KR100710558B1 - A continuous process for the production of optically pure S-4-hydroxy-2-pyrrolidone - Google Patents

Abstract

The present invention relates to a method for continuously producing optically pure (S) -4-hydroxy-2-pyrrolidone, and more particularly, to (S) -3-acetyloxysuccinimide in the presence of an acid catalyst or a base catalyst. Hydrolyzing under (S) -3-hydroxysuccinimide to obtain (S) -3-hydroxysuccinimide, and continuously passing the (S) -3-hydroxysuccinimide to the fixed bed reactor in the presence of a catalyst system supported on a metal A process for the continuous production of optically pure (S) -4-hydroxy-2-pyrrolidone, comprising the step of selectively hydrogenating to obtain (S) -4-hydroxy-2pyrrolidone. The method according to the present invention can obtain (S) -4-hydroxy-2-pyrrolidone having high purity and high optical purity in a high yield through a simple and environmentally friendly process as compared to the conventional method, as well as production per hour Since the efficiency is increased and economical, industrial mass production is easy.

(S) -4-hydroxy-2-pyrrolidone, pharmaceutical intermediates, (S) -3-hydroxysuccinimide, hydrogenation, catalysts, fixed bed reactors, optical purity, continuous production

Description

A continuous process for the production of optically pure (S) -4-hydroxy-2-pyrrolidone}

The present invention relates to a process for the continuous production of optically pure (S) -4-hydroxy-2-pyrrolidone, and more particularly, (S) -3-hydroxysuccinic acid using L-malic acid as a starting material. After obtaining the imide, the present invention relates to a continuous process for producing pure (S) -4-hydroxy-2-pyrrolidone while maintaining the optical activity by hydrogenation in a fixed bed reactor in the presence of a catalyst.

Optically pure (S) -4-hydroxy-2-pyrrolidone has been widely used as an intermediate substance in medicine, agricultural chemicals, etc., and the prior art for producing the same has been reported in various patents and literature, but these methods Has limitations in industrial application.

For example, Japanese Patent Laid-Open No. 1982-183756, Tetrahedron Lett., 41, 5603 (1985), and Japanese Patent Laid-Open No. 1986-176564 disclose methods for preparing from 4-chloro-3-hydroxybutyrate and ammonia. Japanese Patent Laid-Open No. 1989-45360 discloses a process for preparation from 4-chloro-3-hydroxybutyrate and benzylamine, but from 4-chloro-3-hydroxybutyrate and ammonia according to the above document. The production method of yields various by-products, and it is difficult to obtain the product in high yield.

Synthetic Comm., 21, 693 (1991), discloses preparations from cyclobutanone derivatives and optional active α-methylbenzylamine, see J. Chem. Research (s), 376, 1990 disclose a process for the preparation from 3,4-epoxybutyramid and optionally active α-methylbenzylamine, while the process from benzylamine or α-methylbenzylamine is known as pyrroli. After formation of the pig skeleton, a debenzylation or demethylbenzylation process is required, in which the alkali metal is difficult to use in the ammonia of the low temperature liquid.

Meanwhile, Tetrahedron Lett., 21, 2443 (1980) and J. Org. The method of heating and dehydration of 4-amino-3-hydroxybutyric acid (hereinafter referred to as GABOB) disclosed in Chem., 19, 1589 (1954) has a low yield, in which case the use of any active compound causes Disadvantages and methods of preparation from any active GABOB and hexamethyldisilazane described in Synthesis, 1978, 614 are high in product yield but the hexamethyldisilazane is expensive and the process is not only in the formation of pyrrolidone backbones. Thereafter, a desilylation process is required and economically disadvantageous, and a process from any active 4-hydroxyproline disclosed in Japanese Patent Laid-Open No. 1988-250352 and J. Org. The process from the 4-bromo crotonic acid ester disclosed in Chem., 44, 2798 (1979) consists of a number of steps and is not practical.                         

In addition, Japanese Patent Laid-Open Nos. 11-286479 and European Patent No. 947505 use methyl azidooxobutanoi by using methyl azidobutanoate (methyl-4-chloro-3-oxobutanoate) using sodium azide in a nitrogen atmosphere. (Methyl-4-azido-3-oxobutanoate) was prepared, followed by methylaminooxobutanoate with a palladium (Pd / C) catalyst in a methanol solvent and a hydrogen atmosphere at 3 atm. ) And then producing a (S) -4-hydroxy-2-pyrrolidone through hydrogenation and cyclization reaction using a ruthenium binep catalyst or the like, but the method according to the patent Since the production process is complicated, the production cost is high by using a low yield and expensive palladium catalyst and ruthenium bineb catalyst, and a large amount of waste is generated in a batch reaction, which is not environmentally friendly.

