JP4855446B2 - Process for the production of optically pure (S) -3-hydroxypyrrolidine - Google Patents

Description

  The present invention relates to a method for producing optically pure (S) -3-hydroxypyrrolidine, and more specifically, optically reacting 4-amino- (S) -2-hydroxybutyric acid ester salt in the presence of a reducing agent. And a process for directly producing chemically pure (S) -3-hydroxypyrrolidine.

  It is already known that chiral 3-hydroxypyrrolidine or a derivative compound thereof is useful as a core intermediate of various chiral drugs such as antibiotics, analgesics, thrombolytic agents, antipsychotics and the like. Although there are many examples derived from chiral 3-hydroxypyrrolidine or its derivative compounds among currently marketed pharmaceuticals, examples of actual use in pharmaceutical production are as follows. Raw material for core intermediate of vasodilator (calcium antagonist: valnidipine) [European Patent Publication No. 160451, J. MoI. Med. Chem., 1986, 29, 2504-2511, JP-A-61-267577, JP-A-61-63652], carbapenem antibiotics [Heterocycles, Vol 24, No. 5, 1986, Tetrahedron Lett., 1984, 25 2793, International Publication No. WO 88/008845, J. Am. Org. Chem., 1992, 57, 4352-4361], quinolone antibiotics [US Pat. No. 4,916,141, European Patent Publication No. 311169, European Patent Publication No. 304087], analgesics (κ-receptor agonist) [European Patent Publication No. 398720, European Patent Publication No. 366720, European Patent Publication No. 366327, J. Med. Med. Chem., 1994, 37, 2138-2144], neurotransmitter [International Publication No. WO01 / 019817]. Furthermore, chiral 3-hydroxypyrrolidine or its derivative compounds have a very wide range of applications as a core intermediate of new drugs under clinical trials.

  A conventional technique related to the production of chiral 3-hydroxypyrrolidine is as follows.

  The first conventional method is a decarboxylation reaction using (R) -3-hydroxy-L-proline as a starting material, and is a method of synthesizing 3- (R) -hydroxypyrrolidine by a one-step reaction [JP No. 2001-220372, International Publication No. WO97 / 043256, JP-A-5-255204, Synlett, 1995, 55-57, Syn. Comm., 1994, 24, 1381-1387, Korean J. of Med. Chem., 1993, 3, 72-80, Syn. Comm., 1993, 23, 2691-2699, J.A. Chem. Soc. Perkin Trans. 1., 1993, 1421-1424, Bioorganic & Medicinal Chemistry Letters, 2, 827]. However, since (S) -3-hydroxy-L-proline used as a starting material is very expensive, it cannot be used as an economical method for mass production.

  The second conventional method is a method of obtaining (S) -3-hydroxypyrrolidine through several production steps using D-malic acid as a raw material [Syn. Commun., 1985, 15, 587-598. Med. Chem., 1994, 37, 2138-2144]. However, since this method goes through several stages, it cannot be used as an economical method for mass production.

  The third conventional method is a method of obtaining (S) -3-hydroxypyrrolidine by performing an ionic pentagonal ring-forming reaction in an epoxy ring-opening reaction of 3,4-epoxy-1-butanol with an amine [International Publication WO2003]. / 099754]. However, in this method, 3,4-epoxy-1-butanol used for the reaction is not commercially available, and the production process of the raw material is very complicated, and there is a problem in the supply and demand of raw materials.

  The fourth conventional method uses 1,2,4-trihydroxybutane, which is a derivative of 3,4-epoxy-1-butanol, as a starting material, followed by a hydroxyl group activation reaction followed by an amine double substitution reaction. , (S) -3-hydroxypyrrolidine or a derivative thereof [International Publication WO2000 / 015610]. However, this method is also not usable as an economical method for mass production because the supply and demand of starting materials is not easy.

  As other conventional methods, a method for synthesizing (S) -3-hydroxypyrrolidine from a derivative of 3,4-dihydroxy-1-butanol [Japanese Patent Laid-Open No. 60-104061], from 3,4-dihydroxy-1-butylamine ( S) Synthesis method of 3-hydroxypyrrolidine [Japanese Patent Laid-Open No. 57-56457], 3-chloro-1,2-propanediol or a derivative thereof, a cyan substitution reaction, a cyan group reduction reaction and a ring formation reaction ( A method for synthesizing S) -3-hydroxypyrrolidine [European Patent No. 431521, European Patent No. 347818] and the like are known. However, the conventional method is also very difficult to supply raw materials industrially.

