WO2001072681A1 - PROCEDE D'OBTENTION D'α-HYDROXY-η-BUTYROLACTONE OPTIQUEMENT ACTIF - Google Patents

PROCEDE D'OBTENTION D'α-HYDROXY-η-BUTYROLACTONE OPTIQUEMENT ACTIF Download PDF

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WO2001072681A1
WO2001072681A1 PCT/JP2001/002736 JP0102736W WO0172681A1 WO 2001072681 A1 WO2001072681 A1 WO 2001072681A1 JP 0102736 W JP0102736 W JP 0102736W WO 0172681 A1 WO0172681 A1 WO 0172681A1
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acid
group
formula
butyrolactone
carbon atoms
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PCT/JP2001/002736
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English (en)
Japanese (ja)
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Akira Nishiyama
Narumi Kishimoto
Kenji Inoue
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Kaneka Corporation
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Priority to AU2001244657A priority Critical patent/AU2001244657A1/en
Publication of WO2001072681A1 publication Critical patent/WO2001072681A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

Definitions

  • the present invention is a pharmaceutical intermediate, particularly antiasthmatics Intermediate (WO 9 7 24 3 6 5 ) usefulness optically active ⁇ - arsenide Dorokishi _ gamma as - relates Puchiroraku ton production method. Background art
  • Racemic ⁇ - hydroxy- butyrolactone was prepared using (Bu) acetate and lipase to produce (S) - ⁇ -hydroxy-butyrolactone and (R) _ ⁇ -acetyloxy ⁇ -butyrate ratatone. Separation of (S) - ⁇ -hydroxy-1- ⁇ -butyrolactone by column chromatography and deacetylation of (R) - ⁇ -acetyloxy-y-petit mouth rataton with potassium carbonate in ethanol. And a method for producing (R) - ⁇ -hydroxy-1- ⁇ -butyrolactone (Japanese Patent Application Laid-Open No. 3-228686).
  • Racemic ⁇ -hydroxy ⁇ -butyrolactone is added selectively by microorganisms.
  • (R) — 2,4-dihydroxybutyric acid is produced by water splitting, and unreacted phenhydroxy-1- y -butyrolactone is extracted and removed, followed by deicing and cyclization in the presence of an acid catalyst.
  • (JP-A-9-308479) is produced by water splitting, and unreacted phenhydroxy-1- y -butyrolactone is extracted and removed, followed by deicing and cyclization in the presence of an acid catalyst.
  • prior art 1 uses an expensive reducing agent, borane-dimethyl sulfide complex, and conventional technology 2) uses expensive quinine-pursin as a resolving agent, and conventional technology 3). Since these methods are complicated in operation, it is difficult to carry out these methods industrially.
  • prior arts 4) and 5 the optically active substance is separated from the expensive racemic rho-hydroxyl-y-butyrolactone, and the other optically active substance is not required. This is not an advantageous method.
  • an object of the present invention is to provide a method for easily producing an optically active ⁇ -butyrolactone, which is useful as a pharmaceutical intermediate, from inexpensive and easily available raw materials.
  • optically active hydroxy-y-butyrolactone can be converted from optically active 4-amino-12-hydroxybutanoic acid derivative, which is a cheap and easily available raw material.
  • the hydroxyl group of (S) - ⁇ -hydroxy-1- ⁇ -butyrolactone which is manufactured from a less expensive (S)-4-amino-2-hydroxybutanoic acid derivative, can be efficiently sterically converted.
  • the first present invention provides the following formula (1):
  • the first invention provides an optically active compound represented by the above formula (2) by reacting an optically active 4-amino-2-hydroxybutanoic acid derivative represented by the above formula (1) with nitrous acid. It is also a method for producing 4-monosubstituted-2-hydroxybutanoic acid derivatives.
  • the first present invention is represented by the above formula (3) by cyclizing the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the above formula (2) under acidic conditions. It is also a method for producing optically active ⁇ -hydroxy ⁇ -butyrolactone. Furthermore, a first aspect of the present invention is to react an optically active 4-amino-12-hydroxybutanoic acid derivative represented by the above formula (1), wherein R 1 is a hydrogen atom, with nitrous acid. Thus, this is also a method for producing the optically active c-hydroxy y monobutyrolactone represented by the above formula (3).
  • the second present invention provides the following formula (4):
  • R 2 is an alkyl group having 1 to 12 carbon atoms which may have a substituent, an aralkyl group having 7 to 12 carbon atoms which may have a substituent, or a substituent.