In US Pat. No. 6,153,766 and Japanese Patent Laid-Open No. 10-158239, ethyl azidohydroxybutylate ((S) -4-azido-3-hydroxybutyrate) was prepared, and then cyclization reaction was performed using sodium methoxide. It discloses a method for preparing (S) -4-hydroxy-2-pyrrolidone through the process, which is also a batch reaction is expensive manufacturing cost, generates a large amount of waste and industrially harmful Difficult to apply

On the other hand, European Patent No. 829472 and Japanese Patent Laid-Open No. 83-11025 use methylchlorohydroxybutylate ((S) -methyl-4-chloro-3-hydroxybutyrate) as DMF or methyl-isobutyl-ketone and DMAP. The mixture was reacted with sodium azide to produce ethyl azidohydroxybutylate ((S) -methyl-4-azido-3-hydroxybutyrate), and then hydrogenated with a palladium catalyst in methanol solvent to prepare ethylaminohydroxybutylate. Afterwards, a method of preparing (S) -4-hydroxy-2-pyrrolidone through a cyclization reaction is disclosed, but the manufacturing process according to the patent is complicated and a large amount of waste is generated. There is a limit.

As described above, the conventional manufacturing processes not only economically separate using expensive reaction reagents, but also adopt a batch process that is likely to generate side reactions, resulting in low productivity, large amount of waste, and complicated processes. Since the yield is low, mass production is impossible, so there is a limit to industrial application.

In order to solve the problems described above, the inventors have conducted extensive research to obtain (S) -3-hydroxysuccinimide using L-malic acid as a starting material, which is then used as a noble metal in the inorganic oxide carrier. A method of continuously producing pure (S) -4-hydroxy-2-pyrrolidone while maintaining optical activity by hydrogenation in a fixed bed continuous reactor in the presence of a catalyst supported by this high dispersion, and the present invention is based on this. Was completed.

Accordingly, an object of the present invention is to provide a method for obtaining pure (S) -4-hydroxy-2-pyrrolidone with high productivity while maintaining high optical purity through an economical and environmentally friendly process.

The method of the present invention for achieving the above object is (S) -3 represented by the following formula (S) -3 by hydrolyzing (S) -3-acetyloxysuccinimide represented by the following formula (1) in the presence of an acid catalyst or a base catalyst Obtaining hydroxysuccinimide,                         

Wherein R is alkyl or acyl having 1 to 10 carbon atoms;

(S) -4-hydroxy-2 represented by the following Chemical Formula 3 by selectively hydrogenating the (S) -3-hydroxysuccinimide continuously through a fixed bed reactor in the presence of a catalyst system on which a metal is supported on a carrier. Obtaining pyrrolidone.

Hereinafter, the present invention will be described in more detail.

As described above, the present invention relates to a method for continuously producing optically pure (S) -4-hydroxy-2-pyrrolidone, and more particularly, using (L) -malic acid as a starting material. (S) -3-hydroxysuccinimide was obtained from 3-acetyloxysuccinimide, which was then hydrogenated in a fixed bed reactor in the presence of a catalyst to keep pure (S) -4-hydroxy-2- while maintaining optical activity. It relates to a continuous production method of pyrrolidone.

According to the present invention, L-malic acid represented by the following formula (4) is used as a starting material to obtain (S) -3-acetyloxysuccinimide represented by the following formula (1) according to a known method (J. Am. Chem. Soc 1983.105.3653).

Formula 1

Wherein R is alkyl or acyl having 1 to 10 carbon atoms.

Then, the (S) -3-acetyloxysuccinimide is hydrolyzed in the solvent in the presence of a catalyst to obtain (S) -3-hydroxysuccinimide represented by the following formula (2).

Formula 2

Catalysts usable in the reaction include hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and the amount of the catalyst is 0.01 to 1 mol, preferably 0.02 to 0.2 mol per mol of (S) -3-acetyloxysuccinimide. good. The reaction may be carried out in the presence of a base catalyst such as sodium hydroxide, potassium hydroxide and lithium hydroxide instead of the above-described acid catalyst.

