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WO2009139438A1 - Procédé de production d'un acide carboxylique optiquement actif - Google Patents

Procédé de production d'un acide carboxylique optiquement actif Download PDF

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Publication number
WO2009139438A1
WO2009139438A1 PCT/JP2009/058988 JP2009058988W WO2009139438A1 WO 2009139438 A1 WO2009139438 A1 WO 2009139438A1 JP 2009058988 W JP2009058988 W JP 2009058988W WO 2009139438 A1 WO2009139438 A1 WO 2009139438A1
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alkyl
optionally substituted
formula
carboxylic acid
cycloalkyl
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Japanese (ja)
Inventor
和利 菅原
將太 利川
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses

Definitions

  • the present invention relates to a method for producing optically active carboxylic acid from racemic carboxylic acid.
  • a phenylacetamide derivative represented by the following formula is known as a compound having a glucokinase activating action and useful as a therapeutic agent for diabetes (Patent Documents 1 to 10).
  • R 1 represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, or an optionally substituted heterocyclic group.
  • R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —N (C 0-2 alkyl) (C 0 -2 alkyl) or cyclic amino.
  • R 3 represents a hydrogen atom, a halogen atom or trifluoromethyl.
  • R 6 represents a hydrogen atom, or C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these Groups of: halogen atom, cyano, nitro, hydroxyl group, C 1-2 alkoxy, —N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4 To 7-membered heterocyclic group, CF n H 3-n , aryl, heteroaryl, CO 2 H, —COC 1-2 alkyl, —CON (C 0-2 alkyl) (C 0-2 alkyl), SOCH 3 , Optionally substituted with 1 to 6 substituents independently selected from the group of SO 2 CH 3 and —SO 2 N (C 0-2 alkyl) (C 0-2 alkyl)] To express.
  • R 7 and R 8 independently represent a hydrogen atom, or C 1-4 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these groups are halogen Atom, cyano, nitro, hydroxyl group, C 1-2 alkoxy, —N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycle Groups, CF n H 3-n , aryl, heteroaryl, COC 1-2 alkyl, —CON (C 0-2 alkyl) (C 0-2 alkyl), SOCH 3 , SO 2 CH 3 and —SO 2 N ( C 0-2 alkyl) (optionally substituted with 1 to 6 substituents independently selected from the group of C 0-2 alkyl), or R 7 and R 8 are 6-8 together with the N atom to which they are bonded Bicyclo nitrogen-containing heterocyclic
  • the phenylacetamide derivative has an asymmetric carbon (marked with *), and among the optical isomers related to the asymmetric carbon, R 1 —CH 2 group (hereinafter, R 1 -methyl group) is shown in the figure. It is known that ⁇ -coordinate isomers in the structural formula have high glucokinase activity.
  • a method for producing an optically active phenylacetamide derivative in which the R 1 -methyl group is ⁇ -coordinated is described in, for example, Patent Documents 1, 5 and 9.
  • Patent Document 1 a racemic carboxylic acid of formula (2) is reacted with (R)-(+)-4-benzyl-2-oxazolidinone to form an imide of a diastereo mixture, which is separated by column chromatography and then hydrolyzed.
  • an optically active carboxylic acid of the formula (1) is produced, and an optically active phenylacetamide derivative is produced by further amidation.
  • R 1 , R 2 and R 3 have the same meanings as described above.
  • a method is described in which the racemic carboxylic acid of the formula (2) is used as it is, and a racemic phenylacetamide derivative is introduced and separated by chiral HPLC.
  • Patent Document 5 as described below, an asymmetric induction is attempted by alkylating and hydrolyzing an amide compound of a phenylacetate compound unsubstituted at the benzyl position and (1R, 2R)-( ⁇ )-pseudoephedrine. ing. However, the asymmetric yield is not described. Patent Documents 8 and 10 also report similar reactions. However, none of the patent documents describes the degree of asymmetric induction.
  • Patent Document 9 an optically active carboxylic acid is produced by hydrogenating an olefin compound in the presence of an asymmetric catalyst.
  • R 2 has the same meaning as described above.
  • a high hydrogen pressure of 50 bar is required, there is a problem that it cannot be produced by ordinary production equipment, and the catalyst and asymmetric ligand used are both expensive.
  • Non-Patent Documents 1 to 7 disclose that an optically active carboxylic acid is obtained by reacting a ketene compound derived from a racemic carboxylic acid represented by the following formula or the like with D-(-)-pantolactone or a lactic acid ester and hydrolyzing it.
  • a method for producing an acid is described.
  • R is a hydrogen atom, methyl, isopropyl, phthaloylamino- (CH 2 ) m —, etc. (m is 0, 1 or 2).
  • Phenyl is unsubstituted or phenyl substituted at the 4-position by methoxy, nitro, isobutyl or the like, or is replaced with methoxynaphthyl.
  • the chemical yield and asymmetric yield of this reaction may vary greatly depending on the compound and conditions.
  • phenyl although the asymmetric yield did not decrease so much even when methoxy, nitro, or isobutyl was substituted at the 4-position in Non-Patent Document 1, diastereomeric excess was observed in the compound in which phenyl was changed to 6-methoxynaphthyl. The rate dropped to 80% de.
