KR100711938B1 - Method for preparing stereoselective 4-hydroxy-2-pyrrolidinone - Google Patents

Abstract

The present invention provides a novel and efficient process for the preparation of stereoselective 4-hydroxy-2-pyrrolidinone, wherein the hydroxy ester obtained by high-pressure hydrogenation of a nitrogen-substituted beta ketobutanoic acid derivative under a ruthenium catalyst is deprotected and cyclic. The method of the present invention which is subjected to the polymerization reaction is large in stereoselectivity, high in yield, and economical.

Description

Method for producing stereoselective 4-hydroxy-2-pyrrolidinone {METHOD FOR PREPARING STEREOSELECTIVE 4-HYDROXY-2-PYRROLIDINONE}

The present invention relates to a novel and efficient method for preparing stereoselective 4-hydroxy-2-pyrrolidinone, which is a substance that can be used as a key intermediate for antibiotics, brain disease improvers, and anticancer derivatives.

Stereoselective 4-hydroxy-2-pyrrolidinone is to be used as a key intermediate of the antibiotic CS-834 having the structure of Formula 1, the brain disease improving agent oxyracetam of Formula 2, and the CHIR 200,131 derivative, which is an anticancer agent of Formula 3 As a material which can be represented, it may be represented by the following Chemical Formula 4a or 4b.

Wherein R represents hydrogen, benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl, methyl, ethyl, isopropyl, isobutyl, t-butyl and other lower alkyl groups. In general, stereoselective 4-hydroxy-2-pyrrolidinone is synthesized by a chemical method from chiral hydroxybutyrolactone, as shown in Scheme 1 below, or by chemical and enzymatic methods from epichlorohydrin. Synthesis (JACS 2000. 122. 168-169 and US Pat. No. 4,705,572) or by enzymatic reaction of pyrrolidinone (JOC 2002. 67. 7869-7871).

Wherein R is as defined above.

However, when synthesizing the stereoselective 4-hydroxy-2-pyrrolidinone, the reaction conditions are difficult, the stereoselectivity is low, there is a problem that the synthesis of hydroxy piperidinone substituted with nitrogen is uneconomical.

It is therefore an object of the present invention to provide a more efficient process for the preparation of stereoselective 4-hydroxy-2-pyrrolidinone.

In order to achieve the above object, in the present invention, 1) the nitrogen bi-substituted beta keto butanoic acid ester of the formula (5) is hydrogenated in the presence of a ruthenium catalyst to the nitrogen hydroxy beta hydroxy butanoic acid of the formula 6a or 6b After synthesizing the ester, 2) it provides a method for producing 4-hydroxy-2-pyrrolidinone of the general formula (4a) or 4b comprising the deprotection and cyclization.

Formula 4a

Formula 4b

In which R denotes a benzyl, hydrogen, benzyloxycarbonyl, t- butyloxycarbonyl, benzoyl or acetyl, R'denotes a lower alkyl group of C _{1 -4.}

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

The preparation method of the stereoselective 4-hydroxy-2-pyrrolidinone according to the present invention can be represented by the following Scheme 2.

In the formula, R represents benzyl, hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl and the like, and R 'represents a lower alkyl group such as methyl, ethyl, propyl, butyl, t-butyl, propyl and the like.

Specifically, in step 1), the nitrogen-substituted beta keto butanoic acid derivative (5) is subjected to a suitable solvent such as methanol, ethanol, isopropanol, butanol, at a high pressure of about 30-100 atm in the presence of a ruthenium catalyst. Economically synthesizing high purity stereoselective hydroxy esters of formula 6a or 6b by hydrogenation in tetrahydrobutane, acetonitrile and dimethylformamide, and then subjecting them to the desired formulas 4a or 4b To obtain stereoselective 4-hydroxy-2-pyrrolidinone.

In the above reaction, in step 1), the stereoselection of 4-hydroxy-N-benzyl-2-pyrrolidinone is different depending on which of the R and S forms the ruthenium catalyst is used. The degree can be determined.

