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WO1992016541A1 - Synthese de l'acide sianique et intermediaire synthetique utilise pour cette synthese - Google Patents

Synthese de l'acide sianique et intermediaire synthetique utilise pour cette synthese Download PDF

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Publication number
WO1992016541A1
WO1992016541A1 PCT/JP1992/000298 JP9200298W WO9216541A1 WO 1992016541 A1 WO1992016541 A1 WO 1992016541A1 JP 9200298 W JP9200298 W JP 9200298W WO 9216541 A1 WO9216541 A1 WO 9216541A1
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group
compound
carbon atoms
hydrogen atom
alkyl
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PCT/JP1992/000298
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English (en)
Japanese (ja)
Inventor
Tetsuo Shiba
Tadashi Teshima
Toshihiro Yamamoto
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Mect Corporation
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Publication of WO1992016541A1 publication Critical patent/WO1992016541A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to a novel method for synthesizing sialic acid (N-acetylneuraminic acid) and a synthetic intermediate used for the method. Furthermore, the present invention relates to isosialic acid, a novel isomer of sialic acid, a method for synthesizing the same, and a synthetic intermediate used therefor.
  • Background art N-acetylneuraminic acid
  • Sialic acid is an important component of the glycolipid ganglion involved in various biological functions. Sialic acid is also being used as a pharmaceutical product by utilizing its physiological activity [Japanese Patent Publication No. 63-028411, US Patent No. 4,988, 332, European Patent Publication 0 1 7 7 7 8 3 A 2].
  • sialic acid is mainly obtained by an extraction method from natural products. Therefore, in order to supply a relatively large amount of sialic acid, it is desired to provide a simple lithography method.
  • Many methods for synthesizing sialic acid have been reported. Among them, the simplest method is the synthesis from N-acetylmannosamine and oxa mouth acetic acid (MJ How, MDA Iialford, M. Stacey. And E. Vickers, Carbohydr, Res. 11. 313 (1969)).
  • N-acetylmannosamine is very expensive. Therefore, this method is not practical.
  • the present inventors have searched for a method capable of relatively efficiently synthesizing sialic acid using inexpensive raw materials.
  • a method for synthesizing sialic acid from readily available and inexpensive glucose and oxalic acetic acid have searched for a method capable of relatively efficiently synthesizing sialic acid using inexpensive raw materials.
  • Another object of the present invention is to provide an isomer of sialic acid expected to have a physiological activity.
  • an object of the present invention is to provide an intermediate useful for a method for synthesizing an isomer of sialic acid and a method for producing the same. Disclosure of the invention
  • the present invention relates to compounds represented by the following general formulas (Ia), (Ua). (Illa), (Ib), (Ub), (Id) or (nd).
  • R 1 represents a hydrogen atom or R ie - Ph-NHCO group
  • R 'D represents a a hydrogen atom or an alkyl group having a carbon number 1 ⁇ 6
  • R 2 is a hydrogen atom or a triflate Ruo b methane
  • R 3 and R 5 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 1 represents an N 3 group or a C 3 C 0 NH group, provided that when R 4 is a CH 3 C 0 Nll group, R 1 , R 3 and R 5 are not simultaneously a hydrogen atom, and R 6 is a hydrogen atom or R ′ -A Ph-NHCO group (R 1 (1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms); R 7 represents a 0 H group, a 0 SO 2 CF 3 group, a N 3 group,
  • R 8 and R B are the same or different.
  • the present invention includes reacting D-glucose with oxa-mouth acetic acid, reacting the obtained reaction product with an alkyl alcohol having 1 to 6 carbon atoms, and separating a mixture of the obtained products. And (IVa), (IVb) and (IVd).
  • the present invention provides the above-mentioned alkyl glycoside alkyl ester compound
  • the present invention provides a step of opening the lactone (IIIa) to obtain a hydroxyester (Va),
  • Via A step of deprotecting the protected sialic acid (Villa) to obtain sialic acid (where R is a R ID -Ph-NHC0 group (R 1 D is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) And R 3 and R 5 each represent an alkyl group having 1 to 6 carbon atoms.)