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be present, or an aryl group having 6 to 12 carbon atoms which may have a substituent, wherein ⁇ represents an alkali metal, an alkaline earth metal or ⁇ represents an integer of 1 or 2.) is reacted with a carboxylate represented by the following formula:
  • the second present invention provides the above-mentioned (S) -heasulfonyloxy-1-y-butyrolactone represented by the above formula (6) by reacting with a carboxylate represented by the above formula (7).
  • This is also a method for producing (R) - ⁇ -asyloxy_ ⁇ -butyrolactone represented by the formula (8).
  • optically active 4-amino-2-hydroxybutanoic acid derivative has the general formula (1)
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • the alkyl group include a methyl group, an ethyl group, an ⁇ _propyl group, an isopropyl group, an ⁇ -butyl group, a sec-butyl group, and a tert-butyl group.
  • it is a methyl group or an ethyl group.
  • optically active 4-amino-2-hydroxybutanoic acid in which R 1 is a hydrogen atom can be easily produced from glutamic acid according to the method described in JP-A-50-409.
  • An optically active 4-amino-2-hydroxybutanoic acid derivative in which R 1 is an alkyl group having 1 to 5 carbon atoms is obtained from Org. Prep. Proce d. Int. It can be easily manufactured by referring to the methods described in 1998, 17 (2), 91-97.
  • optically active methyl 4-amino-2-hydroxybutanoate or optically active ethyl 4-amino-2-hydroxybutanoate wherein R 1 is a methyl group or an ethyl group is optically active 4-amino-2-hydroxybutanoic acid.
  • R 1 is a methyl group or an ethyl group
  • 4-amino-2-hydroxybutanoic acid can be easily produced by reacting the compound with sulfuric acid, hydrogen chloride or thionyl chloride in methanol or ethanol.
  • Q represents a hydroxyl group, a halogen, or an alkoxy group having 1 to 5 carbon atoms.
  • the halogen include fluorine, chlorine, bromine and iodine, and chlorine or bromine is preferable.
  • the acyloxy group include, for example, a formyloxy group, an acetyloxy group, a propionyloxy group, an n-butyryloxy group, an isobutyryloxy group, and a bivaloyloxy group. Preferably, it is an acetyloxy group.
  • Sulfonyl chloride has the general formula (5)
  • R 2 is an alkyl group having 1 to 12 carbon atoms which may have a substituent, an aralkyl group having 7 to 12 carbon atoms which may have a substituent, or having a substituent.
  • Alkyl group of the R 2 as the substituent in Ararukiru group and Ariru group, for example, include fluorine, chlorine, halogens such as bromine, nitro group, Shiano group, a carboxyl group, an alkoxy group of number 1-1 2 carbon And the number of substituents is 0 to 3.
  • the carboxylate is represented by the general formula (7)
  • R 3 is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, or a substituent.
  • Examples of the substituent in the alkyl group, alkenyl group, aralkyl group and aryl group of R 3 include halogen such as fluorine, chlorine and bromine, nitro group, cyano and the like. Groups, a carboxyl group, an alkoxy group having 1 to 12 carbon atoms, and the like, and the number of substituents is 0 to 3.
  • M represents an alkali metal, an alkaline earth metal, or ammonium.
  • alkali metal include lithium, sodium, potassium, norevidium, and cesium, and preferably sodium or potassium.
  • alkaline earth metal include magnesium, calcium, barium and the like.
  • ammonium include ammonium, diisopropylammonium, triethylammonium, pyridinium, tetraethylammonium, tetrabutylammonium, triethylbenzylammonium and the like, and preferably triethylammonium.
  • N represents an integer of 1 or 2.
  • the carboxylic acid has the general formula (10)
  • an optically active 4-monosubstituted compound represented by the above formula (2) is reacted with nitrous acid to cause the optically active 4-mono-2-hydroxybutanoic acid derivative represented by the above formula (1).
  • the amount of nitrous acid used is preferably based on the 4-amino-12-hydroxybutanoic acid derivative.
  • the molar amount is preferably 1 to 20 times, more preferably 1 to 5 times.
  • nitrous acid may be generated in the system by mixing an acid and a nitrite.