  As described above, the production method of (S) -3-hydroxypyrrolidine known to date is not easily mass-produced industrially due to the use of expensive raw materials and complicated production processes. Absent.

Therefore, the (S) -3-hydroxypyrrolidine which can be easily purchased or uses an inexpensive raw material as a starting material, has an easy and economical manufacturing process, and can be used industrially (S) -3-hydroxypyrrolidine. Development of a new manufacturing method is urgently required.
European Patent Publication No. 160451 JP-A 61-267577 JP-A-61-63652 International Publication WO88 / 008845 Pamphlet U.S. Pat. No. 4,916,141 European Patent Publication No. 3911169 European Patent Publication No. 304087 European Patent Publication No. 398720 European Patent Publication No. 366327 International Publication WO01 / 019817 Pamphlet JP 2001-220372 A International Publication WO97 / 043256 Pamphlet JP-A-5-255204 International Publication WO2003 / 097594 International Publication WO2000 / 015610 Pamphlet Japanese Patent Application Laid-Open No. 60-104061 JP 57-56457 A European Patent No. 431521 European Patent No. 347818 J. Med. Chem., 1986, 29, 2504-2511 Heterocycles, Vol 24, No. 5, 1986 Tetrahedron Lett., 1984, 25, 2793 J. Org. Chem., 1992, 57, 4352-4361 J. Med. Chem., 1994, 37, 2138-2144 Synlett, 1995, 55-57 Syn. Comm., 1994, 24, 1381-1387 Korean J. of Med. Chem., 1993, 3, 72-80 Syn. Comm., 1993, 23, 2691-2699 J. Chem. Soc. Perkin Trans. 1., 1993, 1421-1424 Bioorganic & Medicinal Chemistry Letters, 2,827 Syn. Commun., 1985, 15, 587-598

  The object of the present invention is to use an optically active 4-amino- (S) -2-hydroxybutyric acid ester salt which is easily purchased as a starting material or inexpensive, and performs the reduction and cyclization reaction in one container. An object of the present invention is to provide a method for producing (S) -3-hydroxypyrrolidine by a one-step production process performed simultaneously.

  Furthermore, another object of the present invention is to provide a method for separating and obtaining optically or chemically pure (S) -3-hydroxypyrrolidine from a reactant by simple vacuum distillation.

  Furthermore, another object of the present invention is to provide a method for producing (S) -3-hydroxypyrrolidine comprising steps capable of industrial mass production.

  The present invention for realizing the above object includes the following features.

  That is, in the present invention, an optically active 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the following chemical formula (2) is reacted in the presence of a reducing agent to represent an optical compound represented by the following chemical formula (1). A method for producing optically active (S) -3-hydroxypyrrolidine comprising the step of producing active (S) -3-hydroxypyrrolidine is characterized.

  In the chemical formula (1) or (2), R is linear or branched alkyl having 1 to 10 carbon atoms, aryl, or aralkyl, and HX is an inorganic acid such as halide acid, sulfuric acid, phosphoric acid, or methane Organic acids such as sulfonic acids.

  Furthermore, the present invention is characterized in that the reducing agent is selected from the group consisting of borane, lithium triethylborohydride (superhydride (registered trademark)), lithium aluminum hydride and sodium borohydride.

  Furthermore, the present invention further comprises an additive selected from the group consisting of acid, base, boron trifluoride diethyl ether, iodo, aluminum trichloride, quaternary ammonium salt and quaternary phosphonium salt, together with the reducing agent. It is characterized by its use.

  Furthermore, the present invention provides a reaction solvent, water; linear, branched or cyclic ether having 2 to 10 carbon atoms; diglyme; dioxane; linear, branched or cyclic alcohol having 1 to 10 carbon atoms; It is characterized by using a single or mixed solvent selected from the group consisting of group hydrocarbons; and alkyl halides having 1 to 6 carbon atoms.

  Furthermore, the present invention is characterized in that the reaction temperature is maintained in the range of 0 to 150 ° C.

  Furthermore, the present invention is characterized in that the optically active (S) -3-hydroxypyrrolidine represented by the chemical formula (1) produced by the production method is purified by a vacuum distillation method.

