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WO2007034909A1 - Procédé pour la production d'un dérivé de l'acide (3r,5r)-7-amino-3,5-dihydroxyheptanoïque - Google Patents

Procédé pour la production d'un dérivé de l'acide (3r,5r)-7-amino-3,5-dihydroxyheptanoïque 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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acid derivative
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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

L'invention concerne un dérivé de l'acide (3R,5R)-7-amino-3,5-dihydroxyheptanoïque lequel est utile comme intermédiaire pour un produit pharmaceutique. On peut produire un dérivé de l'acide (3R,5R)-7-amino-3,5-dihydroxyheptanoïque ou un sel de celui-ci par un procédé comprenant les étapes consistant à : (1) produire un dérivé de l'acide 5-halo-3-oxopentanoïque à partir d'un chlorure d'acide et d'un sel de métal alcalin d'un monoester de l'acide malonique lesquels sont disponibles dans le commerce à faible coût, (2) effectuer la réduction du produit résultant d'une manière S-sélective, (3) faire réagir le produit réduit avec un énolate préparé à partir d'un dérivé ester de l'acide acétique pour produire un dérivé de l'acide (5S)-7-halo-5-hydroxy-3-oxopentanoïque, (4) effectuer la réduction du produit résultant d'une manière diastéréosélective et, si nécessaire, protéger un groupe hydroxyle présent dans le produit et (5) aminer le produit résultant avec de l'ammoniac pour produire le composé souhaité ou un sel de celui-ci. Le procédé peut produire le composé d'une manière simple, avec un bon rendement et à l'échelle industrielle.
PCT/JP2006/318834 2005-09-22 2006-09-22 Procédé pour la production d'un dérivé de l'acide (3r,5r)-7-amino-3,5-dihydroxyheptanoïque WO2007034909A1 (fr)

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CN111556872A (zh) * 2017-11-01 2020-08-18 梅琳塔治疗公司 硼酸酯衍生物的合成及其用途
US11535643B2 (en) 2015-03-25 2022-12-27 President And Fellows Of Harvard College Macrolides with modified desosamine sugars and uses thereof
AU2020281043B2 (en) * 2013-04-04 2023-02-02 President And Fellows Of Harvard College Macrolides and methods of their preparation and use

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Publication number Priority date Publication date Assignee Title
CN103384659A (zh) * 2011-02-21 2013-11-06 公益财团法人微生物化学研究会 硫代酰胺化合物、生产硫代酰胺化合物的方法、生产 [(4r,6r)-6-氨乙基-1,3-二噁烷-4-基]乙酸酯衍生物的方法和生产阿托伐他汀的方法
CN103384659B (zh) * 2011-02-21 2015-11-25 公益财团法人微生物化学研究会 硫代酰胺化合物及生产该化合物、[(4r,6r)-6-氨乙基-1,3-二噁烷-4-基]乙酸酯衍生物和阿托伐他汀的方法
AU2020281043B2 (en) * 2013-04-04 2023-02-02 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
AU2020281043B9 (en) * 2013-04-04 2023-02-09 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US11634449B2 (en) 2013-04-04 2023-04-25 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
AU2020281043C1 (en) * 2013-04-04 2023-06-01 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US11535643B2 (en) 2015-03-25 2022-12-27 President And Fellows Of Harvard College Macrolides with modified desosamine sugars and uses thereof
CN111556872A (zh) * 2017-11-01 2020-08-18 梅琳塔治疗公司 硼酸酯衍生物的合成及其用途
JP2021501205A (ja) * 2017-11-01 2021-01-14 メリンタ セラピューティクス インコーポレイテッド ボロン酸エステル誘導体の合成およびその使用
JP7480050B2 (ja) 2017-11-01 2024-05-09 メリンタ セラピューティクス インコーポレイテッド ボロン酸エステル誘導体の合成およびその使用
CN111556872B (zh) * 2017-11-01 2024-05-10 梅琳塔治疗公司 硼酸酯衍生物的合成及其用途
US11999757B2 (en) * 2017-11-01 2024-06-04 Melinta Subsidiary Corp. Synthesis of boronate ester derivatives and uses thereof

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