Solvents usable in the reaction are selected from methanol, ethanol, isopropanol, t-butanol, ethylene glycol monoethyl ether, water and mixtures thereof.

The reaction is carried out at a reaction temperature between room temperature and the reflux temperature of the solvent. If the reaction temperature is out of the above range, the reaction rate is lowered and the production yield decreases, which is not practical.

Subsequently, (S) -3-hydroxysuccinimide obtained from the reaction was subjected to selective hydrogenation by continuously passing through a fixed bed reactor in the presence of a catalyst system in which a metal was supported on a carrier. Obtain 2-pyrrolidone.

Formula 3

On the other hand, the production method according to the present invention is not limited to the preparation of (S) -4-hydroxy-2-pyrrolidone, it can also be applied to the preparation of (R) -4-hydroxy-2-pyrrolidone. have.

The catalyst used in the hydrogenation reaction of the present invention is used by supporting a metal or metal on a carrier, and the metal is selected from the group consisting of ruthenium, rhodium, nickel, palladium, platinum, iridium, osmium and mixtures thereof. Ruthenium is most preferred. Chlorides, nitrides, acetyl acetonates and the like can be used as their precursors in the preparation of ruthenium catalysts. As the carrier of the present invention, an inorganic oxide such as silica, alumina, silica-alumina, zirconia, titania, zeolite, or molecular sieve can be used, and among these, silica is most preferred. The silica used as the carrier of the present invention has a surface area of 100 m 2 / g or more, preferably 200 to 600 m 2 / g, as measured by the BET method by nitrogen adsorption, to prepare a high dispersion degree of the metal supported on the carrier. It is preferable.

The degree of dispersion of the precious metal supported on the carrier is measured by chemical adsorption of CO or H ₂ , and the molarity of the adsorbed CO is maintained at 2 to 50% based on the product of 100 divided by the number of atoms of the metal. good.

The carrier particles may be circular, cylindrical, granular, or in the form of any type, but may have a circular or cylindrical shape in order to have suitable mechanical properties.

The content of the metal of the present invention is preferably maintained at 0.1 to 15% by weight based on the entire catalyst system, more preferably 0.5 to 10% by weight. If the content of the metal is less than 0.1% by weight, the hydrogenation activity and selectivity decrease. If the content of the metal exceeds 15% by weight, the economical efficiency of the process is lowered due to the high price of the metal. In addition, as a method of supporting the metal on the carrier, any of methods such as incipient wetness impregnation, excess water impregnation, spraying, or physical mixing may be used.

The catalyst on which the metal is supported should be calcined for 2 hours or more in an air atmosphere or an inert gas atmosphere. At this time, the temperature should be maintained at 300 to 700 ° C, more preferably 300 to 600 ° C. At this time, when the firing temperature is less than 300 ℃, the firing is incomplete, the decomposition of the precursor of the metal used in the metal support is lowered, and if the firing temperature exceeds 600 ℃, the dispersibility of the metal is lowered, the catalyst has a proper performance I can't show it.

Then, the calcined catalyst should be charged into a fixed bed reactor and the catalyst is reduced with hydrogen before the reactants are introduced, wherein the reducing conditions are at least 2 hours at 50-500 ° C. depending on the type of metal supported. It is preferable to maintain the above.

Meanwhile, the hydrogenation reaction has a reaction pressure of 1 to 370 bar, a reaction temperature of 50 to 300 ° C. and an hourly weight space velocity of 0.1 to 10 h ⁻¹ , preferably of a reaction pressure of 50 to 350 bar, a reaction temperature of 60 to 200 ° C. and a weight of space velocity of 0.2 It is preferable to carry out under the conditions of -10h- ¹ , More preferably, reaction pressure of 80-300 bar, reaction temperature of 60-150 degreeC, and the hourly weight space velocity 0.2-6h- ¹ . In this case, when the reaction conditions are outside the above-mentioned range, the optical purity and yield of the product (S) -4-hydroxy-2-pyrrolidone may be lowered or the deactivation rate of the catalyst may be increased. The advantages of the continuous manufacturing process are lost.