  • R in Non-Patent Documents 3 to 5, m is 0 in a reaction using a racemic carboxylic acid (m is 0, 1 or 2) in which R is phthaloylamino- (CH 2 ) m —.
  • the problem to be solved by the present invention is to provide a method for producing optically active carboxylic acid from racemic carboxylic acid with a normal production facility at a good yield and at a low cost.
  • the present inventors have conducted intensive research. As a result, the racemic carboxylic acid of the formula (2) is dehydrated into a ketene compound, reacted with D-(-)-pantolactone, and hydrolyzed.
  • the present invention was completed by finding that the optically active carboxylic acid of the formula (1) was produced with high yield and asymmetric yield.
  • the present invention is as follows.
  • [1] A process for producing an optically active carboxylic acid of the formula (1) by dehydrating the carboxylic acid of the formula (2) into a ketene compound, reacting with D-( ⁇ )-pantolactone and hydrolyzing it.
  • [2] A process for producing an optically active carboxylic acid of the formula (1) by reacting a ketene compound of the formula (2a) with D-( ⁇ )-pantolactone and hydrolyzing it.
  • R 1 , R 2 and R 3 have the same meanings as described above.
  • Alkyl includes, for example, C 1-6 , preferably C 1-4 linear or branched alkyl, specifically methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, And hexyl.
  • C 0-4 denotes an alkyl carbon number of 0, 1, 2, 3 or 4 in the C 0-4 alkyl etc., it means a hydrogen atom and alkyl 0 carbon atoms (alkenyl, alkynyl, The same meaning is also applied to cycloalkyl and the like).
  • Cycloalkyl includes, for example, C 3-8 , preferably C 3-6 cycloalkyl, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • halogen atom include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
  • aryl examples include phenyl and naphthyl, with phenyl being particularly preferred.
  • heterocyclic group include a 4- to 8-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Examples of the “4- to 8-membered nitrogen-containing heterocyclic group” include heterocyclic groups containing a 4- to 8-membered nitrogen atom among the above heterocyclic groups.
  • Examples of the “6- to 8-membered bicyclo nitrogen-containing heterocyclic group” include cyclohexanothiazolyl, dihydrothiazolopyridinyl, thiazolopyridinyl and the like.
  • the sulfur atom may be oxidized with 1 or 2 oxygen atoms.
  • Heteroaryl includes 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms, specifically furyl, thienyl, Examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • Cyclic amino includes a “heterocyclic group” having a nitrogen atom and a group substituted with the nitrogen atom. Specific examples include pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl and the like.
  • substituent of “substituted aryl”, “substituted heteroaryl”, “substituted cycloalkyl” and “substituted heterocyclic group” in R 1 a hydroxyl group, a halogen atom, cyano, nitro, vinyl, ethynyl, methoxy, OCF n H 3-n , —N (C 0-2 alkyl) (C 0-2 alkyl), CHO, C 1-2 alkyl [alkyl is a halogen atom, hydroxyl group, cyano, methoxy, —N (C 0-2 alkyl) ) (C 0-2 alkyl), optionally substituted with 1 to 5 substituents independently selected from the group of —SOCH 3 and —SO 2 CH 3 ], and the like.
  • One or two substituents may be substituted.
  • the two substituents may be bonded together to form a carbonyl group, or may be condensed with a bonded ring after forming a carbocyclic or heterocyclic ring. .
  • substituents of “substituted alkyl”, “substituted cycloalkyl”, “substituted aryl” and “substituted heteroaryl” in R 2 include a halogen atom, cyano, nitro, hydroxyl group, C 1-2 alkoxy, —N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, CF n H 3-n , aryl, heteroaryl, —COC 1-2 alkyl, —CON (C 0-2 alkyl) (C 0 -2 alkyl), CH 3 , SOCH 3 , SO 2 CH 3 , —SO 2 N (C 0-2 alkyl) (C 0-2 alkyl), etc., and the substituent is independently 1 to 6 May be substituted.
  • Examples of the “aromatic ring” include benzene and naphthalene, and benzene is particularly preferable.
  • Examples of the “heteroaromatic ring” include a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. Thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.
  • Examples of the “carbocycle” include C 3-8 , preferably C 3-6 cycloalkane, and specifically include cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.
  • heterocycle examples include a 4- to 8-membered non-aromatic heterocycle containing 1 or 2 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, specifically, an oxetane , Tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, azetidine, pyrrolidine, piperidine, azepane, dioxolane, piperazine, homopiperazine, morpholine, thiomorpholine and the like.
  • the sulfur atom may be oxidized with 1 or 2 oxygen atoms.
  • heterocyclic ring or heterocyclic ring formed with —N ⁇ C— to which T is bonded include 2-pyrazinyl, 2-thiazolyl and 3-pyrazolyl.
  • each of R 4 and R 5 is preferably independently a hydrogen atom, methyl or fluoro.
  • each of R 4 and R 5 is preferably independently hydrogen or C 1-2 alkyl.
  • Particularly preferred examples of the ring substituted with R 4 and R 5 include 2-pyrazinyl, 5-fluoro-2-thiazolyl, 1-methyl-1H-pyrazol-3-yl.
  • R 1 examples include cycloalkyl, hydroxycycloalkyl, oxocycloalkyl, tetrahydropyranyl and the like.
  • R 2 examples include methyl, cyclopropyl, cyclobutyl and the like.
  • Preferred examples of the optically active phenylacetamide derivative of the formula (4) include (2R) -2- (4-cyclobutanesulfonylphenyl) -N-pyrazin-2-yl-3- (tetrahydropyran-4-yl).
  • Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, or acetate, fumarate, oxalate, citrate, methane Organic acid salts such as sulfonate, benzenesulfonate, tosylate or maleate are listed. Moreover, when it has a substituent such as carboxyl, examples of the salt include salts with bases such as alkali metal salts such as sodium salt or potassium salt or alkaline earth metal salts such as calcium salt. Pharmacologically acceptable salts also include internal salts and can be in the form of solvates such as hydrates thereof.
  • the optically active carboxylic acid of the formula (1) is produced by dehydrating the carboxylic acid of the formula (2) to form a ketene compound, reacting with D-(-)-pantolactone and hydrolyzing.
  • R 1 , R 2 and R 3 have the same meanings as described above.
  • Various known methods can be applied to dehydrate the racemic carboxylic acid of formula (2) to form a ketene compound.
  • the carboxylic acid can be converted into an acid chloride and subsequently treated with a base.
  • An acid chloride can be obtained by, for example, reacting a chlorinating agent in a reaction solvent at a temperature from 0 ° C.
  • the chlorinating agent examples include phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like.
  • the amount used is, for example, 1 to 2 equivalents based on the racemic carboxylic acid, or the reaction is carried out using a large excess in combination with a solvent. However, it is preferably 1 to 1.2 equivalents.
  • an excess chlorinating agent it may be distilled off after completion of the reaction and replaced with the solvent used in the next step, but when a small excess amount that does not adversely affect the next step is used, It can be used for the next reaction without distilling off the solvent.
  • DMF dimethylformamide
  • Any reaction solvent can be used as long as it can dissolve raw materials, reagents and the like and does not adversely affect the reaction.
  • hydrocarbon solvents hexane, heptane, benzene, toluene, chlorobenzene, etc.
  • Halogen solvents methylene chloride, chloroform, 1,2-dichloroethane, etc.
  • ether solvents diethyl ether, tetrahydrofuran (THF), dioxane, etc.
  • Preferable solvents include methylene chloride, toluene, THF and the like.
  • the subsequent treatment with a base can be carried out by adding the base as it is to the reaction solution of the above reaction.
  • the base include tertiary amines (triethylamine, trimethylamine, dimethylethylamine, N-methylmorpholine, tetramethylethylenediamine, 1,4-diazabicyclo [2.2.2.] Octane, etc.) and the like.
  • the amount of the base used is, for example, 2 to 5 equivalents, preferably 2.1 to 3 equivalents with respect to the racemic carboxylic acid.
  • An example of a reaction temperature is ⁇ 50 to 30 ° C., preferably ⁇ 20 to 15 ° C.
  • the reaction of the produced ketene compound and D-(-)-pantolactone can be carried out, for example, by adding D-(-)-pantolactone as it is to the reaction solution of the above reaction.
  • the amount of D-( ⁇ )-pantolactone used is, for example, 1.1 to 2 equivalents, preferably 1.2 to 1.5 equivalents, relative to the racemic carboxylic acid.
  • Examples of the reaction temperature include ⁇ 100 to 30 ° C., but it is preferable to start the reaction at a temperature of ⁇ 78 to 0 ° C. and gradually raise the temperature. Subsequently, isolation and purification can be performed by conventional methods.
  • D-(-)-pantolactone is represented by the following structural formula and is also called (R) -pantolactone.
  • the optically active carboxylic acid of the formula (1) can be produced by hydrolyzing and purifying the resulting D-( ⁇ )-pantolactone ester. Hydrolysis is preferably performed under conditions that do not cause isomerization at the asymmetric carbon site as much as possible.
  • the hydrolysis method include, for example, an alkali hydroxide (lithium hydroxide, lithium hydroxide) in a mixed solvent of alcohol solvent (methanol, ethanol, etc.) or ether solvent (THF, dioxane, etc.) and water in the presence of hydrogen peroxide. And a method of treating with sodium hydroxide, potassium hydroxide, etc.).
  • the amount of hydrogen peroxide to be used is 0.1 to 5 equivalents, preferably 1 to 3 equivalents, relative to D-(-)-pantolactone ester.
  • the amount of alkali hydroxide used is, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents.
  • the reaction temperature include ⁇ 5 ° C. to 30 ° C. Subsequently, isolation and purification can be performed by conventional methods. Further, by performing recrystallization, unnecessary isomers by-produced can be separated and removed.
  • the pantolactone ester can be hydrolyzed without racemization by a method of treating with various acids in the presence of water. Examples of the acid used include acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, and mixtures thereof. Examples of the reaction temperature include 0 ° C. to 100 ° C.
  • the optically active carboxylic acid of formula (1) is subsequently condensed with an amine of formula (3) to produce a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 and T are as defined above].
  • Patent Document 1 mentioned above. 10 to 10 are described in detail together with many examples, and can be easily produced by referring to these descriptions.
  • Reference example 1 (4-Cyclopropylsulfanylphenyl) -hydroxyacetic acid ethyl ester
