obtained in the step (3) may be used as it is, or an isolated and purified product may be used. You can also use the one obtained by another method.
  • the reduction method in this step is not particularly limited as long as it is a method capable of diastereoselectively reducing the carbo group of the compound (VII), and a reduction method using a hydride reducing agent.
  • a method of hydrogenation in the presence of a metal catalyst examples include a method of hydrogenation in the presence of a metal catalyst, a method of reduction by a hydrogen transfer type in the presence of an asymmetric transition metal catalyst, or a method of reduction using a microorganism or an enzyme derived from a microorganism.
  • Preferred examples include a reduction method using a hydride reducing agent, a hydrogenation method in the presence of an asymmetric transition metal catalyst, and a reduction method using a microorganism or a microorganism-derived enzyme.
  • a preferable method for reducing with a hydride reducing agent is a known method (Japanese Patent No. 2843627) in which sodium borohydride is used in the presence of methoxyjetylborane.
  • the amount of the methoxyethylborane to be used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the compound (VII).
  • the amount of the sodium borohydride to be used is preferably 0.25 to: LO times molar amount, more preferably 0.5 to 3 times molar amount relative to the compound (VII). .
  • the reaction temperature is preferably ⁇ 100 to 0 ° C., more preferably ⁇ 80 to ⁇ 30 ° C. from the viewpoint of improving the yield.
  • the reaction solvent methanol, ethanol, tetrahydrofuran and the like are preferred, and two or more of these may be used in combination.
  • a general process may be performed in order to obtain the reaction fluid force after completion of the reaction.
  • the reaction solution after completion of the reaction is mixed with a general inorganic acid or organic acid, such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, etc.
  • a general inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, etc.
  • the desired product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure.
  • the target product obtained in this way is almost pure, but it can be purified by general techniques such as crystallization purification, fractional distillation, column chromatography, etc. And the purity may be further increased.
  • a method for hydrogenation in the presence of an asymmetric transition metal catalyst will be described.
  • a metal complex of a Group VIII element of the periodic table such as ruthenium, rhodium, iridium, or platinum is preferable, and the stability, availability, and economical viewpoint are preferred. From this point, ruthenium complexes are preferred.
  • the asymmetric ligand in the metal complex is preferably a bidentate ligand as a phosphine ligand, preferably a phosphine ligand.
  • Examples of the bidentate ligand include those described in the step (2).
  • BIN AP (2, 2, 1-bisdiphenylphosphino 1, 1, 1-binaphthyl) is preferable, and (R) -BINAP may be used to selectively reduce the carbo group at the 3-position.
  • (R) -B INAP complex is preferably ((R) -BINAP) RuBr, ((R) -BINAP) RuCl, or
  • it is 0.1 mol or less, more preferably 0.05 to 0.0001 mol, relative to the compound (VII).
  • reaction conditions such as hydrogen pressure, reaction solvent, solvent usage, reaction temperature, and post-treatment method are the same as in the method of hydrogenation in the presence of the asymmetric transition metal catalyst in step (2).
  • derived from a microorganism may be a cell of the microorganism itself, a culture solution of the microorganism, a treated product of the microorganism, or an enzyme obtained from the microorganism, and furthermore, derived from the microorganism. And a transformant introduced with a DNA encoding an enzyme having the above reducing activity. These may be used alone or in combination of two or more. These enzyme sources may be immobilized so that they can be used repeatedly by a known method.
  • a microorganism having the ability to selectively reduce the carbonyl group of the compound (VII) can be found by the method described below. For example, it is performed as follows. Glucose 40 g, yeast extract 3 g, dihydrogen phosphate 6.5 g, potassium dihydrogen phosphate lg, magnesium sulfate heptahydrate 0.8 g, zinc sulfate heptahydrate 60 mg, iron sulfate 7 water Japanese 90mg, Copper sulfate pentahydrate 5mg, Manganese sulfate tetrahydrate 10mg, Sodium chloride 100m Put 5 ml of liquid medium (pH 7) with composition (g, V, deviation per liter) into a test tube, sterilize, inoculate aseptically, and incubate with shaking at 30 ° C for 2-3 days.
  • the cells are collected by centrifugation, suspended in 0.5-5 ml of phosphate buffer containing 2-10% glucose, and added beforehand to a test tube containing 0.5-25 mg of the compound (VII). Shake at 30 ° C for 2-3 days.
  • cells obtained by centrifugation can be used in a desiccator or dried with acetone. Furthermore, when reacting these microorganisms or processed products thereof with the compound (VII), NAD + and Z or NADP + described later, glucose dehydrogenase and glucose, or formate dehydrogenase and formic acid may be added. Good. It is also possible to coexist an organic solvent in the reaction system.
  • the microorganisms that can be used in the present invention include the ability to use any microorganism that has the ability to selectively reduce the carbonyl group of the compound (VII).
  • VI carbonyl group of the compound
  • Eremothecium Eremothecium
  • SaccharomvcoDsis SaccharomvcoDsis
  • Candida Citeromvces, ClavisDora, CrvDtococcus
  • Debariomyces ebar Debariomyces ebar
  • Debariomyces ebar Debariomyces ebar
  • Dipodascus rot Galactomvces genus, Geotrichum genus, Hansenias pora genus, Ambrosiozvma genus, Hipphopichia genus Issatchenkia, Kluweromvces, Pichi, Lipomvce s)
  • Metschnikowia Pachvsolen, Rhodotorula, Rhodsporidium, Saccha
  • Debarvomvces 7 ⁇ Noriomas' Debarvomvces robertsiae, Dekkera anomala, Ipodascus ovetensis, Kepodoscus tetrasperma, Galactomyces resi Galactom vces reessii) , Geotrichum candidum, Geotrichum fermentans, Geotrichum fraera ns, Geotrichum loubieri, Hanseniaspora gu Ma phiren ⁇ mus (Ambrosioz harm a ph ilentomus), Ambrosiozima platvpodis ⁇ Hippo Pichia.
  • Minuta Triconopsis variabilis, Willopsis saturnus var. Mrakn, Willopsis saturnus var. ⁇ Nus (Willopsis sat urn us var. Saturnus), Pichia farinosa, Alcalieenes xvlosoxidans, Arthrobacter protophormiae Microtocterium Estellalomaticum Microbacterium esteraro maticum, Bacillus sphaericus, Buttiauxella aerestis, Cedecea davisiae, Cellolemonas sp. Ia, Oschovia turbata), Citrobacter freun dii), Clostridium cylindrosporum
  • Chronobacterium arborescens Micrococcus luteus, Ochrobactrum sp., Proteus inconstans, Proteus mirabilis ( Proteus mirabilis), Proteus' retrogeri (froteus rettgeri), Proteus Proteus vulgaris, Providencia stuartii, Pseudomonas putida, Pseudomonas stutzeri, Rhodococer liquei 'Sphingobactenum ulcerivorum', Absidia 'Absidia orchidis', Acremmo'um' Acremonium bacillisporum, Amvlostereum areolatum, 7 ⁇ ⁇ ⁇ ⁇ , ' ⁇ ⁇ (Aspergillus soiae), /' ⁇ ⁇ A A A A ⁇ ⁇ Chaetomidium fimeti, Chietosanoretoriya-Stromatozaes, Hormoconis resina
  • these microorganisms can obtain stock strength that can be easily obtained or purchased, but they can also separate natural forces. It is also possible to obtain strains having more advantageous properties for this reaction by causing mutations in these microorganisms.
  • any medium containing a nutrient source that can be assimilated by these microorganisms can be used.
  • sugars such as glucose, sucrose and maltose
  • organic acids such as lactic acid, acetic acid, citrate and propionic acid
  • alcohols such as ethanol and glycerin
  • hydrocarbons such as paraffin, fats and oils such as soybean oil and rapeseed oil, Or a carbon source such as a mixture thereof
  • nitrogen sources such as ammonium sulfate, ammonium phosphate, urea, yeast extract, meat extract, peptone, corn steep liquor; and other inorganic salts, vitamins A normal medium containing a mixture of various nutrient sources;
  • These mediums should be selected appropriately according to the type of microorganism used.
  • Microorganisms can be cultured under normal conditions, for example, aerobically for 10 to 96 hours at a pH of 4.0 to 9.5 and a temperature range of 20 ° C to 45 ° C. It is preferable to do.
  • a concentrate of a force culture solution that can be used in the reaction as it is.
  • a microbial cell or a microbial cell-treated product obtained by treating the culture solution by centrifugation or the like can also be used.
  • the microorganism-treated product of the microorganism is not particularly limited.
  • a dried microorganism obtained by dehydration using acetone or nitric pentoxide or drying using a desiccator or a fan examples include lysed enzyme-treated products, immobilized cells, or cell-free extract preparations obtained by disrupting cells.
  • an enzyme that catalyzes the reduction reaction stereoselectively from the culture may be purified and used.
  • the compound (VII) as a substrate may be added all at once at the beginning of the reaction, or may be added in portions as the reaction proceeds.
  • the reaction temperature is usually 10-60. C, preferably 20-40. C, and the pH during the reaction is in the range of 2.5-9, preferably 5-9.
  • the amount of the enzyme source in the reaction solution may be appropriately determined according to the ability to reduce these substrates.
  • the substrate concentration in the reaction solution is preferably 0.01 to 50% (WZV), more preferably 0.1 to 30% (WZV).
  • the reaction is usually not shaken or agitated. Do it.
  • the reaction time is appropriately determined depending on the substrate concentration, the amount of enzyme source, and other reaction conditions. Usually, it is preferable to set each condition so that the reaction is completed in 2 to 168 hours.
  • an energy source such as glucose, ethanol, isopropanol or the like is added to the reaction solution at a ratio of 0.5 to 30% so that excellent results can be obtained.
  • an energy source such as glucose, ethanol, isopropanol or the like
  • NADH adenine dinucleotide
  • NADPH reduced nicotinamide 'adenine dinucleotide phosphate
  • the reaction can also be promoted by adding a coenzyme. In this case, specifically, these are added directly to the reaction solution.
  • the oxidized coenzyme (NAD + or NADP +) is reduced to the respective reduced form (NADH or NADPH) (having coenzyme regeneration ability) and reduced. It is preferable to carry out the reaction in the presence of a substrate for obtaining excellent results.
  • a substrate for obtaining excellent results.
  • glucose dehydrogenase as an enzyme that reduces to the reduced form
  • glucose coexisting as the substrate for reduction or formate dehydrogenase as the enzyme that reduces to the reduced form
  • formic acid as the substrate to reduce .
  • a transformant containing DNA encoding the enzyme may be used, and the carbo group of the compound (VII) is similarly used. Diastereoselective reduction of can be performed. Further, even when a transformant containing both DNA encoding the reductase of the present invention and DNA encoding a polypeptide having a coenzyme regeneration ability is used, the carbohydrate of the compound (VII) is similarly used. -Diastereoselective reduction of a group can be performed.
  • a transformant containing a DNA encoding the polypeptide of the present invention, or a DNA encoding the reductase of the present invention and a polypeptide having coenzyme regeneration ability is encoded.
  • the transformant containing both of the DNAs can be used for diastereoselective reduction of the carbonyl group of the compound (VII) as well as the treated product, not to mention the cultured cells.
  • the treated product of the transformant referred to here is, for example, a cell treated with a surfactant or an organic solvent, a dried cell, a disrupted cell, a crude cell extract or the like, or a known method. Means a fixed value.
  • a transformant containing both the DNA encoding the reductase of the present invention and the DNA encoding a polypeptide having a coenzyme regeneration ability is a DNA encoding the reductase of the present invention, and
  • these two types of DNA are different in incompatibility groups. They can also be obtained by integrating each into a vector of the species and introducing the two vectors into the same host cell.
  • coli HB101 (pNTDRGl) FERM BP— 08458 was deposited on May 29, 2002 by the National Institute of Advanced Industrial Science and Technology. It is deposited with the Center (IPOD: ⁇ 305-8566, 1-chome, 1-chome Tsukuba, Ibaraki 1).
  • a surfactant such as Triton strength light tester Co., Ltd.), Span (manufactured by Kanto Igaku Co., Ltd.), Queen strength power tester Co., Ltd. Is.
  • 3-hydroxybutyrate that is the substrate and Z or the product of the reduction reaction.
  • an organic solvent insoluble in water such as ethyl acetate, butyl acetate, isopropyl ether, toluene, hexane may be added to the reaction solution.
  • an organic solvent soluble in water such as methanol, ethanol, acetone, tetrahydrofuran, dimethyl sulfoxide, etc. can be added.
  • the collection of the (3R, 5S) -7,5 dihydroxyheptanoic acid derivative produced by the reduction reaction is not particularly limited, but it is possible to collect ethyl acetate, toluene directly from the reaction solution or after separating the cells. Extraction with a solvent such as tert-butyl methyl ether or hexane, dehydration, and purification by distillation or silica gel column chromatography, etc., to selectively reduce the carboxylic group of the high purity compound (VII).
  • the obtained (3R, 5S) 7 3,5-dihydroxyheptanoic acid derivative can be easily obtained.
  • 3,5-Dihydroxyheptanoic acid derivative that is, obtained by the diastereoselective reduction, wherein in the formula (VIII), R 3 and R 4 are hydrogen atoms (3R, 5S) —7 3,5-dihydroxyheptane
  • the acid derivative may protect the hydroxyl group as necessary.
  • “as necessary” means that the hydroxyl group may be protected or may not be protected. From the later reactivity, it is preferable to protect the hydroxyl group.
  • a method for protecting the hydroxyl group a method commonly used may be used, for example, the method described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, third edition, pages 17-245, etc. be able to.
  • a preferred protecting group is a protecting group for a crosslinked hydroxyl group, and the protecting method will be described below.
  • a known acetal formation reaction for example, by treatment with an acetal formation reagent in the presence of an acid catalyst, the following formula (Villa):
  • R 1Q and R 11 are each independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted group.
  • the aralkyl group having 7 to 12 carbon atoms specifically, methyl group, ethyl group, tert-butyl group, hexyl group, phenyl group, benzyl group, p-methoxybenzyl group, etc.
  • both R 1Q and R 11 are methyl groups.
  • R 1Q and R 11 may be bonded to each other to form a ring.
  • R 1Q and R 11 form a ring to form a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, etc.
  • a spiro structure is formed with the 1,3-dioxane ring.
  • X 1 and R 1 are the same as described above.
  • acetal-forming reactants that can be used in this step include ketones such as acetone and cyclohexanone, aldehydes such as formaldehyde and benzaldehyde, dimethoxymethane, 2,2-dimethoxypropane, and 1,1-dimethoxycyclohexane.
  • ketones such as acetone and cyclohexanone
  • aldehydes such as formaldehyde and benzaldehyde
  • dimethoxymethane 2,2-dimethoxypropane
  • 1,1-dimethoxycyclohexane 1,1-dimethoxycyclohexane.
  • alkoxyalkanes such as xane
  • alkoxyalkenes such as 2-methoxypropene
  • Preferred are acetone, 2-methoxypropene, and 2,2-dimethoxypropane.
  • the amount of the acetal-forming reaction agent to be used is preferably 1 to 10-fold mol amount, more preferably 1 to 5-fold mol amount based on Compound (VIII).
  • an acetal-forming reagent may be used as a reaction solvent for the purpose of promptly accelerating the reaction.
  • Examples of the acid catalyst that can be used in this step include Lewis acid and Bronsted acid.
  • Examples of the Lewis acid or Bronsted acid include Lewis acids such as trisalt-aluminum, boron trifluoride, disalt-zinc, and tin tetrachloride; oxalic acid, formic acid, acetic acid, benzoic acid, Carboxylic acids such as rifluoroacetic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid pyridinium; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.
  • p-Toluenesulfonic acid pyridinium can be prepared by known methods with p-toluenesulfonic acid and pyridine. P-toluenesulfonic acid, camphorsulfonic acid, and p-toluenesulfonic acid pyridinium are preferable.
  • the amount of the acid catalyst to be used is preferably 0.001 to 0.5 times the molar amount relative to the compound (VIII), more preferably 0.005 to 0.1 times the monole amount.
  • This reaction can be carried out without a solvent, but various organic solvents may be used as a reaction solvent.
  • organic solvent examples include aprotic organic solvents. Specific examples are the same as described above.
  • the organic solvents may be used alone or in combination of two or more. Preferred are toluene, methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide, and ⁇ ⁇ ⁇ -methylpyrrolidone.
  • the reaction temperature in this step is preferably 0 to L00 ° C from the viewpoint of yield improvement, and more preferably 20 to 70 ° C.
  • a general process may be performed in order to obtain a reaction fluid force after completion of the reaction.
  • water is added to the reaction solution after completion of the reaction, and the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like.
  • the target product is obtained by distilling off the reaction solvent and extraction solvent from the resulting extract by an operation such as heating under reduced pressure. Also, immediately after the reaction is completed, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and the same operation may be performed.
  • the target product thus obtained is almost pure, but the purity may be further increased by performing purification by a general method such as crystallization purification, fractional distillation, column chromatography or the like.
  • the reaction solution obtained in the step (4) may be used as it is, or an isolated and purified product may be used. Also, use something obtained by another method.
  • the ammonia used in this step may be ammonia gas dissolved in an organic solvent or ammonia water dissolved in water.
  • the amount of ammonia used is preferably 1 to 200-fold mol amount, more preferably 1 to 50-fold mol amount based on Compound (VIII).
  • This step can be carried out without a solvent.
  • a reaction solvent may be used.
  • the reaction solvent that can be used in this step is not particularly limited, and examples thereof include water, alcohol solvents, and aprotic organic solvents. Specific examples include those described above. These may be used alone or in combination of two or more. Alcohol solvents are preferred, and methanol is more preferred.
  • the reaction temperature in this step is preferably 0 to 200 ° C, more preferably 50 to 150 ° C, from the viewpoint of yield improvement.
  • the reaction in order to suppress the volatilization of ammonia, the reaction is performed under pressure using a pressure-resistant sealed reaction equipment such as an autoclave.
  • a pressure-resistant sealed reaction equipment such as an autoclave.
  • the preferred pressure when a 1 ⁇ 1 OOkgZcm 2, further preferably 1 ⁇ 20kgZcm 2.
  • a general process may be performed in order to obtain a reaction fluid force after completion of the reaction.
  • the solvent is distilled off from the reaction solution after completion of the reaction by an operation such as heating under reduced pressure
  • the target product is obtained as a salt of amine hydrochloride.
  • the amine hydrochloride salt of the amine is dissolved in an alkaline aqueous solution, and a general extraction solvent such as ethyl acetate or jetyl ether is used.
  • Chloride Extraction operation is performed using tylene, toluene, hexane or the like.
  • the target product obtained in this manner is almost pure, it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography, etc.
  • the obtained free amine is converted into mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; sulfonic acids such as methanesulfonic acid, ⁇ -toluenesulfonic acid and camphorsulfonic acid; acetic acid, propionic acid, Purify by crystallization by forming a salt with carboxylic acids such as mandelic acid and tartaric acid.
  • mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid
  • sulfonic acids such as methanesulfonic acid, ⁇ -toluenesulfonic acid and camphorsulfonic acid
  • acetic acid, propionic acid Purify by crystallization by forming a salt with carboxylic acids such as mandelic acid and tartaric acid.
  • n-butyllithium hexane solution (1.6 mol / L) llmL (17.7 mmol) is cooled to 5 ° C, and this is a solution consisting of 1.97 g (19.5 mmol) of diisopropylamine and 10 ml of tetrahydrofuran.
  • n-butyllithium hexane solution (1.6 mol / L) llmL (17.7 mmol) is cooled to 5 ° C, and this is a solution consisting of 1.97 g (19.5 mmol) of diisopropylamine and 10 ml of tetrahydrofuran.
  • n-butyllithium hexane solution (1.6 mol / L) llmL (17.7 mmol) is cooled to 5 ° C, and this is a solution consisting of 1.97 g (19.5 mmol) of diisopropylamine and 10 ml of tetra
  • (S) -5 obtained by the method of Example 4 was obtained.
  • Ethyl hydroxypentanoate 1. Og (5.54 mmol), tert-butyl acetate 1.28 g (llmmol), tetrahydrofuran ( 10 ml) was added and ice-cooled under a nitrogen atmosphere.
  • 3.lg (5.54 mmol) of a mixed solution of sodium tert-butylmagnesium in toluene Z tetrahydrofuran (1.8 mol / kg) was added dropwise over 30 minutes, and the mixture was further stirred at 5 ° C for 30 minutes.
  • Example 8 (3R.5S) —7 Chloro-3.5— (2′.2′-isopropylidenedioxy) butanoic acid tert p
  • Toluenesulfonic acid 18 mg (0.095 mmol) was dissolved in acetone 0.5 ml, and pyridine 13 mg (0.16 mmol) was obtained by the method of Example 14
  • (3R, 5S) 7-mouth 3,5-dihydroxyheptanoic acid tert
  • a solution of butyl 0.21 g (0.82 mmol) in acetone (4 ml) and 2,2 dimethoxypropane 0.34 g (3.3 mmol) were sequentially added, and the mixture was stirred at 40 ° C. for 23 hours.
  • a part of the organic layer was analyzed for the amount of product produced by gas chromatography equipped with HP-5 column (0.32 mm x 30 m) manufactured by Agilent Technologies.
  • HP-5 column (0.32 mm x 30 m) manufactured by Agilent Technologies.
  • a part of the organic layer is phenylurethane-modified with phenyl isocyanate (see Bjorkqvist, B. et al., J. Chromatography, 153, 265 (1978))
  • a Chiralpak AD-H column manufactured by Daicel Chemical Industries ( 4. The optical purity of the product was measured by HPLC equipped with 6 mm X 25 cm).
  • Injector temperature 170 ° C
  • liquid medium pH 7 ml of liquid medium (pH 7) with composition power of 10 g of meat extract, 10 g of peptone, 5 g of yeast extract and 3 g of sodium chloride (each per liter) was dispensed into a large test tube and steam sterilized at 120 ° C for 20 minutes .
  • These liquid media were aseptically inoculated with one platinum loop of the microorganisms shown in Table 2 below, and cultured with shaking at 30 ° C for 72 hours. After culturing, each culture solution was centrifuged to collect the cells, and the cells were suspended in 0.5 ml (pH 6.5) of lOOmM phosphate buffer containing 1% glucose.
  • This bacterial cell suspension was (S) -7-chloro-5-Hy obtained by the method of Example 5.
  • 1 mg of tert-butyl droxy-3-oxoheptanoate was added to a test tube and reacted at 30 ° C. for 24 hours.
  • 2 ml of ethyl acetate was added to each reaction solution and mixed well, and a part of the organic layer was analyzed under the analysis conditions described in Example 10 to determine the yield of the reaction and the optical purity of the product. .
  • Table 4 The results are summarized in Table 4.
  • E. coli HB101 (pNTDRGl) FERM BP—08458 (see International Publication No. WO2004Z0 27055) is cultured in 2 ⁇ X medium containing 120 ⁇ g / ml ampicillin, and 2 g glucose is added to 30 ml of the obtained culture solution.
  • NAD 50 mg, 3 g of tert-butyl (S) -7 chloro-5-hydroxy-3-oxoheptanoate obtained by the method of Example 5 were added, and the mixture was stirred at 30 ° C. Meanwhile, the pH of the reaction solution was maintained at 6.5 with 6NNaOH.

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Abstract

Disclosed is a (3R,5R)-7-amino-3,5-dihydroxyheptanoic acid derivative which is useful as an intermediate for a pharmaceutical. A (3R,5R)-7-amino-3,5-dihydroxyheptanoic acid derivative or a salt thereof can be produced by a process comprising the steps of: (1) producing a 5-halo-3-oxopentanoic acid derivative from an acid chloride and an alkali metal salt of a malonic acid monoester which are commercially available at low costs, (2) reducing the resulting product in an S-selective manner, (3) reacting the reduced product with an enolate prepared from an acetic acid ester derivative to yield a (5S)-7-halo-5-hydroxy-3-oxopentanoic acid derivative, (4) reducing the resulting product in a diastereo-selective manner and, if necessary, protecting a hydroxyl group in the product, and (5) aminating the resulting product with ammonia to produce the desired compound a salt thereof. The process can produce the compound in a simple manner, with good efficiency, and in a commercial scale.

Description

(3R， 5R) _ 7—ァミノ— 3， 5—ジヒドロキシヘプタン酸誘導体の製造法 技術分野  (3R, 5R) _ 7-Amino-3,5-Dihydroxyheptanoic acid derivative production method Technical Field
[0001] 本発明は、医薬品中間体、特に HMG— CoA還元酵素阻害剤中間体として有用 な（3R, 5R)— 7—アミノー 3, 5—ジヒドロキシヘプタン酸誘導体の製造法に関するも のである。  [0001] The present invention relates to a method for producing a (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative useful as a pharmaceutical intermediate, particularly an HMG-CoA reductase inhibitor intermediate.
背景技術  Background art
[0002] 従来、 7 アミノー 3, 5 ジヒドロキシヘプタン酸誘導体の製造法としては、以下の 様な方法が知られている。  Conventionally, the following methods are known as methods for producing 7-amino-3,5-dihydroxyheptanoic acid derivatives.
(1) 3 ヒドロキシダルタル酸ジェチルを原料とし、数工程を経て得られる（3R, 5S) 7—クロロー 3, 5—ジヒドロキシヘプタン酸ェチルのァセトニド化を行った後、アジ 化ナトリウムと反応させ、パラジム炭素触媒存在下に水素化することにより、 (3R, 5R )ー7 アミノー 3, 5- (2', 2 '—イソプロピリデンジォキシ）ヘプタン酸ェチルを製造 する。全製造工程数は 9である（特許文献 1)。  (1) After acetylation of (3R, 5S) 7-chloro-3,5-dihydroxyheptanoic acid ethyl obtained from ethyl 3-hydroxydartrate using several steps, it is reacted with sodium azide, (3R, 5R) -7amino-3,5- (2 ', 2'-isopropylidenedioxy) heptanoic acid ethyl is produced by hydrogenation in the presence of a paradium carbon catalyst. The total number of manufacturing processes is nine (Patent Document 1).
