Synthesis of key intermediates for levetiracetam development

Abstract

The present invention relates to pharmaceutical drugs, particularly to synthesize potential levetiracetam intermediates from simple starting materials such as pyrrolidone and 2-bromo butyric acid to yield 2-(2-oxopyrrolidin-1-yl) butanoic acid. Subsequently, it was subjected to esterification to acquire the purest form of 2-(2-oxopyrrolidin-1-yl) butanoate with quantitative yield.

Description

[0001] SYNTHESIS OF KEY INTERMEDIATES FOR LEVETIRACETAM DEVELOPMENT RELATED PATENT APPLICATION

[0002] This application claims the priority to and benefit of Indian Patent Application No.

[0003] 202541008274 filed on January 31, 2025 the disclosures of which are incorporated herein by reference

[0004] FIELD OF INVENTION

[0005] The present invention relates to pharmaceutical drugs, particularly to synthesize potential levetiracetam intermediates from simple starting materials such as pyrrolidone and 2 -bromo butyric acid to yield 2-(2-oxopyrrolidin-l-yl) butanoic acid. Subsequently, it was subjected to esterification to acquire the purest form of 2-(2-oxopyrrolidin-l-yl) butanoate with quantitative yield.

[0006] BACKGROUND OF THE INVENTION

[0007] Levetiracetam (1) is an FDA-approved antiepileptic drug that will bind with the synaptic vesicle glycoprotein 2A (SV2A) in the brain with a unique antiepileptic mechanism. Its structurally similar brivaracetam (2) also binds with SV2A but there is a strong correlation between the binding affinity of the drug to SV2A and potency in the audiogenic seizure. Due to this reason levetiracetam (1) is better and more beneficial than other racetam drugs for patients to treat various problems like bipolar disorders, migraines, chronic or neuropathic pain, and diabetic complications because of its advantageous pharmacokinetics, pharmacoresistant, epileptogenesis and lower potential for drug-drug interactions. When levetiracetam (1) is used for monotherapy, the results show less teratogenic than other anti-seizure medications (ASMs), this makes its use viable for women in their gestation period.

[0008]

[0009] Levetiracetam Brivaracetam

[0010] Levetiracetam synthesis predominantly focuses on its production from either the acid precursor (-)-3 (a-ethyl-2-oxo- 1 -pyrrolidine acetic acid) or the ester precursor (-)-4 (a-ethyl-2-oxo-l-pyrrolidine acetic acid methyl or ethyl ester), utilizing an amidation process with either aqueousor gaseous ammonia. The synthesis of the acid precursor (±)-3 typically involves the condensation of 2-halobutyric acid (±)-5a with 2-pyrrolidone 6 in the presence of a strong base. On the other hand, the ester precursor (±)-4 is produced by condensing 2-halobutyrate (±)-5b with 2-pyrrolidone 6, also using a strong base. However, the esterification of (±)-4 results in an oily liquid that resists purification by conventional techniques such as crystallization or chromatography. Consequently, this compound is often used in its crude form for the chiral resolution process to obtain the desired stereoisomer (-)-4.

[0011] Although chiral resolution ensures the purity of the stereoisomer, the resulting compound still contains impurities originating from the racemic mixture (±)-4 as well as from earlier synthesis stages. Notably, the compounds (-)-4 and (±)-4 remain identical following the chiral resolution process. These residual impurities can carry over into the subsequent amidation step, potentially affecting the quality of the final levetiracetam (1) product. Such impurities can compromise both the safety and efficacy of the drug, underscoring the importance of achieving high purity in the intermediate compounds.

[0012] BRIEF DESCRIPTION OF THE INVENTION

[0013] To overcome these challenges, we have developed a novel method for synthesizing these intermediates with high yields and exceptional purity. This innovative approach not only improves the overall quality of levetiracetam with a cost-effective solution for large-scale production. By addressing issues related to impurity carryover and eliminating the need for inefficient purification processes, our method ensures the production of high-quality intermediates (and used for chiral resolution process to access chiral levetiracetam), which significantly enhances the consistency and safety of the final drug product, ultimately benefiting both manufacturers and patients.

