A preparation method of levetiracetam intermediate

Abstract

A method for preparing a levetiracetam intermediate, particularly by optimizing a post-treatment process, so that the reaction yield and product purity are significantly improved.

Description

[0001] This application claims the priority of Chinese patent application filed with the China Patent Office on June 30, 2020, with application number 202010612071.2 and invention name “A method for preparing a levetiracetam intermediate”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The invention relates to a synthetic method for preparing a levetiracetam intermediate, and belongs to the field of pharmaceutical chemical industry. Background Art

[0003] Levetiracetam is a highly effective, broad-spectrum anti-epileptic drug with low toxicity and side effects developed by UCB of Belgium. It is mainly used to treat localized and secondary systemic epilepsy. Its chemical name is (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, and its structural formula is shown in Formula I.

[0004]

[0005] Patent WO2019028671 reports the following method: 2-bromobutyrate and 2-pyrrolidone are used as raw materials, condensed to generate α-ethyl-2-oxo-1-pyrrolidine acetate; split under the action of ester hydrolase to obtain (S)-α-ethyl-2-oxo-1-pyrrolidine acetate; then aminolysis is performed to obtain crude levetiracetam; and finally, levetiracetam is refined. The synthetic route of this method is as follows:

[0006]

[0007] Wherein R is a C1-C6 alkyl group.

[0008] In the above route, there is a large amount of (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid in the mother liquor of enzyme resolution, and the method disclosed in CN110003074 can be referred to for racemization recovery to obtain (R / S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid. The recovered (R / S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid can be further used as a substrate for enzyme resolution after esterification. There are few reports on the esterification of (R / S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid in the prior art. For example, CN10590635 reported that (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid was reacted in anhydrous ethanol and p-toluenesulfonic acid at 60°C, and after the reaction was completed, (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid was obtained by vacuum concentration, and then further ammoniation was performed to obtain levetiracetam, and the two-step yield was only 59%. In general, the amination yield can reach 90%, which means that the esterification yield is only 65%, which is low. The inventors found that the direct concentration of α-ethyl-2-oxo-1-pyrrolidineacetic acid after alcoholization under acid catalysis will lead to unstable yield, which is generally below 75%, and the purity is less than 80%, with more than 15% of raw materials remaining. Summary of the invention

[0009] The object of the present invention is to provide an improved method for preparing α-ethyl-2-oxo-1-pyrrolidine acetate shown in formula II.

[0010]

[0011] In the above formula II, R is a C1-C6 alkyl group,

[0012] The steps include:

[0013] (1) α-ethyl-2-oxo-1-pyrrolidineacetic acid undergoes esterification reaction with C1-C6 alcohol in the presence of a catalyst.

[0014] (2) After the reaction is completed, an appropriate amount of water is added, and an alkali solution is added dropwise at a certain temperature range to adjust the pH to 6.0-8.0, and the residual alcohol is evaporated under reduced pressure. The residual liquid is extracted with an organic solvent, and the organic phase is evaporated to dryness to obtain α-ethyl-2-oxo-1-pyrrolidine acetate (II).

[0015] In the above method for preparing α-ethyl-2-oxo-1-pyrrolidine acetate:

[0016] α-Ethyl-2-oxo-1-pyrrolidine acetate is (R / S)-α-ethyl-2-oxo-1-pyrrolidine acetate or (S)-α-ethyl-2-oxo-1-pyrrolidine acetate.

[0017] The catalyst is selected from concentrated sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or thionyl chloride, preferably concentrated sulfuric acid;

[0018] The mass ratio of the catalyst to α-ethyl-2-oxo-1-pyrrolidineacetic acid (IV) is 0.02:1 to 0.5:1, preferably 0.03:1 to 0.1:1;

[0019] The C1-C6 alcohol is preferably methanol or ethanol;

[0020] The mass ratio of alcohol to α-ethyl-2-oxo-1-pyrrolidineacetic acid (IV) is 1:1 to 15:1, preferably 2:1 to 4:1; the reaction temperature is 40 to 90°C, preferably, when methanol is used, the reaction temperature is 65 to 70°C, and when ethanol is used, the reaction temperature is 75 to 80°C.