(2) 3 ヒドロキシダルタル酸ジェチルを原料とし、数工程を経て得られる（R)— 6— ジベンジルカルバモイル 5—ヒドロキシ 3—ォキソへキサン酸 tert ブチルをジ ァステレオ選択的に還元、ァセトニド化、ボラン還元、加水素分解することにより、 (3 R, 5R)— 7 アミノー 3, 5- (2', 2 '—イソプロピリデンジォキシ）ヘプタン酸 tert— ブチルを製造する。全製造工程数は 9である（特許文献 2)。  (2) (R) -6-Dibenzylcarbamoyl 5-hydroxy-3-oxohexanoate tert-butyl diastereoselectively obtained by using diethyl 3-hydroxydartrate as a raw material, converted into acetonide, Borane reduction and hydrogenolysis produce (3 R, 5R) -7 amino-3, 5- (2 ', 2'-isopropylidenedioxy) heptanoic acid tert-butyl. The total number of manufacturing processes is nine (Patent Document 2).
(3) N ベンジルォキシカルボ-ル— β—ァラニンを原料とし、数工程を経て得られ る、（R)—7 ベンジルォキシカルボ-ルァミノ一 5— (2—テトラヒドロビラ-ルォキシ )一 3—ォキソへキサン酸 tert ブチルをジァステレオ選択的に還元、脱保護、ァセト -ドィ匕を行い、最後に加水素分解することにより、 (3R, 5R)— 7 ァミノ一 3, 5— (2' , 2'—イソプロピリデンジォキシ)ヘプタン酸 tert—ブチルを製造する。全製造工程数 は 8である（特許文献 3)。  (3) (R) -7 Benzyloxycarbolamino 1- (2-tetrahydrobiraloxy) 1 obtained from N-benzyloxycarbol-β-alanine as a raw material through several steps. — Diastereoselective reduction of tert-butyl oxohexanoate, deprotection, aceto-deoxy, and finally hydrogenolysis to give (3R, 5R) — 7 Amino 1, 3, 5— (2 ' , 2'-isopropylidenedioxy) heptanoic acid tert-butyl. The total number of manufacturing processes is eight (Patent Document 3).
(4)ラタトースを原料とし、（R)— 4—ブロモ—3—ヒドロキシ酪酸ェチルを得、更にシ アンィ匕ナトリウムと反応させることにより、 (R)—4—シァノ 3—ヒドロキシ酪酸ェチル を製造する。数工程を経て（3R, 5R)— 6 シァノー 3, 5- (2', 2 '—イソプロピリデ ンジォキシ)へキサン酸 tert—ブチルを製造し、最後に、ラネーニッケル触媒存在下 に水素化することにより、 (3R, 5R)— 7 アミノー 3, 5- (2', 2 '—イソプロピリデンジ ォキシ)ヘプタン酸 tert—ブチルを製造する。全製造工程数は 9である（特許文献 4) (4) By using latato as a raw material, (R) -4-bromo-3-hydroxybutyrate is obtained, and further reacted with cyano sodium (R) -4-cyano-3-hydroxybutyrate. Manufacturing. After several steps (3R, 5R) -6 cyanane 3, 5- (2 ', 2'-isopropylidenedioxy) hexanoic acid tert-butyl is prepared, and finally hydrogenated in the presence of Raney nickel catalyst, (3R, 5R) — 7 Amino-3,5- (2 ′, 2′-isopropylidenedioxy) heptanoic acid tert-butyl is produced. The total number of manufacturing processes is 9 (Patent Document 4)
(5)多段階を経て合成した（3R, 5S)— 6 ヒドロキシ—3, 5- (2', 2 '—イソプロピリ デンジォキシ）へキサン酸 tert ブチルをスワン酸化により、対応するホルミル体に誘 導化し、これに-トロメタンを付加させる。次に、水酸基をァセチル保護して |8—脱離 させ、ォレフィンと-トロ基を還元することにより、 (3R, 5R)— 7 アミノー 3, 5- (2', 2' イソプロピリデンジォキシ)ヘプタン酸 tert ブチルを製造する（非特許文献 1)。 (5) (3R, 5S) -6 hydroxy-3,5- (2 ', 2'-isopropylidenedioxy) hexanoic acid tert-butyl synthesized through multiple steps is derivatized to the corresponding formyl form by swan oxidation Add to this -tromethane. Next, the hydroxyl group is protected by acetyl and | 8-eliminated and the olefin and -tro groups are reduced to give (3R, 5R) -7 amino-3,5- (2 ', 2' isopropylidenedioxy ) Tert-butyl heptanoate is produced (Non-patent Document 1).
[0003] し力しながら、これらの製造方法はいずれも工程数が多ぐ煩雑な操作を必要とす る。更に（1)では爆発性のアジィ匕ナトリウム、（4)では猛毒性のシアンィ匕ナトリウムを 使用するなど、工業的な生産を行う上で効率的な方法ではな！、。 [0003] However, all these manufacturing methods require complicated operations with many steps. Furthermore, (1) uses explosive azido sodium and (4) uses highly toxic cyanide sodium, which is not an efficient method for industrial production! ,.
特許文献 1： ¾2004- 533479  Patent Document 1: ¾2004- 533479
特許文献 2 :特表 2004— 533481  Patent Document 2: Special Table 2004— 533481
特許文献 3：特開平 08 - 198832  Patent Document 3: Japanese Patent Laid-Open No. 08-198832
特許文献 4：特表 2000— 515882  Patent Document 4: Special Table 2000—515882
非特許文献 1 : Synthetic Communications, 2003, 33(13), 2275.  Non-Patent Document 1: Synthetic Communications, 2003, 33 (13), 2275.
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 本発明は上記現状に鑑みて、安価且つ入手容易な原料力 簡便且つ効率的に商 業規模で実施できる、 (3R, 5R)— 7—アミノー 3, 5—ジヒドロキシヘプタン酸誘導体 、またはその塩の製造法を提供することが目的である。 [0004] In view of the above situation, the present invention is a cheap and easily available raw material power that can be easily and efficiently implemented on a commercial scale. (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative, or It is an object to provide a method for producing the salt.
課題を解決するための手段  Means for solving the problem
[0005] 本発明者らは鋭意検討を行った結果、安価に入手容易な酸塩化物から 5 ハロー 3—ォキソペンタン酸誘導体を製造した後、これを S選択的に還元し、続いて酢酸ェ ステル誘導体と塩基または 0価の金属のいずれかを作用させて調製されるエノラート と反応させることにより、（S)—7—ハロー 5—ヒドロキシ一 3—ォキソヘプタン酸誘導 体を製造する。これをジァステレオ選択的に還元した後、必要に応じて水酸基を保 護し、更にアンモニアでァミノ化することにより、 (3R, 5R)— 7—アミノー 3, 5—ジヒド ロキシヘプタン酸誘導体、またはその塩が簡便に製造できることを見出し、本発明を 兀成し 7こ。 [0005] As a result of intensive investigations, the present inventors have produced a 5-halo 3-oxopentanoic acid derivative from an acid chloride that is readily available at low cost, and then selectively reduced this, followed by ester acetate. (S) -7-halo 5-hydroxy-1-oxoheptanoic acid derivative by reacting the derivative with an enolate prepared by the action of either a base or a zerovalent metal. Manufacture the body. After diastereoselective reduction of this, the hydroxyl group is protected if necessary and further amination with ammonia to give a (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative or its derivative. Found that salt can be easily produced, and developed the present invention.
[0006] すなわち本発明は、下記式 (VIII)；  [0006] That is, the present invention provides the following formula (VIII):
[0007] [化 14]
Figure imgf000004_0001
[0007] [Chemical 14]
Figure imgf000004_0001
( VIII )  (VIII)
[0008] (式中、 R1は水素原子、置換もしくは無置換の炭素数 1〜12のアルキル基、置換もし くは無置換の炭素数 6〜 12のァリール基、又は置換もしくは無置換の炭素数 7〜 12 のァラルキル基のいずれかを表す。 R3、 R4は水素又は水酸基の保護基であり、 R3 、 R4が一緒になつて架橋の水酸基の保護基であってもよい。 X1はハロゲン原子を表 す。）で表される（3R, 5S)— 7—ノヽロー 3, 5—ジヒドロキシヘプタン酸誘導体を、アン モユアでァミノ化することを特徴とする、下記式 (I)； [Wherein, R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted carbon. It represents any of the aralkyl groups of formulas 7 to 12. R 3 and R 4 are hydrogen or a hydroxyl protecting group, and R 3 and R 4 may be taken together to form a bridging hydroxyl protecting group. X 1 represents a halogen atom.) (3R, 5S) — 7-Noro 3,5-dihydroxyheptanoic acid derivative is aminated with ammonia, and is represented by the following formula (I );
[0009] [化 15]
Figure imgf000004_0002
[0009] [Chemical 15]
Figure imgf000004_0002
( I )  (I)
[0010] (式中、 R1、 R3、 R4は上記に同じ。）で表される（3R, 5R)—7—ァミノ— 3, 5—ジヒド ロキシヘプタン酸誘導体、又はその塩の製造法に関する。 [0010] (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative represented by the formula (wherein R 1 , R 3 and R 4 are the same as above), or a salt thereof Regarding the law.
[0011] また本発明は、下記式 (IV)； [0011] The present invention also provides the following formula (IV):
[0012] [化 16] o [0012] [Chemical 16] o
xi^^^c°2R2 xi ^^^ c ° 2R 2
( IV )  (IV)
[0013] (式中、 R2は置換もしくは無置換の炭素数 1〜12のアルキル基を表す。 X1は前記に 同じ。）で表される 5—ハロー 3—ォキソペンタン酸誘導体を S選択的に還元すること を特徴とする、下記式 (V) ; (Wherein R 2 represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. X 1 represents the same. ), A 5-halo 3-oxopentanoic acid derivative represented by the following formula (V):
[化 17]  [Chemical 17]
Figure imgf000005_0001
Figure imgf000005_0001
[0015] (式中、 R2 、 X1は前記に同じ）で表される（S)—5—ハロー 3—ヒドロキシペンタン酸 誘導体の製造法に関する。 [0015] The present invention relates to a method for producing a (S) -5-halo 3-hydroxypentanoic acid derivative represented by the formula (wherein R 2 and X 1 are the same as above).
[0016] 更に本発明は、下記式 (VII)； [0016] Further, the present invention provides the following formula (VII):
[0017] [化 18]
Figure imgf000005_0002
[0017] [Chemical 18]
Figure imgf000005_0002
( VII )  (VII)
[0018] (式中、 R^ X1は前記に同じ。）で表される（S)— 7—ハロ— 5—ヒドロキシ— 3—ォキ ソヘプタン酸誘導体をジァステレオ選択的に還元し、必要に応じて水酸基の保護を 行う下記式 (VIII) ; [0018] (wherein, R ^ X 1 is as defined above.) Is represented by (S) - 7- halo - 5-hydroxy - 3-O key Soheputan acid derivatives was reduced Jiasutereo selectively, needs In accordance with the following formula (VIII) for protecting the hydroxyl group accordingly:
[0019] [化 19]  [0019] [Chemical 19]
OR3 OR4 { VHI ) OR 3 OR 4 {VHI)
[0020] (式中、 R^ R3 Ι^ Χ1は前記に同じ。）で表される（3R, 5S)— 7—ハロー 3, 5—ジ ヒドロキシヘプタン酸誘導体の製造法に関する。 [0020] (wherein, R ^ R 3 Ι ^ Χ 1 is as defined above.) Is expressed by (3R, 5S) - 7- Halo 3 relates to a process for the preparation of 5-di-hydroxy heptanoic acid derivative.
[0021] また本発明は、下記式 (XI)；  [0021] The present invention also provides the following formula (XI):
[0022] [化 20]
Figure imgf000006_0001
[0022] [Chemical 20]
Figure imgf000006_0001
[0023] で表される（3R, 5S)-7- クロロー 3, 5—ジヒドロキシヘプタン酸 tert—ブチルであ り、下記式 (XII); (3R, 5S) -7-chloro-3,5-dihydroxyheptanoic acid tert-butyl represented by the following formula (XII);
[0024] [化 21]
Figure imgf000006_0002
[0024] [Chemical 21]
Figure imgf000006_0002
(XII)  (XII)
[0025] で表される（3R, 5S)— 7-クロロー 3, 5—（2', 2 [0025] (3R, 5S) — 7-chloro-3, 5— (2 ', 2
タン酸 tert—ブチルであり、下記式 (V)；  Tert-butyl tanoate, represented by the following formula (V):
[0026] [化 22]
Figure imgf000006_0003
[0026] [Chemical 22]
Figure imgf000006_0003
(V)  (V)
[0027] (式中、 X^R2は前記に同じ。）で表される（S)— 5—ハロー 3—ヒドロキシペンタン酸 誘導体であり、下記式 (VII); [0027] (wherein X ^ R 2 is the same as defined above) is a (S) -5-halo 3-hydroxypentanoic acid derivative represented by the following formula (VII);
[0028] [化 23]
Figure imgf000006_0004
[0028] [Chemical 23]
Figure imgf000006_0004
(VII)  (VII)
[0029] (式中、 X^R1は前記に同じ。）で表される（S)— 7—ハロー 5—ヒドロキシー3—ォキ ソヘプタン酸誘導体に関する。 [0029] (wherein X ^ R 1 is the same as defined above) relates to a (S) -7-halo 5-hydroxy-3-oxoheptanoic acid derivative represented by:
発明の効果  The invention's effect
[0030] 本発明によれば、安価且つ入手容易な原料から簡便且つ効率的に、また商業規 模で（3R, 5R)— 7—アミノー 3, 5—ジヒドロキシヘプタン酸誘導体、またはその塩を 製造することが可能である。 [0030] According to the present invention, it is simple and efficient to use commercial materials from inexpensive and readily available raw materials. For example, a (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative or a salt thereof can be produced.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0031] 本発明は下記反応式に示されるように、（1)から（5)の 5工程力 なる。  [0031] As shown in the following reaction formula, the present invention has five process powers (1) to (5).
[0032] [化 24] o 工程 (1) 工程 （2) OH ， ,CO,R2 一 C02R2 [0032] [Chemical 24] o Process (1) Process (2) OH,, CO, R 2 C0 2 R 2
(II) (IV) (V) (II) (IV) (V)
Figure imgf000007_0001
Figure imgf000007_0001
工程 （5) OR3 OR4 Process (5) OR 3 OR 4
,C02R , C0 2 R
Η,Ν'  Η, Ν '
(I )  (I)
[0033] 以下に、本発明を工程ごとに順をおつて詳述する。 [0033] Hereinafter, the present invention will be described in detail step by step.
なお、本明細書にぉ 、て炭素数とは置換基の炭素数を含まな 、数を表す。  In the present specification, the carbon number means a number that does not include the carbon number of the substituent.
また、置換基としては、水酸基、アルコキシ基、ニトロ基、アミノ基、ァシル基、カルボ キシル基、ハロゲン原子などがあげられる。  Examples of the substituent include a hydroxyl group, an alkoxy group, a nitro group, an amino group, an acyl group, a carboxyl group, and a halogen atom.
[0034] 工程（1)  [0034] Step (1)
本工程では、下記式 (II);  In this step, the following formula (II);
[0035] [化 25] [0035] [Chemical 25]
0 0
X1' V、CI X 1 'V, CI
(ID  (ID
[0036] で表される酸塩ィ匕物から下記式 (IV); [0036] From the acid salt represented by the following formula (IV);
[0037] [化 26]
Figure imgf000008_0001
[0037] [Chemical 26]
Figure imgf000008_0001
( IV )  (IV)
[0038] で示される 5—ハロー 3—ォキソペンタン酸誘導体を製造する。前記化合物（II)から 前記化合物 (IV)を製造する方法は特に限定されな!、が、例えば酸塩化物 (II)と下記 式（III)； [0038] A 5-halo-3-oxopentanoic acid derivative represented by the formula: The method for producing the compound (IV) from the compound (II) is not particularly limited !, but for example, acid chloride (II) and the following formula (III);
[0039] [化 27]
Figure imgf000008_0002
[0039] [Chemical 27]
Figure imgf000008_0002
(ill)  (ill)
[0040] で示される酢酸エノラートを反応させて製造する方法、酸塩化物 (Π)と下記式 (ΧΠΙ)； [0041] [化 28]
Figure imgf000008_0003
[0040] A process for producing an acetate enolate represented by the following formula: acid chloride (Π) and the following formula (と); [0041] [Chemical 28]
Figure imgf000008_0003
(XI I I)  (XI I I)
[0042] で示されるマロネートを反応させた後に脱炭酸させて製造する方法、酸塩化物とマロ ン酸ジエステルやメルドラム酸など力 調製されるカルボア-オンを反応させ、生成 物を加水分解又は加アルコール分解させて製造する方法などがあげられる。好ましく は、酸塩化物（Π)と酢酸エノラート (III)を反応させて製造する方法、又は酸塩化物（II )とマロネート (ΧΙΠ)を反応させた後に脱炭酸させて製造する方法である。 [0042] A method of producing by decarboxylation after reacting a malonate represented by the following formula, reacting an acid chloride with a carbo-on prepared by a malonate diester or meldrum acid, etc., and hydrolyzing or adding the product. For example, a method of decomposing alcohol can be used. Preferably, the acid chloride (Π) and acetic acid enolate (III) are reacted with each other, or the acid chloride (II) and malonate (ΧΙΠ) are reacted and then decarboxylated.
[0043] 前記酸塩化物（II)において、 X1はハロゲン原子を表し、具体的にはフッ素原子、 塩素原子、臭素原子、又はヨウ素原子であり、好ましくは塩素原子、又は臭素原子が あげられる。更に好ましくは塩素原子である。また、前記化合物（111)、（XIII)、（IV)に おいて、 R2は置換もしくは無置換の炭素数 1〜12のアルキル基であり、具体的には 、メチル基、ェチル基、イソプロピル基、 tert—ブチル基、 n—ォクチル基などであり、 好ましくはメチル基、又はェチル基があげられる。更に好ましくはェチル基である。 [0044] まず、酸塩化物（II)と酢酸エノラート（III)を反応させて 5—ハロー 3—ォキソペンタン 酸誘導体 (IV)を製造する方法について説明する。前記酢酸エノラート (III)は、酢酸 エステルと塩基を反応させて調製する方法、ハロ酢酸エステルと 0価の金属を反応さ せて調製する方法、又は酢酸エステルと金属塩と第 3級ァミンを反応させて調製する 方法のいずれであってもよい。酢酸エステル、ハロ酢酸エステルとしては特に制限さ れず、酢酸メチル、酢酸ェチル、酢酸 tert—ブチル、クロ口酢酸メチル、クロ口酢酸ェ チル、ブロモ酢酸メチルなどがあげられる。 In the acid chloride (II), X 1 represents a halogen atom, specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a chlorine atom or a bromine atom. . More preferably, it is a chlorine atom. In the compounds (111), (XIII), and (IV), R 2 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, specifically, a methyl group, an ethyl group, isopropyl Group, tert-butyl group, n-octyl group, etc., preferably methyl group or ethyl group. More preferred is an ethyl group. [0044] First, a method for producing 5-halo-3-oxopentanoic acid derivative (IV) by reacting acid chloride (II) and enolate acetate (III) will be described. The acetic acid enolate (III) is prepared by reacting an acetic acid ester with a base, by reacting a haloacetic acid ester with a zero-valent metal, or by reacting an acetic acid ester with a metal salt and a tertiary amine. Any of the methods of preparing them may be used. Acetic acid esters and haloacetic acid esters are not particularly limited, and include methyl acetate, ethyl acetate, tert-butyl acetate, methyl acetate, ethyl acetate, and methyl bromoacetate.
[0045] ここで、酢酸エステルと塩基を反応させて酢酸エノラート (III)を調製する方法にお いては、塩基として具体的には例えば、マグネシウムアミド類、リチウムアミド類、ダリ 二ヤール (Grignard)試薬類、ナトリウムアミド類、カリウムアミド類、アルキルリチウム類 、金属アルコキシド類、金属水素化物があげられる。  [0045] Here, in the method of preparing acetic acid enolate (III) by reacting an acetic ester and a base, specific examples of the base include magnesium amides, lithium amides, and Grignard. Examples include reagents, sodium amides, potassium amides, alkyllithiums, metal alkoxides, and metal hydrides.
[0046] 前記マグネシウムアミド類としては、下記式 (XIV)；  [0046] Examples of the magnesium amides include the following formula (XIV):
[0047] [化 29]
Figure imgf000009_0001
[0047] [Chemical 29]
Figure imgf000009_0001
( XIV)  (XIV)
[0048] で表される化合物があげられる。ここで 、 R9は、置換もしくは無置換の炭素数 1〜 12のアルキル基、置換もしくは無置換の炭素数 6〜12のァリール基、置換もしくは無 置換の炭素数 7〜 12のァラルキル基、または炭素数 3〜 12のシリル基の!/、ずれかを 表し、具体的には、メチル基、ェチル基、イソプロピル基、 tert—ブチル基、シクロへ キシル基、 n—ォクチル基、フエ-ル基、ナフチル基、 p—メトキシフエ-ル基、 p— -ト 口べンジル基、トリメチルシリル基、トリェチルシリル基、フ -ルジメチルシリル基など があげられ、好ましくはイソプロピル基があげられる。また X3はハロゲン原子を表し、 好ましくは塩素原子、臭素原子、又はヨウ素原子があげられる。なお、前記マグネシ ゥムアミド類は、安価で入手容易な第 2級ァミン類とグリニャール (Grignard)試薬とか ら公知の方法 (例えば特開平 8— 523420明細書）により調製できる。あるいは、リチ ゥムアミドとマグネシウムハロゲン化物とから公知の方法（例えば、 J. Org. Chem., 199 1, 56, 5978-5980)により調製できる。 [0048] A compound represented by Here, R 9 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or Represents! / Of a silyl group having 3 to 12 carbon atoms, specifically, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclohexyl group, an n-octyl group, or a phenyl group. , A naphthyl group, a p-methoxyphenol group, a p-totobenzyl group, a trimethylsilyl group, a triethylsilyl group, and a dimethyldimethylsilyl group, preferably an isopropyl group. X 3 represents a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom. The magnesium amides can be prepared by known methods (for example, JP-A-8-523420) from secondary amines that are inexpensive and readily available and Grignard reagents. Alternatively, a known method (for example, J. Org. Chem., 199) from lithium amide and magnesium halide. 1, 56, 5978-5980).
[0049] 前記リチウムアミド類としては、下記式 (XV)； [0049] Examples of the lithium amides include the following formula (XV);
[0050] [化 30] [0050] [Chemical 30]
R6 R 6
Li-N  Li-N
R'  R '
( XV)  (XV)
[0051] で表される化合物があげられる。ここで 、 R7は置換もしくは無置換の炭素数 1〜12 のアルキル基、置換もしくは無置換の炭素数 6〜12のァリール基、置換もしくは無置 換の炭素数 7〜 12のァラルキル基、または炭素数 3〜 12のシリル基の 、ずれかを表 し、具体的には、前述の R8、 R9と同じものがあげられる。好ましくはイソプロピル基で ある。 [0051] A compound represented by: R 7 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or This represents any deviation of the silyl group having 3 to 12 carbon atoms, specifically, the same as R 8 and R 9 described above. An isopropyl group is preferred.
[0052] 前記グリニャール (Grignard)試薬類としては、下記式 (X)；  [0052] Examples of the Grignard reagents include the following formula (X):
X4MgR5 (X) X 4 MgR 5 (X)
で表される化合物があげられる。ここで は、置換もしくは無置換の炭素数 1〜12の アルキル基、置換もしくは無置換の炭素数 6〜 12のァリール基又は置換もしくは無置 換の炭素数 7〜 12のァラルキル基等であり、具体的には、メチル基、ェチル基、 n— プロピル基、イソプロピル基、 n—ブチル基、 tert—ブチル基、 n—ォクチル基、フエ二 ル基、ナフチル基、 p—メトキシフヱ-ル基、 p— -トロベンジル基等があげられ、好ま しくはメチル基、ェチル基、イソプロピル基、 n—ブチル基、 tert—ブチル基であり、さ らに好ましくは tert—ブチル基である。また X4はハロゲン原子を表し、好ましくは塩 素原子、臭素原子、又はヨウ素原子であり、さらに好ましくは塩素原子である。 The compound represented by these is mention | raise | lifted. Here, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, etc. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, n-octyl group, phenyl group, naphthyl group, p-methoxyphenyl group, p —-Trobenzyl group and the like are preferable, and a methyl group, an ethyl group, an isopropyl group, an n-butyl group, and a tert-butyl group are preferable, and a tert-butyl group is more preferable. X 4 represents a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom, and more preferably a chlorine atom.
[0053] 前記ナトリウムアミド類としては、ナトリウムアミド、ナトリウムジイソプロピルアミド等が あげられる。前記カリウムアミド類としては、カリウムアミド、カリウムジイソプロピルアミド 、カリウムジシクロへキシルアミド、カリウムへキサメチルジシラジド等があげられる。前 記アルキルリチウム類としては、メチルリチウム、 n—ブチルリチウム、 tert—ブチルリ チウム等があげられる。前記金属アルコキシド類としては、ナトリウムメトキシド、ナトリ ゥムェトキシド、マグネシウムエトキシド、カリウム tert—ブトキシド等があげられる。金 属水素化物としては、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化力 ルシゥム等があげられる。 [0053] Examples of the sodium amides include sodium amide and sodium diisopropylamide. Examples of the potassium amides include potassium amide, potassium diisopropylamide, potassium dicyclohexylamide, potassium hexamethyldisilazide and the like. Examples of the alkyl lithium include methyl lithium, n-butyl lithium, tert-butyl lithium and the like. Examples of the metal alkoxides include sodium methoxide, sodium methoxide, magnesium ethoxide, potassium tert-butoxide and the like. Money Examples of genus hydrides include lithium hydride, sodium hydride, potassium hydride, and hydrogenation power.