[0014] BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

[0015] Figure 1 is related to H1NMR Spectra of Compound rac-4a

[0016] Figure 2 is related to C13NMR Spectra of Compound rac- 4a

[0017] Figure 3 is related to C13(DEPT 135) NMR Spectra of Compound rac-4aFigure 4 is related to H1NMR Spectra of Compound rac-4b

[0018] Figure 5 is related to C13NMR Spectra of Compound rac- 4b

[0019] Figure 6 is related to C13(DEPT 135) NMR Spectra of Compound rac-4b

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention is related to a process of preparing the intermediate compounds 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) and 2-(2-oxopyrrolidin-l-yl) butanoate (rac-4) which are useful in the preparation of levetiracetam drug compound in higher yield with higher purity. The present invention relates to synthesize potential levetiracetam intermediates from simple starting materials such as pyrrolidone and 2-bromo butyric acid to yield 2-(2-oxopyrrolidin-l-yl) butanoic acid. Subsequently, it was subjected to esterification to acquire the purest form of 2-(2-oxopyrrolidin-l-yl) butanoate with quantitative yield.

[0022] The present invention offers a method for obtaining a pure form of levetiracetam intermediates, which in turn enhances the purity of compound (-)-4 and the final levetiracetam drug. To accomplish this objective, the invention employs the following technique.

[0023] The following is the schematic representation of the present invention that relates to a novel process of preparing the intermediates useful for the preparation of levetiracetam in higher yield and purity.

[0024]

[0025] Synthetic route for the levetiracetam intermediates

[0026] In an embodiment of the present invention, 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) is prepared by quaternary ammonium salt catalyzed dehydrohalogenation reaction of 2-bromobutyric acid or ester (rac-5a) and 2-pyrrolidone (6) with an excess amount of inorganicbase in toluene. To get a pure compound, an acidic solution, preferably HC1 solution was used to acidify the reaction medium, and the crude product was extracted using organic solvent. After concentration, the crude compound was subjected to recrystallization using organic solvents at low temperature and yielded the pure product rac-3 with moderate yield.

[0027] In the above process, the quaternary ammonium salt is preferably selected from tetra butyl ammonium chloride, tetra butyl ammonium bromide or tetra butyl ammonium iodide, wherein the said salt is taken around 10 mol%.

[0028] In the above process, the inorganic base is selected from alkali metal hydroxides and alkaline earth metal hydroxides. Preferably the inorganic base is an alkali metal hydroxide. Most preferably the inorganic base is selected from sodium hydroxide and potassium hydroxide wherein the quantity of base is around 5 equivalents.

[0029] In the above process, the organic solvent used for extraction is selected from dichloromethane and ethyl acetate though other solvents or solvent mixtures are not ruled out.

[0030] In the above process, the organic solvent used for recrystallization is preferably THF (Tetrahydro Furan) though other solvents or solvent mixtures are not ruled out.

[0031] In another embodiment of the present invention, 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) is prepared by subjecting methyl 2-(2-oxopyrrolidin-l-yl) butanoate to hydrolysis in presence of aqueous solution of strong base at elevated temperature for an hour. Once the ester was exhausted, the reaction medium is quenched by adjusting to acidic pH and precipitated at a lower temperature. Then the targeted compound was obtained quantitatively after extracted using DCM in water.

[0032] In the above process, strong base is selected from alkali metal hydroxides and alkaline earth metal hydroxides. Preferably the inorganic base is an alkali metal hydroxide. Most preferably the inorganic base is selected from sodium hydroxide and potassium hydroxide wherein the quantity of base is around 1.4 equivalents.

[0033] In the above process, the temperature maintained for the reaction ranges from 30 ° C to 80 ° C, most preferably around 50 ° C.