  • the acid include mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, perchloric acid, phosphoric acid, and boric acid; formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, vivalic acid, valeric acid, Carboxylic acids such as isovaleric acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, methoxyacetic acid, diethoxyacetic acid, hydroxyacetic acid, chloroacetic acid, dichloroacetic acid, triflenoacetic acid, oxalic acid, and malonic acid; Examples thereof include sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
  • carboxylic acids Preferred are carboxylic acids, and more preferred are formic acid, acetic acid and propionic acid.
  • the amount of the acid to be used is preferably 1 to 50 times, more preferably 2 to 20 times the molar amount of the 4-amino-2-hydroxybutanoic acid derivative.
  • nitrite examples include an alkali metal salt, an alkaline earth metal salt, an ammonium salt and the like, preferably an alkali metal salt, and more preferably a sodium salt or a potassium salt.
  • the amount of nitrite used is preferably 1 to 10 times, more preferably 1 to 5 times the amount of 4-amino-2-hydroxybutanoic acid derivative, relative to the 4-amino-2-hydroxybutanoic acid derivative.
  • the reaction solvent that can be used in this reaction is not particularly limited, and is preferably water or a carboxylic acid such as formic acid, acetic acid, or propionic acid. These may be used alone or in combination of two or more.
  • the reaction temperature of this reaction is preferably 0 to 100 ° C, more preferably 0 to 40 ° C.
  • nitrite or nitrite or an aqueous solution thereof may be added to an aqueous acid solution or a carboxylic acid solution of an optically active 4-amino-2-hydroxybutanoic acid derivative. It is added over 1 to 20 hours, preferably 1 to 10 hours, or an aqueous acid solution or a carboxylic acid solution of an optically active 4-amino-2-hydroxybutanoic acid derivative is added to an aqueous solution of nitrite or nitrite. It is advisable to add over 0.1 to 20 hours, preferably 1 to 10 hours.
  • an acid or acid aqueous solution is added to a solution of the optically active 4-amino-2-hydroxybutanoic acid derivative and nitrite for 0.1 to 20 hours, preferably 1 to 10 hours.
  • a solution of an optically active 4-amino-2-hydroxybutanoic acid derivative and nitrite is added to an aqueous acid solution for 0.1 to 20 hours, preferably 1 to 10 hours.
  • reaction solvent or carboxylic acid is distilled off by an operation such as heating under reduced pressure to obtain the desired product, or a common extraction solvent such as ethyl acetate, dimethyl ether, methylene chloride, toluene
  • the reaction solvent and the extraction solvent are distilled off from the extracted liquid by an operation such as heating under reduced pressure to obtain the desired product. In some cases, it can be used in the next step without isolation.
  • the substituent Q of the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2) is determined by the acid used and the reaction solvent.
  • hydrochloric acid or hydrobromic acid when hydrochloric acid or hydrobromic acid is used as the acid, if water is used as the reaction solvent, Q is a hydroxyl group and a halogen, and if a carboxylic acid such as formic acid, acetic acid or propionic acid is used as the reaction solvent, Q Is a hydroxyl group, a halogen and an acyloxy group.
  • Mineral acids such as sulfuric acid, perchloric acid, phosphoric acid, and boric acid as the acid; when sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid are used, the reaction solvent is used.
  • Q is a hydroxyl group
  • a carboxylic acid such as formic acid, drunk acid or propionic acid is used as a reaction solvent
  • Q is an acyloxy group
  • acids formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, vivalic acid, valeric acid, isovaleric acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, methoxyacetic acid, ethoxyacetic acid, hydroxyacetic acid
  • carboxylic acids such as chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, oxalic acid, and malonic acid
  • Q is a hydroxyl group or a hydroxyl group and an acyloxy group.
  • (S) -2,4-dihydroxybutanoic acid or (S) _4-acetyloxyl-2 is used as an optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2). -It is preferred to obtain hydroxybutanoic acid.
  • the optically active ⁇ - hydroxyl represented by the above formula (3) is treated. — Convert to ⁇ -ptyrolactone.
  • the treatment may be performed in an aqueous acid solution without isolation.
  • the acid include mineral acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid and phosphoric acid, and preferably hydrochloric acid or sulfuric acid.
  • the acid may be used in such an amount that the pH of the aqueous acid solution becomes 0 to 3, for example.
  • examples of the organic solvent include ester solvents such as ethyl acetate, butyl acetate, and methyl propionate; acetyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethyloxetane, and diethylene glycol dimethyl ether.