  • the present invention relates to a method for synthesizing sialic acid comprising the steps of
  • the present invention provides a method for reacting an azide agent with a trifluorene sulfonyl form (Via), (VIb) or (VI d) to obtain an azide form (Vil a), (VII b) or (VII d)
  • R represents an R 1 P -Ph-NHC0 group (R ′ ° represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).
  • R 3 and R s and R 8 and R 9 each represent an alkyl group having 1 to 6 carbon atoms.
  • the present invention provides a step of opening the rataton form (lib) or (lid) to obtain a hydroxyester form (Vb) or (Vd),
  • R represents a R ID -Ph-NHC0 group (R ID represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and R 8 and R 9 represent 1 to 6 carbon atoms.
  • the present invention relates to a method for synthesizing isosialic acid comprising the steps of Hereinafter, the present invention will be described according to the scheme.
  • Schemes 1-3 are schemes for the synthesis of sialic acids and their synthetic intermediates.
  • Compounds (2), (3), (4), (6), (7) and (8) in Scheme 1 are compounds (IVa), (flla), (Va). (VIa), respectively. , (Vila) and (Villa).
  • Compound (9) is an embodiment of compound (IVa).
  • Scheme 2 is a scheme for a method for synthesizing isosialic acid (1b) and its synthetic intermediate.
  • Compounds (2b), (3b), (4b), (5b), (6b) in Scheme 2 are (7b), (9b), and (1Ob) are compounds ( Embodiments of IVb :), (IIb), (Vb :), (VIb), (VEb), (Mb), (IXb) and (Xb).
  • Scheme 3 is a scheme for a method for synthesizing isosialic acid (1d) and a synthetic intermediate thereof.
  • the compounds (2d), (3d), (4d), (5d), (6d), (8d), (9d), and (10d) in Scheme 3 are the compounds ( IV d), (II d), (V d), (VI d), (VHd), (Vlfld), (IX d) and (Xd).
  • the aldol condensation of oxaoxalic acetic acid and D-glucose yields a mixture of compound (1) and isomers that are precursors to compounds (2b) and (2d) [Shirai, II. Ogura. Tetrahedron Lett. 30, 2263 (1989) 3.
  • This reaction is suitably performed by adjusting the pH to 9 to 13, setting the reaction temperature to 0 ° C. to room temperature, and setting the reaction time to 1 hour to 7 days.
  • the compound (1) and a mixture of the isomers which are the precursors of the compounds (2b) and (2d) are esterified with an alkyl alcohol having 1 to 6 carbon atoms in the presence of hydrogen chloride.
  • an alkyl alcohol having 1 to 6 carbon atoms Preferably, after methyl esterification using methanol, it is converted to a complete acetyl group.
  • the hydrogen chloride-methanol (alkyl alcohol) treatment can be performed, for example, in a temperature range from ice cooling to reflux temperature for 1 hour to 7 days.
  • the product is a mixture of the alkyl glycosyl alkyl esters (IVa), (IVb) and (Wd). This mixture is separated and purified by means such as HPLC to obtain the alkyl glycosyl alkyl ester. (IVa), (IVb) and (IVd) are obtained respectively. When methanol is used as the alkyl alcohol, compounds (2), (2b) and (2d) are obtained, respectively.
  • Alkyl glycoside alkyl ester (IVa), for example, compound (2), is dealkylated when treated with an aqueous sodium hydroxide solution to obtain alkyl glycoside (9). Further, the alkyl glycoside (9) can be dealkylated with an acid, for example, Amberlist (acidic ion exchange resin) to obtain the compound (1).
  • an acid for example, Amberlist (acidic ion exchange resin)
  • the alkyl ester compound (IVa), for example, the compound (2) is genated with water or a mixed solvent of water and a water-soluble solvent using a hydroxide hydroxide or the like.
  • the saponification reaction can be performed at ⁇ X: ⁇ reflux temperature ⁇ .