According to the present invention, in order to completely convert the (S) -3-hydroxysuccinimide to (S) -4-hydroxy-2-pyrrolidone through hydrogenation, the (S) -3-hydroxy The molar ratio of hydrogen added during the reaction to succinimide may be 1.0 or more, and there is no limitation on the numerical value above. However, the molar ratio of hydrogen to (S) -3-hydroxysuccinimide is preferably maintained at 2.0 to 10 in view of the economics of the process. At this time, hydrogen not used in the reaction and passed through the reactor is recompressed and circulated to the reactor. In addition, depending on the reaction conditions, the reaction product may be separated into a desired product or recycled to increase the conversion rate of the unconverted reactant and then separated.

In addition, a specific solvent should be used in the hydrogenation reaction, and the solvent should dissolve (S) -3-hydroxysuccinimide well and supply smoothly to the reactor, and easily remove the heat of reaction generated during the hydrogenation reaction. In addition, it should not react with the reactants (S) -3-hydroxysuccinimide and hydrogen. Accordingly, solvents usable in the hydrogenation of the present invention include water, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, dioxane, gamma butyrolactone and tetrahydrofuran. When using the solvent, the concentration of (S) -3-hydroxysuccinimide in the total reaction solution is not limited but is preferably 1 to 50% by weight.

In order to improve the selectivity of the continuous hydrogenation reactant, it is preferable to use an additive such as an organic acid or an inorganic acid in the aforementioned solvent system. Additives usable in the present invention include acetic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, and mixtures thereof, preferably using acetic acid or nitric acid among these additives. At this time, the amount of the additive used is preferably maintained at 0.1 to 50% by weight, preferably 0.1 to 20% by weight relative to the applied solvent. It may also be diluted with water before use to the desired acidity. When the amount of the additive used is out of the range as described above, the selectivity of hydrogenation of (S) -4-hydroxy-2-pyrrolidone is lowered, thereby decreasing the production yield.

As described above, the present invention hydrogenates (S) -3-hydroxysuccinimide in the presence of a catalyst system in which a metal is supported on a carrier to obtain optically pure (S) -4-hydroxy-2-pyrrolidone. It can be manufactured in high yield, and it is economical because the yield is higher and the catalyst can be regenerated compared to the conventional method by using a continuous process using a fixed bed reactor. Can be simplified.

The fixed bed reaction system according to the present invention is not limited in the form of the reactor or the direction of the input and flow of the reactants, but the hydrocarbon and hydrogen reactants flow together from the top of the reactor to the bottom so that contact between the reactants occurs smoothly. It is best to use a trickle-bed reactor equipped with an evenly distributed device.

The reaction product flowing out of the reactor is sent to a device for recovering the solvent, where at least some of the solvent is separated from the rest of the reaction product. The recovery device may be any type of device such as a distillation column or a flash vaporizer. The product, or concentrate, which flows out from the lower end of the solvent recovery apparatus is transferred to a vacuum distillation apparatus.                     

According to the present invention, in the method for preparing (S) -4-hydroxy-2-pyrrolidone, it is possible to improve reaction yield and productivity by using an improved catalyst, and in particular, by using inorganic acid as an additive, Pure (S) -4-hydroxy-2-pyrrolidone can be prepared via a continuous hydrogenation process.

The (S) -4-hydroxy-2-pyrrolidone prepared as described above can be prepared in high yield and high purity through conventional purification processes such as recrystallization.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto.

Example 1

Preparation of catalysts

After putting 250 mL of secondary distilled water into a 500 cc flask, 18 g of ruthenium chloride (RuCl ₃ ) was added thereto to prepare an aqueous ruthenium chloride solution. After putting 100 g (1/8) of spherical silica in a metal carrying container mounted on a motor capable of adjusting the rotation speed, the prepared ruthenium solution was evenly dispersed in silica while the container was rotated. After the addition of the ruthenium solution was completed, the motor was further rotated at the same speed for about 60 minutes, and then, the ruthenium-supported catalyst was transferred to a muffle furnace and calcined at 500 ° C. for 3 hours in an air atmosphere. Ruthenium content in the catalyst after calcining was 3.0% by weight as measured by X-ray fluorescence.

Example 2                     

Preparation of (S) -3-acetyloxysuccinimide

After addition of 30 ml of acetyl chloride to L-malic acid (8.00 g, 0.060 mmol), the mixture was heated to reflux with stirring at 50-60 ° C. for 1.5 hours. After cooling, acetic acid and acetic anhydride produced after the reaction with acetyl chloride were distilled under reduced pressure, and 50 ml of dried THF was added to the residue. The mixture was reacted by injecting gaseous ammonia for 0.5 hour. The reaction was distilled under reduced pressure to remove THF, and 30 ml of acetyl chloride was added to the resulting solid mixture, followed by heating to reflux with stirring at 50 to 60 ° C. for 2 hours. After cooling, the acetic acid and acetic anhydride produced after the reaction with acetyl chloride were distilled under reduced pressure and separated by silica gel chromatography to give (S) -3-acetyloxysuccinimide (5.05 g, 0.032 mol, yield: 53.3%). Obtained as a white crystalline solid.

