KR20060010000A - Process for preparation of (s) or (r)-oxiracetam - Google Patents

Abstract

The present invention readily facilitates the optical (S) -isomer or (R) -isomer of 1-carbamoylmethyl-4-hydroxy-2-pyrrolidinone (oxyracetam), which exhibits brain function improving and dementia treatment effects. A process for the preparation, wherein according to the invention 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone is acetylated in the presence of an organic solvent and produced 1 4- (S or R) -alkoxy-2 produced after debenzylation of-(S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone in the presence of an organic solvent Reacting pyrrolidinone with acetate substituted with halogen in the presence of an organic solvent and a base, and then reacting the resulting 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone with ammonia 1-carbamoyl-4- (S or R) -hydroxy-2-pyrrolidinone production method comprising a (S)- Shirakawa setam or (R) -, so that the oxy-La ride can be produced in a high yield and a high purity can be useful in improving brain function and development of dementia.

Description

TECHNICAL FIELD OF THE INVENTION A process for producing oxirastam with optical activity {PROCESS FOR PREPARATION OF (S) OR (R) -OXIRACETAM}

The present invention relates to a method for easily preparing (S) -isomers or (R) -isomers having the optical activity of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (oxyracetam). .

Oxyracetam exhibits excellent brain function improvement and dementia treatment effects, and is currently widely used as a raw material for dementia treatment. Existing techniques for preparing (S) or (R) -oxyracetams with the optical activity of such oxyracetams include M. Cruz Carballero, Tetrahedron: Asymmetry , 3 (11), 1431-1440, 1992; International Application Publication No. WO 93-06826; M. Larcheveque et al., Tetraedron , 46, 4277, 1990; And Korean Patent Publication No. 2000-9465.

Specifically, in M. Cruz Carballero, Tetrahedron: Asymmetry , 3 (11), 1431-1440, 1992, as shown in Scheme 1, (S) -maleic acid was used as a starting material (S) -oxyracetam. Although it provides a method for preparing the present invention, it is difficult to apply industrially due to the use of expensive silane compounds and fluorine compounds and difficult reaction conditions.

Furthermore, in WO 93-06826 and M. Larcheveque et al., Tetrahedron , 46, 4277, 1990, (S) -2-hydroxy-gamma-butyrolactone is used as starting material, as shown in Scheme 2 below. It provides a method for producing (S)-oxyracetam, but also has the disadvantage that industrial application is also difficult due to the use of expensive compounds such as silver oxide and lactone, and the limitation of equipment due to the use of iodine.

In addition, Korean Patent Publication No. 2000-9465 discloses a method of preparing (S) -oxyracetam using (S) -2-hydroxy-gamma-butyrolactone as a starting material as in Scheme 3 below. However, the use of expensive lactones, hydrobromic acid and acetic acid mixed acid is difficult to apply industrially and the final product is not easy to purify.

An object of the present invention is to provide an optical activity of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (oxyracetam), which shows an improvement in brain function and treatment of dementia by using an industrially easy process. It is to provide a method for producing the (S) -isomer or the (R) -isomer having high yield and high purity.

According to the above object, in the present invention, as shown in Scheme 4,

1) acetylating 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone (Compound 1) in the presence of an organic solvent;

2) debenzylating 1- (S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone (Compound 2) produced in step 1 in the presence of an organic solvent;

3) reacting 4- (S or R) -alkoxy-2-pyrrolidinone (compound 3) produced in step 2 with acetate substituted with halogen in the presence of an organic solvent and a base; And

4) 1-carbamoyl-4- (comprising reacting 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone (Compound 4) produced in step 3 with ammonia) Provided are methods for the preparation of S or R) -hydroxy-2-pyrrolidinone ((S) -oxyracetam or (R) -oxyracetam).

Wherein R ² is methyl or ethyl.

Hereinafter, the present invention will be described in detail.

In the process of the present invention, 1- (S or R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone (Compound 1) used as starting material in step 1 is represented by the following scheme 5. As such, it may be obtained according to the method disclosed in Korean Patent Publication No. 2004-58612.

Wherein R is a C _1-4 lower alkyl group optionally substituted with methyl, ethyl, n-propyl, i-propyl or t-butyl; R ¹ is methyl or ethyl; X is a chlorine atom or a hydroxyl group.