  • Ether solvents hydrocarbon solvents such as toluene, benzene, and xylene
  • halogen solvents such as dichloromethane, 1,2-dichloroethane, and chloroform.
  • an organic solvent having low compatibility with water is used, and specific examples thereof include ethyl acetate, toluene, tetrahydrofuran, methynole tert-butyl ether, and the like.
  • the reaction temperature of this reaction is preferably from 0 to 100 ° C, more preferably from 30 to 70 ° C.
  • R 1 is an alkyl group having 1 to 5 carbon atoms and Q is a hydroxyl group
  • the acid is contained in the organic solvent of the optically active 4-substituted 12-hydroxybutanoic acid derivative.
  • the cyclization can be carried out by adding
  • the organic solvent include ester solvents such as ethyl acetate, butyl acetate, and methyl propionate; getinoleatenole, tetrahydrofuran, methinole tert-butylinoleatenole, 1,4-dioxane, dimethoxetane, diethylene glycol dimethyl ether Ether solvents such as acetonitrile, propionitrile and the like; nitrile solvents such as acetonitrile and propionitrile; ketone solvents such as acetone, methyl ethyl ketone, 3-pentanone, cyclopentanone and cyclohexanone; toluene, benzene, Hydrocarbon solvents such as xylene; and halogen solvents such as dichloromethane, 1,2-dichloroethane and chlorophonolem.
  • e eth
  • Examples of the acid include mineral acids such as sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric acid, and phosphoric acid, or methanesulfonic acid, benzenesnolefonic acid, and p-toluenesnole Organic acids such as sulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid are exemplified.
  • Preferred are sulfuric acid, hydrogen chloride and methanesulfonic acid.
  • the acid is used in an amount of 0.01 to 10 times, preferably 0.1 to 2 times, the molar amount of the optically active 4-amino-12-hydroxybutanoic acid derivative.
  • the reaction temperature of this reaction is preferably 0 to 100 ° C, more preferably 30 to 70 ° C.
  • R 1 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and Q is an acyloxy group having 1 to 5 carbon atoms
  • the dehydration is performed in an alcohol in the presence of an acid. It is advisable to carry out cyclization together with acylation.
  • the acid sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric acid, mineral acid such as phosphoric acid, or methansnolephonic acid, benzenesnolephonic acid, p_tonoreensnorehon Acids, organic acids such as trisulfonic acid, methanesulfonic acid, and trifluoroacetic acid.
  • sulfuric acid, hydrogen chloride and methanesulfonic acid and more preferred is sulfuric acid.
  • the acid is used in an amount of 0.01 to 10 moles, preferably 0.01 to 2 moles, per mole of the optically active 4-amino-12-hydroxybutanoic acid derivative.
  • Examples of the alcohols include methanol, ethanol, n- propanol one Honoré, Isopurono ⁇ 0 Nonore, n- Butanonore ethyleneglycidyl Konore, diethylene recall etc., include alcohols of from 1 to 5 carbon atoms, preferably methanol or Ethanol is mentioned.
  • the reaction temperature of this reaction is preferably from 0 to 100 ° C, more preferably from 40 to 90 ° C.
  • the cyclization yield can be further increased by distilling off the alcohol by an operation such as heating under reduced pressure.
  • General post-treatment may be performed as post-treatment of this reaction.
  • the target product can be obtained by distilling off the reaction solvent and the extraction solvent from the reaction solution or the extract by an operation such as heating under reduced pressure.
  • the target substance can be purified by a general method such as column chromatography or fractional distillation to increase the purity.
  • optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2) (S) -2,4-dihydroxybutanoic acid or (S) -4-acetyloxy1-2- It is preferable to use hydroxybutanoic acid to obtain (S) -hydroxy-1- y -ptyrolactone as the optically active ⁇ -hydroxy- ⁇ -butyrolataton represented by the formula (3).
  • 4-amino-2-hydroxybutanoic acid in which R 1 is a hydrogen atom can be produced using glutamic acid as a raw material as described above, but natural L-glutamic acid is used as a raw material.
  • (S) —4-Amino-12-hydroxybutanoic acid is available at a lower cost than (R) —4-amino-12-hydroxybutanoic acid starting from D-glutamic acid. . Therefore, the above reaction is a more effective method for producing (S) - ⁇ -hydroxy- y -butyrolactone.