  • a solution of aluminum chloride (127.7 g) in chlorobenzene (480 mL) was added dropwise at 30 ° C. over 15 minutes, followed by cyclopropylphenyl sulfide.
  • a solution of (80.0 g) in chlorobenzene (160 mL) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 4 hours.
  • Reference example 2 (4-Cyclopropylsulfanylphenyl) -acetic acid ethyl ester Boron trifluoride diethyl ether was added to a solution of (4-cyclopropylsulfanylphenyl) -hydroxyacetic acid ethyl ester (6.9 g) and triethylsilane (5.2 mL) prepared in Reference Example 1 in methylene chloride (100 mL) under ice-cooling. (3.8 mL) was added, and the mixture was stirred at room temperature for 17 hours.
  • Triethylsilane (5.2 mL) and boron trifluoride diethyl ether (3.8 mL) were sequentially added, and the mixture was further stirred at room temperature for 26 hours.
  • the reaction solution was added to saturated aqueous sodium hydrogen carbonate solution (50 mL), and after liquid separation, the organic layer was washed successively with water (25 mL) and saturated brine (25 mL), and dried (magnesium sulfate).
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane (1: 4 to 1: 1)) to obtain the title compound (5.3 g).
  • Reference example 3 (4-Cyclopropylsulfanylphenyl) -acetic acid ethyl ester
  • the ester of Reference Example 2 can also be produced by the following method.
  • Patent Document 9 (4-cyclopropylsulfanylphenyl) -oxoacetic acid ethyl ester
  • boron trifluoride diethyl ether (1.5 mL)
  • the reaction mixture is added to a 7% aqueous sodium hydrogen carbonate solution (15 mL), and the layers are separated.
  • Reference example 4 2- (4-Cyclopropylsulfanylphenyl) -3- (4-tetrahydropyranyl) -propionic acid ethyl ester
  • 4-cyclopropylsulfanylphenyl) -acetic acid ethyl ester (2.4 g) prepared in Reference Example 2 in THF (50 mL) was added 1M lithium hexamethyldisilazide THF solution (10.9 mL) at ⁇ 13 ° C. The mixture was stirred at the same temperature for 1 hour.
  • Patent Document 6 A solution of 4-tetrahydropyranylmethyl iodide (Patent Document 6; 2.9 g) in toluene (10 mL) and N, N′-dimethylpropyleneurea (1.8 mL) were added, and the mixture was warmed to room temperature and stirred for 2 hours. . Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried (magnesium sulfate), and the solvent was evaporated under reduced pressure to give a residue.
  • Patent Document 6 A solution of 4-tetrahydropyranylmethyl iodide (Patent Document 6; 2.9 g) in toluene (10 mL) and N, N′-dimethylpropyleneurea (1.8 mL) were added, and the mixture was
  • a 10% aqueous sodium sulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • a 10% aqueous sodium carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (30 mL).
  • the organic layer was washed successively with water (10 mL) and saturated brine (10 mL), dried (magnesium sulfate), and the residue obtained by evaporating the solvent under reduced pressure was directly used in the next reaction.
  • the residue was dissolved in ethanol (18 mL), 2M aqueous sodium hydroxide solution (2.5 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 14 hr.
  • Reference Example 6 2- (4-Cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid
  • the racemic carboxylic acid of Reference Example 5 can also be produced by the following method. To a solution of (4-cyclopropylsulfanylphenyl) -acetic acid ethyl ester (1.7 g) prepared in Reference Example 2 in acetone (26 mL), a solution of Oxone (registered trademark: 6.0 g) in water (17 mL) at room temperature. Was dripped.
  • the precipitated inorganic salt was filtered, and 20% aqueous sodium thiosulfate solution (2 mL) and 7% aqueous sodium hydrogen carbonate solution (20 mL) were sequentially added to the filtrate, and ethyl acetate (50 mL) was added. After liquid separation, the aqueous layer was extracted twice with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, dried (magnesium sulfate), evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate-hexane (1: 6 to 1: 1)).
  • Example 1 (R) -2- (4-Cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid
  • 2- (4-cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid 5.0 g
  • DMF 32 mg
  • Reference Example 5 methylene chloride
  • 20 Oxalyl chloride 1.5 mL was added at ° C and stirred at the same temperature for 2 hours.
  • the reaction mixture was cooled to ⁇ 15 ° C., dimethylethylamine (5.3 mL) was added, and the mixture was stirred for 30 min.
  • reaction solution was cooled to ⁇ 78 ° C., and a solution of D-( ⁇ )-pantolactone (2.5 g) in methylene chloride (30 mL) was added dropwise over 20 minutes, and the same temperature was maintained for 30 minutes and at ⁇ 60 ° C. for 2 hours.
  • the mixture was stirred at ⁇ 40 ° C. for 17 hours and further at 20 ° C. for 2 hours.
  • Water (50 mL) was added to the reaction mixture, the organic layer was separated, washed with saturated brine (30 mL), dried (magnesium sulfate), evaporated under reduced pressure, and the resulting residue was used as is. Used for the reaction.
  • the above residue was dissolved in methanol (100 mL), 30% aqueous hydrogen peroxide solution (4.5 mL) and 4M aqueous lithium hydroxide solution (4.4 mL) were successively added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. A 10% aqueous sodium sulfite solution (90 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • optically active carboxylic acid can be produced from racemic carboxylic acid with ordinary production equipment at a good yield and at low cost.