[0054] 塩基として好ましくは、リチウムアミド類、マグネシウムアミド類であり、具体的には、リ チウムジイソプロピルアミド、リチウムジシクロへキシルアミド、リチウムへキサメチルジ ドであり、更に好ましくはリチウムジイソプロピルアミドである。前記塩基の使用量は前 記酢酸エステルに対し、好ましくは 1〜10倍モル量であり、更に好ましくは 1〜3倍モ ル量である。また、ハロ酢酸エステルと 0価の金属を反応させて酢酸エノラート（III)を 調製する方法においては、ハロ酢酸エステルとしてクロ口酢酸エステル、ブロモ酢酸 エステル、又はョード酢酸エステルが好ましぐ更に好ましくはブロモ酢酸エステルで ある。前記 0価の金属として好ましくは、亜鉛、マグネシウム、スズ等であり、更に好ま しくは亜鉛、又はマグネシウムである。前記 0価の金属の使用量は、前記ハロ酢酸ェ ステルに対し、好ましくは 1〜10倍モル量であり、更に好ましくは 1〜3倍モル量であ る。  [0054] The base is preferably lithium amides or magnesium amides, specifically lithium diisopropylamide, lithium dicyclohexylamide, or lithium hexamethylzide, and more preferably lithium diisopropylamide. The amount of the base used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount of the above-mentioned acetate ester. Further, in the method of preparing enoacetate (III) by reacting a haloacetic acid ester with a zero-valent metal, chloroacetic acid ester, bromoacetic acid ester, or odoacetic acid ester is more preferable as haloacetic acid ester. Bromoacetic acid ester. The zero-valent metal is preferably zinc, magnesium, tin or the like, and more preferably zinc or magnesium. The amount of the zerovalent metal used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the haloacetic acid ester.
[0055] 次に、酢酸エステルと金属塩と第 3級ァミンを反応させて酢酸エノラート (III)を調製 する方法について説明する。本方法において、前記金属塩として好ましくは四塩ィ匕 チタン、四塩ィ匕ジルコニウム、又は四塩化スズ等であり、更に好ましくは四塩ィ匕チタン である。前記金属塩の使用量としては、前記酢酸エステルに対し、好ましくは 1〜： LO 倍モル量であり、更に好ましくは 1〜3倍モル量である。また、前記第 3級ァミンとして 好ましくは、ピリジン、イミダゾール、メチルイミダゾール、 N—メチルモルホリン、 N—メ チルピロリジン、ジイソプロピルェチルァミン、トリエチルァミン、又はトリ n—ブチルアミ ンであり、更に好ましくはジイソプロピルェチルァミン、トリェチルァミン、又はトリ n—ブ チルァミンである。前記第 3級ァミンの使用量としては、前記酢酸エステルに対し、好 ましくは 1〜10倍モル量であり、更に好ましくは 1〜3倍モル量である。このようにして 調製した酢酸エノラート (III)の使用量としては、前記酸塩化物（II)に対し、好ましくは 1〜 10倍モル量であり、更に好ましくは 1〜 3倍モル量である。  [0055] Next, a method for preparing an enolate acetate (III) by reacting an acetate ester, a metal salt and a tertiary amine will be described. In the present method, the metal salt is preferably tetrachloride-titanium, tetrachloride-zirconium, or tin tetrachloride, and more preferably tetrachloride-titanium. The amount of the metal salt used is preferably 1 to: LO times the molar amount, more preferably 1 to 3 times the molar amount with respect to the acetate ester. The tertiary amine is preferably pyridine, imidazole, methylimidazole, N-methylmorpholine, N-methylpyrrolidine, diisopropylethylamine, triethylamine, or tri-n-butylamine, and more preferably. Is diisopropylethylamine, triethylamine, or tri-n-butylamine. The amount of the tertiary amine used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the acetate ester. The amount of the enolate acetate (III) thus prepared is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the acid chloride (II).
[0056] 本工程に使用できる溶媒としては、非プロトン性の有機溶媒があげられる。非プロト ン性の有機溶媒としては、例えば、ベンゼン、トルエン、 n—へキサン、シクロへキサン 、メチルシクロへキサン等の炭化水素系溶媒;ジェチルエーテル、テトラヒドロフラン、[0056] Examples of the solvent that can be used in this step include aprotic organic solvents. Examples of non-protonic organic solvents include benzene, toluene, n-hexane, and cyclohexane. , Hydrocarbon solvents such as methylcyclohexane; jetyl ether, tetrahydrofuran,
1, 4 ジォキサン、メチル tert ブチルエーテル、ジメトキシェタン、エチレングリコ ールジメチルエーテル等のエーテル系溶媒；酢酸ェチル、酢酸イソプロピルなどのェ ステル系溶媒;アセトン、メチルェチルケトン等のケトン系溶媒;ァセトニトリル、プロピ ォ-トリル等の-トリル系溶媒;塩化メチレン、クロ口ホルム、 1, 1, 1 トリクロロェタン 等のハロゲン系溶媒； N, N ジメチルホルムアミド、 N, N ジメチルァセトアミド、 N メチルピロリドン等のアミド系溶媒；ジメチルスルホキシド等のスルホキシド系溶媒； ジメチルプロピレンゥレア等のウレァ系溶媒；へキサメチルリン酸トリアミド等のホスホ ン酸トリアミド系溶媒等があげられる。前記溶媒は単独で用いてもよぐ 2種以上を併 用してもよい。前記溶媒において、炭化水素系溶媒またはエーテル系溶媒が好まし ぐなかでも好ましいのは、テトラヒドロフランである。 1, 4 Dioxane, methyl tert butyl ether, dimethoxyethane, ethylene glycol dimethyl ether and other ether solvents; ethyl acetate, isopropyl acetate and other ester solvents; acetone, methyl ethyl ketone and other ketone solvents; -Tolyl solvents such as propio-tolyl; Halogen solvents such as methylene chloride, black-form, 1,1,1 trichloroethane; N, N dimethylformamide, N, N dimethylacetamide, N methylpyrrolidone, etc. Amide solvents; sulfoxide solvents such as dimethyl sulfoxide; urea solvents such as dimethylpropylene urea; phosphonic triamide solvents such as hexamethylphosphoric triamide. The above solvents may be used alone or in combination of two or more. Of the above solvents, tetrahydrofuran and ether solvents are preferable, and tetrahydrofuran is more preferable.
[0057] 反応温度として好ましくは— 100〜30°Cであり、更に好ましくは— 80〜10°Cである 。酢酸エノラート (πΐ)を調製するための試剤及び酸塩化物 (Π)の混合順序は任意で あるが、好ましくは酢酸エノラート (III)を調製し、ここに酸塩ィ匕物（II)を添加して反応 を行うとよい。 The reaction temperature is preferably −100 to 30 ° C., more preferably −80 to 10 ° C. The mixing order of the reagent and acid chloride (Π) for preparing enolate acetate (πΐ) is arbitrary, but preferably enolate acetate (III) is prepared, and acid chloride (II) is added thereto. It is better to react.
[0058] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液に一般的な無機酸または有機酸、 例えば塩酸、硫酸、硝酸、酢酸、クェン酸等を混合し、一般的な抽出溶媒、例えば酢 酸ェチル、ジェチルエーテル、塩化メチレン、トルエン、へキサン等を用いて抽出操 作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒及び抽出溶媒を 留去すると、 目的物が得られる。このようにして得られる目的物は、ほぼ純粋なもので あるが、晶析精製、分別蒸留、カラムクロマトグラフィー等の一般的な手法により精製 を行い、さらに純度を高めてもよい。  [0058] In this step, a general process may be performed in order to obtain a reaction fluid force after completion of the reaction. For example, a general inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate or the like is mixed in the reaction solution after completion of the reaction, and a general extraction solvent such as ethyl acetate, jetyl ether, chloride or the like is mixed. Perform extraction with methylene, toluene, hexane, etc. The desired product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure. The target product obtained in this way is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography or the like.
[0059] 次に、酸塩ィ匕物（II)とマロネート (XIII)を反応させた後に脱炭酸させて 5—ハロ 3 —ォキソペンタン酸誘導体 (IV)を製造する方法につ!、て説明する。前記マロネート ( XIII)は、マロン酸モノエステルアルカリ金属塩とアルカリ土類金属ハロゲン化物と第 3 級ァミンを反応させることにより調製することが出来る。  [0059] Next, a method for producing 5-halo 3 -oxopentanoic acid derivative (IV) by reacting acid chloride (II) with malonate (XIII) followed by decarboxylation will be described. . The malonate (XIII) can be prepared by reacting a malonic acid monoester alkali metal salt, an alkaline earth metal halide and a tertiary amine.
[0060] 前記マロン酸モノエステルアルカリ金属塩として好ましくは、マロン酸モノエステルリ チウム塩、マロン酸モノエステルナトリウム塩、マロン酸モノエステルカリウム塩、又は マロン酸モノエステルセシウム塩などがあげられ、好ましくはマロン酸モノエステルナト リウム塩、又はマロン酸モノエステルカリウム塩であり、更に好ましくはマロン酸モノエ ステルカリウム塩である。前記マロン酸モノエステルアルカリ金属塩の使用量は、前記 酸塩化物（II)に対して、好ましくは 1〜10倍モル量であり、更に好ましくは 1〜5倍モ ル量である。 [0060] The malonic acid monoester alkali metal salt is preferably malonic acid monoester alkali metal salt. Examples thereof include a sodium salt, a malonic acid monoester sodium salt, a malonic acid monoester potassium salt, or a malonic acid monoester cesium salt, preferably a malonic acid monoester sodium salt or a malonic acid monoester potassium salt. Malonic acid monoester potassium salt is preferred. The amount of the malonic acid monoester alkali metal salt used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
[0061] 前記アルカリ土類金属ハロゲン化物として好ましくは、塩ィ匕カルシウム、塩化マグネ シゥム、臭化マグネシウム、ヨウ化マグネシウム等であり、更に好ましくは塩ィ匕マグネシ ゥムである。前記アルカリ土類金属ハロゲン化物の使用量は、前記酸塩化物（II)に 対して、好ましくは 1〜10倍モル量であり、更に好ましくは 1〜5倍モル量である。  [0061] The alkaline earth metal halide is preferably calcium chloride, magnesium chloride, magnesium bromide, magnesium iodide or the like, and more preferably salt magnesium. The amount of the alkaline earth metal halide used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
[0062] 前記第 3級ァミンとしては例えば、ジイソプロピルェチルァミン、ジイソプロピルメチ ルァミン、トリェチルァミン、 N, N—ジメチルァニリン、 N—メチルモルホリン、 1, 4— ジァザビシクロ [2, 2, 2]オクタン、 1, 8—ジァザビシクロ [5, 4, 0]ゥンデク一 7—ェン 、 N, N, Ν', Ν'—テトラメチルエチレンジァミン、キノリン、ピリジン等があげられる。 好ましくはジイソプロピルェチルァミン、トリェチルァミン等であり、更に好ましくはトリ ェチルァミンである。前記第 3級ァミンの使用量は、前記酸塩化物（II)に対して、好ま しくは 1〜 10倍モル量であり、更に好ましくは 1〜 5倍モル量である。  [0062] Examples of the tertiary amine include diisopropylethylamine, diisopropylmethylamine, triethylamine, N, N-dimethylaniline, N-methylmorpholine, 1,4-diazabicyclo [2,2,2] octane. 1,8-diazabicyclo [5,4,0] undek 7-en, N, N, Ν ', Ν'-tetramethylethylenediamine, quinoline, pyridine and the like. Preferred are diisopropylethylamine, triethylamine and the like, and more preferred is triethylamine. The amount of the tertiary amine used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the acid chloride (II).
[0063] 本工程に使用できる溶媒としては、非プロトン性の有機溶媒等があげられる。具体 例としては前述のものがあげられる。前記溶媒は単独で用いてもよぐ 2種以上を併 用してもよい。前記溶媒において、エステル系溶媒またはエーテル系溶媒が好ましく 、なかでも好ましいのは、酢酸ェチルまたはテトラヒドロフランである。  [0063] Examples of the solvent that can be used in this step include an aprotic organic solvent. Specific examples are those mentioned above. The above solvents may be used alone or in combination of two or more. Among the solvents, ester solvents or ether solvents are preferable, and ethyl acetate or tetrahydrofuran is particularly preferable.
[0064] 反応温度として好ましくは 0〜100°Cであり、更に好ましくは 10〜40°Cである。反応 試剤の混合順序は任意である力 好ましくはマロン酸モノエステルアルカリ金属塩、 アルカリ土類金属ハロゲンィ匕物及び第 3級ァミンを先に混合し、最後に酸塩化物 (II) を添加して反応を行うとよい。得られた反応液に塩酸あるいは臭化水素酸などの酸を 添加し、攪拌すると脱炭酸が進行し、 目的とする化合物 (IV)が得られる。  [0064] The reaction temperature is preferably 0 to 100 ° C, more preferably 10 to 40 ° C. The mixing order of the reaction reagents is arbitrary. Preferably, malonic acid monoester alkali metal salt, alkaline earth metal halide and tertiary amine are mixed first, and acid chloride (II) is finally added. It is better to carry out the reaction. When an acid such as hydrochloric acid or hydrobromic acid is added to the obtained reaction solution and stirred, decarboxylation proceeds to obtain the desired compound (IV).
[0065] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液に一般的な無機酸または有機酸、 例えば塩酸、硫酸、硝酸、酢酸、クェン酸等を混合し、一般的な抽出溶媒、例えば酢 酸ェチル、ジェチルエーテル、塩化メチレン、トルエン、へキサン等を用いて抽出操 作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒及び抽出溶媒を 留去すると、目的物が得られる。このようにして得られる目的物は、ほぼ純粋なもので あるが、晶析精製、分別蒸留、カラムクロマトグラフィー等の一般的な手法により精製 を行い、さらに純度を高めてもよい。 [0065] In this step, a general process may be performed in order to obtain a reaction fluid force after completion of the reaction. For example, a general inorganic acid or organic acid in the reaction solution after completion of the reaction, For example, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, and the like are mixed, and the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like. The target product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure. The target product obtained in this way is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography or the like.
[0066] 工程（2)  [0066] Step (2)
本工程では、前記式 (IV)で表される 5—ハロー 3—ォキソペンタン酸誘導体を S選 択的に還元することにより、下記式 (V)；  In this step, the 5-halo-3-oxopentanoic acid derivative represented by the above formula (IV) is selectively reduced by S to give the following formula (V);
[0067] [化 31]
Figure imgf000014_0001
[0067] [Chemical 31]
Figure imgf000014_0001
[0068] で表される (S) 5 ハロー 3 ヒドロキシペンタン酸誘導体を製造する。なお、前記 式 (V)で表される（S)— 5—ハロー 3—ヒドロキシペンタン酸誘導体は医薬中間体とし て有用な文献未知の新規化合物である。ここで、 X1、 R2は前記に同じであり、好まし くは X1が塩素原子であり、 R2力メチル基またはェチル基である。さらに好ましくは R2が ェチル基である。 [0068] A (S) 5 halo 3 hydroxypentanoic acid derivative represented by the formula: The (S) -5-halo 3-hydroxypentanoic acid derivative represented by the formula (V) is a novel compound unknown in the literature that is useful as a pharmaceutical intermediate. Here, X 1 and R 2 are the same as described above, and preferably X 1 is a chlorine atom, and is an R 2 force methyl group or an ethyl group. More preferably, R 2 is an ethyl group.
[0069] 本工程に使用される化合物（IV)は工程（1)で得られた反応液をそのまま用いても 良いし、単離、精製したものを用いても良い。  [0069] As the compound (IV) used in this step, the reaction solution obtained in the step (1) may be used as it is, or an isolated and purified product may be used.
[0070] 本工程における不斉還元方法としては、前記化合物（IV)のカルボ二ル基を S選択 的に還元できる方法であれば特に限定されず、光学活性ィ匕合物によって修飾された ヒドリド還元剤を用いて還元する方法、不斉遷移金属触媒存在下に水素化する方法 、不斉遷移金属触媒存在下に水素移動型で還元する方法、若しくは微生物、或い は微生物由来の酵素を用いて還元する方法等が挙げられる。好ましくは不斉遷移金 属触媒存在下に水素化する方法である。  [0070] The asymmetric reduction method in this step is not particularly limited as long as it can selectively reduce the carbonyl group of the compound (IV), and a hydride modified with an optically active compound. Reduction using a reducing agent, hydrogenation in the presence of an asymmetric transition metal catalyst, hydrogen transfer reduction in the presence of an asymmetric transition metal catalyst, or a microorganism or an enzyme derived from a microorganism And a reduction method. A method of hydrogenation in the presence of an asymmetric transition metal catalyst is preferred.
[0071] ここで、不斉遷移金属触媒存在下に水素化する方法について説明する。前記不斉 遷移金属触媒としては、ルテニウム、ロジウム、イリジウム、又は白金等の周期律表第 VIII族元素の金属錯体が好ましぐ錯体の安定性や入手容易さ、経済性の観点から ルテニウム錯体がより好まし ヽ。該金属錯体中の不斉配位子としてはホスフィン系配 位子が好ましぐホスフィン系配位子として好ましくは二座配位子である。 [0071] Here, a method for hydrogenation in the presence of an asymmetric transition metal catalyst will be described. Examples of the asymmetric transition metal catalyst include ruthenium, rhodium, iridium, and platinum. Ruthenium complexes are more preferred from the viewpoints of stability, availability, and economics of complexes where group VIII metal complexes are preferred. The asymmetric ligand in the metal complex is preferably a bidentate ligand as a phosphine ligand preferred by a phosphine ligand.
[0072] 二座配位子としては、 BINAP (2, 2'—ビスジフエニルホスフイノ一 1, 1，一ビナフ チル）； Tol— BINAP (2, 2， 一ビス（ジ一 p—トリルホスフイノ一 1, 1， 一ビナフチル） 等の BINAP誘導体； BDPP (2, 4—ビス（ジフエ-ルホスフイノ）ペンタン）； DIOP (4 , 5—ビス（ジフエ-ルホスフイノメチル）一2, 2—ジメチルー 1, 3—ジォキサン； BPP FA ( 1— [ 1，， 2—ビス（ジフエ-ルホスフイノ）フエロセ -ル]ェチルァミン）； CHIRAP HOS (2, 3—ビス（ジフエ-ルホスフイノ）ブタン）； DEGPHOS (l—置換一 3, 4—ビ ス（ジフエ-ルホスフイノ）ピロリジン）； DuPHOS (l, 2—ビス（2, 5—置換ホスホラノ） ベンゼン）； DIPAMP d, 2—ビス [ (o—メトキシフエ-ル）フエ-ルホスフイノ]ェタン） 等があげられ、好ましくは BINAP (2, 2， 一ビスジフエ-ルホスフイノ一 1, 1， 一ビナフ チル）であり、 S選択的にカルボ-ル基を還元するためには（R)— BINAPを用いれ ばよい。ここで、（R)— BINAP錯体として好ましくは、（（R)—BINAP)RuBr 、 （（R)  [0072] Bidentate ligands include BINAP (2, 2'-bisdiphenylphosphino-1,1,1-binaphthyl); Tol- BINAP (2,2,1-bis (di-p-tolylphosphino-one) 1,1,1, binaphthyl) and other BINAP derivatives; BDPP (2,4-bis (diphenylphosphino) pentane); DIOP (4,5-bis (diphenylphosphinomethyl) -1,2,2-dimethyl-1, 3—dioxane; BPP FA (1— [1,2,2-bis (diphenylphosphino) ferroceyl] ethylamine); CHIRAP HOS (2,3-bis (diphenylphosphino) butane); DEGPHOS (l—substituted one 3, 4-bis (diphenylphosphino) pyrrolidine); DuPHOS (l, 2-bis (2,5-substituted phosphorano) benzene); DIPAMP d, 2-bis [(o-methoxyphenol) phenolphosphino] Etc., preferably BINAP (2, 2, 1bisdiphenylphosphino-1,1,1, binaphth (R) —BINAP may be used to reduce the carbo group selectively with S. Here, (R) —BINAP complex is preferably ((R) —BINAP) RuBr. , ((R)
2 2
- BINAP) RuCl ,又は [ ( (R) - BINAP) RuCl ] NEt等があげられる。不斉遷移 -BINAP) RuCl, or [((R)-BINAP) RuCl] NEt. Asymmetric transition
2 2 2 3  2 2 2 3
金属触媒の使用量として好ましくは、前記化合物（IV)に対して 0. 1倍モル量以下で あり、更に好ましくは 0. 05〜0. 0001倍モル量である。  The amount of the metal catalyst to be used is preferably 0.1 times or less by mole, more preferably 0.05 to 0.0001 times by mole, relative to the compound (IV).
[0073] 水素圧として、好ましくは l〜100kgZcm2であり、更に好ましくは l〜30kgZcm2 である。 As [0073] a hydrogen pressure, preferably L～100kgZcm 2, more preferably from l~30kgZcm 2.
[0074] 反応溶媒としては、水；メタノール、エタノール、イソプロパノール等のアルコール系 溶媒;非プロトン性の有機溶媒等があげられる。非プロトン性の有機溶媒の具体例と しては前述のものがあげられる。これらは単独で用いてもよぐ 2種以上を併用しても よい。好ましくは、水またはアルコール系溶媒であり、更に好ましくはメタノールと水、 または、エタノールと水の混合溶媒である。前記メタノールと水またはエタノールと水 混合溶媒の混合比率は任意に選択できる力 好ましくはメタノール Z水またはェタノ ール Z水の容量比が 100Zl〜lZlであり、更に好ましくは 20Zl〜4Zlである。 前記溶媒の使用量としては、前記化合物 (IV)に対し、好ましくは 50倍重量以下、更 に好ましくは 5〜20倍重量である。 [0075] 反応温度として好ましくは、—20〜100°Cであり、更に好ましくは 0〜60°Cである。 [0074] Examples of the reaction solvent include water; alcohol solvents such as methanol, ethanol and isopropanol; aprotic organic solvents and the like. Specific examples of the aprotic organic solvent include those mentioned above. These may be used alone or in combination of two or more. Preferred is water or an alcohol solvent, and more preferred is a mixed solvent of methanol and water or ethanol and water. The mixing ratio of the methanol / water or ethanol / water mixed solvent can be selected arbitrarily. The volume ratio of methanol Z water or ethanol Z water is preferably 100 Zl to lZl, more preferably 20 Zl to 4 Zl. The amount of the solvent to be used is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (IV). [0075] The reaction temperature is preferably -20 to 100 ° C, more preferably 0 to 60 ° C.
[0076] 反応終了後の反応液から生成物を取得するためには、一般的な処理を行えばよい 。例えば、反応終了後の反応液から減圧、もしくは加圧濾過にて遷移金属触媒を除 去した後、減圧加熱等の操作により、反応溶媒を留去すると目的物が得られる。この ようにして得られた目的物は、後続工程に使用できる十分な純度を有している力 晶 析、分別蒸留、カラムクロマトグラフィー等の一般的な精製手法により、さらに純度を 高めてもよい。 [0076] In order to obtain a product from the reaction solution after completion of the reaction, a general process may be performed. For example, after removing the transition metal catalyst from the reaction solution after completion of the reaction by decompression or pressure filtration, the reaction solvent is distilled away by an operation such as heating under reduced pressure to obtain the desired product. The target product thus obtained may be further purified by a general purification technique such as power crystallization, fractional distillation, column chromatography, etc., having sufficient purity that can be used in subsequent steps. .
[0077] 工程（3) [0077] Step (3)
本工程では、下記式 (VI) ;  In this step, the following formula (VI);
X2CH CO R1 (VI) X 2 CH CO R 1 (VI)
2 2  twenty two
で表される酢酸エステル誘導体と塩基または 0価の金属の 、ずれかを作用させてェ ノラートを調製し、これと前記式 (V)で表される（S)—5—ハロ— 3—ヒドロキシペンタ ン酸誘導体を反応させて、下記式 (VII)；  An enolate is prepared by reacting an acetate derivative represented by formula (I) with a base or a zero-valent metal, and (S) -5-halo-3-hydroxy represented by the formula (V). A pentanoic acid derivative is reacted to form the following formula (VII):
[0078] [化 32]
Figure imgf000016_0001
[0078] [Chemical 32]
Figure imgf000016_0001
[0079] で表される（S)— 7 ハロー 5 ヒドロキシ 3 ォキソヘプタン酸誘導体を製造する [0079] (S) — 7 Halo 5 Hydroxy-3-oxoheptanoic acid derivative represented by
[0080] ここで、 X1は前記に同じであり、 R1は、水素、置換もしくは無置換の炭素数 1〜12 のアルキル基、置換もしくは無置換の炭素数 6〜12のァリール基、置換もしくは無置 換の炭素数 7〜 12のァラルキル基等であり、具体的には、水素及び R5であげた具体 例と同様なものがあげられる。 R1として好ましくは tert ブチル基があげられる。また 、 X2は水素原子、又はハロゲン原子を表し、具体的には、水素原子、塩素原子、臭 素原子、又はヨウ素原子などがあげられ、好ましくは水素原子、又は臭素原子があげ られる。 [0080] Here, X 1 is the same as above, R 1 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted group Alternatively, it is an unsubstituted aralkyl group having 7 to 12 carbon atoms, and specific examples thereof are the same as those given for hydrogen and R 5 . R 1 is preferably a tert butyl group. X 2 represents a hydrogen atom or a halogen atom, and specifically includes a hydrogen atom, a chlorine atom, an iodine atom, or an iodine atom, preferably a hydrogen atom or a bromine atom.
[0081] なお、前記式 (VII)で表される（S)—7—ハロー 5 ヒドロキシー3 ォキソヘプタン 酸誘導体は医薬中間体として有用な文献未知の新規化合物である。 [0081] (S) -7-halo-5 hydroxy-3oxoheptane represented by the formula (VII) Acid derivatives are novel compounds unknown in the literature that are useful as pharmaceutical intermediates.
[0082] 本工程に用いる（S)— 5—ハロー 3—ヒドロキシペンタン誘導体 (V)は工程（2)で得 られた反応液をそのまま用いても良いし、単離精製したものを用いても良い。またェ 程 (2)以外の方法で別途合成したものでもよ!/、。  [0082] As the (S) -5-halo 3-hydroxypentane derivative (V) used in this step, the reaction solution obtained in step (2) may be used as it is, or an isolated and purified product may be used. good. It can also be synthesized separately by methods other than (2)! /.