  • sulfonyl chloride for example, methanesulfonyl chloride, ethanesnorefonyl chloride, isopropylsulfonyl chloride, ⁇ -butansnorefoninochloride, tert-butansnorefoninochloride , Methanesolephoninolek mouth light, pheninolemethanesnorefoninolek mouth light, p-methoxyphenolenomethanesnorefoninolecride light, benzenesnorefoninolek mouth light, p — tonorenence / Refoninochloride, p-nitrobenzenetin renochloride, o_nitrobenzenesnorefoninolechloride, p-chloroben
  • examples thereof include zensulfonyl chloride and the like, preferably, methanesulfonyl chloride,
  • Examples of the base include ammonia; primary amines such as methylamine, ethylamine, benzylamine, and aniline; secondary amines such as getylamine, diisopropylamine, dibenzylamine, and diphenylamine; trimethylamine, triethylamine, and tributylamine.
  • tertiary amines are used, and more preferably, triethylamine or pyridine.
  • the amount of base used is the amount of base used,
  • the amount is preferably 1 to 20 times, more preferably 1 to 5 times, the amount of (S) - ⁇ -hydroxy- ⁇ -butyrolataton.
  • the reaction temperature of this reaction is preferably from 120 to 80 ° C, more preferably from 0 to 50 ° C.
  • Non-protonic solvents include, for example, ester solvents such as ethyl acetate, butyl acetate, methyl alcohol propionate and propyl formate; ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone; acetonitrile, propio!
  • Nitrile solvents such as nitrile; ether solvents such as getyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethoxetane, diethylene glycol dimethyl ether; pentane, hexane, toluene, benzene, xylene Hydrocarbon solvents such as dichloromethane; 1,2-dichloromethane Halogen-based solvents such as roethane, chloroform, carbon tetrachloride, and cyclobenzene; dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylpropylene perrea, dimethylsulfoxide, and hexamethylphosphoric triamide And non-protonic polar solvents such as The above solvents may be used alone or in combination of two or more.
  • ether solvents such as getyl ether, tetrahydrofuran, methyl
  • ethynol ethers such as getyl ether, tetrahydrofuran, methynole tert-butynoleatenole, 1,4-dioxane, dimethoxetane, and diethylene glycol dimethyl ether; pentane, hexane, toluene, Hydrocarbon solvents such as benzene and xylene.
  • post-treatment of this reaction general post-treatment for obtaining a product from the reaction solution may be performed.
  • water is added to the reaction solution after completion of the reaction, and an extraction operation is performed using a common extraction solvent, for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and the like.
  • a common extraction solvent for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and 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 thus obtained may be purified by a general method such as crystallization purification, fractional distillation, or column chromatography, and the purity may be further increased.
  • R 2 is a phenyl group
  • (S) - ⁇ -phenylsulfonyloxy- ⁇ -butyrolataton and R 2 Is a ⁇ -methylphenyl group
  • (S) - ⁇ - ( ⁇ _methylphenyl) sulfonyloxy_ ⁇ -butyrolactone is a novel compound not described in the literature.
  • examples of the carboxylate include sodium formate, potassium formate, lithium acetate, magnesium formate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, magnesium acetate, calcium acetate, barium acetate, ammonium acetate, Tetrabutylammonium acetate, triethylammonium acetate, Sodium onate, Sodium butyrate, Sodium isobutyrate, Sodium valerate, Sodium bivalate, Sodium acetoacetate, Potassium dichloroacetate, Sodium trichloroacetate, Sodium trifluoroacetate, Sodium oxalate, Dipotassium malonate, Maleic acid Disodium, sodium acrylate, sodium methacrylate, sodium cinnamate, sodium pyruvate, sodium phenylacetate, potassium p-chlorophenylacetate, sodium benzoate, potassium benzoate, cesium benzoate, magnesium benzoate , Ammonium
  • the above carboxylate is preferably sodium formate, sodium acetate, potassium acetate, cesium acetate, sodium butyrate, sodium isobutyrate, sodium vivalate, sodium benzoate, potassium benzoate, cesium benzoate, o-methyl Examples thereof include sodium benzoate, sodium m-methylbenzoate, and sodium p-methylbenzoate, and more preferably sodium benzoate or benzoic acid rim.
  • the amount of the carboxylate used is preferably 1 to 10 times, and more preferably 1 to 5 times the molar amount of the optically active polysulfonyloxy-y-butyrolactone.
  • the carboxylate may be generated in the system from the carboxylic acid represented by the above formula (10) and a base.