^{_{Non-rotation: [α] D 22 - 57.6}} (c = 1.00, H 2 O).

Example 3

Preparation of (S) -3-hydroxysuccinimide

To a mixture of (S) -3-acetyloxysuccinimide (15.70, 0.10 mol) and methanol (120 ml) was added 1 g of 35% hydrochloric acid and 4 ml of water, followed by stirring at 50 to 60 ° C. for 5 hours. After cooling, the reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated by rotary distillation, and separated by silica gel chromatography to give (S) -3-hydroxysuccinimide (9.78 g, 0.085 mol, yield: 85.0%) as a white. Obtained as a crystalline solid of.                     

Example 4

Preparation of (S) -3-hydroxysuccinimide

To a mixture of (S) -3-acetyloxysuccinimide (8.50 g, 0.054 mole) and methanol (90 mL) was added concentrated sulfuric acid (0.3 g, 0.003 mM) and 4 mL of water, followed by 50 to 60 ° C. Stir for 5 hours. After cooling, the reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated by rotary distillation, and separated by silica gel chromatography, to give (S) -3-hydroxysuccinimide (5.71 g, 0.050 mol, yield: 92.6%). Obtained as a crystalline solid

Example 5

Preparation of (S) -3-hydroxysuccinimide

To a mixture of (S) -3-acetyloxysuccinimide (15.7 g, 0.10 mol) and methanol (120 mL) was added sodium hydroxide (4 g, 0.10 mM) and 20 g of water, followed by 6 hours at 30 to 40 ° C. Was stirred. After cooling, the reaction solution was neutralized with an aqueous solution of ammonium chloride, concentrated by rotary distillation, and separated by silica gel chromatography to give (S) -3-hydroxysuccinimide (10.2 g, 0.089 mol, yield: 88.7%) as white crystals. Obtained as a sexual solid

Examples 6-8

-Continuous production reaction of (S) -4-hydroxy-2-pyrrolidone

10 g of the catalyst prepared by the method of Example 1 was charged to a continuous high pressure reactor made of 316 stainless steel. The catalyst in the reactor was raised to 350 ° C. at a heating rate of 2 ° C. per minute in a hydrogen atmosphere, followed by a reduction process for 6 hours, and then the reactor was cooled and blown with nitrogen. 100 sccm of hydrogen was flowed while raising the temperature inside the reactor at a temperature increase rate of 1 ° C. per minute from room temperature to the reaction temperature. The amount of hydrogen injected was increased to twice the amount required for the reaction, and the (S) -3-hydroxysuccinimide prepared in Example 2 was dissolved in a water solvent mixed with acetic acid as an additive (S) -3-hydrate. After introducing the reactant prepared so that the content of oxysuccinimide 1 to 10% by weight with respect to the solution, the reaction temperature was changed to 60 to 100 ° C. under a hydrogen pressure of 230 bar and an hourly space velocity of 1.0 h ⁻¹ . Hydrogenated. The reaction product thus obtained was collected and analyzed by a gas ion chromatography (FID) detector of a gas chromatograph (30m × 0.25mm × 0.25m HP-5 column), and the optical purity (ee) analysis of the reaction product was performed to collect the reaction product. Was analyzed by HPLC (CHIRALPAK AD (4.6 mm diameter x 250 mm length)) column, and the results are shown in Table 1 below.

Example Reaction temperature (℃) Reaction pressure (bar) % Conversion Selectivity (%) ¹⁾ ee (%) 6 80 230 99 71 〉 99 7 100 230 99 68 〉 99 8 60 230 72 56 〉 99

1) Selectivity of (S) -4-hydroxy-2-pyrrolidone

Examples 9-13

In order to increase the reaction selectivity while securing the stability of the starting material in the hydrogenation reaction of (S) -3-hydroxysuccinimide prepared in Example 2, the components shown in Table 2 as an additive 5% mixed with the solvent Except as used in the same manner as in Example 6, by measuring the conversion and selectivity of the reaction product obtained in the same manner as in Example 6, the results are shown in Table 2 below.