[0083] 酢酸エステル誘導体 (VI)の使用量は、前記化合物 (V)に対し、 1〜： LO倍モル量で あり、好ましくは 1〜5倍モル量である。  [0083] The use amount of the acetate derivative (VI) is 1 to: LO times molar amount, preferably 1 to 5 times molar amount with respect to the compound (V).
[0084] 一般に、酢酸エステル誘導体 (VI)の X2が水素であるとき、エノラート調製に塩基が 用いられ、 X2がハロゲン原子のとき、エノラート調製に 0価の金属が用いられる。 [0084] In general, when X 2 of the acetic ester derivative (VI) is hydrogen, a base is used in the enolate prepared when X 2 is a halogen atom, 0-valent metal enolate prepared is used.
[0085] エノラート調製時に用いられる塩基としては、工程（1)で例示したものと同様なマグ ネシゥムアミド類、リチウムアミド類、グリニャール (Grignard)試薬類、ナトリウムアミド類 、カリウムアミド類、アルキルリチウム類、金属アルコキシド類、金属水素化物などがあ げられる。塩基として好ましくは、マグネシウムアミド類、リチウムアミド類あるいはダリ 二ヤール（Grignard)試薬である。なかでもリチウムジイソプロピルアミドゃ tert—ブチ ルマグネシウムクロリドが好ましい。なお、これらの塩基は単独もしくは組み合わせて 使用してもよい。例えば、前記リチウムアミド類は、前記グリニャール (Grignard)試薬 類と組み合わせて用いると効果的である。塩基の使用量は、酢酸エステル誘導体 (V I)に対し、 1〜10倍モル量であり、好ましくは 1〜3倍モル量である。  [0085] Bases used in the preparation of the enolate include the same magnesium amides, lithium amides, Grignard reagents, sodium amides, potassium amides, alkyllithiums as exemplified in step (1), Examples thereof include metal alkoxides and metal hydrides. Preferred bases are magnesium amides, lithium amides or Grignard reagents. Of these, lithium diisopropylamide is preferably tert-butylmagnesium chloride. These bases may be used alone or in combination. For example, the lithium amides are effective when used in combination with the Grignard reagents. The amount of the base used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount relative to the acetate derivative (VI).
[0086] 本工程のエノラート調製時に使用できる 0価の金属は、亜鉛、マグネシウム、スズ等 であり、好ましくは亜鉛、又はマグネシウムである。 0価の金属の使用量は、酢酸エス テル誘導体 (VI)に対し、 1〜10倍モル量であり、好ましくは 1〜3倍モル量である。  The zero-valent metal that can be used in preparing the enolate in this step is zinc, magnesium, tin or the like, preferably zinc or magnesium. The amount of the zero-valent metal used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount relative to the ester acetate derivative (VI).
[0087] 本工程の反応溶媒としては例えば、非プロトン性の有機溶媒があげられる。具体例 としては、前述のものがあげられる。前記溶媒は、単独で用いてもよぐ 2種以上を併 用してもよい。前記溶媒においては、炭化水素系溶媒またはエーテル系溶媒が好ま しい。特に好ましくはテトラヒドロフランである。  [0087] Examples of the reaction solvent in this step include aprotic organic solvents. Specific examples are those mentioned above. The solvents may be used alone or in combination of two or more. As the solvent, a hydrocarbon solvent or an ether solvent is preferable. Particularly preferred is tetrahydrofuran.
[0088] 本工程の反応温度として好ましくは— 30〜100°Cであり、更に好ましくは— 10〜6 0°Cである。  [0088] The reaction temperature in this step is preferably -30 to 100 ° C, more preferably -10 to 60 ° C.
[0089] 本工程において、反応剤の混合順序は任意である力 好ましくは、 5—ハロー 3—ヒ ドロキシペンタン酸誘導体 (V)と酢酸エステル誘導体 (VI)の混合溶液に対し、塩基ま たは 0価の金属の 、ずれかを添加して反応を行うとよ!/ヽ。酢酸エステル誘導体 (VI)の X2が水素である場合は、 5—ハロー 3—ヒドロキシペンタン酸誘導体 (V)と酢酸エステ ル誘導体 (VI)の混合溶液に対し、予め、臭ィ匕メチルマグネシウム、塩化イソプロピル マグネシウム、塩化 tert ブチルマグネシウム等のグリニャール（Grignard)試薬、あ [0089] In this step, the mixing order of the reactants is arbitrary. Preferably, the base is mixed with the mixed solution of 5-halo-3-hydroxypentanoic acid derivative (V) and acetate derivative (VI). Or you can add a zero-valent metal and react it! / ヽ. When X 2 of the acetic acid ester derivative (VI) is hydrogen, the odorous methylmagnesium is previously added to the mixed solution of the 5-halo 3-hydroxypentanoic acid derivative (V) and the acetic acid ester derivative (VI). Grignard reagents such as isopropyl magnesium chloride, tert butyl magnesium chloride,
、ヨウ化マグネシウムジイソプロピルアミド、塩化マグネシウムジシクロへキシルアミド等 のマグネシウムアミド類の溶液を滴下した後、例えばリチウムアミド、リチウムジィソプ 口ピルアミド、リチウムジシクロへキシルアミド、リチウムへキサメチルジシラジド等のリ チウムアミド類あるいはマグネシウムアミド類の溶液を滴下して反応を行うとよ 、。 After dropping a solution of magnesium amides such as magnesium iodide diisopropylamide, magnesium chloride dicyclohexylamide, etc., for example, lithium amide, lithium disodium pyramide, lithium dicyclohexylamide, lithium hexamethyldisilazide, etc. The reaction is performed by dropping a solution of lithium amides or magnesium amides.
[0090] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液と、一般的な無機酸または有機酸 、例えば塩酸、硫酸、硝酸、酢酸、クェン酸等を混合し、一般的な抽出溶媒、例えば 酢酸ェチル、ジェチルエーテル、塩化メチレン、トルエン、へキサン等を用いて抽出 操作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒及び抽出溶媒 を留去すると、 目的物が得られる。このようにして得られる目的物は、ほぼ純粋なもの であるが、晶析精製、分別蒸留、カラムクロマトグラフィー等一般的な手法により精製 を行い、さらに純度を高めてもよい。 [0090] In this step, a general process may be performed in order to obtain a reaction fluid force after completion of the reaction. For example, the reaction solution after completion of the reaction is mixed with a general inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, etc., and a general extraction solvent such as ethyl acetate, jetyl ether, chloride, etc. Extraction is performed using methylene, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. The target product obtained in this way is almost pure, but it may be further purified by a general method such as crystallization purification, fractional distillation, column chromatography or the like.
[0091] 工程 (4) [0091] Process (4)
本工程では、前記式 (VII)で表される（S)— 7—ハロー 5—ヒドロキシ 3—ォキソへ ブタン酸誘導体をジァステレオ選択的に還元し、また必要に応じて水酸基の保護を 行うことにより、下記式 (VIII) ;  In this step, (S) -7-halo 5-hydroxy-3-oxo represented by the formula (VII) is diastereoselectively reduced, and hydroxyl groups are protected as necessary. The following formula (VIII);
[0092] [化 33] [0092] [Chemical 33]
OR3 OR4 ( VIII ) OR 3 OR 4 (VIII)
[0093] で表される（3R, 5S)— 7—ノヽロー 3, 5 ジヒドロキシヘプタン酸誘導体を製造する。 [0093] A (3R, 5S) -7-noro 3,5 dihydroxyheptanoic acid derivative represented by the formula:
前記式 (VIII)において、
Figure imgf000018_0001
R4は水素原子、又は水酸基の保護基であり、 R4が 一緒になつて架橋の水酸基の保護基であってもよい。 R3, R4として具体的には一般 的に水酸基の保護基として用いられているものであれば特に制限されないが、プロテ クティブ'グループス'イン'オーガニック'シンセシス第 3版（Protective Groups in Org anic Synthesis, 3rd Ed.)、テオドラ ダブリュ.グリーン（Theodora W.Green)著、ジョン 'ゥイリ一'アンド'サンズ (JOHN WILEY & SONS)出版、 1999年の 17頁〜 200頁に 記載された保護基が挙げられる。 In the above formula (VIII),
Figure imgf000018_0001
R 4 is a hydrogen atom or a hydroxyl-protecting group, and R 4 may be taken together to form a bridging hydroxyl-protecting group. Specifically as R 3 and R 4 The protective group is not particularly limited as long as it is used as a protective group for a hydroxyl group, but the protective 'Groups' in 'Organic Synthesis' 3rd edition (Protective Groups in Organic Synthesis, 3rd Ed.), Theodora W. Protecting groups described in pages 17-200 of 1999, published by JOHN WILEY & SONS by Theodora W. Green.
[0094] 具体的には、メトキシメチル基、ベンジロキシメチル基、メチルチオメチル基、 p—メト キシベンジロキシメチル基、 p -トロベンジロキシメチル基、 t ブトキシメチル基、 2 —メトキシエトキシメチル基、 2— (トリメチルシリル)エトキシメチル基、テトラヒドロビラ -ル基、テトラヒドロフラ-ル基、 1 エトキシェチル基、 1ーメチルー 1ーメトキシェチ ル基、ァリル基、 t ブチル基、シクロへキシル基等のエーテル型保護基；ベンジル 基、 ρ—メトキシベンジル基、ジフエ-ルメチル基、フエネチル基、トリフエ-ルメチル基 等のベンジル型保護基；トリメチルシリル基、トリェチルシリル基、トリイソプロピルシリ ル基、 t—ブチルジメチルシリル基等のシリル型保護基;ァセチル基、クロロアセチル 基、トリフルォロアセチル基、ピバロイル基、ベンゾィル基、 p メチルベンゾィル基等 のァシル、又はァロイル型保護基;メトキシカルボニル基、エトキシカルボ-ル基、ベ ンジロキシカルボ-ル基、 t—ブトキシカルボニル基等のカーボネート型保護基;ジメ チルホスフィエル基等のホスフィネート型保護基が挙げられる。 R3と R4が一緒になつ て架橋の水酸基の保護基としては上述の文献の 201頁〜 245頁に記載された架橋 保護基があげられる。具体的にはイソプロピリデン基、メチレン基、ェチリデン基、 ter tーブチルメチリデン基、 1 フエ-ルェチリデン基などがあげられる。好ましくは水素 原子、又は架橋の水酸基の保護基であり、更に好ましくは水素原子、又はイソプロピ リデン基である。 [0094] Specifically, a methoxymethyl group, a benzyloxymethyl group, a methylthiomethyl group, a p-methoxybenzyloxymethyl group, a p-trobenzyloxymethyl group, a t-butoxymethyl group, a 2-methoxyethoxymethyl group, Ether-type protecting groups such as 2- (trimethylsilyl) ethoxymethyl group, tetrahydrovinyl group, tetrahydrofuranyl group, 1 ethoxyethyl group, 1-methyl-1-methoxyethyl group, aryl group, tbutyl group, cyclohexyl group; benzyl Benzyl type protecting groups such as ρ-methoxybenzyl group, diphenylmethyl group, phenethyl group, triphenylmethyl group; silyl type protection such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group Group: acetyl group, chloroacetyl group, trifluoroacetyl group, Royl group, benzoyl group, p-methylbenzoyl group and other acyl or aroyl type protective groups; methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbon group, t-butoxycarbonyl group and other carbonate type protective groups; dimethylphosphier group And other phosphinate-type protecting groups. Examples of the protecting group for the hydroxyl group for crosslinking when R 3 and R 4 are combined include the crosslinking protecting groups described on pages 201 to 245 of the above-mentioned literature. Specific examples include an isopropylidene group, a methylene group, an ethylidene group, a tert-butylmethylidene group, and a 1-phenylethylidene group. A hydrogen atom or a protecting group for a hydroxyl group of a bridge is preferred, and a hydrogen atom or an isopropylidene group is more preferred.
[0095] なお、 X1が塩素原子であり、 R3と R4がともに水素原子であり、 R1が tert ブチル基 である下記式 (XI) ; [0095] X 1 is a chlorine atom, R 3 and R 4 are both hydrogen atoms, and R 1 is a tert butyl group represented by the following formula (XI);
[0096] [化 34]
Figure imgf000019_0001
[0096] [Chemical 34]
Figure imgf000019_0001
( XI) [0097] で表される（3R, 5S)— 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert—ブチルは医 薬中間体として有用な文献未知の新規ィ匕合物である。 (XI) [0097] (3R, 5S) -7-chloro-3,5-dihydroxyheptanoic acid tert-butyl is a novel compound unknown in the literature useful as a pharmaceutical intermediate.
[0098] また本工程で使用する前記式 (VII)で表される化合物は、工程 (3)で得られた反応 液をそのまま用いても良いし、単離精製したものを用いても良い。また、別の方法で 得られたものを用いてもょ 、。  [0098] As the compound represented by the formula (VII) used in this step, the reaction solution obtained in the step (3) may be used as it is, or an isolated and purified product may be used. You can also use the one obtained by another method.
[0099] 本工程の還元方法としては、前記化合物（VII)のカルボ-ル基をジァステレオ選択 的に還元できる方法であれば特に限定されず、ヒドリド還元剤を用いて還元する方法 、不斉遷移金属触媒存在下に水素化する方法、不斉遷移金属触媒存在下に水素 移動型で還元する方法、もしくは微生物或 、は微生物由来の酵素を用いて還元する 方法などがあげられる。好ましくはヒドリド還元剤を用いて還元する方法、不斉遷移金 属触媒存在下に水素化する方法、又は微生物或いは微生物由来の酵素を用いて還 元する方法があげられる。  [0099] The reduction method in this step is not particularly limited as long as it is a method capable of diastereoselectively reducing the carbo group of the compound (VII), and a reduction method using a hydride reducing agent. Examples thereof include a method of hydrogenation in the presence of a metal catalyst, a method of reduction by a hydrogen transfer type in the presence of an asymmetric transition metal catalyst, or a method of reduction using a microorganism or an enzyme derived from a microorganism. Preferred examples include a reduction method using a hydride reducing agent, a hydrogenation method in the presence of an asymmetric transition metal catalyst, and a reduction method using a microorganism or a microorganism-derived enzyme.
[0100] まず、ヒドリド還元剤で還元する方法にっ 、て説明する。ヒドリド還元剤で還元する 方法として好ましくは、メトキシジェチルボラン存在下に、水素化ホウ素ナトリウムを用 いて還元する公知の方法（日本特許第 2843627号）があげられる。前記メトキシジェ チルボランの使用量としては、前記化合物 (VII)に対して好ましくは 1〜 10倍モル量 であり、更に好ましくは 1〜3倍モル量である。前記水素化ホウ素ナトリウムの使用量と しては、前記化合物 (VII)に対して好ましくは 0. 25〜： LO倍モル量であり、更に好まし くは 0. 5〜3倍モル量である。反応温度としては、収率向上の観点から— 100〜0°C が好ましぐ更に好ましくは— 80〜― 30°Cである。反応溶媒としては、メタノール、ェ タノール、テトラヒドロフラン等が好ましぐこれらは 2種以上併用してもよい。  [0100] First, a method of reducing with a hydride reducing agent will be described. A preferable method for reducing with a hydride reducing agent is a known method (Japanese Patent No. 2843627) in which sodium borohydride is used in the presence of methoxyjetylborane. The amount of the methoxyethylborane to be used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the compound (VII). The amount of the sodium borohydride to be used is preferably 0.25 to: LO times molar amount, more preferably 0.5 to 3 times molar amount relative to the compound (VII). . The reaction temperature is preferably −100 to 0 ° C., more preferably −80 to −30 ° C. from the viewpoint of improving the yield. As the reaction solvent, methanol, ethanol, tetrahydrofuran and the like are preferred, and two or more of these may be used in combination.
[0101] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液と一般的な無機酸または有機酸、 例えば塩酸、硫酸、硝酸、酢酸、クェン酸等を混合し、一般的な抽出溶媒、例えば酢 酸ェチル、ジェチルエーテル、塩化メチレン、トルエン、へキサン等を用いて抽出操 作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒及び抽出溶媒を 留去すると、 目的物が得られる。このようにして得られる目的物は、ほぼ純粋なもので あるが、晶析精製、分別蒸留、カラムクロマトグラフィー等一般的な手法により精製を 行い、さらに純度を高めてもよい。 [0101] In this step, a general process may be performed in order to obtain the reaction fluid force after completion of the reaction. For example, the reaction solution after completion of the reaction is mixed with a general inorganic acid or organic acid, such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citrate, etc. Perform extraction with methylene, toluene, hexane, etc. The desired product is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure. The target product obtained in this way is almost pure, but it can be purified by general techniques such as crystallization purification, fractional distillation, column chromatography, etc. And the purity may be further increased.
[0102] 次に、不斉遷移金属触媒存在下に水素化する方法について説明する。ここで、前 記不斉遷移金属触媒としては、ルテニウム、ロジウム、イリジウム、又は白金等の周期 律表第 VIII族元素の金属錯体が好ましぐ錯体の安定性や入手容易さ、経済性の観 点からルテニウム錯体がより好ま ヽ。該金属錯体中の不斉配位子としてはホスフィ ン系配位子が好ましぐホスフィン系配位子として好ましくは二座配位子である。  [0102] Next, a method for hydrogenation in the presence of an asymmetric transition metal catalyst will be described. Here, as the asymmetric transition metal catalyst, a metal complex of a Group VIII element of the periodic table such as ruthenium, rhodium, iridium, or platinum is preferable, and the stability, availability, and economical viewpoint are preferred. From this point, ruthenium complexes are preferred. The asymmetric ligand in the metal complex is preferably a bidentate ligand as a phosphine ligand, preferably a phosphine ligand.
[0103] 二座配位子としては工程（2)記載のものと同様のものがあげられる。好ましくは BIN AP (2, 2，一ビスジフエ-ルホスフイノ 1 , 1，一ビナフチル）であり、 3位のカルボ- ル基を R選択的に還元するためには（R)—BINAPを用いればよい。ここで、（R)—B INAP錯体として好ましくは、（（R) -BINAP)RuBr 、（（R) - BINAP) RuCl ,又は  [0103] Examples of the bidentate ligand include those described in the step (2). BIN AP (2, 2, 1-bisdiphenylphosphino 1, 1, 1-binaphthyl) is preferable, and (R) -BINAP may be used to selectively reduce the carbo group at the 3-position. Here, (R) -B INAP complex is preferably ((R) -BINAP) RuBr, ((R) -BINAP) RuCl, or
2 2  twenty two
[ ( (R) - BINAP) RuCl ] NEt等があげられる。不斉遷移金属触媒の使用量として  [((R)-BINAP) RuCl] NEt. As usage of asymmetric transition metal catalyst
2 2 3  2 2 3
好ましくは、前記化合物 (VII)に対して 0. 1倍モル量以下であり、更に好ましくは 0. 0 5〜0. 0001倍モル量である。  Preferably, it is 0.1 mol or less, more preferably 0.05 to 0.0001 mol, relative to the compound (VII).
[0104] 水素圧、反応溶媒、溶媒使用量、反応温度、後処理方法などの反応条件としては 、工程 (2)の不斉遷移金属触媒存在下に水素化する方法と同様である。  [0104] The reaction conditions such as hydrogen pressure, reaction solvent, solvent usage, reaction temperature, and post-treatment method are the same as in the method of hydrogenation in the presence of the asymmetric transition metal catalyst in step (2).
[0105] 次に、微生物或いは微生物由来の酵素を用いて還元する方法について説明する。  [0105] Next, a method of reducing using a microorganism or an enzyme derived from a microorganism will be described.
本発明で使用される酵素源は、前記式化合物 (VII)のカルボ-ル基をジァステレオ 選択的に還元する能力を有する微生物由来のものを用いることができる。ここでいう「 微生物由来のもの」としては、該微生物の菌体そのもの、微生物の培養液、微生物の 菌体処理物、または該微生物力 得られる酵素であってもよいし、さらには該微生物 由来の上記還元活性を有する酵素をコードする DNAが導入された形質転換体も含 む。これらを単独で用いても、 2種類以上組み合わせてもよい。また、これらの酵素源 は周知の方法でくり返し使用できるように固定ィ匕してもよい。  As the enzyme source used in the present invention, those derived from microorganisms having the ability to diastereoselectively reduce the carbo group of the compound of formula (VII) can be used. As used herein, “derived from a microorganism” may be a cell of the microorganism itself, a culture solution of the microorganism, a treated product of the microorganism, or an enzyme obtained from the microorganism, and furthermore, derived from the microorganism. And a transformant introduced with a DNA encoding an enzyme having the above reducing activity. These may be used alone or in combination of two or more. These enzyme sources may be immobilized so that they can be used repeatedly by a known method.
[0106] 前記化合物 (VII)のカルボ二ル基を選択的に還元する能力を有する微生物は、以 下に説明する方法によって見いだすことができる。例えば、以下のようにして行なう。 グルコース 40g、酵母エキス 3g、リン酸水素二アンモ-ゥム 6. 5g、リン酸二水素カリ ゥム lg、硫酸マグネシウム 7水和物 0. 8g、硫酸亜鉛 7水和物 60mg、硫酸鉄 7水和 物 90mg、硫酸銅 5水和物 5mg、硫酸マンガン 4水和物 10mg、塩化ナトリウム 100m g (V、ずれも 1L当たり）の組成力もなる液体培地 (pH7) 5mlを試験管に入れて殺菌 後、無菌的に微生物を接種し、 30°Cで 2〜3日間振とう培養する。その後、菌体を遠 心分離により集め、グルコース 2〜10%を含んだリン酸緩衝液 0. 5〜5mlに懸濁し、 あらかじめ前記化合物（VII)を 0. 5〜25mgいれた試験管に加えて、 2〜3日間 30°C で振とうする。 [0106] A microorganism having the ability to selectively reduce the carbonyl group of the compound (VII) can be found by the method described below. For example, it is performed as follows. Glucose 40 g, yeast extract 3 g, dihydrogen phosphate 6.5 g, potassium dihydrogen phosphate lg, magnesium sulfate heptahydrate 0.8 g, zinc sulfate heptahydrate 60 mg, iron sulfate 7 water Japanese 90mg, Copper sulfate pentahydrate 5mg, Manganese sulfate tetrahydrate 10mg, Sodium chloride 100m Put 5 ml of liquid medium (pH 7) with composition (g, V, deviation per liter) into a test tube, sterilize, inoculate aseptically, and incubate with shaking at 30 ° C for 2-3 days. Thereafter, the cells are collected by centrifugation, suspended in 0.5-5 ml of phosphate buffer containing 2-10% glucose, and added beforehand to a test tube containing 0.5-25 mg of the compound (VII). Shake at 30 ° C for 2-3 days.
[0107] この際、遠心分離により得た菌体をデシケーター中またはアセトンにより乾燥したも のを用いることもできる。更に、これら微生物もしくはその処理物と前記化合物 (VII)を 反応させる際に、後述する NAD+及び Zまたは NADP+と、グルコース脱水素酵素及 びグルコース、もしくはギ酸脱水素酵素及びギ酸、を添加してもよい。また、反応系に 有機溶媒を共存させても力まわな 、。  [0107] At this time, cells obtained by centrifugation can be used in a desiccator or dried with acetone. Furthermore, when reacting these microorganisms or processed products thereof with the compound (VII), NAD + and Z or NADP + described later, glucose dehydrogenase and glucose, or formate dehydrogenase and formic acid may be added. Good. It is also possible to coexist an organic solvent in the reaction system.
[0108] 変換反応ののち適当な有機溶媒で抽出を行ない、生成する前記式ィ匕合物 (VII)の カルボ-ル基が選択的に還元された（3R, 5S)— 7—ノヽロー 3, 5—ジヒドロキシヘプ タン酸誘導体を高速液体クロマトグラフィーなどにより分析する。  [0108] After the conversion reaction, extraction was performed with a suitable organic solvent, and the carbo group of the compound (VII) thus formed was selectively reduced (3R, 5S) — 7-Noro 3 , 5-Dihydroxyheptanoic acid derivatives are analyzed by high performance liquid chromatography.