  • the carboxylic acid include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, vivalic acid, cyclohexanecarboxylic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, and oxalic acid , Malonic acid, maleic acid, fumaric acid, acrylic acid, methacrylic acid, cinnamic acid, vivalic acid, phenylacetic acid, p-clophenylphenylacetic acid, diphenylacetic acid, benzoic acid, o-methylbenzoic acid, m-methylbenzoic acid , P-methylbenzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, o-methoxybenzoic
  • the amount of rubonic acid to be used is preferably 1 to 10 times, more preferably 1 to 5 times the molar amount of optically active ⁇ -sulfonyloxy- ⁇ -butyrolactone.
  • Examples of the base include lithium hydroxide, sodium hydroxide, rhodium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium fluoride, and the like.
  • Inorganic bases metal alkoxides such as sodium methoxide, sodium ethoxide and lithium tert-butoxide; metal hydrides such as lithium hydride, sodium hydride and lithium hydride; ammonia, butyramine, aniline, diisopropyla Min, cyclohexylamine, diphenylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, diisopropylethylamine, N-methylmorpholine, N-methylbiperidine, imidazole, pyridine, Amines such as p-chloropyridine, 2-picoline, 3-picoline, 4-N, N-dimethylaminoviridine, 1,7-diazabicyclo [5,4,0] -ndecou-7-ene and the like.
  • metal alkoxides such as sodium methoxide, sodium ethoxide and lithium tert-butoxide
  • metal hydrides such as lithium
  • sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine and the like are mentioned.
  • the amount of the base to be used is preferably 0.5 to 10 times, more preferably 0.5 to 5 times, the molar amount of the optically active monosulfonyloxy_ ⁇ -butyrolataton.
  • the reaction temperature of this reaction is preferably 0 to 120 ° C, more preferably 20 to 80 ° C.
  • Organic solvents that can be used in this reaction include, for example, nonprotonic solvents.
  • Non-protonic solvents include, for example, ester solvents such as ethyl acetate, butyl acetate, methyl propionate, and propyl formate; ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone, and cyclohexanone; acetonitrile, N-tolyl solvents such as propio-tolyl; etc .; Ethanol solvents such as getyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethoxetane, diethylene glycol resin methinolate ethereol; pentane , Hexane, tonolen, benzene, xylene, etc .; hydrocarbon solvents; dichloromethane, 1,2-dichlor
  • ether solvents such as getyl ether, tetrahydrofuran, methinole tert-butyl ether, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide, dimethinoreacetamide, N—
  • Non-protonic polar solvents such as methylpyrrolidone, dimethylpropylenediarea, dimethylsulfoxide and hexamethylphosphoric triamide, and the like, more preferably dimethylformamide, dimethylacetamide, N-methylpyrrolidone, Non-protonic polar solvents such as dimethyl sulfoxide.
  • the (R) - ⁇ -acyloxy- ⁇ -butyrolact represented by the above formula (8) can be obtained at an unexpectedly high optical yield by suitably selecting the reaction reagent and reaction conditions. Tons can be produced.
  • the carboxylate represented by is reacted in, for example, dimethylformamide to produce (R) -hydroxy- ⁇ -butyrolactone which is completely stereoinverted and R 3 is a phenyl group. You can do this.
  • the post-treatment of this reaction general post-treatment for obtaining a product from the reaction solution may be performed.
  • water is added to the reaction solution after completion of the reaction, and an extraction operation is performed using a common extraction solvent, for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and the like.
  • a common extraction solvent for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and 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 thus obtained may be purified by a general method such as crystallization purification, fractional distillation, or column chromatography to further increase the purity.
  • R 3 is a hydrogen atom, an ⁇ -propyl group, an isopropyl group, an ⁇ -butyl group, a sec-butyl group, a tert-butynole group, a chloromethyl group, or a phenyl group (R ) — ⁇ -butyrolactone is referred to in the literature.
  • an acid or a base is allowed to act on the optically active ⁇ -acylsoxy- ⁇ -petit mouth lactone represented by the above formula (8) in an alcohol solvent to deacylate the compound, whereby the above formula (9) (R) - ⁇ -hydroxy ⁇ -petit ratatone represented by
  • examples of the alcohol include alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propanol, isopropanol, ⁇ -butanol, and ethylene glycol, and preferably methanol or ethanol.
  • examples of the acid include mineral acids such as sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, perchloric acid, and phosphoric acid; and organic acids such as ⁇ -toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. Acids, preferably sulfuric acid or hydrogen chloride.