Specifically, the malonic acid monoalkyl (compound 5, alkyl malonate) in the organic solvent such as DMF or acetonitrile in the presence of 1,1-carbonyldiimidazole (CDI) N-((S or R) -1- Phenylethyl) glycine alkylester (Compound 6) to produce alkyl N- (2-ethoxycarbonylacetyl) -N- (2-alkoxycarbonylmethyl) aminoacetate (Compound 7), which is then dissolved in a solvent Reaction with potassium t-butoxide to cyclize at room temperature (compound 8), followed by decarboxylation (compound 9) and reduction reaction to N-((S or R) -1-phenylethyl) -4- (S or R) -hydroxy-2-oxopyrrolidine (Compound 1) can be prepared.

In the acetylation reaction of step 1 of the process according to the invention, 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone (Compound 1) is converted into an organic solvent and a base. In the presence of acetic anhydride or acetylchloride. In this case, usable organic solvents include methylene chloride and chloroform, and may be used in a range of 15 to 30 weight times, preferably 15 to 20 weight times, based on Compound 1. Examples of bases that can be used include N, N-dimethylaminopyridine (DMAP), pyridine and triethylamine, and the like, and can be used in the range of 1 to 2 equivalents, preferably 1 to 1.2 equivalents based on compound 1. . In addition, acetic anhydride may be used in the range of 1 to 10 equivalents, preferably 1 to 3 equivalents of compound 1, the reaction is -10 to 30 ℃, preferably 0 to 30 ℃ 2 to 24 hours, preferably It can be performed for 2 to 10 hours.

In the debenzylation reaction of step 2, 1- (S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone (Compound 2) produced by the acetylation reaction is present in an organic solvent. React with a positive asset under At this time, usable organic solvents include toluene, methylene chloride and ethanol, and can be used in the range of 10 to 30 times by weight, preferably 12 to 20 times by weight, based on Compound 2. In addition, the amphoteric assets usable in the reaction include methanesulfonic acid, trifluoroacetic acid, and the like, and may be used in the range of 3 to 15 equivalents, preferably 3 to 8 equivalents of compound 2. The reaction can be carried out at 20 to 150 ℃, preferably 30 to 140 ℃ for 2 to 30 hours, preferably 2 to 10 hours.

In addition, in step 3, 4- (S or R) -acetoxy-2-pyrrolidinone (compound 3) produced in step 2 is reacted with halogen-substituted acetate in the presence of an organic solvent and a salt. In this case, a lower alcohol such as methanol or tetrahydrofuran may be used as the organic solvent, and may be used in a range of 10 to 40 weight times, preferably 12 to 30 weight times, based on Compound 3. In addition, salts that can be used include potassium carbonate, sodium hydride, and the like, and can be used in the range of 1 to 10 equivalents, preferably 1.2 to 10 equivalents, based on compound 3. Halogen-substituted acetates include bromoacetate or chloroacetate, and can be used in the amount of 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents of compound 3. The reaction can be carried out at -30 to 80 ° C, preferably 0 to 75 ° C for 2 to 20 hours, preferably 2 to 12 hours.

In step 4, 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone (Compound 4) produced in step 3 is reacted with ammonia in an organic solvent to prepare 1-carbamoyl- according to the present invention. Prepare 4- (S) -hydroxy-2-pyrrolidinone. At this time, usable organic solvents include lower alcohols such as methanol, and may be used in the range of 10 to 40 weight times, preferably 12 to 35 weight times, based on compound 4. In addition, ammonia can be used in 2 to 15 equivalents, preferably 5 to 12 equivalents of compound 4, and the reaction is carried out at -30 to 30 ° C, preferably at -20 to 25 ° C, for 2 to 20 hours, preferably It may be performed for 3 to 16 hours.

The method for preparing 1-carbamoyl-4- (S or R) -hydroxy-2-pyrrolidinone of the present invention comprising the above steps is a process that is easy to apply industrially using inexpensive raw materials (S). -Oxyracetam or (R) -oxyracetam can be prepared in high yield and high purity, so it can be usefully used for improving brain function and developing dementia treatment.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Preparation Example 1 Preparation of 1- (R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone

<Step 1> Preparation of N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl ester

After diluting 42.2 g of ethyl malonic acid in 500 ml of acetonitrile at room temperature, 46.73 g of 1,1-carbonyldiimidazole was slowly added under water bath and reacted at room temperature for 20 minutes. After diluting 54.3 g of N-((R) -1-phenylethyl) glycine ethyl ester in 20 ml of acetonitrile, the reaction mixture was slowly added to the mixture and left for about 2 hours to remove the starting materials. .