  • the reaction is rapid and can be completed in a relatively short time.
  • the product is then reacted with a carbodiimide compound in an organic solvent in the presence of pyridine.
  • 4-dimethylaminopyridine etc. should be present in addition to pyridine. You can also.
  • carbodiimide compound examples include dicyclohexylcarbodiimide (DCC), diisopropylpropylcarbodimid-ethyldimethylaminopropylcarbodiimid, and the like. It is appropriate that the carbodiimide compound is used in an amount of 1 equivalent or more with respect to the genide of the alkyl ester (IVa).
  • the reaction is carried out at 0 ° C to reflux temperature for 1 hour to 7 days.
  • a lactone (IIIa) for example, a compound (3) can be obtained by reacting the product with at least 1 equivalent (4 mol) of phenylisocyanate or an alkyl-substituted phenylisocyanate having 1 to 6 carbon atoms. it can.
  • the reaction can be carried out, for example, in an organic solvent such as pyridine or 4-dimethylaminopyridine at () ° C. to a reflux temperature for 1 hour to 7 days.
  • alkyl ester (IV b), for example, the compound (2b) and the alkyl ester (IV d), for example, the compound (2d), are subjected to the same reaction as described above to give a lactone (lib :), for example.
  • Compound (3b) and lactone form (li d), for example, compound (3d) can be obtained.
  • a lactone for example, compound (3)
  • an alkyl alcohol having 1 to 6 carbon atoms for example, methanol
  • a hydroquine ester for example, a compound (3) 4
  • the reaction can be carried out, for example, at 0 ° C. to reflux temperature for 5 minutes to 24 hours.
  • lactone form ( ⁇ b :), for example, compound (3b) and the rataton form (D d), for example, compound (3d), are subjected to the same reaction as above to give a hydroxy ester residue (V b), for example.
  • Compound (4b) and hydroxyester (V d), for example, compound (4d) can be obtained.
  • V a Hydroxyester (V a), for example, compound (4), is reacted with trifluoromethanesulfonic anhydride in an organic solvent such as methylene chloride in the presence of pyridine, 4-dimethylaminopyridine, or the like.
  • a trifluoromethanesulfonyl compound (Via) for example, a compound (6) can be obtained.
  • Pyridine or 4-dimethylaminopyridine It is appropriate to use at least one equivalent of the trifluoromethanesulfonic anhydride with respect to the hydroxyester (V).
  • hydroquinone ester (Vb), for example, the compound (4b) and the hydroxyester (Vd), for example, the compound (4d) are subjected to the same reaction as described above to give the trifluoromethanesulfonyl (VIb ),
  • compound (5b) and a trifluoromethanesulfonyl compound (Vld), for example, compound (5d) can be obtained.
  • Trifluoromethanesulfonyl form (Via), for example, compound (6), can be reacted with an azidating agent in an organic solvent such as benzene to give an azide form (Vila), for example, compound (7) .
  • This reaction can be carried out, for example, at 0 ° C. to reflux temperature for 5 minutes to 24 hours.
  • the azide agent tetra-n-butylammonium azide NaN 3 or NaN 3 and crown ether can also be used.
  • the trifluoromethanesulfonyl compound (VIb), for example, the compound (5b) and the trifluoromethanesulfonyl compound (Vld), for example, the compound (5d) are subjected to the same reaction as described above to give the azide (VDb)
  • compound (6b) and azide form (VEd), for example, compound (6d) can be obtained.
  • the azide form (Wa), for example, compound (7), can be catalytically reduced and then acetylated to give a protected sialic acid (Via), for example, compound (8).
  • the catalytic reduction, Pd- (;., Pd- black, Pd- (OH) - C, can be used Pt0 2 or the like of the catalyst addition, besides catalytic reduction, Zn / liCl -H 2 0, CrCl / Reduction can also be performed using H *, H 2 S / pyridine, Sn (SPh) 2 / PhSH, etc.