  • the base examples include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate and the like; sodium methoxide Metal alkoxides such as sodium, sodium ethoxide, magnesium ethoxide, sodium isopropoxide, lithium tert-butoxide; ammonia, methylamine, diisopropylamine, trimethinoleamine, triethylamine, tributylamine, triphenylenoleamine, diisopropylamine Tinoleamine, N-methylmorpholine, N-methylbiperidine, imidazole, pyridine, p-cyclopyridine, 3-picoline, 2-picoline, 4-N, N-dimethylaminopyridine, 1,7- Amines such as azabicyclo [5,4,0] -index-17-ene; and the like, preferably sodium carbonate, carbonated sodium,
  • the amount of the acid or base to be used is 0.01 to 10 times, more preferably 0.01 to 1 times the molar amount of the optically active ⁇ -acyloxy- ⁇ -butyrolactone.
  • the reaction temperature in the case of an acid the reaction is preferably performed at 0 to 120 ° C, more preferably at 40 to 100 ° C.
  • the temperature in the case of a base preferably 20 to 7
  • the temperature is preferably 0 ° C, more preferably 0 to 40 ° C.
  • the target product can be obtained by distilling off the reaction solvent from the reaction solution after the reaction by heating under reduced pressure or the like.
  • the excess acid or base may be removed by filtration after neutralization, and purified by a general method such as column chromatography and fractional distillation to further increase the purity.
  • 20.0 g (150 mm o 1) of a 33 wt% aqueous solution of caustic soda was added, and the mixture was cooled in an ice bath, and a 12 wt% aqueous solution of sodium hypochlorite 46.56 g (75 m mo 1) was added, and the mixture was stirred for 10 minutes, and then heated and stirred at 70 ° C. for 30 minutes.
  • the optical purity was determined by derivatizing tert-butyldiphenylsilyl ether. That is, to the above (R) - ⁇ -hydroxy-1- ⁇ -butyrolataton 100 mg, add tert-butynolefiefenii / resilinorecole mouth 4.12 mg, imidazo-monole 204 mg, dimethylformamide 3 mL, and add 40 mL The mixture was stirred for 16 hours. 7 mL of water and 10 mL of hexane were added, the aqueous layer was removed, washed with 1 OmL of water, and concentrated to obtain 505 mg of a pale yellow oil.
  • Example 4 Production of (S) - ⁇ -hydroxy_ ⁇ -butyrolactone 6.0 g (100 mm o 1) of acetic acid was added to 1.19 g (1 Omm o 1) of (S) —4-amino-2-hydroxybutanoic acid (Aldrich No. 46735-9) commercially available. 1.38 g (20 mm o 1) of sodium nitrite was added at 15 ° C for 1 hour. After performing the reaction at 15 ° C. for 3 hours, a methanol solution (20 mL) of concentrated sulfuric acid (1.225 g (12.5 mmo 1)) was added, and the mixture was heated and stirred at 70 ° C. for 3 hours.
  • Example 20 Production of 0 (R) - ⁇ -benzoyloxy- ⁇ -butyrolatatone (S) -a- (p-methylphenyl) sulfonyloxy- ⁇ -butyrolactone prepared in Example 9 256 mg (1 mm o 1), sodium benzoate 288 mg (2 mm o 1), A solution of 3 mL of tetrahydrofuran was stirred at 50 ° C for 16 hours. According to the method described in Example 13, the reaction yield of (R)-(1-benzoyloxy) - ⁇ -butyrolatatone was determined to be 31%. The optical purity measured by the method described in Example 12 was 100% ee.
  • Example 2 Production of 1 (R) - ⁇ -benzoyloxy- ⁇ -butyrolactone
  • Example 2 Production of 7 (R) - ⁇ -acetyloxy-v-butyrolactone- (S) -a- (p-methylphenyl) sulfonyloxy-gamma-butyrolactone prepared in Example 9 5.0 g (1 9.5 mm o 1), a solution of sodium acetate 3.20 g (3 9. O mm o 1), dimethylformamide 50 mL, 60. C, and stirred for 7 hours. 70 mL of water and 7 OmL of ethyl acetate were added, the aqueous layer was removed, and the aqueous layer was further extracted with 70 mL of ethyl acetate, and the organic layers were combined.