[0109] 本発明に使用しうる微生物としては、前記式化合物 (VII)のカルボ二ル基を選択的 に還元する能力を有する微生物であればいずれも使用しうる力 例えば、エレモセシ ゥム（Eremothecium)属、サッカロマイコプシス（SaccharomvcoDsis)属、ブレタノマイセ ス (Brettanomvces)属、キャンディダ (Candida)属、シテロマイセス (Citeromvces)属、 クラビスポラ（ClavisDora)属、クリプトコッカス（CrvDtococcus)属、デバリオマイセス ebarvomvces)腐、アツケフ (Dekkera)鼠、ディポゲスカス (Dipodascus)腐、ガフク卜マ イセス（Galactomvces)属、ゲォトリカム（Geotrichum)属、ノヽンセニァスポラ（Hansenias pora)属、アンブロジオジーマ (Ambrosiozvma)属、ヒポピキア（Hvphopichia)属、イツ サチェンキア (Issatchenkia)属、クルイべロマイセス (Kluweromvces)属、ピキア (Pichi ）属、リポマイセス（Lipomvces)属、メシエニコウイァ（Metschnikowia)属、パキソレン（ Pachvsolen)属、ロドトノレーラ（Rhodotorula)属、ロドスポリディウム（Rhodsporidium)属 、サッカロマイセス（Saccharomvces)属、シゾブラストスポリン（Schizoblastosporion)属 、シゾサッカロマイセス (Schizosaccharomvces)属、シュヮニォマイセス（Schwanniomvc es)属、スボリディオボラス (Sporidiobolus)属、スポロボロマイセス (Sporobolomvces) 属、トルラスポラ（TorulasjDora)属、トリゴノプシス（Tri_ggnqpsis)属、ウイロプシス（Willo psis)属、ァノレカリゲネス（Alcaligenes)属、アースロノ クタ一（Arthrobacter)属、マイク ロバクテリウム (Microbacterium)属、バチラス (Bacillus)属、ブッティォゥキシラ (Buttia uxella)属、セデシァ (Cedecea)属、セルロモナス (Cellulomonas)属、オーシュコビア（ Oerskovia)属、シトロノ クタ一（Citrobacter)属、クロストリディウム（Clostridium)属、コ マモナス（Comamonas)属、ェンテロパクター（Enterobacter)属、ぺクトバクテリウム（£ ectobacterium)属、ェシエリチア (Escherichia)属、ラオテレ (Raoultelle)属、ノレテオコ ッカス（Luteococcus)属、ミクロノくクテリウム（Microbacterium)属、ミクロコッカス (Micro coccus)属、ォクロノくクトラム (Ochrobactrum)属、プロテウス（Proteus)属、プロビデン シァ (Providencia)属、シユードモナス (Pseudomonas) 、ロドコッカス (Rhodococcus) 属、セラチア（Serratia)属、スフインゴパクテリゥム（SDhingobacterium)属、アブシディ ァ（Absidia)属、アクレモニゥム（Acremonium)属、ァエゲリータ（Aegerita)属、ァグロ サイべ（Agrocvbe)属、アミロステレゥム（Amylostereum)属、ァスぺノレギノレス (Aspereill )属、プリッソシラミス (Bvssochlamvs)属、チヤエトミディゥム（Chaetomidium)属、チ ヤエトサノレトーリャ（Chaetosartorva)属、ホノレモコニス（Hormoconis)属、スタキボトリス (Stachvbotrvs)属、クリニペリス（CriniDellis)属、エンドファラグミア（EndoDhragmia)属 、フサリウム（Fusarium)属、ガノダーマ (Ganoderma)属、グロメレーラ（Glomerella)鼠 、レンジテイス (Lenzites)属、マクロフォーマ (Macrophoma)属、モナスカス（Monascus )属、ぺニシリウム（Penidllium)属、フィァロフオーラ（PhialoDhora)属、フオリオタ（Pholi ota)属、スコブラリオプシス (ScoDulariopsis)属、セフィゾフィラム (Sehizophvllum)属、 セフィゾフィラム (Sehizophvllum)属、スポロトリカム (Sporotrichum)属、ノノムラエア (N onomuraea)属、テボンァ (Devosia) J¾、及びストレフ。トマィセス (Streptomvcesj属に 属する微生物等が挙げられる。 [0109] The microorganisms that can be used in the present invention include the ability to use any microorganism that has the ability to selectively reduce the carbonyl group of the compound (VII). For example, Eremothecium (Eremothecium) ), SaccharomvcoDsis, Brettanomvces, Candida, Citeromvces, ClavisDora, CrvDtococcus, Debariomyces ebar, Debariomyces ebar (Dekkera) 鼠, Dipodascus rot, Galactomvces genus, Geotrichum genus, Hansenias pora genus, Ambrosiozvma genus, Hipphopichia genus Issatchenkia, Kluweromvces, Pichi, Lipomvce s), Metschnikowia, Pachvsolen, Rhodotorula, Rhodsporidium, Saccharomvces, Schizoblastosporion, Schizoblastosporion (Schizosaccharomvces), Schwanniomvces, Sporidiobolus, Sporobolomvces, TorulasjDora, Trigoggis (Tri_ggnqpsis), Willopsis (Willops) psis), Alcaligenes, Arthrobacter, Microbacterium, Bacillus, Buttia uxella, Cedecea, Cellulomonas ) Genus, Oerskovia genus, Citrobacter genus, Clostridium genus, Comamonas genus, Enterobacter genus, Pectobacterium genus, Ecielicia (Escherichia), Raoultelle, Luteococcus, Microbacterium, Micro coccus, Ochrobactrum, Proteus, Providencia (Providencia), Pseudomonas, Rhodococcus, Serrat ia), SDhingobacterium, Absidia, Acremonium, Aegerita, Agrocvbe, Amylostereum, Noreginoles (Aspereill), Prisosilamis (Bvssochlamvs), Chaetomidium, Chaetosortorva, Horemoconis, Stachyvobotris EndoDhragmia genus, Fusarium genus, Ganoderma genus, Glomerella as, Lenzites genus, Macroroma genus, Monascus genus, Penicillium (Penidllium) ), PhialoDhora, Pholiota, Scobraulopsis (ScoDul) genus ariopsis, genus Sehizophvllum, genus Sephizovllum, genus Sporotrichum, genus Nonomuraea, Devosia J¾, and Streff. Tomyces (microbes belonging to the genus Streptomvcesj).
更に好ましくは、ェレモセシウム ·ゴシッピ（Eremothecium gossvpii)、サッカロマイコ プシス ·シナエデンドノレス (Saccharomvcopsis svnnaedendrus)、ブレタノマイセス ·クス タ' ~~、ノー ヌス (Brettanomvces custersianus)、ヤヤンアイダ · 7 " 7"ヌフ ~~タ (Candida cat enulata)、キャンディダ .フエ-一力 (Candida fennica)、キャンディダ .ガラクタ (Candid a galacta)、キャンディダ'ノヽェムロニ (Candida haemulonii)、キャンディダ 'マグノリエ ( し andida magnoliae;ゝキャンァイタ 'ノヽフプンロンス ( andida garapsilosis)ゝンァロマイ セス ·マトリテンシス (Citeromvces matritensis)、クラビスポラ ·ノレシタニェ (Clavispora 1 usitaniae)、クリプトコッカス ·ラウレンティ（Crvptococcus laurentii)、デノ リオマイセス. カーソニイ (Debarvomvces carsonii)、 テノ リオマイセス 'ノヽンセニイ'ノ一'ファブリィ ( Debarvomvces hansenii var. fabrvi)、 テノ リオマイセス.ノヽンセニイ ·ノ一.ノヽンセ -ィ (Debarvomvces hansenn var. hansenii)、ァノ リオマ でス'マフマス（Debaryomypes maramus 、テバリオマ でス 'シユードポリモーフ。ス (Debarvomvces pseudopolvmorph )、 7~ノ リオマづ ス 'ロノ一トシ一 (Debarvomvces robertsiae)、テツケラ ·ァノマー フ (Dekkera anomala)、アイポダスカス.ォべアンシス (Dipodascus ovetensis)、ケィポ グスカス 'テトラス一マ (Dipodascus tetrasperma)、ガラクトマィセス ·レシ一 (Galactom vces reessii)、ゲ才トリカム ·キャンディタ、'ム（Geotrichum candidum)、ゲォトリカム'フエ ノレメンタンス (Geotrichum fermentans)、ゲォトリカム'フラグランス (Geotrichum fraera ns)、ゲォトリカム'ロウビエリ (Geotrichum loubieri)、ハンセニァスポラ 'ギゥモンディ（ Hanseniaspora guilliermondn)、アンブロンオン ~~マ ·フィレン卜ムス (Ambrosioz害 a ph ilentomus)、アンブロジオジーマ ·プラティポディス (Ambrosiozvma platvpodis)ゝヒポ ピキア.バートニイ (HvphoDichia burtonii)、イツサチェンキア'オリエンタリス (Issatchen kia orientalis)、イツサチェンキア ·テリコーラ (Issatchenkia terricolaJ、クノレイべ口マイ セス'フクアイス'ノヽー · ロソフィフゥム (Klu eromvces lactis var. drosophilarum)、ク ノレィベロマイセス ·マノレキアヌス (Kluweromvces marxianus)、タノレイべロマイセス ·ポリ スホフス (Kluweromvces polvsporus )、クノレイベロマイセス ·サーモトレランス (Kluwer omvces thermotolerans)、ピキア ·ノストリス (Pichia pastoris)、リポマイセス 'スターケリ (Lipomvces starkevi)、シェニコウイァ ·ビクスビダータ 'バー'ビクスビダータ (Metschn ikowia bicuspidata var. bicuspmata)、シェニコウイ Τ ·プルセリ1 (Metschnikowia lcherrima)、ピキア ·ピニ (Pichia pini)、ピキア ·アングスタ (Pichia angusta)、ピキア ·フ インランディ力 (Pichia finlandica)、パキソレン ·タンノフィラス (Pachvsolen tannophilus) ゝピキア ·ファリノーサ (Pichia farinosa)、ピキア ·ジヤンディ-一 (Picha iandinii)、ピキ ァ ·サイトイ (Pichia saitoi)、ピキア ·キシローサ (Pichia xvlosa)、ピキア ·トリアングラリス (Pichia triangularis)、ピキァ ·ウィッカーミ (Pichia wickerhamii)、ロドトノレーラ ·グブミニ ス (Rhodotorula graminis)、ロドトノレーフ. ヌータ (Rhodotorula minuta)、ロドスポリティ ゥム .ディオボノ タム (Rhodsporidium diobovatum)、サッカロマイセス ·ノ ャヌス (Sacch aromvces bavanus)、サッ yロマイセス'ノヽストリアメス (Saccharomvces pastonanus)、 サッカロマイセス ·セレビシェ (Saccharomvces cerevisiae)、サッカロマイセス ·ゥニスポ フス (aaccaromvces unisporus)、サッカロマイコプンス · 7プスフリス (aaccharomvcopsi s capsulans)、シンゾフストスポリン'コノ ヤン (Schizoblastosponon kobavasii)、ンゾサ ッカロマイセス ·ボンべ (Schizosaccharomvces pombe)、シュヮニ才マイセス ·才シデン タイス ·ノ ~~ ·オンァンタリス (achwanniomvces occidentalis var. occidentalis)、スボリ ディオボラス'ジョンソニー (Sporidiobolus iohnsonii)、スポロボロマイセス 'ノ ラロセゥ ス (Sporobolomvces pararoseus 、トノレフスホフ ·ァノレブノレェツキ ~~ (Torulaspora delbr ueckii)、ピキァ ·ミヌータ ·ノ一' ヌータ (Pichia minuta var. minuta)、トリコノプシス · バリアビリス (Trigonopsis variabilis)、ウイロプシス ·サターヌス ·バ^ ~ ·マラキ一 (Willop sis saturnus var. mrakn)、ウイロプンス ·サタ ~~ヌス ·ノ ~~ ·サタ ~~ヌス (Willopsis sat urn us var. saturnus)、ピキア ·ファリノーサ (Pichia farinosa)、アルカリゲネス ·キシロソキ シダンス (Alcalieenes xvlosoxidans)、 アースロノくクタ一 ·プロトフォーミエ (Arthrobacter protophormiae マイクロノくクテリウム ·エステラロマティカム（Microbacterium esteraro maticum)、バチラス ·スファエリカス（Bacillus sphaericus)、ブッティォゥキシラ'ァグレ ステイス (Buttiauxella aerestis)、セデシァ'ダビシェ (Cedecea davisiae)、セノレ口モナ ス ·スピーシズ (Cellulomonas sp.)、オーシュコビア'ターバタ (Oerskovia turbata)、シ トロノくクタ^ ~ ·フレゥンディ (Citrobacter freundii)、クロストリディウム'シリンドロスポラムMore preferably, Eremothecium gossvpii, Saccharomvcopsis svnnaedendrus, Brettanomyces custard ~~, Brettanomvces custersianus 7 ~ 7 "7" Candida cat enulata, Candida fennica, Candid a galacta, Candida haemulonii, Candida magnoliae, andida magnoliae Hupunrons (andida garapsilosis) Citeromvces matritensis, Clavispora 1 usitaniae, Cryptococcus laurentii, Deno Rio Myces. Debarvomvces carsonii, Tenno riom fabrvi), Tenor Riomyces. Nounsenii Noichi. Noonse-de (Debarvomvces hansenn var. hansenii), Anno Lioma in S'Muffus (Debaryomypes maramus, In Tébarrioma in Syudo polymorph. Debarvomvces 7 ~ Noriomas' Debarvomvces robertsiae, Dekkera anomala, Ipodascus ovetensis, Kepodoscus tetrasperma, Galactomyces resi Galactom vces reessii) , Geotrichum candidum, Geotrichum fermentans, Geotrichum fraera ns, Geotrichum loubieri, Hanseniaspora gu Ma phiren 卜 mus (Ambrosioz harm a ph ilentomus), Ambrosiozima platvpodis ゝ Hippo Pichia. Kloweromvces marxianus, Kluweromvces marxianus, Kluweromvces polvsporus, Kluweromvces polvsporus, Kluweromvces marxianus, Kluweromvces polvsporus, Kluweromvces polvsporus Seth thermo-tolerance (Kluwer omvces thermotolerans), Pichia Nosutorisu (Pichia pastoris), Lipomyces' Sutakeri (Lipomvces starkevi), Shenikouia-Bikusubidata 'bar' Bikusubidata (Metschn ikowia bicuspidata var. Bicuspmata) , Shenikoui Τ · Puruseri 1 (Metschnikowia lcherrima ) 、 Pichia pini 、 Pichia angusta 、 Pichia finlandica 、 Pachvsolen tannophilus ゝ Pichia farinosa 、 Pichia farinosa (Picha iandinii), Pichia saitoi, Pichia xvlosa, Pichia triangularis, Pichia wickerhamii, Rhodotorula graminis, Rhododorula granos. Nouta (Rhodotorula minuta) , Rhodospoliti Rhodsporidium diobovatum, Sacch aromvces bavanus, Saccharomvces pastonanus, Saccharomvces cerevisiae, acer rusevis Mycopuns 7 psfris (aaccharomvcopsi s capsulans), Shinzofustosporin 'Konoyang (Schizoblastosponon kobavasii), Nzosa Saccharomyces bombe, Schizisaccharomvces pombe vcc. (Pichia minuta var. Minuta), Triconopsis variabilis, Willopsis saturnus var. Mrakn, Willopsis saturnus var. ~ Nus (Willopsis sat urn us var. Saturnus), Pichia farinosa, Alcalieenes xvlosoxidans, Arthrobacter protophormiae Microtocterium Estellalomaticum Microbacterium esteraro maticum, Bacillus sphaericus, Buttiauxella aerestis, Cedecea davisiae, Cellolemonas sp. Ia, Oschovia turbata), Citrobacter freun dii), Clostridium cylindrosporum
(Clostridium cvlindrosporum)、コマモナス'ァス卜スァ口-ィ (Comamonas testosteron i)、ェンテロノくクタ一 ·エアロゲネス (Enterobacter aerogenes)、ェンテロノくクタ一 ·クロ 一力ェ (Enterobacter cloacae)、ぺクトノくクテリゥム '力ロトボーラ ·サブスピーシス、 'カロ トボ ~~フ (Pectobactenum carotovora subsp. carotovora)、ェンエリチ , ·コリ (Eschenc hia coli)、ラオテレ ·プランティコーラ (Raoultelle planticola)、ノレテオコッカス ·ジャポ二 クス (Luteococcus iaponicus)、 ^クロノヽクァリウム ·ァノレボレツセンス (Microbacterium a rborescens)、ミクロコッカス ·ノレテウス（Micrococcus luteus)、ォクロノくクトラム 'スピー シズ（Ochrobactrum sp.)、プロテウス'インコンスタンス (Proteus inconstans)、プロテ ウス'ミラビリス（Proteus mirabilis)、プロテウス'レトゲリ（froteus rettgeri)、プロテウス .ブノレガリス (Proteus vulgaris)、プロビデンシァ.ストゥァリティ (Providencia stuartii)、 シユードモナス ·プテイダ (Pseudomonas putida)、シユードモナス'ストゥトゼリ (Pseudo monas stutzeri)、ロドコッカス ·ェクイ (Rhodococcus eaui)、セラチア .リクエタシエンス (Serratia liquetaciens 、スフィンコノヽクァリゥム 'スピリアイホフム ( Sphingobactenum iritivorum)、アブシディア'オルチデイス (Absidia orchidis)、アクレモ -ゥム 'バシリス ホフム (Acremonium bacillisporum)、 ,ェグリ ~~タ* ヤン丁イタ (Aegerita candma)、 ァグロサイべ .シリンドラセァ (Aerocvbe cvlindracea)、アミロステレゥム ·ァレオラータ ム (Amvlostereum areolatum)、 7スへノレ ノレス ·ノ、 ' ~~ンャ (Aspergillus soiae)、 /'スへ ノレギノレス ·フォェ-シス (Aspergillus phoenicis)、ブリツソシラミス ·フノレノ (Bvssochlamv s lulva)、チヤエトミディゥム ·フィメティ (Chaetomidium fimeti)、チヤエトサノレトーリヤ- ストロマ卜づァス (し haetosartorva stromatoiaes)、ホルモコニス ·レシナェ (Hormoconis resinae)、スタキボトリス ·チヤノレタラム (Stachvbotrvs chartarum)、タリ-ペリス 'スティ ピタリア (Crinipellis stipitaria)、エンドファラダミア .ァノレタナータ (Endophraemia alter nata)、フサリウム ·メリスモイテス ·ノ ー ·ァセティレレゥム (Fusarium merismoides var. acetilereum)、ガノダーマ.ノレシダム (Ganoderma lucidum)、グロメレーラ .シングラータ (Glomerella cineulata)、レンジテイス 'ベツリーナ (Lenzites betulina)、マクロフォーマ •コ ·ィ "ェ (Macrophoma commelinae)、モナス； yス ·ノヽ ~~プレウス (Monascus purpur eus)、ぺニシリウム ·チェノレメシナム（Penicillium chermesinum)、ぺ-シリウム 'クリソゲ ナム (Penicillium chrvsogenum)、へ-シリゾム ·ェクンノヽンサム (Penicillium expansum )、ぺ-シリウム ·リラシ-ゥム（Penicillium lilacinium)、フィァロフオーラ · 7アスティギア タ (Phialophora fastigiata)、フオリオタ *ァゥリヴ ラ (Pholiota aurivella)、フオリ才タ 'リ モネーラ (Pholiota limonella)、スコブラリオプシス .ブレビカウリス (Scopulariopsis brev icaulis)、セフィゾフィラム 'コミューネ (Sehizophvllum commune)、セフィゾフィラム 'コミ ュ. ~~不 (Sehizophvllum commune;、ス^ }、ロトリカム · , - ゥフンアイ 7カム (aporotnchum a urantiacum)、ノノムラエア ·ロセオビオラセァ .ノ一.ロセオビオラセァ (Nonomuraea ro seoviolacea var.roseoviolacea;ゝァボンァ ·リホスフヒ、、ナ (Devosia riboflavina)ゝ及ぴス トレプトマイセス ·クロモゲネス ·サブスピーシズ 'ルボラディリス (Streptomvces achrom o enes subsp. rubradiris)など力めげりれ 。 [0111] これら微生物は一般に、入手または購入が容易な保存株力も得ることができるが、 自然界力も分離することもできる。なお、これらの微生物に変異を生じさせて、より本 反応に有利な性質を有する菌株を得ることもできる。 (Clostridium cvlindrosporum), Comamonas testosteron i, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter cloacae, Force Rotobola subspisis, 'Carotobo ~~ fu (Pectobactenum carotovora subsp. Chronobacterium arborescens, Micrococcus luteus, Ochrobactrum sp., Proteus inconstans, Proteus mirabilis ( Proteus mirabilis), Proteus' retrogeri (froteus rettgeri), Proteus Proteus vulgaris, Providencia stuartii, Pseudomonas putida, Pseudomonas stutzeri, Rhodococer liquei 'Sphingobactenum iritivorum', Absidia 'Absidia orchidis', Acremmo'um' Acremonium bacillisporum, Amvlostereum areolatum, 7 へ レ ス レ ス, '~~ ャ (Aspergillus soiae), /' へ レ A A A ブ リChaetomidium fimeti, Chietosanoretoriya-Stromatozaes, Hormoconis resinae, Stachvbotrvs chartarum (Stachvbotrvs chartarum), Stalitas ), Endophraemia alter nata, Fusarium merismoides var. betulina), macro-former (Macrophoma commelinae), monas; y Susno ~~ Preus (Monascus purpur eus), Penicillium chermesinum (Penicillium chermesinum), Penicillium chrysogenum (Penicillium chrvsogenum) , -Penicillium expansum, Penicillium lilacinium, Phialophora 7Phialophora fastigiata, Foliota aurivella, Foliota aurivella (Pholiota limonella), Scobulariopsis .Scopulariopsis brev icaulis, Cefizophyllum commune, Cefizophyllum commune. urantiacum), Nonomuraea ro seoviolacea var.roseoviolacea; Devosia riboflavina ) And so on. [0111] In general, these microorganisms can obtain stock strength that can be easily obtained or purchased, but they can also separate natural forces. It is also possible to obtain strains having more advantageous properties for this reaction by causing mutations in these microorganisms.
[0112] これらの微生物の培養には、通常これらの微生物が資化しうる栄養源を含む培地 であれば何でも使用しうる。例えば、グルコース、シユークロース、マルトース等の糖 類、乳酸、酢酸、クェン酸、プロピオン酸等の有機酸類、エタノール、グリセリン等の アルコール類、パラフィン等の炭化水素類、大豆油、菜種油等の油脂類、またはこれ らの混合物等の炭素源;硫酸アンモ-ゥム、リン酸アンモ-ゥム、尿素、酵母エキス、 肉エキス、ペプトン、コーンスチープリカー等の窒素源；更に、その他の無機塩、ビタ ミン類等の栄養源;を適宜混合 .配合した通常の培地を用いることが出来る。これら培 地は用いる微生物の種類によって適宜選択すればょ 、。  [0112] For culturing these microorganisms, any medium containing a nutrient source that can be assimilated by these microorganisms can be used. For example, sugars such as glucose, sucrose and maltose, organic acids such as lactic acid, acetic acid, citrate and propionic acid, alcohols such as ethanol and glycerin, hydrocarbons such as paraffin, fats and oils such as soybean oil and rapeseed oil, Or a carbon source such as a mixture thereof; nitrogen sources such as ammonium sulfate, ammonium phosphate, urea, yeast extract, meat extract, peptone, corn steep liquor; and other inorganic salts, vitamins A normal medium containing a mixture of various nutrient sources; These mediums should be selected appropriately according to the type of microorganism used.
[0113] 微生物の培養は通常一般の条件により行うことができ、例えば、 pH4. 0〜9. 5、温 度範囲 20°C〜45°Cの範囲で、好気的に 10〜96時間培養するのが好ましい。前記 化合物 (VII)に微生物を反応させる場合においては、通常、上記微生物の菌体を含 んだ培養液をそのまま反応に使用することもできる力 培養液の濃縮物も用いること ができる。また、培養液中の成分が反応に悪影響を与える場合には、培養液を遠心 分離等により処理して得られる菌体または菌体処理物を使用することも出来る。  [0113] Microorganisms can be cultured under normal conditions, for example, aerobically for 10 to 96 hours at a pH of 4.0 to 9.5 and a temperature range of 20 ° C to 45 ° C. It is preferable to do. In the case of reacting a microorganism with the compound (VII), it is also possible to use a concentrate of a force culture solution that can be used in the reaction as it is. In addition, when a component in the culture solution adversely affects the reaction, a microbial cell or a microbial cell-treated product obtained by treating the culture solution by centrifugation or the like can also be used.
[0114] 上記微生物の菌体処理物としては特に限定されず、例えば、アセトンや五酸化ニリ ンによる脱水処理またはデシケーターや扇風機を利用した乾燥によって得られる乾 燥菌体、界面活性剤処理物、溶菌酵素処理物、固定化菌体または菌体を破砕した 無細胞抽出標品などをあげることができる。更に、培養物より立体選択的に還元反応 を触媒する酵素を精製し、これを使用してもよい。  [0114] The microorganism-treated product of the microorganism is not particularly limited. For example, a dried microorganism obtained by dehydration using acetone or nitric pentoxide or drying using a desiccator or a fan, a surfactant-treated product, Examples include lysed enzyme-treated products, immobilized cells, or cell-free extract preparations obtained by disrupting cells. Furthermore, an enzyme that catalyzes the reduction reaction stereoselectively from the culture may be purified and used.
[0115] 還元反応の際には、基質である前記化合物 (VII)を反応の初期に一括して添加し てもよく、反応の進行にあわせて分割して添加してもよい。反応時の温度は通常 10 〜60。C、好ましくは、 20〜40。Cであり、反応時の pHは 2. 5〜9、好ましくは、 5〜9 の範囲である。反応液中の酵素源の量はこれらの基質を還元する能力に応じ適宜決 定すればよい。また、反応液中の基質濃度は 0. 01〜50% (WZV)が好ましぐより 好ましくは、 0. 1〜30% (WZV)である。反応は通常、振とうまたは通気攪拌しなが ら行なう。反応時間は基質濃度、酵素源の量及びその他の反応条件により適宜決定 される。通常、 2〜 168時間で反応が終了するように各条件を設定することが好まし い。 [0115] During the reduction reaction, the compound (VII) as a substrate may be added all at once at the beginning of the reaction, or may be added in portions as the reaction proceeds. The reaction temperature is usually 10-60. C, preferably 20-40. C, and the pH during the reaction is in the range of 2.5-9, preferably 5-9. The amount of the enzyme source in the reaction solution may be appropriately determined according to the ability to reduce these substrates. The substrate concentration in the reaction solution is preferably 0.01 to 50% (WZV), more preferably 0.1 to 30% (WZV). The reaction is usually not shaken or agitated. Do it. The reaction time is appropriately determined depending on the substrate concentration, the amount of enzyme source, and other reaction conditions. Usually, it is preferable to set each condition so that the reaction is completed in 2 to 168 hours.
[0116] 還元反応を促進させるために、反応液にグルコース、エタノール、イソプロパノール などのエネルギー源を 0. 5〜 30%の割合でカ卩えると優れた結果が得られるので好ま L 、。一般に生物学的方法による還元反応に必要とされて 、る還元型ニコチンアミド •アデ-ンジヌクレオチド（以降 NADHと省略する）、還元型ニコチンアミド 'アデニン ジヌクレオチドリン酸 (以降 NADPHと省略する）等の補酵素を添加することにより、反 応を促進させることもできる。この場合、具体的には、反応液に直接これらを添加する  [0116] In order to promote the reduction reaction, it is preferable that an energy source such as glucose, ethanol, isopropanol or the like is added to the reaction solution at a ratio of 0.5 to 30% so that excellent results can be obtained. In general, reduced nicotinamide, adenine dinucleotide (hereinafter abbreviated as NADH), reduced nicotinamide 'adenine dinucleotide phosphate (hereinafter abbreviated as NADPH), etc., which are required for reduction by biological methods The reaction can also be promoted by adding a coenzyme. In this case, specifically, these are added directly to the reaction solution.