  • the acetylation is performed by removing acetic anhydride in the presence of pyridine, 4-dimethylaminopyridine, etc. In addition, it is preferable that both the contact source and the acetylation are carried out in the presence of a suitable solvent.
  • Protected sialic acid (ia), for example, compound (8), can be deprotected by conventional methods, ie, dephenylcarbamoylation, dealkylesterification, dealkylation. By performing the noreglycosidation, the desired sialic acid can be obtained. Deprotection, using sodium hydroxide or CH 3 0 nA, etc., water or water and a water-soluble organic solvent (e.g. as tetrahydrofuran, alcohol ethers, Jiokisan etc.) process to de-Fuwenirukaruba moil by a mixed solvent of and It can be dealkylated. The dealkylglycosidation can then be performed with an acid (eg, Amberlyst (acidic ion exchange resin)).
  • an acid eg, Amberlyst (acidic ion exchange resin
  • an azide form (Wb), for example, a compound (6b), is subjected to catalytic reduction and acetylation in the same manner as described above to give an acetyl-amino form (ib), for example, a compound (7b).
  • the acetylamino compound (Cor b), for example, the compound (7b) is deprotected with sodium hydroxide in the same manner as described above to obtain the amino compound (Ka), for example, the compound (9b).
  • the amino form (Ka), for example, the compound (9b) is reacted with N-acetoxysuccinic acid imid to obtain the acetylamino form (Xb), for example, the compound (10b).
  • acetylamino compound (Xb) for example, the compound (10b) is subjected to dealkyl glycosidation with an acid (for example, Amberlist (acidic ion exchange resin)) to give the desired product, isosialic acid (lb). Can be obtained.
  • an acid for example, Amberlist (acidic ion exchange resin)
  • the azide form (Wd), for example, the compound (6d), is subjected to catalytic reduction, acetylation, deprotection, acetylaminolation, and dealkyl glycosidation in the same manner as described above to obtain the desired product.
  • P-isosialic acid (Id) can be obtained.
  • the unprotected azide form (Wd), for example, the compound (6d), can be deprotected with sodium hydroxide (decarboxylation and dealkylation) to give the deprotected azide form.
  • D for example, the compound (8d) is obtained.
  • Catalytic reduction of the deprotected azide form (Id), for example, compound (8d) gives an amino form (IXd), for example, compound (9d.
  • the amino form (IXd) for example, compound (9d) Is reacted with N-acetoxysuccinic acid imide to give the acetylamino compound (X d ),
  • the compound (lOd) is obtained.
  • acetylamino compound (Xd) for example, the compound (10d) is dealkylated with an acid (for example, amberlist (acidic ion exchange resin)) to give the desired product, isosialic acid. (Id) can be obtained.
  • an acid for example, amberlist (acidic ion exchange resin)
  • the azide (Vllb), for example, the compound (6b), is also subjected to deprotection, catalytic reduction, acetylamino, and dealkylglycosidation in the same manner as described above to obtain the isocyanate as the desired product.
  • Acid (lb) can be obtained.
  • the product may be purified by a conventional method and then proceed to the next step.
  • sialic acid can be produced efficiently from inexpensive raw materials glucose and oxalic acetic acid.
  • the compounds of the present invention are useful as intermediates during synthesis.
  • the lactone form (111a) and the trifluoromesulfonyl form (Via) are useful as intermediates for the synthesis of sialic acid.
  • the compounds of the present invention also have an inhibitory effect on influenza virus, neuramidase activity.
  • Acetic acid (9.83, 74.4 mmol) was dissolved in water (75 ml) and adjusted to pill 1 with 1 M NaOII.
  • Sodium tetraborate (38.6 g, 192 ramol), glucose (134 g, 743 mmol) and water (175 ml) were added, and the mixture was stirred at pH 1 with 10 M NaOH. To Keep and stir for 72 hours.
  • pH was adjusted to pH2 by adding Dowex50 (H type). One hour later, the resin was filtered off, the filtrate was neutralized with 2.8% ammonia water, and passed through a Dowexl (HC00 type) to adsorb the target substance.