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Abstract

La présente invention concerne un procédé de production d'un acide carboxylique optiquement actif à partir d'un acide carboxylique racémique dans une installation de production conventionnelle avec une efficacité élevée et à faible coût. L'invention concerne spécifiquement un procédé de production d'un acide carboxylique optiquement actif représenté par la formule (1). Le procédé comprend les étapes consistant à : déshydrater un acide carboxylique représenté par la formule (2) afin de produire un composé cétène; et faire réagir le composé cétène avec la D-(-)-pantolactone afin d'hydrolyser le composé cétène. (Dans les formules, R1 représente un aryle qui peut être substitué, un hétéroaryle qui peut être substitué, un cycloalkyle qui peut être substitué, ou un groupe hétérocyclique qui peut être substitué; R2 représente un alkyle qui peut être substitué, un cycloalkyle qui peut être substitué, un aryle qui peut être substitué, un hétéroaryle qui peut être substitué, un -N(alkyle en C0 à C2)(alkyle en C0 à C2) ou un amino cyclique; et R3 représente un atome d'hydrogène, un atome d'halogène ou un trifluorométhyle.
PCT/JP2009/058988 2008-05-15 2009-05-14 Procédé de production d'un acide carboxylique optiquement actif Ceased WO2009139438A1 (fr)

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US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
CN114466833A (zh) * 2019-09-30 2022-05-10 大金工业株式会社 丙酸衍生物的制造方法

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* Cited by examiner, † Cited by third party
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US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
CN114466833A (zh) * 2019-09-30 2022-05-10 大金工业株式会社 丙酸衍生物的制造方法

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