500 ml of ethyl acetate was added to the residue, followed by washing twice with 50 ml of a cold 5% aqueous HCl solution. The organic solvent layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The resultant was separated by column chromatography (eluent: ethyl acetate / hexane = 1/5), and 76.19 g of the title compound N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl An ester was obtained.

¹ H NMR (200 MHz, CDCl ₃ ): δ 1.14-1.25 (3H, m), 1.45, 1.64 (3H, d, J = 7 Hz), 1.47 (9H, d, J = 1 Hz), 3.37-4.16 (6H, m), 5.15 (0.5H, q, J = 7Hz), 6.08 (0.5H, q, J = 7Hz), 7.26 ~ 7.36 (5H, m)

<Step 2-1> Preparation of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone

20 g of N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl ester prepared in step 1 was diluted in 400 ml of toluene, and the temperature was maintained at 0 ° C or below. 7.7 g of potassium t-butoxide was slowly added and then slowly raised to room temperature and left for 10 hours.

After the reaction was completed, the mixture was cooled with an ice cooling bath, 100 ml of cold water was added thereto, stirred vigorously, and left standing to separate the water layer. The toluene layer was extracted three times with 30 ml of water. In an ice cooling bath below 5 ° C, concentrated hydrochloric acid was slowly added to the water layer until pH 1 and stirred for 30 minutes at room temperature, and the resulting solid was filtered and dried without refining. 100/1, v / v) was mixed with 200 ml and heated to reflux for 1 hour.

When no more bubbles were generated, the reaction mixture was cooled, the solvent was concentrated under reduced pressure, dried in a vacuum pump, and dissolved in 200 ml of ethanol, and 3.0 g of sodium borohydride (NaBH ₄ ) was slowly added at an internal temperature of 0 ° C. or lower. . When the reaction was completed after 2 hours, 18% hydrochloric acid was added so that the pH of the reaction mixture was 6 to 7 under ice-cooling bath conditions and stirred for 30 minutes. The resulting solid was filtered and the filtrate was concentrated under reduced pressure, and 200 ml of methylene chloride was added to the residue. Anhydrous magnesium sulfate was added to the reaction mixture, followed by vigorous stirring and drying sufficiently, and the filtrate was filtered under reduced pressure. To the residue was added 200 ml of methanol and 5.0 g of activated charcoal, and the mixture was stirred under reflux for 2 hours, and the filtrate was concentrated under reduced pressure to give 1- (R) -phenylethyl-4- (S) -hydroxy-2. 7.1 g of a racemic mixture of -pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone were obtained.

Of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone obtained The racemic mixture was recrystallized twice with 10 ml of acetonitrile to prepare 2.9 g of the title compound Compound 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone.

¹ H NMR (300MHz, CDCl ₃ ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)

<Step 2-2> Preparation of 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone

1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy- produced in step 2-1 The racemic mixture of 2-pyrrolidinone was recrystallized from acetonitrile to filter Compound 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone, and the filtrate was obtained by evaporation under reduced pressure. The residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone 3.2 g was obtained. It was recrystallized from ethyl acetate.

¹ H NMR (300MHz, CDCl ₃ ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)

Preparation Example 2 Preparation of 1- (S) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone

<Step 1> Preparation of N-ethoxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester

Except for using N-((S) -1-phenylethyl) glycine ethyl ester in place of N-((R) -1-phenylethyl) glycine ethyl ester, The oxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester can be prepared.

¹ H NMR (200 MHz, CDCl ₃ ): δ 1.15-1.29 (3H, m), 1.45, 1.64 (3H, d, J = 7 Hz), 1.48 (9H, d, J = 1 Hz), 3.37-4.17 (6H, m), 5.16 (0.5H, q, J = 7Hz), 6.09 (0.5H, q, J = 7Hz), 7.25-7.36 (5H, m)

<Step 2-1> Preparation of 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone

1- (S according to the method of Step 2-1 of Preparation Example 1 using N-ethoxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester prepared in Step 1 A racemic mixture of) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone was obtained.

Of 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone obtained The racemic mixture was recrystallized with acetonitrile to prepare the title compound Compound 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone.