[0117] また、還元反応を促進させるために、酸化された該補酵素 (NAD+もしくは NADP+) をそれぞれの還元型 (NADHまたは NADPH)へ還元する（補酵素再生能を有する )酵素、及び還元するための基質を共存させて反応を行うと優れた結果が得られるの で好ましい。例えば、還元型へ還元する酵素としてグルコース脱水素酵素、還元する ための基質としてグルコースを共存させる力、または、還元型へ還元する酵素として ギ酸脱水素酵素、還元するための基質としてギ酸を共存させる。 [0117] Further, in order to promote the reduction reaction, the oxidized coenzyme (NAD + or NADP +) is reduced to the respective reduced form (NADH or NADPH) (having coenzyme regeneration ability) and reduced. It is preferable to carry out the reaction in the presence of a substrate for obtaining excellent results. For example, glucose dehydrogenase as an enzyme that reduces to the reduced form, glucose coexisting as the substrate for reduction, or formate dehydrogenase as the enzyme that reduces to the reduced form, and formic acid as the substrate to reduce .
[0118] 本発明の還元反応を触媒する酵素 (還元酵素）のかわりに、該酵素をコードする D NAを含む形質転換体を使用しても、同様に前記化合物 (VII)のカルボ-ル基のジ ァステレオ選択的還元を行うことができる。また、本発明の還元酵素をコードする DN A、および、補酵素再生能を有するポリペプチドをコードする DNAの両者を含む形 質転換体を使用しても、同様に前記化合物 (VII)のカルボ-ル基のジァステレオ選 択的還元を行うことができる。とりわけ、本発明の還元酵素をコードする DNA、および 、補酵素再生能を有するポリペプチドをコードする DNAの両者を含む形質転換体を 使用した場合には、補酵素を再生するための酵素を別途調製 '添加する必要がなく 、前記化合物 (VII)のカルボニル基のジァステレオ選択的還元をより効率良く行なうこ とがでさる。  [0118] In place of the enzyme (reductase) that catalyzes the reduction reaction of the present invention, a transformant containing DNA encoding the enzyme may be used, and the carbo group of the compound (VII) is similarly used. Diastereoselective reduction of can be performed. Further, even when a transformant containing both DNA encoding the reductase of the present invention and DNA encoding a polypeptide having a coenzyme regeneration ability is used, the carbohydrate of the compound (VII) is similarly used. -Diastereoselective reduction of a group can be performed. In particular, when a transformant containing both the DNA encoding the reductase of the present invention and the DNA encoding a polypeptide having a coenzyme regeneration ability is used, an enzyme for regenerating the coenzyme is separately provided. Preparation 'There is no need for addition, and diastereoselective reduction of the carbonyl group of the compound (VII) can be carried out more efficiently.
[0119] なお、本発明のポリペプチドをコードする DNAを含む形質転換体、または本発明 の還元酵素をコードする DNAおよび補酵素再生能を有するポリペプチドをコードす る DNAの両者を含む形質転換体は、培養菌体は言うまでもなぐその処理物として も前記化合物 (VII)のカルボニル基のジァステレオ選択的還元に使用することができ る。ここで言う形質転換体の処理物とは、例えば、界面活性剤や有機溶媒で処理し た細胞、乾燥細胞、破砕処理した細胞、細胞の粗抽出液等のほか、公知の手段でそ れらを固定ィ匕したものを意味する。 [0119] It should be noted that a transformant containing a DNA encoding the polypeptide of the present invention, or a DNA encoding the reductase of the present invention and a polypeptide having coenzyme regeneration ability is encoded. The transformant containing both of the DNAs can be used for diastereoselective reduction of the carbonyl group of the compound (VII) as well as the treated product, not to mention the cultured cells. The treated product of the transformant referred to here is, for example, a cell treated with a surfactant or an organic solvent, a dried cell, a disrupted cell, a crude cell extract or the like, or a known method. Means a fixed value.
[0120] 本発明の還元酵素をコードする DNA、および、補酵素再生能を有するポリべプチ ドをコードする DNAの両者を含む形質転換体は、本発明の還元酵素をコードする D NA、および、補酵素再生能を有するポリペプチドをコードする DNAの両者を、同一 のベクターに組み込み、これを宿主細胞に導入することにより得られるほ力、これら 2 種の DNAを不和合性グループの異なる 2種のベクターにそれぞれ組み込み、それら 2種のベクターを同一の宿主細胞に導入することによつても得られる。 [0120] A transformant containing both the DNA encoding the reductase of the present invention and the DNA encoding a polypeptide having a coenzyme regeneration ability is a DNA encoding the reductase of the present invention, and As a result of incorporating both of the DNAs encoding polypeptides having coenzyme-regenerating ability into the same vector and introducing them into host cells, these two types of DNA are different in incompatibility groups. They can also be obtained by integrating each into a vector of the species and introducing the two vectors into the same host cell.
[0121] 本発明の還元酵素をコードする DNA、及び、補酵素再生能を有するポリペプチド をコードする DNAの両者が組込まれたベクターの例としては、国際公開第 WO200 4/027055号公報に記載の発現ベクター pNTDRにバシラス'メガテリゥム由来のグ ルコース脱水素酵素遺伝子を導入した、 pNTDRGlが挙げられる。また、本発明の 還元酵素をコードする DNA、及び、補酵素再生能を有するポリペプチドをコードする DNAの両者を含む形質転換体の例としては、当該ベクターで E. coli HB101を形 皙転椽して得られる、 E. coli HB101 (pNTDRGl) FERM BP— 08458力挙げ られる E. coli HB101 (pNTDRGl) FERM BP— 08458は平成 14年 5月 29日 に独立行政法人産業技術総合研究所 特別生物寄託センター (IPOD： τ 305-8566 茨城県つくば巿東 1丁目 1番地 1)に寄託されている。  [0121] Examples of vectors in which both the DNA encoding the reductase of the present invention and the DNA encoding a polypeptide capable of coenzyme regeneration are incorporated are described in International Publication No. WO200 4/027055 PNTDRGl in which a glucose dehydrogenase gene derived from Bacillus megaterium has been introduced into the expression vector pNTDR. In addition, as an example of a transformant containing both the DNA encoding the reductase of the present invention and the DNA encoding a polypeptide having a coenzyme regeneration ability, E. coli HB101 was transformed with the vector. E. coli HB101 (pNTDRGl) FERM BP— 08458 can be obtained E. coli HB101 (pNTDRGl) FERM BP— 08458 was deposited on May 29, 2002 by the National Institute of Advanced Industrial Science and Technology. It is deposited with the Center (IPOD: τ 305-8566, 1-chome, 1-chome Tsukuba, Ibaraki 1).
[0122] 本発明の還元酵素をコードする DNAを含む形質転換体の培養、及び、本発明の 還元酵素をコードする DNAと補酵素再生能を有するポリペプチドをコードする DNA とを含む形質転換体の培養は、それらが増殖する限り、通常の、炭素源、窒素源、無 機塩類、有機栄養素などを含む液体栄養培地を用いて実施できる。  [0122] Culture of a transformant containing the DNA encoding the reductase of the present invention, and a transformant comprising a DNA encoding the reductase of the present invention and a DNA encoding a polypeptide capable of coenzyme regeneration. As long as they grow, the culture can be carried out using a normal liquid nutrient medium containing a carbon source, a nitrogen source, organic salts, organic nutrients and the like.
[0123] また更に、トリトンけ力ライテスタ株式会社製)、スパン (関東ィ匕学株式会社製)、ッ ィーンけ力ライテスタ株式会社製)などの界面活性剤を反応液に添加することも効 果的である。更に、基質及び Zまたは還元反応の生成物である 3—ヒドロキシ酪酸ェ ステル類による反応の阻害を回避する目的で、酢酸ェチル、酢酸ブチル、イソプロピ ルエーテル、トルエン、へキサンなどの水に不溶な有機溶媒を反応液に添カ卩してもよ い。更に、基質の溶解度を高める目的で、メタノール、エタノール、アセトン、テトラヒド 口フラン、ジメチルスルホキシドなどの水に可溶な有機溶媒を添加することもできる。 [0123] In addition, it is also effective to add a surfactant such as Triton strength light tester Co., Ltd.), Span (manufactured by Kanto Igaku Co., Ltd.), Queen strength power tester Co., Ltd. Is. In addition, 3-hydroxybutyrate that is the substrate and Z or the product of the reduction reaction. In order to avoid inhibition of the reaction by stealth, an organic solvent insoluble in water such as ethyl acetate, butyl acetate, isopropyl ether, toluene, hexane may be added to the reaction solution. Further, for the purpose of increasing the solubility of the substrate, an organic solvent soluble in water such as methanol, ethanol, acetone, tetrahydrofuran, dimethyl sulfoxide, etc. can be added.
[0124] 還元反応により生成した（3R, 5S)— 7 3, 5 ジヒドロキシヘプタン酸誘導 体の採取は、特に限定されないが、反応液から直接、あるいは菌体等を分離後、酢 酸ェチル、トルエン、 t—ブチルメチルエーテル、へキサン等の溶剤で抽出し、脱水 後、蒸留あるいはシリカゲルカラムクロマトグラフィー等により精製すれば高純度の前 記式化合物（VII)のカルボ-ル基が選択的に還元された（3R, 5S) 7 3, 5 -ジヒドロキシヘプタン酸誘導体を容易に得ることができる。  [0124] The collection of the (3R, 5S) -7,5 dihydroxyheptanoic acid derivative produced by the reduction reaction is not particularly limited, but it is possible to collect ethyl acetate, toluene directly from the reaction solution or after separating the cells. Extraction with a solvent such as tert-butyl methyl ether or hexane, dehydration, and purification by distillation or silica gel column chromatography, etc., to selectively reduce the carboxylic group of the high purity compound (VII). The obtained (3R, 5S) 7 3,5-dihydroxyheptanoic acid derivative can be easily obtained.
[0125] 前記式化合物（VII)のカルボ-ル基が選択的に還元された（3R, 5S) 7  [0125] The carbo group of formula (VII) was selectively reduced (3R, 5S) 7
3, 5—ジヒドロキシヘプタン酸誘導体、つまり前記ジァステレオ選択的還元により得ら れた、前記式 (VIII)において R3と R4が水素原子である（3R, 5S)— 7 3, 5— ジヒドロキシヘプタン酸誘導体は、必要に応じて水酸基を保護してもよい。ここで「必 要に応じて」とは水酸基を保護してもよいし、保護しなくてもよい良いことを示す。後ェ 程の反応性からは、水酸基を保護することが好ましい。水酸基を保護する方法として は通常よく行われる方法を用いればよぐ例えばプロテクティブグループ イン ォー ガ-ック シンセシス (PROTECTIVE GROUPS IN ORGANIC SYNTHESIS)、第三版 17— 245頁に記載の方法などを用いることができる。好ましい保護基としては架橋 の水酸基の保護基であり、以下に保護方法について説明する。 3,5-Dihydroxyheptanoic acid derivative, that is, obtained by the diastereoselective reduction, wherein in the formula (VIII), R 3 and R 4 are hydrogen atoms (3R, 5S) —7 3,5-dihydroxyheptane The acid derivative may protect the hydroxyl group as necessary. Here, “as necessary” means that the hydroxyl group may be protected or may not be protected. From the later reactivity, it is preferable to protect the hydroxyl group. As a method for protecting the hydroxyl group, a method commonly used may be used, for example, the method described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, third edition, pages 17-245, etc. be able to. A preferred protecting group is a protecting group for a crosslinked hydroxyl group, and the protecting method will be described below.
[0126] 公知のァセタール形成反応、例えば、酸触媒存在下にァセタール形成反応剤で処 理することにより、下記式 (Villa)；  [0126] A known acetal formation reaction, for example, by treatment with an acetal formation reagent in the presence of an acid catalyst, the following formula (Villa):
[0127] [化 35]
Figure imgf000030_0001
[0127] [Chemical 35]
Figure imgf000030_0001
( Vill a)  (Vill a)
[0128] で表される（3R, 5S)— 7 3, 5 ジヒドロキシヘプタン酸誘導体を製造するこ とができる。ここで、 R1Q、 R11はそれぞれ独立して、水素、置換もしくは無置換の炭素 数 1〜12のアルキル基、置換もしくは無置換の炭素数 6〜12のァリール基、又は置 換もしくは無置換の炭素数 7〜 12のァラルキル基であり、具体的にはメチル基、ェチ ル基、 tert—ブチル基、へキシル基、フエ-ル基、ベンジル基、 p—メトキシベンジル 基等が挙げられる。好ましくは、 R1Q、 R11がともにメチル基である。また、 R1Q、 R11は互 いに結合して環を形成していてもよぐ例えば、 R1Q、 R11が環を形成してシクロペンタ ン環、シクロへキサン環、シクロヘプタン環等となって、 1, 3—ジォキサン環とスピロ 構造を形成している場合があげられる。また、 X1、 R1は前記に同じである。 [0128] (3R, 5S) — 7 3,5 Dihydroxyheptanoic acid derivatives You can. Here, R 1Q and R 11 are each independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted group. The aralkyl group having 7 to 12 carbon atoms, specifically, methyl group, ethyl group, tert-butyl group, hexyl group, phenyl group, benzyl group, p-methoxybenzyl group, etc. . Preferably, both R 1Q and R 11 are methyl groups. R 1Q and R 11 may be bonded to each other to form a ring.For example, R 1Q and R 11 form a ring to form a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, etc. In this case, a spiro structure is formed with the 1,3-dioxane ring. X 1 and R 1 are the same as described above.
[0129] 特に X1が塩素原子であり、 R1Qと R11がともにメチル基であり、 R1が tert—ブチル基で ある下記式 (XII)； [0129] In particular, the following formula (XII), wherein X 1 is a chlorine atom, R 1Q and R 11 are both methyl groups, and R 1 is a tert-butyl group;
[0130] [化 36]
Figure imgf000031_0001
[0130] [Chemical 36]
Figure imgf000031_0001
( XIり  (XI Ri
[0131] で表される（3R, 5S)— 7—クロロー 3, 5—（2', 2'—イソプロピリデン）ジォキシヘプ タン酸 tert—ブチルは医薬中間体として有用な文献未知の新規ィ匕合物である。 [0131] (3R, 5S) — 7-Chloro-3,5- (2 ′, 2′-isopropylidene) dioxyheptanoic acid tert-butyl is a novel compound of unknown literature useful as a pharmaceutical intermediate It is a thing.
[0132] 本工程に使用できるァセタール形成反応剤としては例えば、アセトン、シクロへキサ ノン等のケトン、ホルムアルデヒド、ベンズアルデヒド等のアルデヒド、ジメトキシメタン、 2, 2—ジメトキシプロパン、 1, 1ージメトキシシクロへキサン等のアルコキシアルカン、 2—メトキシプロペン等のアルコキシアルケン等があげられる。好ましくは、アセトン、 2 —メトキシプロペン、 2, 2—ジメトキシプロパンがあげられる。前記ァセタール形成反 応剤の使用量としては、前記化合物 (VIII)に対し、好ましくは 1〜10倍モル量であり 、更に好ましくは 1〜5倍モル量である。また、反応を速やかに促進させる目的で、ァ セタール形成反応剤を反応溶媒として使用してもよい。  [0132] Examples of acetal-forming reactants that can be used in this step include ketones such as acetone and cyclohexanone, aldehydes such as formaldehyde and benzaldehyde, dimethoxymethane, 2,2-dimethoxypropane, and 1,1-dimethoxycyclohexane. Examples include alkoxyalkanes such as xane, alkoxyalkenes such as 2-methoxypropene, and the like. Preferred are acetone, 2-methoxypropene, and 2,2-dimethoxypropane. The amount of the acetal-forming reaction agent to be used is preferably 1 to 10-fold mol amount, more preferably 1 to 5-fold mol amount based on Compound (VIII). In addition, an acetal-forming reagent may be used as a reaction solvent for the purpose of promptly accelerating the reaction.
[0133] 本工程に使用できる酸触媒としては、ルイス酸またはブレンステッド酸があげられる 。前記ルイス酸またはブレンステッド酸としては例えば、三塩ィ匕アルミニウム、三フッ化 ホウ素、二塩ィ匕亜鉛、四塩化スズ等のルイス酸;シユウ酸、ギ酸、酢酸、安息香酸、ト リフルォロ酢酸等のカルボン酸；メタンスルホン酸、 p—トルエンスルホン酸、カンファ ースルホン酸、 p—トルエンスルホン酸ピリジ-ゥム等のスルホン酸；塩酸、硫酸、硝酸 、ホウ酸等の無機酸等があげられる。 p—トルエンスルホン酸ピリジ-ゥムは p—トルェ ンスルホン酸とピリジン力 公知の方法で調製できる。好ましくは、 p—トルエンスルホ ン酸、カンファースルホン酸、 p—トルエンスルホン酸ピリジ-ゥムである。前記酸触媒 の使用量としては、前記化合物 (VIII)に対し、好ましくは 0. 001-0. 5倍モル量であ り、更に好ましく ίま 0. 005〜0. 1倍モノレ量である。 [0133] Examples of the acid catalyst that can be used in this step include Lewis acid and Bronsted acid. Examples of the Lewis acid or Bronsted acid include Lewis acids such as trisalt-aluminum, boron trifluoride, disalt-zinc, and tin tetrachloride; oxalic acid, formic acid, acetic acid, benzoic acid, Carboxylic acids such as rifluoroacetic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid pyridinium; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc. It is done. p-Toluenesulfonic acid pyridinium can be prepared by known methods with p-toluenesulfonic acid and pyridine. P-toluenesulfonic acid, camphorsulfonic acid, and p-toluenesulfonic acid pyridinium are preferable. The amount of the acid catalyst to be used is preferably 0.001 to 0.5 times the molar amount relative to the compound (VIII), more preferably 0.005 to 0.1 times the monole amount.
[0134] 本反応は無溶媒でも実施できるが、各種有機溶媒を反応溶媒に使用してもよい。  [0134] This reaction can be carried out without a solvent, but various organic solvents may be used as a reaction solvent.
前記有機溶媒としては例えば、非プロトン性の有機溶媒があげられる。具体例として は前述と同じものがあげられる。前記有機溶媒は、単独で用いてもよぐ 2種以上を併 用してもよい。好ましくは、トルエン、塩化メチレン、テトラヒドロフラン、ジメチルホルム アミド、ァセトニトリル、ジメチルスルホキシド、 Ν—メチルピロリドンがあげられる。  Examples of the organic solvent include aprotic organic solvents. Specific examples are the same as described above. The organic solvents may be used alone or in combination of two or more. Preferred are toluene, methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide, and メ チ ル -methylpyrrolidone.
[0135] 本工程の反応温度として好ましくは、収率向上の観点から 0〜： L00°Cであり、更に 好ましくは 20〜70°Cである。  [0135] The reaction temperature in this step is preferably 0 to L00 ° C from the viewpoint of yield improvement, and more preferably 20 to 70 ° C.
[0136] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液に水を加え、一般的な抽出溶媒、 例えば酢酸ェチル、ジェチルエーテル、塩化メチレン、トルエン、へキサン等を用い て抽出操作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒及び抽 出溶媒を留去すると、 目的物が得られる。また、反応終了後、直ちに減圧加熱等の 操作により反応溶媒を留去してから同様の操作を行ってもょ 、。このようにして得られ る目的物は、ほぼ純粋なものであるが、晶析精製、分別蒸留、カラムクロマトグラフィ 一等の一般的な手法により精製を行い、さらに純度を高めてもよい。  [0136] In this step, a general process may be performed in order to obtain a reaction fluid force after completion of the reaction. For example, water is added to the reaction solution after completion of the reaction, and the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like. The target product is obtained by distilling off the reaction solvent and extraction solvent from the resulting extract by an operation such as heating under reduced pressure. Also, immediately after the reaction is completed, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and the same operation may be performed. The target product thus obtained is almost pure, but the purity may be further increased by performing purification by a general method such as crystallization purification, fractional distillation, column chromatography or the like.
[0137] 工程（5)  [0137] Process (5)
本工程では、前記式 (VIII)で表される（3R, 5S)— 7—ノヽロー 3, 5—ジヒドロキシへ ブタン酸誘導体を、アンモニアでァミノ化することにより、下記式 (I)；  In this step, the (3R, 5S) -7-noro 3,5-dihydroxyhexanoic acid derivative represented by the above formula (VIII) is aminated with ammonia to give the following formula (I);
[0138] [化 37]
Figure imgf000033_0001
[0138] [Chemical 37]
Figure imgf000033_0001
( I )  (I)
[0139] で表される（3R, 5R) ー7—アミノー 3, 5—ジヒドロキシヘプタン酸誘導体、又はその 塩を製造する。ここで、 R1
Figure imgf000033_0002
及び R4は前記に同じである。本工程の反応性から、 R 3及び R4としては水酸基の保護基であることが好ましぐより好ましくはイソプロピリデン 基である。また、前記化合物 (VIII)は工程 (4)で得られた反応液をそのまま用いても 良いし、単離精製したものを用いても良い。また、別の方法で得られたものを用いて ちょい。 [0139] A (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative represented by the formula: Where R 1
Figure imgf000033_0002
And R 4 is the same as above. From the reactivity of this step, R 3 and R 4 are preferably a protecting group for a hydroxyl group, more preferably an isopropylidene group. As the compound (VIII), the reaction solution obtained in the step (4) may be used as it is, or an isolated and purified product may be used. Also, use something obtained by another method.
[0140] 本工程に用いるアンモニアは、アンモニアガスを有機溶媒に溶解したものや、水に 溶解したアンモニア水であってもよ 、。  [0140] The ammonia used in this step may be ammonia gas dissolved in an organic solvent or ammonia water dissolved in water.
[0141] 前記アンモニアの使用量としては、前記化合物 (VIII)に対し、好ましくは 1〜200倍 モル量であり、更に好ましくは 1〜 50倍モル量である。  [0141] The amount of ammonia used is preferably 1 to 200-fold mol amount, more preferably 1 to 50-fold mol amount based on Compound (VIII).
[0142] 本工程は無溶媒でも実施できる力 反応溶媒を使用してもよい。本工程に使用でき る反応溶媒はとくに限定されないが、例えば、水、アルコール系溶媒、非プロトン性の 有機溶媒をあげることができる。具体例としては前述のものがあげられる。これらは単 独で用いてもよぐ 2種以上を併用してもよい。好ましくはアルコール系溶媒であり、更 に好ましくはメタノールである。  [0142] This step can be carried out without a solvent. A reaction solvent may be used. The reaction solvent that can be used in this step is not particularly limited, and examples thereof include water, alcohol solvents, and aprotic organic solvents. Specific examples include those described above. These may be used alone or in combination of two or more. Alcohol solvents are preferred, and methanol is more preferred.
[0143] 本工程の反応温度としては、収率向上の観点から好ましくは 0〜200°Cであり、更 に好ましくは 50〜 150°Cである。  [0143] The reaction temperature in this step is preferably 0 to 200 ° C, more preferably 50 to 150 ° C, from the viewpoint of yield improvement.
[0144] 本工程はアンモニアの揮発を抑えるために、オートクレープなどの耐圧密閉反応設 備を使用して加圧条件下に反応を行うとよ 、。この場合の圧力として好ましくは 1〜 1 OOkgZcm2であり、更に好ましくは 1〜 20kgZcm2である。 [0144] In this process, in order to suppress the volatilization of ammonia, the reaction is performed under pressure using a pressure-resistant sealed reaction equipment such as an autoclave. As the preferred pressure when a 1~ 1 OOkgZcm 2, further preferably 1~ 20kgZcm 2.
[0145] 本工程において、反応終了後の反応液力も生成物を取得するためには、一般的な 処理を行えばよい。例えば、反応終了後の反応液から減圧加熱等の操作により溶媒 を留去すると、目的物がァミンの塩ィ匕水素酸塩として得られる。また、遊離のァミンと して目的物を取得するためには、前記ァミンの塩ィ匕水素酸塩をー且アルカリ性の水 溶液に溶解し、一般的な抽出溶媒、例えば酢酸ェチル、ジェチルエーテル、塩化メ チレン、トルエン、へキサン等を用いて抽出操作を行う。得られた抽出液から、減圧カロ 熱等の操作により反応溶媒及び抽出溶媒を留去すると、 目的物が遊離のァミンとし て得られる。 [0145] In this step, a general process may be performed in order to obtain a reaction fluid force after completion of the reaction. For example, when the solvent is distilled off from the reaction solution after completion of the reaction by an operation such as heating under reduced pressure, the target product is obtained as a salt of amine hydrochloride. In addition, in order to obtain the desired product as a free amine, the amine hydrochloride salt of the amine is dissolved in an alkaline aqueous solution, and a general extraction solvent such as ethyl acetate or jetyl ether is used. , Chloride Extraction operation is performed using tylene, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as reduced pressure caloric heat, the desired product is obtained as a free amine.
[0146] このようにして得られる目的物は、ほぼ純粋なものであるが、晶析精製、分別蒸留、 カラムクロマトグラフィー等の一般的な手法により精製を行い、さらに純度を高めても よい。  [0146] Although the target product obtained in this manner is almost pure, it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography, etc.
[0147] また、得られた遊離のアミンを塩ィ匕水素、臭化水素、硫酸等の鉱酸;メタンスルホン 酸、 ρ—トルエンスルホン酸、カンファースルホン酸等のスルホン酸；酢酸、プロピオン 酸、マンデル酸、酒石酸等のカルボン酸と塩形成させて晶析することにより精製して ちょい。  [0147] Further, the obtained free amine is converted into mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; sulfonic acids such as methanesulfonic acid, ρ-toluenesulfonic acid and camphorsulfonic acid; acetic acid, propionic acid, Purify by crystallization by forming a salt with carboxylic acids such as mandelic acid and tartaric acid.