[0021] After the reaction is completed, water and α-ethyl-2-oxo-1-pyrrolidineacetic acid (IV) are added in a mass ratio of 1:1 to 5:1, preferably 1.5:1 to 3:1;

[0022] When the alkaline solution is added dropwise, the temperature of the reaction system is 30 to 70°C, preferably 40 to 60°C;

[0023] The alkaline solution is selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution or sodium bicarbonate solution, preferably 5-20% sodium carbonate solution or 5% to saturated sodium bicarbonate solution;

[0024] Adding alkaline solution dropwise to adjust the pH to 6.0-8.0, preferably 7.0-7.5;

[0025] The distillation temperature for removing the residual alcohol under reduced pressure is 30 to 70°C, preferably 40 to 50°C;

[0026] The organic solvent used in the extraction is selected from toluene, ethyl acetate or dichloromethane; the number of extractions is 2 to 3 times, and the mass ratio of the extraction solvent used each time to α-ethyl-2-oxo-1-pyrrolidineacetic acid (IV) is 1:1 to 5:1, preferably 1.5:1 to 2.5:1.

[0027] The preparation method provided by the present invention can inhibit the hydrolysis of the product α-ethyl-2-oxo-1-pyrrolidineacetic acid ester during the post-treatment process, and obtain the product with excellent yield and purity. When the preferred reaction and post-treatment conditions are used, the product yield reaches more than 90% and the purity reaches more than 99% based on α-ethyl-2-oxo-1-pyrrolidineacetic acid. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical scheme, and advantages of the present invention more clearly understood, the present invention is further described in detail with reference to the following embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0029] The detection methods used in the following examples are as follows:

[0030] Purity HPLC analysis method:

[0031] Instrument: High performance liquid chromatography with UV detector

[0032] Column: Agilent Zobax Eclipse XDB C18 150×4.6mm, 5μm

[0033] Mobile phase: 0.01 mol / L ammonium dihydrogen phosphate aqueous solution: acetonitrile = 1:9.

[0034] Example 1

[0035] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0036] α-Ethyl-2-oxo-1-pyrrolidineacetic acid (50 g, 0.29 mol) and methanol (100 g) were added to a reaction flask, concentrated sulfuric acid (2 g) was added dropwise, the temperature was raised to 65-70° C. under stirring, refluxed for 2 hours, water (100 g) was added, the temperature was controlled within the range of 40-50° C., 10% Na2CO3 solution was added dropwise under stirring until the pH of the reaction system was 7.0-7.5, the temperature was controlled within the range of 40-50° C., the remaining methanol was evaporated under reduced pressure, the residual liquid was extracted twice with toluene (100 g), the organic phases were combined, and the mixture was distilled under reduced pressure until no liquid flowed out to obtain methyl α-ethyl-2-oxo-1-pyrrolidineacetate with a yield of 49.1 g, a yield of 90.7%, and an HPLC purity of 99.2%.

[0037] Example 2

[0038] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0039] α-Ethyl-2-oxo-1-pyrrolidineacetic acid (50 g, 0.29 mol) and methanol (100 g) were added to a reaction flask, concentrated sulfuric acid (4 g) was added dropwise, the temperature was raised to 65-70° C. under stirring, refluxed for 3 hours, water (100 g) was added, the temperature was controlled within the range of 40-50° C., 10% NaHCO3 solution was added dropwise under stirring until the pH of the reaction system was 7.0-7.5, the temperature was controlled within the range of 40-50° C., the remaining methanol was evaporated under reduced pressure, the residual liquid was extracted twice with ethyl acetate (100 g), the organic phases were combined, and the mixture was distilled under reduced pressure until no liquid flowed out to obtain methyl α-ethyl-2-oxo-1-pyrrolidineacetate with a yield of 49.3 g, a yield of 91.2%, and an HPLC purity of 99.4%.