  According to the method for producing optically pure (S) -3-hydroxypyrrolidine according to the present invention, the optically active 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the chemical formula (2) is described above. The method of reacting in the presence of the reducing agent and directly synthesizing the optically active (S) -3-hydroxypyrrolidine represented by the chemical formula (1) is a novel production method that has not been announced so far.

  Furthermore, in the present invention, the 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the chemical formula (2) used as a starting material is industrially inexpensive and can be used in large quantities.

  Furthermore, the production method of the present invention has a high yield and is suitable for being applied to a mass production process with mild reaction conditions.

  The 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the chemical formula (2) used as a starting material in the present invention is a 4-amino- (S) represented by the following chemical formula (3). It can be produced from 2-hydroxybutyric acid through a normal esterification reaction using an alcohol and an acid catalyst.

  As the alcohol used in the esterification reaction, alkyl alcohol having 1 to 12 carbon atoms or benzyl alcohol can be used. Preferably, methanol, ethanol, isopropanol, butanol or benzyl alcohol is used as the alcohol. The alcohol can be used in an excessive amount as a solvent amount, but the amount used can be in the range of 1 to 20 equivalents, preferably in the range of 1 to 7 equivalents. As an acid catalyst, halide acids, sulfuric acid, phosphoric acid, inorganic acids such as nitric acid, or organic acids such as methanesulfonic acid and trifluoroacetic acid can be used. The acid catalyst is used in an amount of 1 to 4 equivalents, preferably 1 to 2 equivalents. And esterification reaction is performed on the conditions which maintain the temperature range of 0-150 degreeC, or maintain reflux reaction temperature.

  In the present invention, a 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the chemical formula (2) prepared through the simple esterification reaction as described above is cyclized in the presence of a reducing agent. The desired (S) -3-hydroxypyrrolidine represented by the following chemical formula (1) is produced.

  As the reducing agent used in the present invention, borane, lithium triethylborohydride (super hydride (registered trademark)), lithium aluminum hydride, sodium borohydride, and the like can be used. Preferably, sodium borohydride is used as the reducing agent. The amount of the reducing agent used is in the range of 1 to 10 equivalents, preferably in the range of 1 to 5 equivalents, based on the 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the chemical formula (2). Used in.

  Furthermore, in the present invention, an additive may be used in addition to the reducing agent to perform the cyclization reaction. At this time, an acid, a base, boron trifluoride diethyl ether, iodo, aluminum trichloride, a quaternary ammonium salt, a quaternary phosphonium salt, or the like can be used as an additive. By using the additive, the reducing agent can be activated to moderate the cyclization reaction conditions and to increase the reaction yield. These additives can be used in the range of 0.001 to 10 equivalents based on the amount of reducing agent used.

  The additive used together with the reducing agent will be described in more detail as follows.

  Acids used as additives are inorganic acids such as hydrochloric acid, bromic acid, halide acids, sulfuric acid, phosphoric acid, sulfonic acid, or acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, or acetyl halide Organic acids such as can be used. When an acid is used as an additive, it is preferably used in the range of 1 to 5 equivalents, particularly preferably in the range of 1 to 3 equivalents, based on the amount of reducing agent used.

  As the base used as an additive, an alkali metal base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, or potassium hydroxide can be used. When using a base as an additive, it is preferably used in the range of 0.001 to 1 equivalent, particularly preferably in the range of 0.01 to 0.5 equivalent, based on the amount of reducing agent used.

  Boron trifluoride diethyl ether, iodine, and aluminum trichloride used as additives are preferably used in the range of 1 to 5 equivalents, particularly preferably in the range of 1 to 3 equivalents, based on the amount of reducing agent used. To do.

  The quaternary ammonium salt or quaternary phosphonium salt used as the additive includes hydrogen or a halogen compound of quaternary ammonium or quaternary phosphonium substituted with an alkyl group having 1 to 20 carbon atoms. Specific examples of the quaternary ammonium salt include aluminum halide, halogenated monoalkyl ammonium, halogenated dialkyl ammonium, halogenated trialkyl ammonium, and halogenated tetraalkyl ammonium. The quaternary ammonium or quaternary phosphonium is preferably ammonium halide or hexadecyltributylphosphonium halide. When the quaternary salt is used as an additive, it is preferably used in the range of 0.001 to 1 equivalent based on the amount of reducing agent used.