¹ H NMR (200 MHz, CDCl ₃ ): 1.50 (3H, d, J = 7 Hz), 2.39 (1H, dd, J ₁ = 2 Hz, J ₂ = 7 Hz), 2.51 (1H, d, J = 4 Hz), 2.70 (1H, dd, J ₁ = 7Hz, J ₂ = 17Hz), 2.95 (1H, dd, J ₁ = 2Hz, J ₂ = 11Hz), 3.53 (1H, dd, J ₁ = 6Hz, J ₂ = 11Hz), 4.40 (1H, bs), 5.44 (1H, q, J = 7 Hz), 7.21-7.29 (5H, m)

<Step 2-2> Preparation of 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone

1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy- produced in step 2-1 The racemic mixture of 2-pyrrolidinone was recrystallized from acetonitrile, and the compound 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone was filtered, and the filtrate was obtained by evaporation under reduced pressure. The residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone. Got it.

¹ H NMR (300MHz, CDCl ₃ ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)

Example 1: Preparation of 1-carbamoyl-4- (S) -hydroxy-2-pyrrolidinone ((S) -oxyracetam)

<Step 1-1> Preparation of 1- (R) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone

4.5 g of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone produced in Step 2-1 of Preparation Example 1 was suspended in 80 ml of chloroform, followed by anhydrous at 0 ° C. or lower. 8.4 mL of acetic acid and 0.54 g of N, N-dimethylaminopyridine (DMAP) were added thereto, and the mixture was allowed to react for 3 hours while gradually raising the temperature to room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluent: ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- 5.98 g of (S) -acetoxy-2-pyrrolidinone was obtained.

¹ H NMR (300MHz, CDCl ₃ ): δ 1.50 (3H, d, J = 7Hz), 2.02 (3H, s), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz) , 7.23 ~ 7.36 (5H, m)

<Step 1-2> Preparation of 1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone

1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone produced in Step 2-1 of Preparation Example 2 was treated in the same manner as in Step 1-1 of Example 1 1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone was obtained.

¹ H NMR (200 MHz, CDCl ₃ ): 1.50 (3H, d, J = 7 Hz), 2.02 (3H, s), 2.39 (1H, dd, J ₁ = 2 Hz, J ₂ = 7 Hz), 2.51 (1H, d , J = 4Hz), 2.70 (1H, dd, J ₁ = 7Hz, J ₂ = 17Hz), 2.95 (1H, dd, J ₁ = 2Hz, J ₂ = 11Hz), 3.53 (1H, dd, J ₁ = 6Hz , J ₂ = 11 Hz), 4.40 (1H, bs), 5.44 (1H, q, J = 7 Hz), 7.21-7.29 (5H, m)

<Step 2-1> Preparation of 4- (S) -acetoxy-2-pyrrolidinone

To 3.5 g of 1- (R) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone was added 30 ml of toluene and 4.58 ml of methanesulfonic acid (MsOH), and the mixture was refluxed for 6 hours while heating slowly. The reaction product was cooled to room temperature, neutralized by adding sodium bicarbonate, filtered to remove excess sodium bicarbonate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate / methanol = 10/1) to obtain the title compound 4- (S. 1.38 g of) -acetoxy-2-pyrrolidinone was obtained.

¹ H NMR (300MHz, CDCl ₃ ): δ2.08 (3H, s), 2.40 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.72 (1H, dd, J1 = 6Hz, J2 = 18Hz), 3.41 (1H, d, J = 12Hz), 3.76 (1H, dd, J1 = 6Hz, J2 = 12Hz), 5.35 ~ 5.40 (1H, m), 6.95 (1H, bs)

[α] ²⁷ = -56.4 ^° (c = 1.EtOH)

<Step 2-2> Preparation of 4- (S) -acetoxy-2-pyrrolidinone

1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone produced in step 1-2 of Example 1 was treated in the same manner as in step 2-1 of Example 1 4- (S) -acetoxy-2-pyrrolidinone was obtained.

<Step 3> Preparation of 1-ethoxycarbonylmethyl-4- (S) -acetoxy-2-pyrrolidinone

1 g of 4- (S) -acetoxy-2-pyrrolidinone was dissolved in 20 ml of dried tetrahydrofuran, and 1.07 g of 60% potassium fortium carbonate was slowly added thereto at room temperature and the stirring was continued until no bubbles were generated. . After further stirring for 20 minutes, 0.85 ml of ethyl bromoacetate was slowly added dropwise and reacted at room temperature for 3 hours.