[0040] Example 3

[0041] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0042] α-Ethyl-2-oxo-1-pyrrolidineacetic acid (50 g, 0.29 mol) and ethanol (150 g) were added to a reaction flask, concentrated sulfuric acid (5 g) was added dropwise, the temperature was raised to 78-80° C. under stirring, refluxed for 2 hours, water (100 g) was added, the temperature was controlled within the range of 40-60° C., 15% Na2CO3 solution was added dropwise until the pH of the reaction system was 7.0-7.5, the temperature was controlled within the range of 40-50° C., the remaining ethanol was evaporated under reduced pressure, the residual liquid was extracted 3 times with dichloromethane (100 g), the organic phases were combined, and the mixture was distilled under reduced pressure until no liquid flowed out to obtain ethyl α-ethyl-2-oxo-1-pyrrolidineacetate with a yield of 52.4 g, a yield of 90.1%, and a HPLC purity of 99.3%.

[0043] Comparative Example 1:

[0044] α-Ethyl-2-oxo-1-pyrrolidineacetic acid (50 g, 0.29 mol) and methanol (100 g) were added to a reaction flask, concentrated sulfuric acid (5 g) was added dropwise, the temperature was raised to 65-70° C. with stirring, refluxed for 6 hours, cooled to 30-50° C., evaporated to dryness under reduced pressure to obtain α-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester with a yield of 36.5 g, a yield of 68.0%, and a HPLC purity of 79.2%.

[0045] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing α-ethyl-2-oxo-1-pyrrolidine acetate shown in formula II, In the above formula II, R is a C1-C6 alkyl group, The steps include: (1) esterification reaction of α-ethyl-2-oxo-1-pyrrolidineacetic acid with a C1-C6 alcohol in the presence of a catalyst, wherein the catalyst is concentrated sulfuric acid, and the mass ratio of the catalyst to the α-ethyl-2-oxo-1-pyrrolidineacetic acid is 0.02:1 to 0.5:1; (2) After the reaction is completed, an appropriate amount of water is added, and an alkali solution is added dropwise at a certain temperature range to adjust the pH to 6.0-8.0, and the residual alcohol is evaporated under reduced pressure, and the residual liquid is extracted with an organic solvent, and the organic phase is evaporated to dryness to obtain α-ethyl-2-oxo-1-pyrrolidine acetate represented by formula II; The mass ratio of water added in step (2) to α-ethyl-2-oxo-1-pyrrolidineacetic acid is 1:1 to 5:1; The alkaline solution in step (2) is a 5-20% sodium carbonate solution or a 5% to saturated sodium bicarbonate solution.

2. The method according to claim 1, wherein the C1-C6 alcohol is methanol or ethanol.

3. The method according to claim 1 or 2, wherein the mass ratio of water added in step (2) to α-ethyl-2-oxo-1-pyrrolidineacetic acid is 1.5:1 to 3:

1.

4. The method according to claim 1 or 2, wherein the temperature of the reaction system is 30 to 70°C when the alkaline solution is added dropwise in step (2).

5. The method according to claim 4, wherein the temperature of the reaction system is 40-60°C when the alkaline solution is added dropwise in step (2).

6. The method according to claim 1 or 2, wherein in step (2), an alkaline solution is added dropwise to adjust the pH to 7.0 to 7.

5.

7. The method according to claim 1 or 2, wherein the distillation temperature for removing the residual alcohol under reduced pressure in step (2) is 30 to 70°C.

8. The method according to claim 7, wherein the distillation temperature for removing the residual alcohol under reduced pressure in step (2) is 40-50°C.

9. The method according to claim 1 or 2, wherein the organic solvent used in the extraction in step (2) is selected from toluene, ethyl acetate or dichloromethane.

10. The method according to claim 1 or 2, wherein the number of extractions in step (2) is 2 to 3 times, and the mass ratio of the extraction solvent to α-ethyl-2-oxo-1-pyrrolidineacetic acid used each time is 1:1 to 5:

1.

11. The method according to claim 10, wherein the mass ratio of the extraction solvent to α-ethyl-2-oxo-1-pyrrolidineacetic acid used each time in the extraction of step (2) is 1.5:1 to 2.5:

1.

12. The method according to claim 1 or 2, wherein the α-ethyl-2-oxo-1-pyrrolidine acetate is (R / S)-α-ethyl-2-oxo-1-pyrrolidine acetate or (S)-α-ethyl-2-oxo-1-pyrrolidine acetate.

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