[0034] In the above reaction, acidic pH is obtained by using any strong acid to maintain pH at around 2 after quenching.The advantage of the above process is observed that pure compound was obtained without column chromatography or recrystallization process.

[0035] In an embodiment of the inventive process, the pure 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) was subjected to esterification in the presence of the catalytic amount of concentrated acid in an alkyl alcohol solvent with heating. Once the carboxylic acid rac-3 was consumed completely reaction mixture was quenched in an alkaline solution and alkaline pH is maintained. And then extracted the product using organic solvents by three times. The combined solution was concentrated and yielded the desired product quantitatively.

[0036] In the above process, the acid used is selected from halo acids, sulfuric acid and phosphoric acids but preferably concentrated sulfuric acid is used.

[0037] In the above process, alkyl alcohol is either methyl alcohol or ethyl alcohol wherein the alcohol content is 2 times the substrate.

[0038] In the above process, the temperature maintained for the reaction ranges from 50 ° C to 90 ° C. The temperature maintained for the above reaction is around 70 ° C when methanol is used. The temperature maintained for the above reaction is around 80 ° C when ethanol is used. In the above process, the base used for quenching the reaction is selected from saturated sodium carbonate, potassium carbonate and sodium bicarbonate solution and the pH of the medium is maintained at alkaline pH, preferably between 8-10.

[0039] In the above process, the organic solvent used for extraction is selected from dichloromethane and ethyl acetate though other solvents or solvent mixtures are not ruled out.

[0040] In another embodiment of the inventive process, the pure 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) was subjected to esterification in the presence of the catalytic amount of organic base and stoichiometric amount of dehydrating agent in solvent. Then an excess amount of ethanol was added and stirred at room temperature for 24 hours. After completion of the reaction non-polar solvent was added to make precipitate and it was filtered off, the remaining filtrate was concentrated in vacuum to afford colorless oily liquid. The oil in water was washed with DCM, and then the solvent was passed through NaiSCh and concentrated in vacuo to afford product with moderate yield.

[0041]

[0042] In the preparation of compound (±) 4b the organic base catalyst used for this reaction is N,N-dimethylaminopyridine.

[0043] In the preparation of compound (±) 4b the dehydrating reagent used for this reaction is N,N’-dicyclohexylcarbodiimide.

[0044] In the preparation of compound (±) 4b solvent used is THF and non-polar solvent used is hexane.

[0045] EXAMPLES

[0046] EXAMPLE 1

[0047] Preparation of 2-(2-oxopyrrolidin-l-yl) butanoic acid

[0048] Into a 2000 ml round bottom flask, 20 g of 2-pyrrolidone (1.0 equiv.) in 800 mL toluene was taken and 65.93 g of KOH (5.0 equiv.) was added and stirred at RT for an hour. To the stirred solution, a catalytic amount of TB AB (6.42 mL, 0.1 equiv.) and 2 -bromobutyric acid (50.1 mL, 2.0 equiv.) was added and stirred for one more hour at RT. After completion of the reaction 600 mL of 20% HC1 solution was added into the reaction mixture and extracted the compound using 500 mL of DCM. This process was repeated three times then combined the organic layers and concentrated under reduced pressure. The resulting crude oily liquid was recrystallized using THF at -20°C giving the pure form of titled product rac-3 in -50% yield as a white solid. ’H NMR (400 MHz, CDC13) 89.65 (1H, s), 4.66 (1H, dd, J = 4.8, 4.8 Hz), 3.57 (1H, q, J = 6.4 Hz), 3.39-3.33 (1H, m), 2.49 (2H, t, J = 8 Hz), 2.16-1.98 (3H, m), 1.78-1.66 (1H, m), 0.94 (3H, t, J = 7.4 Hz); HRMS (ESI) m / z: 194.0788 [M + Na]+, calculated for C8Hi3NO3Na+; Found 194.0789.EXAMPLE 2

[0049] Preparation of 2-(2-oxopyrrolidin-l-yl) butanoic acid

[0050] Into the 100 mL round bottom flask, 20 g of methyl 2-(2-oxopyrrolidin-l-yl) butanoate was dissolved in 40 mL of 15% aqueous NaOH solution and stirred at 50 °C for an hour. After completion of the reaction, 11.5 N HC1 solution was used to adjust the pH into 2 then the reaction mixture cooled to 0 °C for better precipitation. After filtration the product was extracted using DCM in water and concentrated to get titled compound rac-3 as a white solid with >55% yield.