The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and separated by column chromatography (eluent: ethyl acetate / n-hexane = 2/1, v / v) to give the title compound 1-ethoxycarbonylmethyl-4- (S 1.25 g of) -acetoxy-2-pyrrolidinone was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.28 (3H, t, J = 7 Hz), 1.79 (1H, d, J = 5 Hz), 2.08 (3H, s), 2.52 (1H, dd, J1 = 2 Hz , J2 = 18Hz), 2.83 (1H, dd, J1 = 8Hz, J2 = 18Hz), 3.46 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.88 ~ 3.99 (2H, m), 4.17 ~ 4.24 (3H , m), 5.31-5.36 (1H, m)

Step 4 Preparation of 1-carbamoyl-4- (S) -hydroxy-2-pyrrolidinone ((S) -oxyracetam)

1 g of 1-ethoxycarbonylethyl-4- (S) -acetoxy-2-pyrrolidinone was diluted in 10 ml of methanol and ammonia was injected at 0 ° C or lower. When 0.78 g of ammonia was saturated, the stopper was well sealed and then slowly raised to room temperature and stirred overnight. The solvent was distilled under reduced pressure to remove the solvent, and 4 ml of acetone / methanol (5/1, v / v) mixed solvent was added thereto, followed by stirring. 0.417 g of solid was obtained.

The obtained solid was recrystallized with 1.2 ml of methanol to obtain 0.231 g of a light colored solid, which was dissolved in 10 ml of methanol and heated to reflux for 30 minutes with addition of 0.05 g of activated carbon. The reaction product was filtered, cooled to room temperature, and distilled under reduced pressure to remove the solvent. 0.2 ml of methanol and 1 ml of acetone were added to the resulting syrup mixture, and the resulting solid was filtered to give the title compound, 1-carbamoyl-4-. 0.564 g of (S) -hydroxy-2-pyrrolidinone was obtained.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 2.05 (1H, dd, J1 = 3 Hz, J1 = 17 Hz), 2.54 (1H, dd, J1 = 7 Hz, J1 = 17 Hz), 3.14 (1H, dd, J1 = 2Hz, J1 = 10Hz), 3.60 (1H, dd, J1 = 6Hz, J1 = 10Hz), 3.64 (1H, d, J1 = 17Hz), 3.85 (1H, d, J1 = 17Hz), 4.26 ~ 4.30 (1H , m), 5.21 (1H, d, J 1 = 4 Hz), 7.11 (1 H, s), 7.30 (1 H, s)

¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.81

[a] ²⁷ = -37.25. (c = 1, water)

mp: 134.8 ~ 136.0 ℃

Purity: 99.9% (HPLC, Waters Carbohydrate Column, 5% water in acetonitrile)

Example 2: Preparation of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone ((R) -oxyracetam)

<Step 1> Preparation of 1- (R) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone

4.5 g of 1- (R) -phenylethyl-4- (5) -hydroxy-2-pyrrolidinone produced in step 2-2 of Preparation Example 1 was suspended in 80 ml of chloroform, and then, 0 was added to the reaction mixture. 8.4 mL of acetic anhydride and 0.54 g of N, N-dimethylaminopyridine (DMAP) were added thereto, and the mixture was allowed to react for 3 hours while gradually raising the temperature to room temperature.

The reaction product was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- (R 5.21 g of) -acetoxy-2-pyrrolidinone was obtained. It was recrystallized from ethyl acetate.

¹ H NMR (300MHz, CDCl ₃ ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)

<Step 2-1> Preparation of 4- (R) -acetoxy-2-pyrrolidinone

To 3.5 g of 1- (R) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone was added 30 ml of toluene and 4.58 ml of methanesulfonic acid (MsOH), and the mixture was slowly heated to reflux for 6 hours. The mixture was cooled to room temperature, neutralized by adding sodium bicarbonate, and then filtered to remove excess sodium bicarbonate. The remaining filtrate was concentrated under reduced pressure, and then separated by column chromatography (ethyl acetate / methanol = 10/1) to obtain the title compound (4). 1.21 g of-(R) -acetoxy-2-pyrrolidinone was obtained.

¹ H NMR (300MHz, CDCl ₃ ): δ2.08 (3H, s), 2.40 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.72 (1H, dd, J1 = 6Hz, J2 = 18Hz), 3.41 (1H, d, J = 12Hz), 3.76 (1H, dd, J1 = 6Hz, J2 = 12Hz), 5.35 ~ 5.40 (1H, m), 6.95 (1H, bs)

[α] ²⁷ = +56.1 ^° (c = 1.EtOH)

<Step 2-2> Preparation of 4- (R) -acetoxy-2-pyrrolidinone

1- (S) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone was treated in the same manner as in Step 2-1 of Example 1 to 4- (S) -acetoxy-2-py Obtained Lollidinone.