  The solvent used in the cyclization reaction of the present invention is water; linear, branched or cyclic ether having 2 to 10 carbon atoms; diglyme; dioxane; linear, branched or cyclic alcohol having 1 to 10 carbon atoms; A single or mixed solvent selected from the group consisting of 10 to 10 aromatic hydrocarbons; and alkyl halides having 1 to 6 carbon atoms can be used. More specifically, the solvent used in the cyclization reaction of the present invention is selected from water, diethyl ether, tetrahydrofuran, diglyme, dioxane, methanol, ethanol, propanol, benzene, toluene, xylene, chloroform, dichloromethane. Can be used.

  The cyclization reaction temperature of the present invention is in the range of 0 to 150 ° C, and preferably in the range of 0 to 100 ° C.

  When the cyclization reaction is completed under the conditions as described above, acid treatment is performed so that the pH of the reaction solution becomes 4 or less, the formed salt is removed by filtration, and the filtered filtrate is hydroxylated again. A post-treatment process is performed by treating with an alkali such as sodium or potassium hydroxide and filtering, and (S) -3-hydroxypyrrolidine represented by the chemical formula (1) can be easily obtained.

  Furthermore, the (S) -3-hydroxypyrrolidine represented by the chemical formula (1) obtained in the post-treatment step as described above further improves the chemical and optical purity through a simple purification method, for example, vacuum distillation. You can also.

  As described above, the present invention will be described in more detail based on the following examples. The following examples are for the purpose of illustrating the present invention in detail, and are not intended to limit the present invention, and are easily implemented by those having ordinary knowledge in the technical field to which the present invention is not described. Of course, this is possible and within the scope of the present invention.

Example 1: Preparation of 4-amino- (S) -2-hydroxybutyric acid methyl ester hydrochloride A 10 L 4-neck round bottom flask equipped with a thermometer, reflux condenser and stirrer was charged with 4-amino- (S) -2. -Hydroxybutyric acid (8.4 mol, 1 kg) and methanol (84 mol, 2.688 kg) were added, and the temperature of the mixture was cooled to 5 ° C or lower. Thionyl chloride (4.6 mol, 550 kg) was gradually added dropwise at a temperature of 10 ° C. or lower for 5 hours. When the dropping was completed, the mixture was heated to reflux for 10 hours and stirred. After confirming that the reaction was completed by TLC, the reaction mixture was concentrated under reduced pressure to obtain 1,393 g (98%) of 4-amino- (S) -2-hydroxybutyric acid methyl ester hydrochloride.

Example 2: Preparation of 4-amino- (S) -2-hydroxybutyric acid ethyl ester sulfate In Example 1, 3,864 g of ethanol was used instead of methanol, and sulfuric acid (4.6 mol, 451 g) to give 1,998 g (97%) of 4-amino- (S) -2-hydroxybutyric acid ethyl ester sulfate.

Example 3 Production of (S) -3-hydroxypyrrolidine 5 kg of water and sodium borohydride (8.84 mol, 343 g) were placed in a 10 L 3-neck round bottom flask and cooled to 5 ° C. While adding a solution prepared by dissolving 4-amino- (S) -2-hydroxybutyric acid methyl ester hydrochloride (5.89 mol, 1 kg) in 1.5 kg of water, The reaction temperature was kept at 20 ° C. and stirred for 6 hours. After confirming that the reaction was complete, the reaction mixture was cooled and maintained below 5 ° C. 2 kg of methanol was added and stirred for 1 hour to deactivate sodium borohydride. Concentrated hydrochloric acid was added thereto to adjust the pH of the solution to 1 or less, and the mixture was stirred at 5 ° C. for 1 hour. The formed crystals are removed by filtration under reduced pressure, and 10N aqueous sodium hydroxide solution is gradually added to the obtained filtrate to adjust the pH to 11 or more. The solid produced again was removed by filtration, and concentrated under reduced pressure to obtain (S) -3-hydroxypyrrolidine which was not purified. This unpurified (S) -3-hydroxypyrrolidine was distilled under reduced pressure using a vacuum pump to obtain 436 g (85%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

¹ H NMR (D ₂ O) δ 4.3 (m, 1H), 3.6 (m, 2H), 3.0 (m, 2H), 2.1 (M, 1H), 1.8 (m, 1H).

