WO2019028669A1 - Solvent-free method for preparing levetiracetam - Google Patents

Abstract

The invention relates to a method for preparing levetiracetam, which comprises (S)-α-ethyl-2-oxo-1-pyrrolidine acetate as a raw material and a liquid in the absence of a solvent. Ammonia is subjected to an aminolysis reaction to obtain levetiracetam. The method provided has low waste, good yield and purity, and meets the requirements of industrial production.

Description

Method for preparing levetiracetam without solvent Technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing levetiracetam without solvent.

Background technique

Levetiracetam is a high-efficiency, broad-spectrum antiepileptic drug developed by UCB of Belgium. It is mainly used for the treatment of localized and secondary generalized epilepsy. The chemical name is (S)-α-B. Keto-2-oxo-1-pyrrolidine acetamide.

At present, there are many reports on the preparation methods of levetiracetam at home and abroad, mainly using chemical resolution. There are two types of synthetic methods commonly used in industry:

(1) The (R/S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid was developed from UCB of Belgium, and (R)-α-methylbenzylamine was used as a resolving agent. It is resolved in benzene and treated with a base to give (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid. (S)-α-Ethyl-2-oxo-1-pyrrolidineacetic acid is reacted with ethyl chloroformate, and then left cilacetam is obtained by aminolysis.

(2) Using 2-aminobutyramide as a raw material, it is resolved by L-tartaric acid, ammonia is dissociated, and hydrogen chloride is salted to obtain (S)-2-aminobutanamide hydrochloride. (S)-2-Aminobutyramide hydrochloride is reacted with 4-chlorobutyryl chloride, and finally left cilacetam is obtained by a ring closure reaction.

The above synthetic routes all use the traditional chemical separation method to construct the chiral center, the process route is long, and the atomic utilization rate is low. At the same time, the solvents and reagents used in the chemical decomposition method are harmful to the environment, and the large amount of the three wastes (waste water, waste gas and waste residue) limits the industrial application to a certain extent.

Summary of the invention

It is an object of the present invention to provide a novel solventless process for the preparation of levetiracetam. The method of the present invention is less polluting to the environment. The object of the present invention is achieved by the following technical solutions.

A method for preparing levetiracetam characterized by (S)-α-ethyl-2-oxo-1-pyrrolidine acetate represented by formula (I) in the absence of a solvent As a raw material, the ampicillin shown by the formula (II) is obtained by aminolysis reaction with liquid ammonia, and the synthetic route is as follows:

R in the formula (I) is a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2 -methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3 - dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-three Methylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably methyl or ethyl base.

In the above synthesis method of levetiracetam, the molar ratio of liquid ammonia to the raw material (S)-α-ethyl-2-oxo-1-pyrrolidine acetate (I) is 1:1 to 100. : 1. Preferably, the molar ratio of liquid ammonia to the starting material (S)-α-ethyl-2-oxo-1-pyrrolidine acetate (I) is from 5:1 to 30:1, preferably from 5:1 to 20 : 1.

In the above synthesis method of levetiracetam, the temperature of the aminolysis reaction is -80 to 50 °C. Under low temperature conditions, liquid ammonia is in a liquid state, and the liquid ammonia concentration in the reaction system is large, but when the temperature is low, the reaction rate is slow; under high temperature conditions, liquid ammonia exhibits a gaseous state, and the liquid ammonia concentration in the reaction system is low. Preferably, the temperature of the aminolysis reaction is -30 to 20 °C.

In the above synthesis method of levetiracetam, the reaction system pressure of the aminolysis reaction is 0.2 to 5.0 MPa. The higher the pressure of the reaction system, the more favorable the forward reaction is, but when the pressure of the reaction system is too high, the isomerization of the aminolysis reaction is strengthened. Preferably, the reaction system pressure is from 0.5 to 3.0 MPa, and the reaction time is from 24-96 hours.

The method of the present invention further includes the following post-treatment: after the end of the aminolysis reaction, the liquid ammonia is recovered to obtain a crude levetiracetam. It was recrystallized by adding an organic solvent to obtain levetiracetam. The organic solvent used for recrystallization is selected from a mixture of one or more of C ₁ -C ₄ alcohols, ketones, esters, and ethers. The above C ₁ -C ₄ alcohols are selected from the group consisting of methanol, ethanol, isopropanol or butanol; the ketones are selected from the group consisting of acetone, methyl ethyl ketone or methyl isobutyl ketone; the above esters are ethyl acetate; the above ethers It is methyl tert-butyl ether. Preferably, the organic solvent used for recrystallization is selected from one or a mixture of acetone, ethyl acetate or methyl isobutyl ketone. The recrystallization temperature is -20 to 20 ° C, and the recrystallization temperature is preferably -5 to 5 °C.

Compared with the prior art, the present invention has the following advantages:

The preparation method of levetiracetam of the invention avoids the use of a large amount of organic solvent, reduces the three wastes (waste water, waste gas and waste residue), reduces the cost, and has simple operation and high yield, and the obtained levetiracetam is obtained. The HPLC purity and optical purity are high, and the HPLC purity and optical purity are both above 99.5%, which fully meets the requirements of industrial production.

Detailed ways

The specific embodiments of the present invention are further described in detail below with reference to the embodiments. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1

Add (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (37 g, 0.20 mol) to the autoclave and cool to -20 ° C with stirring, and reduce the filling solution. Ammonia (NH ₃ ) (68 g, 4.00 mol). The valve was closed, the temperature was raised to 15 ° C, and the aminolysis reaction was carried out at a temperature of 10 to 20 ° C and a reactor pressure of 0.5 to 2.0 MPa. After 40 hours of reaction, no residue of the starting material (S)-α-ethyl-2-oxo-1-pyrrolidineacetate was detected by TLC. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. Acetone (200 g) was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, heat crystallization for 2 to 4 hours, filter, and dry to obtain levetiracetam. The yield was 32.7 g, the yield was 96.0%, the HPLC purity was 99.8%, and the isomer: 0.07%.