  • a 28 wt% sodium methoxide solution was prepared by adding a solution of (R)-(1-benzoyloxy- ⁇ -butyrolactone) (12.91 g (62.7 mmol)) prepared in Example 12 to methanol (6 OmL). ⁇ 209 g (6.3 mmo 1) was added at 15 ° C and stirred for 7 hours. To this, an operation of adding 615 mg (6.3 mmo 1) of concentrated sulfuric acid, distilling off methanol by vacuum concentration, further adding 6 OmL of acetonitrile, and reconcentrating was repeated twice.
  • Example 3 Production of 1 (R) -Hydroxy-butyrolactone A solution of 1.333 g (6.94 mmo 1) of (R) - ⁇ -acetyloxy- ⁇ -butyrolactone prepared in Example 27 in methanol (1 OmL) was added with a 28 wt% sodium methoxide solution 13 Omg ( 0.67 mm o 1) was kneaded at 15 ° C and stirred for 1 hour. To this, 68 mg (0.69 mmo 1) of concentrated sulfuric acid was added, methanol was distilled off by concentration under reduced pressure, 10 ml of acetonitrile was further added, and the operation of reconcentration was repeated twice.
  • the present invention has the above-mentioned constitution, and can easily produce optically active ⁇ -hydroxy-ptyrolactone, which is useful as a pharmaceutical intermediate, from inexpensive and easily available raw materials.

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Abstract

Cette invention concerne un procédé selon lequel les deux énantiomères d'un α-hydroxy-ηbutyrolactone, qui sont utiles en tant qu'intermédiaires médicamenteux, peuvent être produits facilement à partir de matériaux peu coûteux faciles à se procurer. Pour obtenir un α-hydroxy-η-butyrolactone optiquement actif, on fait réagir un acide 4-amino-2-hydroxybutanoïque avec de l'acide nitrique, avec cyclisation en conditions acides. On fait ensuite réagir un (S)-α-hydroxy-η-butyrolactone avec un chlorure de sulfonyle en présence d'une base pour obtenir un S-α-sulfonyloxy-η-butyrolactone. Après une autre réaction de ce dernier composé avec un sel d'acide carboxylique, on obtient un (R)-α-acyloxy-η-butyrolactone qui est ensuite déacylé par traitement avec un acide ou une base dans un solvant et donne un (R)-α-hydroxy-η-butyrolactone
PCT/JP2001/002736 2000-03-31 2001-03-30 PROCEDE D'OBTENTION D'α-HYDROXY-η-BUTYROLACTONE OPTIQUEMENT ACTIF WO2001072681A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP1277748A1 (fr) * 2001-07-19 2003-01-22 Takasago International Corporation Procédé pour la préparation de y-butyrolactone optiquement active
JP2014502255A (ja) * 2010-10-15 2014-01-30 アディッソ・フランス・エス．エー．エス． ２−ヒドロキシブチロラクトンを製造する方法
KR101799987B1 (ko) 2016-11-15 2017-11-21 주식회사 씨원켐 2-하이드록시-감마-부티로락톤의 제조방법
WO2018093135A3 (fr) * 2016-11-15 2018-08-09 주식회사 씨원켐 Procédé de préparation de 2-hydroxy-gamma-butyrolactone

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1277748A1 (fr) * 2001-07-19 2003-01-22 Takasago International Corporation Procédé pour la préparation de y-butyrolactone optiquement active
JP2003034687A (ja) * 2001-07-19 2003-02-07 Takasago Internatl Corp 光学活性γ−ブチロラクトンの製造方法
US6608214B2 (en) 2001-07-19 2003-08-19 Takasago International Corporation Process for producing optically active γ-butyrolactone
EP1403262A1 (fr) * 2001-07-19 2004-03-31 Takasago International Corporation Procédé pour la préparation de y-butyrolactone optiquement active
JP2014502255A (ja) * 2010-10-15 2014-01-30 アディッソ・フランス・エス．エー．エス． ２−ヒドロキシブチロラクトンを製造する方法
KR101813089B1 (ko) 2010-10-15 2018-01-30 아디쎄오 프랑스 에스에이에스 2-하이드록시부티로락톤의 제조 방법
KR101799987B1 (ko) 2016-11-15 2017-11-21 주식회사 씨원켐 2-하이드록시-감마-부티로락톤의 제조방법
WO2018093135A3 (fr) * 2016-11-15 2018-08-09 주식회사 씨원켐 Procédé de préparation de 2-hydroxy-gamma-butyrolactone

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