Example 4: Production of (S) -3-hydroxypyrrolidine 5 kg of dioxane and sodium borohydride (8.84 mol, 343 g) were placed in a 10 L 3-neck round bottom flask and cooled to 15 ° C. 4-Amino- (S) -2-hydroxybutyric acid methyl ester hydrochloride (5.89 mol, 1 kg) was added slowly, taking care that the reaction temperature did not exceed 15 ° C. Trifluoroacetic acid (8.84 mol, 1,008 g) was added dropwise to the reaction solution while maintaining the internal temperature at 50 ° C. or lower. After completion of the dropwise addition, the internal temperature was raised to 100 ° C. and then stirred for 15 hours. After completion of the reaction, the solution was cooled and 1 kg of methanol was gradually added dropwise. The produced solid was filtered under reduced pressure, and then the filtrate was cooled. To the cooled filtrate, 500 g of a 10N aqueous sodium hydroxide solution was gradually added to adjust the pH to 11 or more, and the solid produced again was removed by filtration. The unpurified (S) -3-hydroxypyrrolidine was distilled under reduced pressure using a vacuum pump to obtain 466 g (87%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

Example 5: Preparation of (S) -3-hydroxypyrrolidine In Example 4 above, toluene was used instead of dioxane, methanesulfonic acid was used instead of trifluoroacetic acid, and the reaction temperature was changed to 60 ° C. Reaction and purification in a similar manner yielded 4396 g (82%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

Example 6 Production of (S) -3-Hydroxypyrrolidine Sodium 714 g (17.84 mol, 20 eq) was gradually added to 8500 mL of water at 20 ° C. or lower, and then 903 g of hexadecyltributylphosphonium bromide (1.78 mol). 0.2 eq) and 675 g (17.84 mol, 2.0 eq) of sodium borohydride were gradually added. After completion of the addition, the temperature was raised to 100 ° C., and 1,514 g (8.92 mmol) of 4-amino- (S) -2-hydroxybutyric acid methyl ester hydrochloride prepared in Example 1 was gradually added. I put it in. After completion of the dropwise addition, the mixture was reacted at a temperature of 70 ° C. for 5 hours, the reaction solution was cooled to room temperature, and then the aqueous layer was separated. After 1 kg of methanol was gradually added dropwise to the separated aqueous layer, concentrated hydrochloric acid was added to adjust the pH to 1. The produced solid was filtered under reduced pressure, and the filtered filtrate was cooled. To the cooled filtrate, 500 g of a 10N aqueous sodium hydroxide solution was gradually added to adjust the pH to 11 or more, and the solid produced again was removed by filtration. The filtrate was concentrated under reduced pressure to obtain (S) -3-hydroxypyrrolidine which was not purified. The unpurified (S) -3-hydroxypyrrolidine was distilled under reduced pressure using a vacuum pump to obtain 645 g (83%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

Example 7: Preparation of (S) -3-hydroxypyrrolidine In a 5 L 3 neck round bottom flask, 4-amino (S) -2-hydroxybutyric acid ethyl ester sulfate (1 mol, 245 g), diglyme (10.13 mol, 1. 516 kg) and sodium borohydride (4 mol, 151 g) were added at 25 ° C., and 200 g of sulfuric acid was gradually added dropwise over 5 hours. After dropping, when the temperature was raised to 80 ° C. and maintained for 12 hours, the reaction was completed. When the reaction was completed, 1 kg of methanol was added to inactivate the reaction mixture, and concentrated hydrochloric acid (4 mol, 395 g) was added to neutralize. The reaction mixture was made up to pH 11 or more with 350 mL of 10N aqueous sodium hydroxide solution, and the precipitated salt was removed by filtration. The filtrate was concentrated under reduced pressure to obtain (S) -3-hydroxypyrrolidine which was not purified. Unpurified (S) -3-hydroxypyrrolidine was distilled under reduced pressure using a vacuum pump to obtain 72 g (83%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