Example ¹ menstruum additive % Conversion Selectivity (%) ²⁾ 9 H ₂ O Acetic acid 99 71 10 H ₂ O nitric acid 98 45 11 H ₂ O none 99 52 12 Methanol none 97 26 13 Methanol Acetic acid 98 45

1) Catalyst: Use the one prepared in Example 1

2) Selectivity of (S) -4-hydroxy-2-pyrrolidone

Example 14

The hydrogenated reactant obtained in Example 6 was distilled and concentrated, and a small amount of pure (S) -4-hydroxy-2-pyrrolidone crystals was added thereto to concentrate the (S) -4-hydroxy-2-pi in the concentrate. Lolidon crystallized and filtered after adding a THF: ethanol = 10: 1 solution. 16 g of (S) -4-hydroxy-2-pyrrolidone was recrystallized in ethanol solution to obtain 12.5 g (78.1% yield) of pure (S) -4-hydroxy-2-pyrrolidone as white crystals.

^{_{Non-rotation: [α] D 23.5 - 58.3}} (c = 1.0, H 2 O) (. Ref [α] D 20 - 57.8 (c = 1.0, H 2 O) Synthesis, 1999, 745)

As described above, the method according to the present invention obtains (S) -4-hydroxy-2-pyrrolidone having high purity and high optical purity in high yield through a simple and environmentally friendly process compared to the conventional method. In addition, because the production efficiency per hour is increased and economical, industrial mass production is possible, thereby increasing industrial added value.

Claims (13)

Hydrolyzing (S) -3-acetyloxysuccinimide represented by Formula 1 in the presence of an acid catalyst or a base catalyst to obtain (S) -3-hydroxysuccinimide represented by Formula 2 below, Formula 1

Formula 2

Wherein R is alkyl having 1 to 10 carbon atoms; (S) -4-hydroxy-2 represented by the following Chemical Formula 3 by selectively hydrogenating the (S) -3-hydroxysuccinimide continuously through a fixed bed reactor in the presence of a catalyst system on which a metal is supported on a carrier. A process for continuously producing optically pure (S) -4-hydroxy-2-pyrrolidone, comprising the step of obtaining pyrrolidone. Formula 3

The optically pure (S) -4-hydroxy according to claim 1, wherein the fixed bed reactor has a reaction temperature of 50 to 300 ° C., a reaction pressure of ¹ to 370 bar, and an hourly weight space velocity of 0.1 to 10 h ⁻¹ . -2-Pyrrolidone continuous production method. The optically pure (S) -4-hydroxy-2-pi, wherein the metal is selected from the group consisting of ruthenium, rhodium, nickel, palladium, platinum, iridium, osmium and mixtures thereof. Continuous production method of Ralidone. The method of claim 1, wherein the carrier is alumina, silica, silica-alumina, zirconia, titania or zeolite. The method of claim 1, wherein the content of the metal is 0.1 to 15% by weight relative to the catalyst system. The method for continuously producing optically pure (S) -4-hydroxy-2-pyrrolidone according to claim 1, wherein the dispersity of metal in the catalyst system is 2 to 50%. The optically pure (S) -4-hydroxy-2-pyrroli according to claim 1, wherein the molar ratio of hydrogen introduced during the reaction with respect to the (S) -3-hydroxysuccinimide is 1 to 10. How to make money continuously. delete The optically pure (S) -4-hydroxy- according to claim 1, wherein the content of the (S) -3-hydroxysuccinimide in the hydrogenation reaction is 1 to 50% by weight based on the solvent. Continuous production method of 2-pyrrolidone. The optically pure (S) according to claim 1, wherein in the hydrogenation reaction, an additive selected from the group consisting of acetic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, and mixtures thereof is used in an amount of 0.1 to 50 wt% based on the solvent. ) 4-hydroxy-2-pyrrolidone continuous production method. The method of claim 1, wherein the acid catalyst of the hydrolysis reaction is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. . [Claim 2] The continuous optically pure (S) -4-hydroxy-2-pyrrolidone according to claim 1, wherein the base catalyst of the hydrolysis reaction is selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide. Manufacturing method. The optically pure (S) -4-hydroxy-2 according to claim 1, wherein the solvent of the hydrolysis reaction is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, water and mixtures thereof. -Continuous production of pyrrolidone.