Examples of the ruthenium catalyst include (R) Ru ₂ Cl ₄ (BINAP) NEt _3, (S) Ru ₂ Cl ₄ (BINAP) NEt _3, (R) Ru ₂ Cl ₄ (BINAP) _{2, and} (S) Ru ₂ Cl ₄ (BINAP) _2, (R) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt _{3, and} (S) Ru ₂ Cl ₄ (To l-BINAP) ₂ NEt ₃ .

Step 2) may be carried out by deprotection and cyclization in a conventional manner.

Specific examples of the method according to the method of the present invention are shown in Schemes 3 to 5 below.

As shown in Schemes 3 or 4, when the N-protecting group is butoxycarbonyl, N-benzyl-4-hydroxy-pyrrolidin-2one is deprotected in the presence of an acid and then cyclized in the presence of a base. When the N-protecting group is a benzyloxy carbonyl group as in Scheme 5, deprotection is carried out by hydrogenating the resulting betahydroxy butanoic ester for a short time (30 minutes) at atmospheric pressure in the presence of 5% Pd / C. After the reaction, N-benzyl-4-hydroxy-pyrrolidin-2-one can be obtained by subjecting it to a cyclization reaction. On the other hand, when the hydrogenation reaction in the presence of Pd / C is carried out for a long time (for example 10 hours), N-benzyl is removed to obtain a compound having an amine group, and when cyclized with a base, finally R = hydrogen 4-hydroxy-pyrrolidin-2-one can be obtained.

The acid used in the reaction is a solution in which hydrochloric acid gas is saturated in alcohol, inorganic acids such as trifluoroacetic acid and HCl, but the base is potassium carbonate, calcium carbonate, sodium, sodium hydride, tert-butoxylated Inorganic salts of potassium, potassium methoxylate, sodium hydroxide, potassium hydroxide, organic of triethylamine, diisopropylethylamine, DBU (1,8-diaza bicyclo [5,4,0] -7-undecene) Salts, but is not limited thereto.

The temperature range in said reaction is 0 degreeC-100 degreeC, Preferably it is about 30 degreeC. Preferred solvents include, but are not limited to, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl ether, ethyl acetate, acetone, chloroform, methanol, ethanol, isopropanol and butanol.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are not intended to limit the invention only.

Preparation Example 1 Synthesis of Ethyl, 4-t-butoxycarbonyl-4-benzylamino-3-oxo-butanoate

Step 1) Synthesis of Ethyl-2-benzylamino Acetate

Add 10 g (0.093 mole) of benzylamine and 100 ml of ethanol to a 250 ml round flask reactor, stir for 3 minutes, then add 19.4 g (0.116 mole) of ethyl bromoacetate, add 11.75 g (0.116 mole) of triethylamine, and reflux for 2 hours. I was. When the reaction was completed, the reaction mixture was distilled under reduced pressure, the solvent was removed, the mixture was extracted with dichloromethane and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1). 15 g (83.5%) of compound was obtained.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.18 (q, 2H), 3.80 (s, 2H), 3.40 (s, 2H), 1.26 (t, 3H)

Step 2) Synthesis of ethyl-2-t-butoxy carbonyl-2-benzyl amino acetate

50 g (0.259 mole) of ethyl-2-benzylamino acetate and 73.41 g (0.336 mole) of di-t-butyl dicarbonate were added to 250 ml of methanol and reacted at 0 ° C. to room temperature for 24 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove methanol, extracted with ethyl acetate and 1N hydrochloric acid solution, adjusted to pH 6, and the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane / ethyl acetate = 7/1). Separation and purification gave the target compound 67g (88.1%).

¹ H NMR (CDCl ₃ , ppm): δ 7.33-7.22 (m, 5H), 4.16 (q, 2H), 3.80 (s, 2H), 3.39 (s, 2H), 1.97 (s, 9H), 1, 26 (q, 3H)

Step 3) Synthesis of 2-t-butoxy carbonyl-2-benzylamino acetic acid

After dissolving 10 g (0.034 mole) of ethyl-2-t-butoxy carbonyl-2-benzylamino acetate in step 2) in 100 ml of dichloromethane, the solution was added 19.12 g (0.34 mole) of potassium hydroxide to 5 ml of water. And reacted with a solution dissolved in 10ml of methanol at room temperature for 1 hour. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove methanol, extracted with dichloromethane and 1N hydrochloric acid, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a compound 7.8g (86.4%).