[0051] EXAMPLE 3

[0052] Synthesis of methyl 2-(2-oxopyrrolidin-l-yl) butanoate

[0053] Into the 100 mL round bottom flask, 20 g of 2-(2-oxopyrrolidin-l-yl) butanoic acid was dissolved in 40 mL of methanol and stirred at 0°C for 15 min. under an argon atmosphere. Then 1.5 mL of con.HiSCL was added into the reaction mixture and refluxed for an hour. After completion of the reaction, NaiCCh solution was used to adjust the pH range of -8.0-10.0 then concentrated the reaction mixture under reduced pressure. Then 100 mL of distilled water and DCM were added into it and the organic layer was collected using a separating funnel and then dried over anhydrous NaiSCL. After concentrating the organic layer under reduced pressure, the titled compound rac-4a was obtained as a pale-yellow liquid with >95% yield. ’H NMR (400 MHz, CDC13) 84.61(1H, dd, J = 5.1, 5.1 Hz), 3.64 (3H, s), 3.47-3.41 (1H, m), 3.31-3.25 (1H, m), 2.37 (2H, t, J = 8.2 Hz), 2.09-1.89 (3H, m), 1.68-1.56 (1H, m), 0.85 (3H, t, J = 7.4 Hz) );13C NMR (100 MHz, CDCI3, DEPT-135) 6 176.0 (C, N-C=O), 171.5 (C, O-C=O), 55.1 (CH), 52.1 (CH), 43.5 (CH2), 30.8 (CH2), 22.0 (CH2), 18.2 (CH2), 10.7 (CH3); HRMS (ESI) m / z: 208.0944 [M + Na]+, calculated for C9HisNO3Na+; Found 208.0949

[0054] EXAMPLE 4

[0055] Synthesis of ethyl 2-(2-oxopyrrolidin-l-yl) butanoate

[0056] Into the 100 mL round bottom flask, 20 g of 2-(2-oxopyrrolidin-l-yl) butanoic acid was dissolved in 40 mL of ethanol and stirred at 0°C for 15 min. under an argon atmosphere. Thencompletion of the reaction, NaiCCh solution was used to adjust the pH range of -8.0-10.0 then concentrated the reaction mixture under reduced pressure. Then 100 mL of distilled water and DCM were added into it and the organic layer was collected using a separating funnel and then dried over anhydrous NaiSCh. After concentrating the organic layer under reduced pressure, the titled compound was obtained as a pale-yellow liquid with >95% yield.1H NMR (400 MHz, CDC13) 64.59 (1H, dd, J = 5.1, 5.1 Hz), 4.12-4.06 (2H, m), 3.49-3.43 (1H, m), 3.30-3.24 (1H, m), 2.36 (2H, t, J= 8.1 Hz), 2.08-1.90 (3H, m), 1.68-1.56 (1H, m), 1.19 (3H, t, 7.2 Hz), 0.85 (3H, t, J = 7.4 Hz) );13C NMR (100 MHz, CDCI3, DEPT-135) 5 176.0 (C, N-C=O), 171.1 (C, O-C=O), 61.08 (CH2), 55.2 (CH), 43.5 (CH2), 30.9 (CH2), 22.1 (CH2), 18.3 (CH2), 14.1 (CH3), 10.8 (CH3) ); HRMS (ESI) m / z: 200.1281 [M + H]+, calculated for CIOHI8N03+; Found 200.1284.