Example 2

Add (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (37 g, 0.20 mol) to the autoclave and cool to -20 ° C with stirring, and reduce the filling solution. Ammonia (NH ₃ ) (68 g, 4.00 mol). The valve was closed, the temperature was raised to 25 ° C, and the aminolysis reaction was carried out at a temperature of 20 to 30 ° C and a reactor pressure of 0.5 to 2.0 MPa. After the reaction for 32 hours, no raw material (S)-α-ethyl-2- was detected by TLC. Methyl oxo-1-pyrrolidine acetate remained. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. . Acetone (200 g) was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, heat crystallization for 2 to 4 hours, filter, and dry to obtain levetiracetam. The yield was 31.8 g, the yield was 93.4%, the HPLC purity was 99.8%, and the isomer: 0.08%.

Example 3

Add (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (37 g, 0.20 mol) to the autoclave and cool to -30 ° C with stirring, and reduce the filling solution. Ammonia (NH ₃ ) (102 g, 6.00 mol). The valve was closed, the temperature was raised to 0 ° C, and the aminolysis reaction was carried out at a temperature of -5 to 5 ° C and a reactor pressure of 0.5 to 1.0 MPa. After 28 hours of reaction, no raw material (S)-α-ethyl-2 was detected by TLC. - Oxo-1-pyrrolidine acetate methyl ester remaining. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. Acetone (200 g) was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, and heat crystallization for 2 to 4 hours. Filter and dry to obtain levetiracetam. The yield was 32.9 g, the yield was 96.6%, the HPLC purity was 99.9%, and the isomer: 0.05%.

Example 4

Add (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (37 g, 0.20 mol) to the autoclave and cool to 0 °C with stirring, and fill the liquid ammonia with a reduction method. (NH ₃ ) (17 g, 2.00 mol). The temperature was raised to 10 ° C, and the aminolysis reaction was carried out at a temperature of 5 to 15 ° C and a reactor pressure of 1.0 to 3.0 MPa. After 72 hours of reaction, no raw material (S)-α-ethyl-2-oxo was detected by TLC. Methyl 1-pyrrolidine acetate remained. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. Acetone (200 g) was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, and heat crystallization for 2 to 4 hours. Filter and dry to obtain levetiracetam. The yield was 31.6 g, the yield was 92.8%, the HPLC purity was 99.7%, and the isomer: 0.08%.

Example 5

Add (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (37 g, 0.20 mol) to the autoclave and cool to -20 ° C with stirring, and reduce the filling solution. Ammonia (NH ₃ ) (68 g, 4.00 mol). The valve was closed, the temperature was raised to 15 ° C, and the aminolysis reaction was carried out at a temperature of 10 to 20 ° C and a reactor pressure of 0.5 to 2.0 MPa. After 40 hours of reaction, no raw material (S)-α-ethyl-2- was detected by TLC. Methyl oxo-1-pyrrolidine acetate remained. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. Ethyl acetate (200 g) was added to dissolve the solid, and the mixture was warmed to reflux. Slowly cool to 0 ° C, and heat crystallization for 2 to 4 hours. Filter and dry to obtain levetiracetam. The yield was 31.8 g, the yield was 93.4%, the HPLC purity was 99.7%, and the isomer: 0.07%.

Example 6

To the autoclave, ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine (40 g, 0.20 mol) was added and the temperature was lowered to -20 ° C under stirring, and the solution was filled with a reduced amount. Ammonia (NH ₃ ) (68 g, 4.00 mol). The valve was closed, the temperature was raised to 15 ° C, and the aminolysis reaction was carried out at a temperature of 10 to 20 ° C and a reactor pressure of 0.5 to 2.0 MPa. After the reaction for 52 hours, no raw material (S)-α-ethyl-2- was detected by TLC. Methyl oxo-1-pyrrolidine acetate remained. After the completion of the aminolysis reaction, ammonia gas was recovered to obtain a solid. . Acetone (200 g) was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, and heat crystallization for 2 to 4 hours. Filter and dry to obtain levetiracetam. The yield was 32.5 g, the yield was 95.5%, the HPLC purity was 99.8%, and the isomer: 0.08%.

Claims (7)

A method for preparing levetiracetam characterized by (S)-α-ethyl-2-oxo-1-pyrrolidine acetate represented by formula (I) in the absence of a solvent As a raw material, the ampicillin shown by the formula (II) is obtained by aminolysis reaction with liquid ammonia, and the synthetic route is as follows:

R in the formula (I) is a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2 -methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3 - dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-three Methylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably methyl or ethyl base. . The method according to claim 1, wherein the molar ratio of liquid ammonia to (S)-α-ethyl-2-oxo-1-pyrrolidine acetate is from 1:1 to 100:1. The method according to claim 2, wherein the molar ratio of liquid ammonia to (S)-α-ethyl-2-oxo-1-pyrrolidine acetate is from 5:1 to 30:1, preferably 5 : 1 to 20:1. The method according to claim 1, wherein the temperature of the aminolysis reaction is -80 to 50 °C. The method according to claim 4, wherein the temperature of the aminolysis reaction is -30 to 20 °C. The method according to claim 1, wherein the reaction system pressure of the aminolysis reaction is 0.2 to 5.0 MPa. The method according to claim 6, wherein the reaction system pressure of the aminolysis reaction is from 0.5 to 3.0 MPa.