¹ H NMR (CDCl ₃ , ppm): δ 7.30-7.20 (m, 5H), 3.82 (s, 2H), 3.40 (s, 2H), 1.97 (s, 9H)

Step 4) Synthesis of ethyl, 4-t-butoxycarbonyl-4-benzylamino-3-oxo-butanoate

10 g (0.038 mole) of 2-t-butoxycarbonyl-2-benzylamino acetic acid of step 3) and 200 ml of acetonitrile were added to a 1 L reactor, stirred for 15 minutes under nitrogen, and 1,1-carbonyl diimidazole 6.38 was added thereto. g (0.039 mole) was added and stirred for 30 minutes, and the temperature was lowered to 10 ° C. 9.14 g (0.054 mole) of potassium malonate ethyl ester and 3.75 g (0.039 mole) of magnesium chloride were added thereto, followed by stirring for 1 hour. After further stirring at 58 ° C. for 2 hours, when the reaction was completed, the temperature was lowered to room temperature and distilled under reduced pressure to remove the solvent. Then, the mixture was extracted with ethyl acetate and 1N hydrochloric acid solution, adjusted to pH 4, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 11.7 g (91.8%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.30-7.15 (m, 5H), 4.18 (q, 2H), 3.85 (s, 2H), 3.55 (s, 2H), 2.50 (s, 2H), 1.97 ( s, 2H), 1.25 (t, 3H)

Preparation Example 2 Synthesis of Ethyl, 4-benzyloxycarbonyl-4-benzylamino-3-oxo-butanoate

Add 10 g of benzylamine and 17.2 g of ethyl bromoacetate to 50 mL of ethanol, add 15.6 mL of triethylamine, reflux for 3 hours, lower the temperature to room temperature, and add 24 g of di-t-butyl dicarbonate at room temperature for 5 hours. After reacting and distilling under reduced pressure of ethanol, 10 g (0.033 mole) of N-benzyl-N-butoxycarbonylamino acetic acid obtained by silica gel column chromatography was stirred with 200 ml of acetonitrile for 15 minutes under nitrogen, followed by 1,1-carbo 6.38 g (0.039 mole) of nitrile diimidazole was added thereto, followed by further stirring for 30 minutes, and the temperature was lowered to 10 ° C. 9.14 g (0.054 mole) of potassium malonate ethyl ester and 3.75 g (0.039 mole) of magnesium chloride were added thereto and stirred for 1 hour. After further stirring at 58 ° C. for 2 hours, when the reaction is completed, the reaction mixture is cooled to room temperature, distilled under reduced pressure to remove the solvent, and then extracted by adjusting to pH 4 with ethyl acetate and 1N hydrochloric acid solution. The organic layer is dried over anhydrous magnesium sulfate and dried under reduced pressure. Concentration gave 11 g (90.2%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.31-7.40 (m, 10H), 4.20 (q, 2H), 3.85 (s, 2H), 3.60 (s, 2H), 3.55 (s, 2H), 2.50 ( s, 2H), 1.97 (s, 9H), 1.25 (t, 3H)

Example 1: Synthesis of 5- (benzyl, benzyloxycarbonylamino) -3- (S) -hydroxybutyric acid ethyl ester

20 g (0.052 mole) of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-butanoic acid ethyl ester of Preparation Example 2 and dichloro [R (+)-2,2'-bis (diphenolphosphino)- 10 mg of 1,1'-binafyl] ruthenium was added to 100 ml of anhydrous ethanol and reacted at room temperature at 70 atm in a high pressure hydrogen reactor for 24 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove ethanol, extracted with ethyl acetate and water, and then the organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 18.3 g of yellow oil (yield). 93%, ee 97%).