Example 8: Production of (S) -3-hydroxypyrrolidine To a 10 L 3-neck round bottom flask, 5 L of tetrahydrofuran and sodium borohydride (4 mol, 151 g) were added at 25 ° C, and iodine (2 mol, 492 g) was gradually added for 5 hours. It was dripped in. After dropwise addition of 4-amino-2-to this solution, the temperature was raised to 80 ° C. and maintained for 12 hours to complete the reaction. When the reaction was completed, 1 kg of methanol was added to inactivate the reaction mixture, and concentrated hydrochloric acid (4 mol, 395 g) was added to neutralize. The reaction mixture was made up to pH 11 or more with 350 mL of 10N aqueous sodium hydroxide solution, and the precipitated salt was removed by filtration. The filtrate was concentrated under reduced pressure to obtain (S) -3-hydroxypyrrolidine which was not purified. Unpurified (S) -3-hydroxypyrrolidine was distilled under reduced pressure using a vacuum pump to obtain 72 g (83%) of optically and chemically pure (S) -3-hydroxypyrrolidine.

  As described above, the present invention is inexpensive and can be produced from 4-amino- (S) -2-hydroxybutyric acid, which can be used in a large amount commercially, by a normal simple operation. It has proposed a method that can produce (S) -3-hydroxypyrrolidine industrially and economically using 2-hydroxybutyric acid ester salt as a starting material.

  Furthermore, the produced (S) -3-hydroxypyrrolidine can be produced optically or chemically pure (S) -3-hydroxypyrrolidine by simple vacuum distillation without going through a separate purification process. Can be used directly as a raw material for pharmaceuticals.

  Furthermore, the method for producing (S) -3-hydroxypyrrolidine according to the present invention is carried out under mild conditions, so that it can be industrially produced in large quantities.

Claims (13)

Optical activity (S) represented by the following chemical formula (1) by reacting an optically active 4-amino- (S) -2-hydroxybutyric acid ester salt represented by the following chemical formula (2) in the presence of a reducing agent. A process for producing optically active (S) -3-hydroxypyrrolidine, comprising the step of producing -3-hydroxypyrrolidine.

In the chemical formula (1) or (2), R is a linear or branched alkyl, aryl or aralkyl having 1 to 10 carbon atoms, and HX is a halogen acid, sulfuric acid, phosphoric acid, or methanesulfonic acid. R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl or benzyl, HX represents HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ or CH The production method according to claim 1, wherein the production method is ₃ SO ₃ H.   The method according to claim 1, wherein the reducing agent is selected from the group consisting of borane, sodium borohydride, lithium triethylborohydride, and lithium aluminum hydride.   The method according to claim 3, wherein the reducing agent is sodium borohydride.   The reducing agent is used in the range of 1 to 5 equivalents based on the optically active 4-amino- (S) -2-hydroxybutyric acid ester salt compound represented by the chemical formula (2). The manufacturing method according to 1, 3 or 4.   In addition to the reducing agent, an additive selected from the group consisting of acid, base, boron trifluoride diethyl ether, iodo, aluminum trichloride, quaternary ammonium salt and quaternary phosphonium salt is used. The manufacturing method according to claim 1, 3 or 4.   As the additive, the acid is selected from the group consisting of hydrochloric acid, bromic acid, halide acid, sulfuric acid, phosphoric acid, sulfonic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid and acetyl halide. The manufacturing method according to claim 6, wherein:   The method according to claim 6, wherein the base is selected from alkali metal bases consisting of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide and potassium hydroxide as the additive. .   The production method according to claim 6, wherein the additive is a quaternary ammonium salt or a quaternary phosphonium salt selected from ammonium halide and hexadecyltributylphosphonium halide.   As the reaction solvent, water; linear, branched or cyclic ether having 2 to 10 carbon atoms; diglyme; dioxane; linear, branched or cyclic alcohol having 1 to 10 carbon atoms; aromatic hydrocarbon having 6 to 10 carbon atoms; And a single or mixed solvent selected from the group consisting of alkyl halides having 1 to 6 carbon atoms.   The reaction solvent is characterized by using a single or mixed solvent selected from the group consisting of water, diethyl ether, tetrahydrofuran, diglyme, dioxane, methanol, ethanol, propanol, benzene, toluene, xylene, chloroform and dichloromethane. The manufacturing method according to claim 10.   The method according to claim 1 or 10, wherein the reaction temperature is in the range of 0 to 150 ° C.   The method according to claim 1, wherein the optically active (S) -3-hydroxypyrrolidine represented by the chemical formula (1) is purified by a vacuum distillation method.