  • Oxamouth acetic acid (9.83 g, 74.4 mm 01) was dissolved in water (75 ml:) and adjusted to pH 11 by adding 10 M NaOH.
  • the mixture was maintained at pH 11 using 10 M NaOH and stirred for 72 hours, and then adjusted to pH 7 with the addition of acetic acid, followed by addition of Dowex 50 (H type) to pH 2.
  • the resin was collected by filtration, the filtrate was neutralized with 2.8% aqueous ammonia, passed through Dowexl (HCOO type) to adsorb the target substance, and after washing with water, eluted with 0.3 M formic acid.
  • the fractions of the target product were concentrated under reduced pressure, and the residue was dissolved in methanol (250 m1), 3 M hydrogen chloride-methanol (62.5 m1) was added, and the mixture was heated under reflux for 3 hours.
  • Oxamouth acetic acid (9.83 g, 74.4 mm 01) was dissolved in water (75 ml) and adjusted to pH 11 with the addition of 10 M NaOH.
  • Sodium tetraborate (38.6.192 mmol), glucose (134 g, 743 mmol) and water (175 ml) were added, and the mixture was stirred and 10 M, N
  • the pH was maintained at 11 with aOH and stirred for 72 hours.
  • D0weX50 H type
  • the resin was collected by filtration, the filtrate was neutralized with 2.8% aqueous ammonia, and the mixture was passed through Dowex 1 (HCOO type) to adsorb the target substance.
  • each virus-containing solution 501 shown in Table 1 50 fi 1 of the inhibitor shown in Table 1 was added, and incubated at 37 for 15 minutes. Then 1 0
  • the buffer containing the photoin (1) (10 mg gZm1) and the aqueous solution (101) of 50 mM calcium chloride were added, and the mixture was incubated at 37 ° C for 5 hours. After cooling, 0.25 ml of 2.5 mM periodate reagent was added, and the mixture was incubated at 37 ° C for 30 minutes. Then, 0.25 ml of a 2% sodium arsenite reagent was added, and 2.0 ml of a 0.1 M 2 -thiobavituric acid reagent was added, followed by incubating at 100 ° C.

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Abstract

L'invention concerne un procédé efficace de synthèse de l'acide sianique (acide N-acétylneuramique) utile comme matériau de départ de médicaments, un intermédiaire synthétique utilisé dans ledit procédé, l'acide isosialique en tant qu'isomère de l'acide sianique, la synthèse dudit acide isosialique, est un intermédiaire synthétique utilisé dans cette synthèse. L'acide sianique est synthétisé à partir de glucose D et d'acide oxaloacétique, à l'aide des intermédiaires (Ia) et (IIIa), tandis que l'acide isosialique représenté par la formule (IV) est synthétisé à partir d'un isomère de l'intermédiaire (Ia).
PCT/JP1992/000298 1991-03-12 1992-03-12 Synthese de l'acide sianique et intermediaire synthetique utilise pour cette synthese WO1992016541A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP7249991 1991-03-12
JP3/72499 1991-03-12
JP3/89975 1991-03-28
JP8997591 1991-03-28
JP19495891 1991-07-09
JP3/194958 1991-07-09

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WO1992016541A1 true WO1992016541A1 (fr) 1992-10-01

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WO (1) WO1992016541A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF AMERICAN CHEMICAL SOCIETY, Vol. 110, pages 3929 to 3940, (1988), S.T. DANISHERFSKY, "Stereoselective Total Syntheses of the Naturally Occuring Enantiomers of N-Acetylneuraminic Acid and 3-Deoxy-manno-2-octulosonic Acid". *
TETRAHEDRON LETTERS, Vol. 33, No. 3, pages 325 to 328, (1992), T. YAMAMOTO, T. SHIBA, "Synthesis of Sialic acid through Aldol condensation of Glucose with Oxalaceticacid". *
TETRAHEDRON, Vol. 46, No. 1, pages 201 to 214, (1990), C. AUGE et al., "Sialyl Aldolase in Organic synthesis". *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus

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