¹ H NMR (CDCl ₃ , ppm): δ 7.36-7.18 (m, 10H), 5.18 (s, 2H), 4.55-4.35 (m, 2H), 4.14 (q, 2H), 4.09-3.90 (m, 1H ), 3.63 (br, 1H), 3.39-3.01 (m, 2H) 2.47-2.36 (m, 2H), 1.25 (t, 3H)

HPLC analysis results:

Column: Chiralcel-OD

Mobile phase: Hexane: IPA = 90: 10

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 10.16 minutes

Example 2: Synthesis of 5- (benzyl, benzyl oxycarbonylamino) -3- (R) -hydroxy butanoic acid ethyl ester

The ruthenium catalyst was carried out in the same manner as in Example 1 and 16.9 g of the target compound was prepared using dichloro [S (-)-2,2'-bis (diphenyl phosphino) -1,1'-binafthyl] ruthenium. Yield 91%, ee 96%).

¹ H NMR (CDCl ₃ , ppm): δ 7.36-7.18 (m, 10H), 5.20 (s, 2H), 4.54-4.30 (m, 2H), 4.16 (q, 2H), 4.10-3.80 (m, 1H ), 3.55 (br, 1H), 3.35-3.10 (m, 2H), 2.41-2.30 (m, 2H), 1.25 (t, 3H)

HPLC analysis results:

Column: Chiralcel-OD

Mobile phase: Hexane: IPA = 90: 10

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 6.02 minutes

Example 3: Synthesis of 5- (benzyl, t-butoxycarbonylamino) -3- (S) -hydroxy butanoic acid ethyl ester

10 g of 5- (benzyl, t-butoxycarbonylamino) -3-oxo-butanoic acid ethyl ester of Preparation Example 1 and dichloro [R (+)-2,2'-bis (diphenol phosphino) -1, 5 mg of 1'-binafthyl] ruthenium was reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove ethanol, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 8.9 g of yellow oil ( Yield 91%, ee 96.8%).

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.21 (m, 5H), 4.58-4.20 (m, 2H), 4.12 (q, 2H), 4.02-3.92 (m, 1H), 3.70 (br, 1H ), 3.27-2.98 (m, 2H), 2.55-2.38 (m, 2H), 1.80-1.48 (m, 2H), 1.46 (s, 9H), 1.26 (t, 3H)

HPLC analysis results:

Column: Chiralcel-OD

Mobile phase: Hexane: IPA = 90: 10

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 8.21 minutes

Example 4: Synthesis of 5- (benzyl, t-butoxycarbonylamino) -3- (R) -hydroxybutanoic acid ethyl ester

The ruthenium catalyst was carried out in the same manner as in Example 3, and the ruthenium catalyst was prepared using 8.7 g of the target compound using dichloro [S (-)-2,2'-bis (diphenyl phosphino) -1,1'-binafthyl] ruthenium. Yield 89% ee 97.3%).

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.25 (m, 5H), 4.56-4.15 (m, 2H), 4.51-4.15 (m, 2H), 4.12 (q, 2H), 4.04-3.89 (m , 1H), 3.69 (br, 1H), 3.27-2.98 (m, 2H), 2.55-2.38 (m, 2H), 1.46 (s, 9H), 1.26 (t, 3H)

HPLC analysis results:

Column: Chiralcel-OD

Mobile phase: Hexane: IPA = 90: 10

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 7.56 minutes

By changing the catalyst in Example 1-4 to prepare a hydroxy butanoic acid ethyl ester intermediate of formula 6a or 6b according to the present invention, the results are summarized in Table 1 below.

Example 5: Synthesis of N-benzyl-4- (S) -hydroxy pyrrolidin-2-one

5 g of 5- (benzyl, t-butoxy carbonylamino) -3- (S) -hydroxybutanoic acid ethyl ester of Example 3 were placed in a 100 ml reactor, 50 ml of ethanol was added, and 10 ml of 10% HCl methanol was added thereto. Stir at room temperature for 5 hours. After confirming that the t-butyl group was removed by TLC, the solvent was distilled under reduced pressure to obtain 5-benzyl amino-3 (R) -hydroxy acid ethyl ester hydrochloride. Without purification, 50 ml of ethanol was added and 1.5 g of sodium epoxide was added thereto, and the mixture was refluxed for 2 hours. After distillation of the solvent under reduced pressure, silica gel column chromatography was performed with Hex: EA = 1: 1 to obtain 3 g of the desired compound. (Yield 85%)

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H)

HPLC analysis results:

Column: Chiral PAK AS

Mobile phase: Hexane: IPA = 80: 20

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 16.52 minutes

Example 6: Synthesis of N-benzyl-4- (R) -hydroxy pyrrolidin-2-one

5 g of 5- (benzyl, t-butoxycarbonylamino) -3- (R) -hydroxybutanoic acid ethyl ester of Example 4 were reacted similarly to Example 5 to give 3.1 g of the desired target compound. Got it.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H)

HPLC analysis results:

Column: Chiral PAK AS

Mobile phase: Hexane: IPA = 80: 20

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 22.80 minutes

Example 7: Synthesis of N-benzyl-4- (S) -hydroxy pyrrolidin-2-one

5 g of 5- (benzyl, benzyloxycarbonylamino) -3- (S) -hydroxybutyric acid ethyl ester of Example 1 was placed in a 100 ml reactor, 50 ml of methanol was added and 100 mg of 5% Pd / C was added. It was performed for 30 minutes at room temperature and normal pressure. After filtering 5% Pd / C using celite, sodium epoxide was added to the reaction solution and refluxed for 2 hours. After distilling off the solvent under reduced pressure, silica gel column chromatography was performed with hexane: ethyl acetate = 1: 1 to obtain 2.26 g of the desired compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H)

HPLC analysis results:

Column: Chiral PAK AS

Mobile phase: Hexane: IPA = 80: 20

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 16.52 minutes

Example 8: Synthesis of N-benzyl-4- (R) -hydroxy pyrrolidin-2-one

The reaction was carried out using 5 g of 5- (benzyl, benzyl oxycarbonylamino) -3- (R) -hydroxy butanoic acid ethyl ester of Example 2 under similar conditions as in Example 7. 2.2 g of the desired compound were obtained.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H)

HPLC analysis results:

Column: Chiral PAK AS

Mobile phase: Hexane: IPA = 80: 20

Flow rate: 1 ml / min

Detection wavelength: 254 nm

Retention time: 22.80 minutes

According to the present invention, 4-hydroxy-2-pyrrolidinone can be obtained in a short time in a milder reaction condition than the conventional method, and simply high purity, high yield and economical.

Claims (9)

1) Hydrogenation of the nitrogen-substituted beta keto butanoic acid ester of Formula 5 in the presence of a ruthenium catalyst in the form of R or S-isomer to obtain the beta hydroxy butanoic acid ester of nitrogen-substituted beta of formula 6a or 6b, respectively After synthesis 2) a process for preparing 4-hydroxy-2-pyrrolidinone of formula 4a or 4b, comprising deprotecting and cyclizing it: Formula 5

Formula 6a

Formula 6b

Formula 4a

Formula 4b

Where R represents benzyl, hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl or acetyl, and R 'represents a lower alkyl group of C _1-4 . The method of claim 1, wherein the ruthenium catalyst in step 1) is (R) Ru ₂ Cl ₄ (BINAP) NEt _3, (S) Ru ₂ Cl ₄ (BINAP) N Et _3, (R) Ru ₂ Cl ₄ (BINAP) _2, (S) Ru ₂ Cl ₄ (BINAP) _2, (R) Ru ₂ Cl ₄ (Tol-BI NAP) ₂ NEt ₃ and (S) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ The method of manufacture, characterized in that it is selected. The process according to claim 1, wherein step 1) is carried out at 30-100 atmospheres. The process of claim 1, wherein the hydrogenation reaction of step 1) is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, tetrahydrobutane, acetonitrile, dimethylformamide and mixtures thereof. Manufacturing method. The process according to claim 1, wherein the deprotection reaction of step 2) is carried out in the presence of an acid catalyst selected from the group consisting of sulfuric acid, toluenesulphonic acid, oxalic acid, trifluoroacetic acid and mixtures thereof. delete The inorganic base according to claim 1, wherein the cyclization reaction of step 2) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, butoxy potassium, potassium methoxylated and mixtures thereof ; Organic bases selected from the group consisting of triethylamine, diisopropylethylamine, DBU (1,8-diaza bicyclo [5,4,0] -7-undecene) and mixtures thereof; Or a mixture thereof. delete The process according to claim 1, further comprising performing a hydrogenation reaction under atmospheric pressure in the presence of a Pd / C catalyst when R is hydrogen.