実施例  Example
[0148] 以下に実施例をあげて本発明を具体的に説明するが、本発明はこれら実施例のみ に限定されるものではない。  [0148] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
[0149] (実施例 1) 5—クロロー 3—ォキソペンタン酸ェチルの製造  Example 1 Production of 5-ethyl chloro-3-oxopentanoate
窒素雰囲気下、マロン酸モノェチルエステルカリウム塩 39. 3g (230mmol)のテト ラヒドロフラン溶液（200ml)を氷冷し、ここにトリェチルァミン 22. 3g (220mmol)と塩 化マグネシウム 26. 7g (280mmol)を加え、室温まで昇温して 3. 5時間攪拌しマロ ネートを生成させた。この溶液を再度氷冷して塩化 3—クロ口プロピオニル 12. 7g (l OOmmol)を滴下した後、トリェチルァミン 2. 3g (23mmol)をカ卩え、室温で 24時間攪 拌した。減圧下に溶媒を留去した後、あら力じめ氷冷した酢酸ェチル 150ml及び 10 %塩酸水溶液 150mlをカ卩えて抽出した。更に有機層を水 200mlで 3回、飽和炭酸 水素ナトリウム水溶液と飽和食塩水にて順次洗浄後、無水硫酸マグネシウムで乾燥、 ろ別し、ろ液を減圧濃縮することにより、 5—クロ口一 3—ォキソペンタン酸ェチルをほ ぼ無色の液体として得た（15. lg、含量: 85重量％、収率： 72%)。  In a nitrogen atmosphere, a solution of 39.3 g (230 mmol) of malonic acid monoethyl ester potassium salt in tetrahydrofuran (200 ml) was ice-cooled, and then 22.3 g (220 mmol) of triethylamine and 26.7 g (280 mmol) of magnesium chloride were added thereto. In addition, the mixture was warmed to room temperature and stirred for 3.5 hours to form malonate. This solution was ice-cooled again and 12.7 g (l OOmmol) of 3-chloropropionyl chloride was added dropwise, and 2.3 g (23 mmol) of triethylamine was added, followed by stirring at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, 150 ml of cetyl acetate and 150 ml of 10% hydrochloric acid aqueous solution, which had been ice-cooled for a while, were extracted. Further, the organic layer was washed with 200 ml of water three times, successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. —Ethyloxopentanoate was obtained as an almost colorless liquid (15. lg, content: 85% by weight, yield: 72%).
1 H-NMR(CDC1 , 400MHz/ppm) ; 1. 29 (3H, t) , 3. 05 (2H, t) , 3. 49 (2  1 H-NMR (CDC1, 400MHz / ppm); 1.29 (3H, t), 3.05 (2H, t), 3.49 (2
3  Three
H, s) , 3. 75 (2H, t) , 4. 21 (2H, q)。  H, s), 3.75 (2H, t), 4.21 (2H, q).
[0150] (実施例 2) 5—クロロー 3—ォキソペンタン酸ェチルの製诰 Example 2 Production of Ethyl 5-chloro-3-oxopentanoate
窒素雰囲気下、マロン酸モノェチルエステルカリウム塩 78. 3g (460mmol)の酢酸 ェチノレ溶液（1200ml)【こ、卜リエチノレアミン 44. 5g (440mmol)をカ卩免 350C【こて 拌した。ここに 4分割した全量 53. 4gの塩化マグネシウム（560mmol)を 30分おきに 添加し、 2時間攪拌することでマロネートを生成させた。この溶液を室温に戻した後、 塩ィ匕 3 クロ口プロピオ-ル 25. 4g (200mmol)及びトリェチルァミン 4. 6g (46mmo 1)を加え、室温で 12時間攪拌した後、 3%塩酸水溶液 600mlを加え分液操作により 水層を除去した。更に有機層を水 500ml、飽和食塩水にて順次洗浄後、無水硫酸 マグネシウムで乾燥、ろ別し、ろ液を減圧濃縮することにより、 5—クロロー 3—ォキソ ペンタン酸ェチルをほぼ無色の液体として得た（65. 2g、含量: 40重量％、収率： 74 %)。 78.3 g (460 mmol) acetic acid of malonic acid monoethyl ester potassium salt under nitrogen atmosphere Echinore solution (1200ml) [This was Bok Riechinoreamin 44. 5g (440mmol) mosquitoes卩免35 0 C [trowel拌. The total amount of 53.4 g of magnesium chloride (560 mmol) divided into 4 parts was added every 30 minutes, and malonate was produced by stirring for 2 hours. After this solution was returned to room temperature, 25.4 g (200 mmol) of salted 3-chloropropylene and 4.6 g (46 mmo 1) of triethylamine were stirred for 12 hours at room temperature, and then 600 ml of 3% aqueous hydrochloric acid solution was added. The aqueous layer was removed by liquid separation operation. Further, the organic layer was washed successively with 500 ml of water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-3-oxopentanoate as an almost colorless liquid. Obtained (65.2 g, content: 40% by weight, yield: 74%).
[0151] (実施例 3) 5 クロロー 3 ォキソペンタン酸ェチルの製诰  Example 3 Production of 5 Chloro-3-oxopentanoate Ethyl
窒素雰囲気下、酢酸ェチル 1. 4g (16mmol)を含むトルエン（30ml)溶液を 45 °Cに冷却し、ここに塩化 3 クロ口プロピオ-ル 1. 3g (10mmol)を滴下した。そのま ま 10分間攪拌した後、四塩ィ匕チタン 4. 4g (23mmol)、ジイソプロピルェチルァミン 3 . 2g (25mmol)を順次カ卩え、そのまま 1時間攪拌した。水（50ml)をカ卩えて水解し、 水層を除去した後に、有機層を更に水（50ml)で 2回洗浄した。有機層を無水硫酸 マグネシウムで乾燥後、ろ別し、ろ液を減圧濃縮することにより、 5—クロロー 3—ォキ ソペンタン酸ェチルを褐色油状物として得た (収率 16%)。  Under a nitrogen atmosphere, a toluene (30 ml) solution containing 1.4 g (16 mmol) of ethyl acetate was cooled to 45 ° C., and 1.3 g (10 mmol) of 3-chloropropylene chloride was added dropwise thereto. The mixture was stirred for 10 minutes, and then 4.4 g (23 mmol) of tetrachlorotitanium and 3.2 g (25 mmol) of diisopropylethylamine were sequentially added and stirred for 1 hour. Water (50 ml) was added and hydrolyzed, the aqueous layer was removed, and the organic layer was further washed twice with water (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-3-oxopentanoate as a brown oil (yield 16%).
[0152] (実施例 4) (S) 5 クロロー 3 ヒドロキシペンタン酸ェチルの製诰  (Example 4) (S) Production of (S) 5 chloro-3 hydroxypentanoate ethyl
アルゴン雰囲気下、 5—クロ口— 3—ォキソペンタン酸ェチル L 28g (7. 2mmol)、 ( (R) -BINAP)RuBr (0. 05mmol) (BINAPは 2, 2，-ビスジフエ-ルホスフイノ Under argon atmosphere, 5 — black mouth — 3 — ethyl oxopentanoate L 28g (7.2 mmol), ((R) -BINAP) RuBr (0. 05 mmol) (BINAP is 2, 2, -bisdiphenylphosphino
2  2
—1, 1，-ビナフチルを表す。 Tetrahedron Asymmetry, 1994, 5, 675.に記載の方法 により調製した。）にメタノール 3mLを加えた。水素置換を 3回行い、 70°Cの加熱条 件下、 3. OkgZcm2の水素圧で 14時間反応させた。水素を放棄後、減圧濃縮し、シ リカゲルカラムクロマトグラフィーにて精製することにより、 (S)—5—クロ口一 3—ヒドロ キシペンタン酸ェチルを淡黄色油状物として得た（1. 26g、収率： 98%)。このものは 塩化 4—メトキシベンゾィルと反応させてエステル誘導体とし、 HPLC分析 (カラム:ダ イセルキラルパック AD、溶離液：へキサン Zイソプロパノール =80Z20、流速： 1. 0 mL/min.,カラム温度： 24°C、検出器： UV254nm、保持時間：（R)体 = 10. 0分、 (S)体 =13.8分）にて光学純度を算出すると、 98%eeであった。 —1, 1, represents -binaphthyl. It was prepared by the method described in Tetrahedron Asymmetry, 1994, 5, 675. ) Was added with 3 mL of methanol. Hydrogen substitution was performed three times, and the reaction was carried out for 14 hours under a heating condition of 70 ° C and 3. OkgZcm 2 of hydrogen pressure. After abandoning the hydrogen, it was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (S) -5-chloroethyl 3-hydroxypentanoate as a pale yellow oil (1.26 g, yield). Rate: 98%). This was reacted with 4-methoxybenzoyl chloride to give an ester derivative and analyzed by HPLC (column: Daicel Chiralpak AD, eluent: hexane Zisopropanol = 80Z20, flow rate: 1.0 mL / min., Column temperature: 24 ° C, detector: UV254nm, retention time: (R) form = 10.0 minutes, When the optical purity was calculated at (S) body = 13.8 min), it was 98% ee.
1 H-NMR(CDC1 , 400MHz/ppm) ;1.28 (3H, t), 1.82—1.89 (1H, m) 1 H-NMR (CDC1, 400MHz / ppm); 1.28 (3H, t), 1.82-1.89 (1H, m)
3  Three
, 1.93-2.01 (1H, m), 2.42— 2.56 (2H, m), 3.14(1H, d), 3.64— 3.7 7(2H, m), 4.18 (2H, q), 4.21—4.28 (1H, m)。  , 1.93-2.01 (1H, m), 2.42—2.56 (2H, m), 3.14 (1H, d), 3.64— 3.7 7 (2H, m), 4.18 (2H, q), 4.21—4.28 (1H, m ).
[0153] (実施例 5) (S) 7 クロロー 5 ヒドロキシー 3 ォキソヘプタン酸 tert ブチルの 製诰 (Example 5) (S) Production of tert-butyl chloro-5-hydroxy-3-oxoheptanoate
窒素雰囲気下、 n ブチルリチウムのへキサン溶液（1.6mol/L)llmL(17.7m mol)を 5°Cに冷却し、ここにジイソプロピルアミン 1.97g(19.5mmol)とテトラヒドロ フラン 10mlカゝらなる溶液を滴下、リチウムジイソプロピルアミド溶液を調製した。  In a nitrogen atmosphere, n-butyllithium hexane solution (1.6 mol / L) llmL (17.7 mmol) is cooled to 5 ° C, and this is a solution consisting of 1.97 g (19.5 mmol) of diisopropylamine and 10 ml of tetrahydrofuran. Was added dropwise to prepare a lithium diisopropylamide solution.
[0154] 別の容器に実施例 4の方法で得られた（S)—5 クロ口一 3 ヒドロキシペンタン酸 ェチル 1. Og(5.54mmol)、酢酸 tert—ブチル 1.28g(llmmol)、テトラヒドロフラ ン（10ml)をカ卩え、窒素雰囲気下で氷冷した。この溶液に、塩ィ匕 tert—ブチルマグネ シゥムのトルエン Zテトラヒドロフラン混合溶液（1.8mol/kg)3. lg(5.54mmol) を 30分かけて滴下し、さらに 5°Cで 30分攪拌した。ここに、先に調製したリチウムジィ ソプロピルアミド溶液を 15分かけて滴下し、さらに 5°Cで 7時間撹拌した。また別の容 器に 6規定塩酸 5ml、水 5ml、酢酸ェチル 20mlを撹拌混合し、上記の反応液を注い だ。静置の後、水層を分離し、有機層を水で 2回洗浄した。減圧下に溶媒を留去する ことにより、淡黄色油状物 1.58gを得た。このものをシリカゲルカラムクロマトグラフィ 一にて精製することにより、 (S)—7—クロ口一 5—ヒドロキシ一 3—ォキソヘプタン酸 t ert ブチルを無色油状物として得た（1. lg、収率： 79%)。 [0154] In another container, (S) -5 obtained by the method of Example 4 was obtained. Ethyl hydroxypentanoate 1. Og (5.54 mmol), tert-butyl acetate 1.28 g (llmmol), tetrahydrofuran ( 10 ml) was added and ice-cooled under a nitrogen atmosphere. To this solution, 3.lg (5.54 mmol) of a mixed solution of sodium tert-butylmagnesium in toluene Z tetrahydrofuran (1.8 mol / kg) was added dropwise over 30 minutes, and the mixture was further stirred at 5 ° C for 30 minutes. The previously prepared lithium diisopropylamide solution was added dropwise over 15 minutes, and the mixture was further stirred at 5 ° C for 7 hours. In another container, 5 ml of 6N hydrochloric acid, 5 ml of water, and 20 ml of ethyl acetate were mixed with stirring, and the above reaction mixture was poured. After standing, the aqueous layer was separated, and the organic layer was washed twice with water. The solvent was distilled off under reduced pressure to obtain 1.58 g of a pale yellow oil. This was purified by silica gel column chromatography to obtain (S) -7-chloro-5-hydroxy-3-oxoheptanoic acid tert-butyl as a colorless oil (1. lg, yield: 79 %).
1 H-NMR(CDC1 , 400MHz/ppm) ;1.47 (9H, s), 1.80—1.98 (2H, m) 1 H-NMR (CDC1, 400 MHz / ppm); 1.47 (9H, s), 1.80—1.98 (2H, m)
3  Three
, 2.65-2.79 (2H, m), 3.09 (1H, d), 3.39 (2H, s), 3.64— 3.73 (2H, m ), 4.31 (1H, m)。  , 2.65-2.79 (2H, m), 3.09 (1H, d), 3.39 (2H, s), 3.64—3.73 (2H, m), 4.31 (1H, m).
[0155] (実施例 6) (3R.5S)— 7 クロロー 3.5 ジヒドロキシヘプタン酸 tert ブチルの 製诰  (Example 6) (3R.5S) — 7 Chloro-3.5 Dihydroxyheptanoate Production of tert-butyl
窒素雰囲気下、実施例 5の方法で得られた (S)— 7—クロロー 5—ヒドロキシー 3— ォキソヘプタン酸 tert ブチル 0.501g(2. Ommol)のテトラヒドロフラン溶液（3ml) に、ジェチルメトキシボラン Zテトラヒドロフラン溶液（1. OmolZl) 3mlをカ卩えて、室温 で 1時間攪拌した。別の容器で、水素化ホウ素ナトリウム 0. 14g (3. 7mmol)のテトラ ヒドロフラン懸濁液（3ml)を一 70°Cに冷却し、メタノール 0. 5ml (12mmol)を滴下、 そのままの温度で 30分攪拌した。ここに、先の溶液を— 70°Cで滴下し、そのまま 5時 間攪拌した。反応終了後、酢酸 3ml(52mmol)をゆっくり加えて、減圧下に溶媒を留 去した。更にメタノール 5mlを加えて減圧濃縮する操作を 3回繰り返した。残渣に酢 酸ェチルと 10重量％塩酸をカ卩えて抽出し、有機層を飽和重曹水と飽和食塩水にて 順次洗浄後、無水硫酸マグネシウムで乾燥、ろ別し、ろ液を減圧濃縮することにより、 無色油状物を得た。このものをシリカゲルカラムクロマトグラフィーにて精製することに より、 (3R, 5S)— 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert ブチルを無色油 状物として得た (0. 386g、収率： 76%)。また、還元の選択性は HPLC分析 (カラム： ナカライコスモシル 5CN—R、溶離液：ァセトニトリル Z水 = 1Z9、流速： 1. OmL/ min.、カラム温度： 40°C、検出器： UV210nm、保持時間：（3R, 5S)体 = 9. 4分、（ 3S, 5S)体 =8. 6分）により、（3R, 5S)体 / (3S, 5S)体 = 95/5と決定した。 Under a nitrogen atmosphere, to a tetrahydrofuran solution (3 ml) of (S) -7-chloro-5-hydroxy-3-oxoheptanoic acid tert-butyl 0.501 g (2. Ommol) obtained by the method of Example 5, Add 3 ml of solution (1. OmolZl) to room temperature For 1 hour. In a separate container, 0.14 g (3.7 mmol) of sodium borohydride suspension in tetrahydrofuran (3 ml) was cooled to 70 ° C., and 0.5 ml (12 mmol) of methanol was added dropwise. Stir for minutes. The previous solution was added dropwise at −70 ° C. and stirred as it was for 5 hours. After completion of the reaction, 3 ml (52 mmol) of acetic acid was slowly added, and the solvent was distilled off under reduced pressure. The operation of adding 5 ml of methanol and concentrating under reduced pressure was repeated three times. The residue is extracted with ethyl acetate and 10 wt% hydrochloric acid, and the organic layer is washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Gave a colorless oil. This was purified by silica gel column chromatography to obtain tert-butyl (3R, 5S) -7-chloro-3,5-dihydroxyheptanoate as a colorless oil (0.386 g, yield: 76 %). The reduction selectivity was determined by HPLC analysis (column: Nakarai Cosmocil 5CN-R, eluent: acetonitrile Z water = 1Z9, flow rate: 1. OmL / min., Column temperature: 40 ° C, detector: UV210nm, retention Time: (3R, 5S) body = 9.4 minutes, (3S, 5S) body = 8.6 minutes), (3R, 5S) body / (3S, 5S) body = 95/5 was determined.
1 H-NMR(CDC1 , 400MHz/ppm) ; 1. 46 (9H, s) , 1. 51— 1. 67 (2H, m)  1 H-NMR (CDC1, 400MHz / ppm); 1.46 (9H, s), 1.51— 1.67 (2H, m)
3  Three
, 1. 80- 1. 98 (2H, m) , 2. 41 (2H, d) , 3. 63— 3. 75 (2H, m) , 3. 82 (1H, d ) , 3. 85 (1H, d) , 4. 08 -4. 13 (1H, m) , 4. 24—4. 29 (1H, m)。  , 1.80- 1.98 (2H, m), 2.41 (2H, d), 3.63— 3.75 (2H, m), 3.82 (1H, d), 3.85 (1H , d), 4. 08 -4. 13 (1H, m), 4. 24—4. 29 (1H, m).
[0156] (実施例 7) (3R. 5S)— 7 クロロー 3. 5 ジヒドロキシヘプタン酸 tert ブチルの 製诰 (Example 7) (3R.5S) — 7 Chloro-3.5 Production of tert-butyl dihydroxyheptanoate
アルゴン雰囲気下、実施例 5の方法で得られた（S)—7—クロ口— 5—ヒドロキシ— 3 —ォキソヘプタン酸 tert—ブチル 1. Og (4. Ommol)、（（R)— BINAP) RuBr (0. 0  (S) -7-Black-headed 5-hydroxy-3-oxohexeptanoic acid tert-butyl 1. Og (4. Ommol), ((R)-BINAP) RuBr obtained by the method of Example 5 under argon atmosphere (0. 0
2 2
4mmol)にメタノール 3mL及び水 0. 3mlをカ卩えた。水素置換を 3回行い、 70°Cのカロ 熱条件下、 3. OkgZcm2の水素圧で 16時間反応させた。水素を放棄後、減圧濃縮 し、シリカゲルカラムクロマトグラフィーにて精製することにより、 (3R, 5S)— 7—クロ口 - 3, 5 ジヒドロキシヘプタン酸 tert ブチルを無色油状物として得た（0. 983g、 収率： 97%)。また、還元の選択性は前述の方法により、 (3R, 5S)体 Z(3S, 5S)体 = 87Z13と決定した。 4 mmol) was charged with 3 mL of methanol and 0.3 mL of water. Hydrogen substitution was performed three times, and the reaction was carried out for 16 hours under a 70 ° C carothermal condition and 3. OkgZcm 2 hydrogen pressure. After abandoning the hydrogen, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain tert-butyl (3R, 5S) -7-chloro-3,5-dihydroxyheptanoate as a colorless oil (0.983 g Yield: 97%). The selectivity of reduction was determined by the method described above to be (3R, 5S) Z (3S, 5S) = 87Z13.
[0157] (実施例 8) (3R. 5S)— 7 クロロー 3. 5—（2'. 2 '—イソプロピリデンジォキシ）へ ブタン酸 tert ブチノレの p トルエンスルホン酸 18mg(0.095mmol)をアセトン 0.5mlに溶解し、ピリジン 13mg(0.16mmol)、実施例 14の方法で得られた（3R, 5S)— 7 クロ口 3, 5— ジヒドロキシヘプタン酸 tert ブチル 0.21g(0.82mmol)のアセトン溶液（4ml)、 2 , 2 ジメトキシプロパン 0.34g(3.3mmol)を順次加え、 40°Cで 23時間撹拌した。 減圧下に溶媒を留去し、残查に飽和重曹水 10mlを加えて、酢酸ェチルで 3回抽出 した。抽出した有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下 に溶媒を留去することにより、若干黄色の油状物 0.21gを得た。このものをシリカゲ ルカラムクロマトグラフィーにて精製することにより、 (3R, 5S)— 7—クロ口一 3, 5— ( 2', 2' イソプロピリデンジォキシ）ヘプタン酸 tert ブチルを無色油状物として得た (0.20g、収率： 84%)。 Example 8 (3R.5S) —7 Chloro-3.5— (2′.2′-isopropylidenedioxy) butanoic acid tert p Toluenesulfonic acid 18 mg (0.095 mmol) was dissolved in acetone 0.5 ml, and pyridine 13 mg (0.16 mmol) was obtained by the method of Example 14 (3R, 5S) —7-mouth 3,5-dihydroxyheptanoic acid tert A solution of butyl 0.21 g (0.82 mmol) in acetone (4 ml) and 2,2 dimethoxypropane 0.34 g (3.3 mmol) were sequentially added, and the mixture was stirred at 40 ° C. for 23 hours. The solvent was distilled off under reduced pressure, 10 ml of saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 0.21 g of a slightly yellow oil. This was purified by silica gel column chromatography to obtain tert-butyl (3R, 5S) — 7-chloro 1, 3, 5— (2 ′, 2 ′ isopropylidenedioxy) heptanoate as a colorless oil. (0.20 g, yield: 84%).
1 H-NMR(CDC1 , 400MHz/ppm) ;1.22(1H, dd), 1.36 (3H, s), 1.45 ( 1 H-NMR (CDC1, 400MHz / ppm); 1.22 (1H, dd), 1.36 (3H, s), 1.45 (
3  Three
9H, s), 1.46 (3H, s), 1.57(1H, dt), 1.81— 1.95 (2H, m), 2.31 (1H, d d), 2.44 (1H, dd), 3.56— 3.70 (2H, m), 4.07—4.10(1H, m), 4.25—4 .30(1H, m)。  9H, s), 1.46 (3H, s), 1.57 (1H, dt), 1.81— 1.95 (2H, m), 2.31 (1H, dd), 2.44 (1H, dd), 3.56— 3.70 (2H, m) , 4.07-4.10 (1H, m), 4.25-4.30 (1H, m).
(実施例 9) (3R.5R)— 7 アミノー 3.5—（2'.2 '—イソプロピリデンジォキシ）へ プタン酸 tert ブチルの製诰  (Example 9) (3R.5R) -7 amino-3.5- (2'.2'-isopropylidenedioxy) to tert butyl butanoate
実施例 8の方法で得られた（3R, 5S)— 7 クロロー 3, 5-(2', 2 '—イソプロピリデ ンジォキシ）ヘプタン酸 tert ブチル 0.64g(2.4mmol)及び 7規定アンモニア Zメ タノール溶液（13ml)を、オートクレーブ中、 0.23MPaで 100°C、 17時間攪拌した 後、反応溶液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーにて精製す ることにより、（3R, 5R)— 7 アミノー 3, 5-(2', 2 '—イソプロピリデンジォキシ）へ プタン酸 tert ブチルの塩酸塩を白色固体として得た（472mg、収率： 70%)。得ら れた塩酸塩を水酸ィ匕ナトリウム水溶液に溶解し、酢酸ェチルで抽出後、減圧濃縮す ることにより、（3R, 5R)— 7 アミノー 3, 5-(2', 2 '—イソプロピリデンジォキシ）へ プタン酸 tert ブチルを無色油状物として得た（342mg、塩酸塩からの回収率： 88 %)。  (3R, 5S) —7 Chloro-3,5- (2 ′, 2′-isopropylidenedioxy) heptanoic acid 0.64 g (2.4 mmol) obtained in the method of Example 8 and 7 N ammonia Z methanol solution ( 13 ml) was stirred in an autoclave at 0.23 MPa at 100 ° C. for 17 hours, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3R, 5R) -7 amino-3,5- (2 ', 2'-isopropylidenedioxy) hexanoic acid hydrochloride of tertbutyl butanoate as a white solid. (472 mg, yield: 70%). The obtained hydrochloride is dissolved in aqueous sodium hydroxide solution, extracted with ethyl acetate, and concentrated under reduced pressure to give (3R, 5R) -7 amino-3, 5- (2 ', 2'-isopropylate. Ridendioxy) tert-butyl butanoate was obtained as a colorless oil (342 mg, recovery from hydrochloride: 88%).
1 H-NMR(CDC1 , 400MHz/ppm) ;1.18— 1.27(1H, m), 1.36 (3H, s) 1 H-NMR (CDC1, 400 MHz / ppm); 1.18— 1.27 (1H, m), 1.36 (3H, s)
3  Three
, 1.45(12H, s), 1.52-1.66 (3H, m), 2.30(1H, dd), 2.47(1H, dd), 2 . 79 (2H, t) , 3. 95- 3. 99 (1H, m) , 4. 22—4. 28 (1H, m)。 , 1.45 (12H, s), 1.52-1.66 (3H, m), 2.30 (1H, dd), 2.47 (1H, dd), 2 79 (2H, t), 3. 95- 3.99 (1H, m), 4.22-4.28 (1H, m).