<Step 3> Preparation of 1-ethoxycarbonylmethyl-4- (R) -acetoxy-2-pyrrolidinone

2 g of 4- (R) -acetoxy-2-pyrrolidinone was dissolved in 30 ml of dried tetrahydrofuran and slowly added 2.2 g of 60% potassium carbonate at room temperature, followed by continued stirring at room temperature until no bubbles were generated. . After the bubble was stopped, the solution was further stirred for 20 minutes, and 1.7 ml of ethyl bromoacetate was slowly added dropwise. The reaction product was filtered after reacting at room temperature for 3 hours. The filtrate was concentrated under reduced pressure, and then separated by column chromatography (ethyl acetate / n-hexane = 2/1, v / v) to give the title compound 1-ethoxycarbonylmethyl-4- (R) -acetoxy-2. 2.71 g of pyrrolidinone was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.28 (3H, t, J = 7 Hz), 1.79 (1H, d, J = 5 Hz), 2.08 (3H, s), 2.52 (1H, dd, J1 = 2 Hz , J2 = 18Hz), 2.83 (1H, dd, J1 = 8Hz, J2 = 18Hz), 3.46 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.88 ~ 3.99 (2H, m), 4.17 ~ 4.24 (3H , m), 5.31-5.36 (1H, m)

Step 4 Preparation of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone ((R) -oxyracetam)

1 g of 1-ethoxycarbonylethyl-4- (R) -acetoxy-2-pyrrolidinone was diluted in 10 ml of methanol and ammonia was injected at 0 ° C. or lower. When 0.78 g of ammonia was saturated, the stopper was well blocked, and then slowly raised to room temperature, followed by stirring overnight. The reaction product was distilled under reduced pressure to remove the solvent, and 4 ml of acetone / methanol (5/1, v / v) mixed solvent was added thereto, followed by stirring to obtain 0.417 g of a light gray solid. The obtained solid was recrystallized with 1.2 ml of methanol to obtain 0.231 g of a light colored solid, which was dissolved in 10 ml of methanol and heated to reflux for 30 minutes by adding 0.05 g of activated carbon. After filtration and cooling to room temperature, the solvent was removed by distillation under reduced pressure, and 0.2 ml of methanol and 1 ml of acetone were added to the resulting syrup. The resulting white solid was filtered to obtain 0.632 g of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone as the title compound.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 2.05 (1H, dd, J1 = 3 Hz, J1 = 17 Hz), 2.54 (1H, dd, J1 = 7 Hz, J1 = 17 Hz), 3.14 (1H, dd, J1 = 2Hz, J1 = 10Hz), 3.60 (1H, dd, J1 = 6Hz, J1 = 10Hz), 3.64 (1H, d, J1 = 17Hz), 3.85 (1H, d, J1 = 17Hz), 4.26 ~ 4.30 (1H , m), 5.21 (1H, d, J 1 = 4 Hz), 7.11 (1 H, s), 7.30 (1 H, s)

¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.8

[a] ²⁷ = +37.18. (c = 1, water)

mp: 135.8 ~ 136.7 ℃

Purity: 99.8% (HPLC, Waters Carbohydrate Column, 5% water in acetonitrile)

The process for preparing 1-carbamoylmethyl-4- (S or R) -hydroxy-2-oxopyrrolidine ((S) -oxyracetam or (R) -oxyracetam) according to the invention is inexpensive. (S) -Oxyracetam and (R) -Oxyracetam have high yield and high purity (Purity is indicated in the properties of (S or R) -Oxyracetam) by using industrial raw materials Because it can be prepared as may be useful in improving brain function and developing dementia treatment.

Claims (2)

1) acetylating 1- (R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone of Formula 1 in the presence of an organic solvent; 2) debenzylating 1- (R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone of formula 2 produced in step 1 in the presence of an organic solvent; 3) reacting the 4- (S or R) -alkoxy-2-pyrrolidinone of formula 3 produced in step 2 with an acetate substituted with halogen in the presence of an organic solvent and a base; And 4) reacting 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone of formula 4 produced in step 3 with ammonia, 1 of the following structural formula (I) Method for preparing carbamoyl-4- (S or R) -hydroxy-2-pyrrolidinone ((S) -oxyracetam or (R) -oxyracetam):

(I) Wherein R ² is methyl or ethyl. The method of claim 1, Characterized by using methanesulfonic acid in the range of 3 to 15 equivalents of formula (2).