[0159] (実施例 10) (3R. 5S)— 7—クロロー 3. 5—ジヒドロキシヘプタン酸 tert—ブチル の製造 Example 10 (3R.5S) —Production of 7-chloro-3.5-dihydroxyheptanoic acid tert-butyl
グルコース 40g、酵母エキス 3g、リン酸水素二アンモ-ゥム 6. 5g、リン酸二水素カリ ゥム lg、硫酸マグネシウム 7水和物 0. 8g、硫酸亜鉛 7水和物 60mg、硫酸鉄 7水和 物 90mg、硫酸銅 5水和物 5mg、硫酸マンガン 4水和物 10mg、塩化ナトリウム 100m g (V、ずれも 1L当たり）の組成力もなる液体培地 (pH7) 5mlを大型試験管に分注し、 120°Cで 20分間蒸気殺菌を行った。これらの液体培地に以下の表 1に示す微生物 を無菌的に一白金耳接種して、 30°Cで 72時間振とう培養した。培養後、各培養液を 遠心分離にかけて菌体を集め、菌体をグルコース 1%を含んだ lOOmMリン酸緩衝 液 0. 5ml (pH6. 5)に懸濁した。この菌体懸濁液を、あら力じめ実施例 5の方法で得 られた（S)—7—クロ口一 5—ヒドロキシ一 3—ォキソヘプタン酸 tert—ブチル 2. 5mg をいれた試験管に加えて、 30°Cで 24時間反応させた。反応後、各反応液に lmlの 酢酸ェチルを加えて良く混合した。有機層の一部を Agilent Technologies社製 HP— 5カラム（0. 32mm X 30m)を装着したガスクロマトグラフィーによって生成物の生 成量を分析をした。また、有機層の一部をフエ二ルイソシァネートでフエニルウレタン ィ匕したのち（Bjorkqvist, B.ら， J. Chromatography, 153, 265 (1978)参照）、ダイセル 化学工業社製 Chiralpak AD— Hカラム（4. 6mm X 25cm)を装着した HPLC によって生成物の光学純度を測定した。  Glucose 40 g, yeast extract 3 g, dihydrogen phosphate 6.5 g, potassium dihydrogen phosphate lg, magnesium sulfate heptahydrate 0.8 g, zinc sulfate heptahydrate 60 mg, iron sulfate 7 water Dispense 5 ml of liquid medium (pH 7) with a composition of 90 mg of Japanese hydrate, 5 mg of copper sulfate pentahydrate, 10 mg of manganese sulfate tetrahydrate, 100 mg of sodium chloride (V, deviation per liter) into a large test tube. Steam sterilization was performed at 120 ° C for 20 minutes. These liquid media were aseptically inoculated with one platinum loop of the microorganisms shown in Table 1 below, and cultured with shaking at 30 ° C for 72 hours. After cultivation, each culture solution was centrifuged to collect the cells, and the cells were suspended in 0.5 ml (pH 6.5) of lOOmM phosphate buffer containing 1% glucose. This bacterial cell suspension was added to a test tube containing 2.5 mg of tert-butyl (S) -7-chloro-5-hydroxy-3-oxoheptanoate obtained by the method of Example 5. In addition, the mixture was reacted at 30 ° C for 24 hours. After the reaction, 1 ml of ethyl acetate was added to each reaction solution and mixed well. A part of the organic layer was analyzed for the amount of product produced by gas chromatography equipped with HP-5 column (0.32 mm x 30 m) manufactured by Agilent Technologies. In addition, after a part of the organic layer is phenylurethane-modified with phenyl isocyanate (see Bjorkqvist, B. et al., J. Chromatography, 153, 265 (1978)), a Chiralpak AD-H column manufactured by Daicel Chemical Industries ( 4. The optical purity of the product was measured by HPLC equipped with 6 mm X 25 cm).
[0160] [ガスクロマトグラフィー分析条件] [0160] [Gas chromatography analysis conditions]
カラム： Agilent Technologies社製 HP - 5  Column: HP-5 from Agilent Technologies
移動相：空気 50kPa、水素 60kPa、ヘリウム 150kPa  Mobile phase: Air 50kPa, Hydrogen 60kPa, Helium 150kPa
インジェクター温度： 170°C  Injector temperature: 170 ° C
検出器温度： 300°C  Detector temperature: 300 ° C
カラム温度： 170°Cから 250°Cまで 20°CZminで昇温、  Column temperature: Increase from 170 ° C to 250 ° C at 20 ° CZmin,
検出: FID、保持時間:基質 = 3. 3分、生成物 =4. 5分)。  Detection: FID, Retention time: Substrate = 3.3 min, Product = 4.5 min).
[0161] [HPLC分析条件] [0161] [HPLC analysis conditions]
カラム：ダイセル化学工業社製 Chiralpak AD— H 溶離液：へキサン Zエタノール = 98Z2 流速： lmL/ mm Column: Chiralpak AD—H manufactured by Daicel Chemical Industries Eluent: Hexane Z ethanol = 98Z2 Flow rate: lmL / mm
カラム温度： 40°C  Column temperature: 40 ° C
検出器： UV254nm  Detector: UV254nm
保持時間：（3R, 5S)体 = 23分、 (3S, 5S)体 [0162] 結果を表 1、表 2にまとめた。  Retention time: (3R, 5S) body = 23 minutes, (3S, 5S) body [0162] The results are summarized in Tables 1 and 2.
[0163] [表 1] [0163] [Table 1]
Figure imgf000041_0001
[0164] [表 2]
Figure imgf000041_0001
[0164] [Table 2]
Figure imgf000042_0001
Figure imgf000042_0001
[0165] (実施例 11) (3R. 5S)— 7—クロロー 3. 5—ジヒドロキシヘプタン酸 tert—ブチル の觀告 Example 11 (3R. 5S) — 7-Chloro-3.5-Dihydroxyheptanoate Notification of tert-butyl
肉エキス 10g、ペプトン 10g、酵母エキス 5g、塩化ナトリウム 3g (いずれも 1L当たり） の組成力もなる液体培地 (pH7) 7mlを大型試験管に分注し、 120°Cで 20分間蒸気 殺菌を行った。これらの液体培地に以下の表 2に示す微生物を無菌的に一白金耳 接種して、 30°Cで 72時間振とう培養した。培養後、各培養液を遠心分離にかけて菌 体を集め、菌体をグルコース 1%を含んだ lOOmMリン酸緩衝液 0. 5ml (pH6. 5)に 懸濁した。  7 ml of liquid medium (pH 7) with composition power of 10 g of meat extract, 10 g of peptone, 5 g of yeast extract and 3 g of sodium chloride (each per liter) was dispensed into a large test tube and steam sterilized at 120 ° C for 20 minutes . These liquid media were aseptically inoculated with one platinum loop of the microorganisms shown in Table 2 below, and cultured with shaking at 30 ° C for 72 hours. After culturing, each culture solution was centrifuged to collect the cells, and the cells were suspended in 0.5 ml (pH 6.5) of lOOmM phosphate buffer containing 1% glucose.
[0166] この菌体懸濁液を、あら力じめ実施例 5の方法で得られた（S)—7—クロロー 5—ヒ ドロキシー3—ォキソヘプタン酸 tert—ブチル 2. 5mgをいれた試験管に加えて、 30 °Cで 24時間反応させた。反応後、各反応液に lmlの酢酸ェチルを加えて良く混合し 、有機層の一部を実施例 10に記載する分析条件で分析して、反応の収率と生成物 の光学純度を求めた。結果を表 3にまとめた。  [0166] A test tube containing 2.5 mg of tert-butyl (S) -7-chloro-5-hydroxy-3-oxoheptanoate obtained by the method of Example 5 from the suspension of the cells. And reacted at 30 ° C. for 24 hours. After the reaction, lml of ethyl acetate was added to each reaction solution and mixed well, and a part of the organic layer was analyzed under the analysis conditions described in Example 10 to obtain the reaction yield and the optical purity of the product. . The results are summarized in Table 3.
[0167] [表 3]
Figure imgf000043_0001
[0167] [Table 3]
Figure imgf000043_0001
[0168] (実施例 12) (3R. 5S)— 7—クロロー 3. 5—ジヒドロキシヘプタン酸 tert—ブチル の製造  Example 12 (3R.5S) —Production of 7-chloro-3.5-dihydroxyheptanoic acid tert-butyl
グルコース 10g、ペプトン 10g、肉エキス 10g、酵母エキス 5g、塩化ナトリウム lg、硫 酸マグネシウム 7水和物 0. 5g (いずれも 1L当たり）の組成力もなる液体培地 (pH7) 5 mlを大型試験管に分注し、 120°Cで 20分間蒸気殺菌を行った。これらの液体培地 に以下の表 3に示す微生物を無菌的に一白金耳接種して、 28°Cで 72時間振とう培 養した。培養後、各培養液を遠心分離にかけて菌体を集め、菌体をグルコース 1%を 含んだ lOOmMリン酸緩衝液 lml(pH6. 5)に懸濁した。  Glucose 10g, peptone 10g, meat extract 10g, yeast extract 5g, sodium chloride lg, magnesium sulfate heptahydrate 0.5g (all per liter) liquid medium (pH7) 5ml in a large test tube Dispensed and steam sterilized at 120 ° C for 20 minutes. These liquid media were aseptically inoculated with one platinum loop of the microorganisms shown in Table 3 below and cultured with shaking at 28 ° C for 72 hours. After culture, each culture solution was centrifuged to collect the cells, and the cells were suspended in 1 ml of lOOmM phosphate buffer (pH 6.5) containing 1% glucose.
[0169] この菌体懸濁液を、あら力じめ実施例 5の方法で得られた（S)—7—クロロー 5—ヒ ドロキシ 3 ォキソヘプタン酸 tert ブチル lmgを!、れた試験管に加えて、 30°C で 24時間反応させた。反応後、各反応液に 2mlの酢酸ェチルを加えて良く混合し、 有機層の一部を実施例 10に記載する分析条件で分析して、反応の収率と生成物の 光学純度を求めた。結果を表 4にまとめた。 [0169] This bacterial cell suspension was (S) -7-chloro-5-Hy obtained by the method of Example 5. 1 mg of tert-butyl droxy-3-oxoheptanoate was added to a test tube and reacted at 30 ° C. for 24 hours. After the reaction, 2 ml of ethyl acetate was added to each reaction solution and mixed well, and a part of the organic layer was analyzed under the analysis conditions described in Example 10 to determine the yield of the reaction and the optical purity of the product. . The results are summarized in Table 4.
[0170] [表 4] [0170] [Table 4]
Figure imgf000044_0001
Figure imgf000044_0001
[0171] (実施例 13) (3R. 5S)— 7 クロロー 3. 5 ジヒドロキシヘプタン酸 tert ブチル の觀告 [Example 13] (3R. 5S) — 7 Chloro-3.5 Notification of tert-butyl dihydroxyheptanoate
30mlの lOOmMリン酸緩衝液（pH6. 5)に、グルコース 3g、デボシァ'リボフラビナ (Devosia riboflavina)由来のカルボ-ル還元酵素 RDR (国際公開第 WO2004Z02 7055号公報参照） 10kU、グルコース脱水素酵素「GLUCDH"Amano2"」（天野 ェンザィム株式会社製） 500mg、 NAD50mg、実施例 5の方法で得られた（S)—7 クロロー 5 ヒドロキシー3 ォキソヘプタン酸 tert ブチル 4.5gをカ卩えて、 30°Cで 攪拌した。その間、反応液の pHは 6NNaOHによって 6. 5に維持した。 24時間の反 応ののち、反応液を 45mlの酢酸ェチルで 3回抽出し、得られた有機層をあわせて、 無水硫酸ナトリウムで乾燥した。ろ過によって硫酸ナトリウムを除去し、減圧下有機溶 媒を留去したのち、シリカゲルカラムクロマトグラフィーによって、 3. 8gの（3R, 5S) - 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert ブチルを得た。このものの光学純度 は実施例 10に記載する分析条件で分析したところ 95%deであった。 30 ml of lOOmM phosphate buffer (pH 6.5), glucose 3 g, carboreductase RDR derived from Devosia riboflavina (see WO2004Z02 7055) 10 kU, glucose dehydrogenase “GLUCDH” "Amano2""(Amano 500 mg, NAD 50 mg, 4.5 g of tert-butyl (S) -7 chloro-5-hydroxy-3-oxoheptanoate obtained by the method of Example 5 was added and stirred at 30 ° C. Meanwhile, the pH of the reaction solution was maintained at 6.5 with 6NNaOH. After reaction for 24 hours, the reaction solution was extracted three times with 45 ml of ethyl acetate, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration and distilling off the organic solvent under reduced pressure, 3.8 g of (3R, 5S) -7-chloro-3,5-dihydroxyheptanoate tert-butyl was obtained by silica gel column chromatography. . When analyzed under the analysis conditions described in Example 10, the optical purity of this product was 95% de.
[0172] (実施例 14) (3R. 5S)— 7 クロロー 3. 5 ジヒドロキシヘプタン酸 tert ブチル の觀告 [Example 14] (3R.5S) -7 Chloro-3.5 Notification of tert-butyl dihydroxyheptanoate
lmlの lOOmMリン酸緩衝液（pH6. 5)に、グルコース 50mg、キャンディダ 'マグノ リエ（Candida magnoliae)由来のカルボニル還^酵素（¾際公開第 WO01 Z40450 公報参照） 10kU、グルコース脱水素酵素「GLUCDH"Amano2"」（天野ェンザィ ム株式会社製） lmg、 NADPO. 25mg、実施例 5の方法で得られた（S)— 7 クロ口 5 ヒドロキシー3 ォキソヘプタン酸 tert ブチル 25mgを加えて、 24時間、 30 °Cで振とうした。反応終了後、反応液を 2mlの酢酸ェチルで抽出し、収率 99%で (3 R, 5S)— 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert ブチルを得た。このものの 光学純度は実施例 10に記載する分析条件で分析したところ 98%deであった。  lml lOOmM phosphate buffer (pH 6.5), glucose 50mg, carbonyl-reducing enzyme derived from Candida magnoliae (refer to the publication WO01 Z40450), glucose dehydrogenase "GLUCDH" “Amano2” (manufactured by Amano Enzyme Co., Ltd.) lmg, NADPO. 25 mg, obtained by the method of Example 5 (S) —7 Black mouth 5 Hydroxy-3-oxoheptanoate 25 mg of butyl butyl was added for 24 hours, 30 Shake at ° C. After completion of the reaction, the reaction solution was extracted with 2 ml of ethyl acetate to obtain tert-butyl (3R, 5S) -7-chloro-3,5-dihydroxyheptanoate with a yield of 99%. When analyzed under the analysis conditions described in Example 10, the optical purity of this product was 98% de.
[0173] (実施例 15) (3R. 5S)— 7 クロロー 3. 5 ジヒドロキシヘプタン酸 tert ブチル の製造 Example 15 (3R. 5S) — 7 Chloro-3.5 Production of tert-butyl dihydroxyheptanoate
E. coli HB101 (pNTDRGl) FERM BP— 08458 (国際公開第 WO2004Z0 27055号公報参照）を 120 μ g/mlアンピシリンを含む 2 X ΥΤ培地で培養し、得ら れた培養液 30mlに、グルコース 2g、 NAD50mg、実施例 5の方法で得られた（S)— 7 クロロー 5 ヒドロキシ 3 ォキソヘプタン酸 tert ブチル 3gを加えて、 30°Cで 攪拌した。その間、反応液の pHは 6NNaOHによって 6. 5に維持した。 24時間の反 応ののち、反応液を 30mlの酢酸ェチルで 3回抽出し、得られた有機層をあわせて、 無水硫酸ナトリウムで乾燥した。ろ過によって硫酸ナトリウムを除去し、減圧下有機溶 媒を留去したのち、シリカゲルカラムクロマトグラフィーによって、 2. 5gの（3R, 5S) - 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert—ブチルを得た。このものの光学純度 は実施例 10に記載する分析条件で分析したところ 96%deであった。 E. coli HB101 (pNTDRGl) FERM BP—08458 (see International Publication No. WO2004Z0 27055) is cultured in 2 × X medium containing 120 μg / ml ampicillin, and 2 g glucose is added to 30 ml of the obtained culture solution. NAD 50 mg, 3 g of tert-butyl (S) -7 chloro-5-hydroxy-3-oxoheptanoate obtained by the method of Example 5 were added, and the mixture was stirred at 30 ° C. Meanwhile, the pH of the reaction solution was maintained at 6.5 with 6NNaOH. After reaction for 24 hours, the reaction solution was extracted three times with 30 ml of ethyl acetate, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, the organic solvent was distilled off under reduced pressure, and then 2.5 g (3R, 5S) − 7-Chloro-3,5-dihydroxyheptanoic acid tert-butyl was obtained. When analyzed under the analysis conditions described in Example 10, the optical purity of this product was 96% de.

Claims

請求の範囲 下記式 (VIII)； Claims The following formula (VIII);
[化 1]  [Chemical 1]
Figure imgf000047_0001
Figure imgf000047_0001
(式中、 R1は水素原子、置換もしくは無置換の炭素数 1〜12のアルキル基、置換もし くは無置換の炭素数 6〜 12のァリール基、又は置換もしくは無置換の炭素数 7〜 12 のァラルキル基のいずれかを表す。 R3、 R4は水素又は水酸基の保護基であり、 R3 、 R4が一緒になつて架橋の水酸基の保護基であってもよい。 X1はハロゲン原子を表 す。）で表される（3R, 5S)— 7—ノヽロー 3, 5—ジヒドロキシヘプタン酸誘導体を、アン モユアでァミノ化することを特徴とする、下記式 (I)； Wherein R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted carbon number 7 to 7 It represents any one of 12 aralkyl groups, R 3 and R 4 are hydrogen or a hydroxyl protecting group, and R 3 and R 4 together may be a bridging hydroxyl protecting group X 1 is (3R, 5S) — 7-Noro 3,5-dihydroxyheptanoic acid derivative represented by the following formula (I):
[化 2]
Figure imgf000047_0002
[Chemical 2]
Figure imgf000047_0002
( I )  (I)
(式中、 R1、 R3、 R4は上記に同じ。）で表される（3R, 5R)—7—ァミノ— 3, 5—ジヒド ロキシヘプタン酸誘導体、又はその塩の製造法。 (Wherein R 1 , R 3 and R 4 are the same as above). (3R, 5R) -7-amino-3,5-dihydroxyheptanoic acid derivative or a salt thereof.
[2] 下記式 (IV) ; [2] Formula (IV) below;
[化 3]
Figure imgf000047_0003
[Chemical 3]
Figure imgf000047_0003
( IV )  (IV)
(式中、 R2は置換もしくは無置換の炭素数 1〜12のアルキル基を表す。 X1はハロゲ ン原子を表す。）で表される 5—ハロー 3—ォキソペンタン酸誘導体を S選択的に還元 することを特徴とする、下記式 (V)； (Wherein R 2 represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, X 1 represents a halogen atom), and a 5-halo 3-oxopentanoic acid derivative represented by S is selectively selected. The following formula (V):
[化 4] [Chemical 4]
Figure imgf000048_0001
Figure imgf000048_0001
(式中、 R2 、 X1は前記に同じ)で表される（S)—5—ハロ— 3—ヒドロキシペンタン酸 誘導体の製造法。 (Wherein R 2 and X 1 are the same as above), (S) -5-halo-3-hydroxypentanoic acid derivative production method.
前記式 (IV)で表される 5—ハロー 3—ォキソペンタン酸誘導体が、 The 5-halo 3-oxopentanoic acid derivative represented by the formula (IV) is
下記式（II)； Formula (II) below
[化 5]
Figure imgf000048_0002
[Chemical 5]
Figure imgf000048_0002
(式中、 X1は前記に同じ。）で表される酸塩ィ匕物力も得たものである、請求項 2に記 載の製造法。 (Wherein X 1 is the same as defined above).
下記式 (VII)； Formula (VII) below
[化 6]
Figure imgf000048_0003
[Chemical 6]
Figure imgf000048_0003
(式中、 R1は水素原子、置換もしくは無置換の炭素数 1〜12のアルキル基、置換もし くは無置換の炭素数 6〜 12のァリール基、又は置換もしくは無置換の炭素数 7〜 12 のァラルキル基のいずれかを表す。 X1はハロゲン原子を表す。）で表される（S) - 7 ハロー 5—ヒドロキシ 3—ォキソヘプタン酸誘導体をジァステレオ選択的に還元 し、必要に応じて水酸基の保護を行う、下記式 (VIII)； Wherein R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted carbon number 7 to 7 (S) -7 halo 5-hydroxy-3-oxoheptanoic acid derivative represented by (S) -7 represented by any one of 12 aralkyl groups. X 1 represents a halogen atom. The following formula (VIII):
[化 7]
Figure imgf000049_0001
[Chemical 7]
Figure imgf000049_0001
(式中、 R1は前記に同じ。 R3、 R4は水素又は水酸基の保護基であり、 R3、 R4がー 緒になって架橋の水酸基の保護基であってもよい。 X1はハロゲン原子を表す。）で表 される（3R, 5S)— 7—ノヽロー 3, 5—ジヒドロキシヘプタン酸誘導体の製造法。 (In the formula, R 1 is the same as described above. R 3 and R 4 are hydrogen or a hydroxyl-protecting group, and R 3 and R 4 together may be a bridging hydroxyl-protecting group. X 1 represents a halogen atom.) (3R, 5S) — 7-Noro 3,5-dihydroxyheptanoic acid derivatives.
[5] 前記ジァステレオ選択的還元が、該化合物を不斉還元する活性を有する酵素源を 作用させて行なわれることを特徴とする、請求項 4記載の製造法。  [5] The production method according to claim 4, wherein the diastereoselective reduction is carried out by the action of an enzyme source having an activity for asymmetric reduction of the compound.
[6] 前記ジァステレオ選択的還元カ^トキシジェチルボラン存在下に水素化ホウ素ナトリ ゥムを用いて行われることを特徴とする、請求項 4に記載の製造法。  [6] The production method according to claim 4, wherein the diastereoselective reduction is carried out using sodium borohydride in the presence of catoxyjetylborane.
[7] 下記式 (VI) ;  [7] Formula (VI) below;
X2CH CO R1 (VI) X 2 CH CO R 1 (VI)
2 2  twenty two
(式中、 R1は水素原子、置換もしくは無置換の炭素数 1〜12のアルキル基、置換もし くは無置換の炭素数 6〜 12のァリール基、又は置換もしくは無置換の炭素数 7〜 12 のァラルキル基を表す。 X2は水素原子又はハロゲン原子を表す。）で表される酢酸 誘導体を塩基又は 0価の金属と反応させて調製されるエノラートと下記式 (V)； Wherein R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted carbon number 7 to 7 12 represents an aralkyl group, and X 2 represents a hydrogen atom or a halogen atom.) An enolate prepared by reacting an acetic acid derivative represented by a base or a zero-valent metal with the following formula (V);
[化 8]
Figure imgf000049_0002
[Chemical 8]
Figure imgf000049_0002
(式中、 R2は置換もしくは無置換の炭素数 1〜12のアルキル基を表す。 X1はハロゲ ン原子を表す。）で表される（S)— 5—ハロー 3—ヒドロキシペンタン酸誘導体を反応 させることを特徴とする一般式 (VII)； (In the formula, R 2 represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. X 1 represents a halogen atom.) (S) —5-Halo 3-hydroxypentanoic acid derivative General formula (VII) characterized in that
[化 9]
Figure imgf000049_0003
[Chemical 9]
Figure imgf000049_0003
( VII ) (式中、 X1はハロゲン原子であり、 R1は置換もしくは無置換の炭素数 1 12のアルキ ル基を表す。）で表される（S)— 7 5—ヒドロキシー 3—ォキソヘプタン酸誘導 体の製造法。 (VII) (Wherein X 1 is a halogen atom, R 1 represents a substituted or unsubstituted alkyl group having 1 12 carbon atoms) (S) —75-hydroxy-3-oxoheptanoic acid derivative Manufacturing method.
[8] 前記式 (V)で表される（S)— 5 3 ヒドロキシペンタン酸誘導体が請求項 2ま たは 3記載の方法で得られたものである請求項 7記載の製造方法。  [8] The production method according to claim 7, wherein the (S) -5 3 hydroxypentanoic acid derivative represented by the formula (V) is obtained by the method according to claim 2 or 3.
[9] 前記式 (VII)で表される（S)— 7 5—ヒドロキシ 3—ォキソヘプタン酸誘導 体が請求項 7または 8記載の方法で得られたものであることを特徴とする、請求項 4[9] The (S) -7-hydroxy-3-oxoheptanoic acid derivative represented by the formula (VII) is obtained by the method according to claim 7 or 8, Four
6の 、ずれかに記載の製造法。 6. The manufacturing method described in any of the above.
[10] 前記式 (VIII)で表される化合物が請求項 4 5 6または 9の 、ずれかに記載の方法 により得たものである、請求項 1に記載の製造法。 [10] The production method according to claim 1, wherein the compound represented by the formula (VIII) is obtained by the method according to any one of claims 4 56 and 9.
[11] 下記式 (XI) ; [11] The following formula (XI);
[化 10]  [Chemical 10]
Figure imgf000050_0001
で表される（3R, 5S)— 7—クロロー 3, 5—ジヒドロキシヘプタン酸 tert—ブチル, [12] 下記式 (XII) ;
Figure imgf000050_0001
(3R, 5S) — 7-chloro-3,5-dihydroxyheptanoic acid tert-butyl, [12] The following formula (XII);
[化 11]
Figure imgf000050_0002
[Chemical 11]
Figure imgf000050_0002
( XII) で表される（3R, 5S)  Represented by (XII) (3R, 5S)
タン酸 tert ブチ  Tanoic acid tert
下記式 (V)；  Formula (V) below
[化 12]
Figure imgf000051_0001
[Chemical 12]
Figure imgf000051_0001
(V)  (V)
(式中、 X1はハロゲン原子であり、 R2は置換もしくは無置換の炭素数 1〜12のアルキ ル基を表す。）で表される（S)— 5—ハロー 3—ヒドロキシペンタン酸誘導体。 (Wherein X 1 is a halogen atom, R 2 represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms) (S) -5-halo 3-hydroxypentanoic acid derivative .
[14] 下記式 (VII); [14] Formula (VII) below;
[化 13]
Figure imgf000051_0002
[Chemical 13]
Figure imgf000051_0002
(VII)  (VII)
(式中、 X1はハロゲン原子であり、 R1は置換もしくは無置換の炭素数 1〜12のアルキ ル基を表す。）で表される（S)— 7—ハロー 5—ヒドロキシー 3—ォキソヘプタン酸誘導 体。 (Wherein X 1 is a halogen atom, R 1 represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms) (S) —7-halo 5-hydroxy-3-oxoheptane Acid derivative.
PCT/JP2006/318834 2005-09-22 2006-09-22 Process for production of (3r,5r)-7-amino-3,5-dihydroxyheptanoic acid derivative WO2007034909A1 (en)

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