[0057] EXAMPLE 5

[0058] Synthesis of ethyl 2-(2-oxopyrrolidin-l-yl) butanoate

[0059] Into the 1000 mL round bottom flask, 20 g of 2-(2-oxopyrrolidin-l-yl) butanoic acid, 21.2 ml of ethanol and 1.44 g of DMAP was dissolved in 800 mL of THF and stirred at 0°C for 15 min. under an argon atmosphere. Then 25.2 g of DCC was added into the reaction mixture and stirred at room temperature for 24 hours. After completion of the reaction, hexane was used to precipitate in the reaction mixture. The precipitate was filtered off, the remaining filtrate was concentrated in vacuum to afford crude oily liquid. The oil in water was washed with DCM, and then the solvent was passed through Na2SO4 and concentrated in vacuo to afford product with 64% yield as a pale-yellow liquid.

Claims

We claim:

1. A process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield for the preparation of levetiracetam, an antiepileptic drug comprising the steps of;a) reacting 2-bromobutyric acid or ester (rac-5a) with 2-pyrrolidone (6) 2-(2- oxopyrrolidin-l-yl) butanoic acid (±)3 in an organic solvent and in the presence of quaternary ammonium salt and an inorganic base to prepare 2-(2-oxopyrrolidin-l- yl) butanoic acid;b) 2-(2-oxopyrrolidin-l-yl) butanoic acid as in step a) is purified by an acidic solution and the crude is extracted by using an organic solvent;c) The crude as obtained in step b) is subjected to recrystallization by using an organic solvent;d) converting 2-(2-oxopyrrolidin-l-yl) butanoic acid of step d) into 2-(2- oxopyrrolidin-l-yl) butanoic acid ester in the presence of the catalytic amount of concentrated acid in an alkyl alcohol solvent with heating.e) upon completion of reaction of step d), the reaction mixture is quenched in an alkaline solution;f) plurality of extracting the product of step e) by an organic solvent; andg) combining the extracts of step f) and concentrated by known means to obtain the ester intermediate compound.

2. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step a) the quaternary ammonium salt is preferably selected from tetra butyl ammonium chloride, tetra butyl ammonium bromide or tetra butyl ammonium iodide.

3. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step a) the amount of quaternary ammonium salt is 10 mole percent.

4. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step a) the inorganic base is selected from alkali metal hydroxides and alkaline earth metal hydroxides and most preferably the inorganic base is an alkali metal hydroxide.

5. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step a) the inorganic base is selected from sodium hydroxide and potassium hydroxide.

6. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step a) the inorganic base is present in 5 equivalents.

7. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step b) the organic solvent for extraction is selected from dichloromethane and ethyl acetate.

8. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step c) the recrystallization solvent is preferably tetra hydro furan (THF).

9. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step d) the catalytic amount of concentrated acid is selected from halo acids, sulfuric acid and phosphoric acids but preferably concentrated sulfuric acid is used.

10. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yieldas claimed in claim 1 wherein in step d) the alkyl alcohol is either methyl alcohol or ethyl alcohol wherein the alcohol content is 2 times the substrate.

11. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step d) the the temperature maintained for the reaction ranges from 50 °C to 90 °C.

12. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step d) the the temperature maintained for the reaction is 70°C when methanol is used.

13. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step d) the the temperature maintained for the reaction is 80 °C when ethanol is used.

14. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein the alkaline solution in step e) is selected from saturated sodium carbonate, potassium carbonate and sodium bicarbonate solution.

15. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step e) the pH is maintained between 8 and 10.

16. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yield as claimed in claim 1 wherein in step f) the organic solvent for extraction is selected from dichloromethane and ethyl acetate.

17. The process for the preparation of key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid and 2-(2-oxopyrrolidin-l-yl) butanoic acid ester in higher purity and higher yieldas claimed in claim 1 wherein the methyl or ethyl ester of 2-(2-oxopyrrolidin-l-yl) butanoic acid is prepared by the reaction scheme;18. A process for the preparation of one of the key intermediates, 2-(2-oxopyrrolidin-l-yl) butanoic acid in higher purity and higher yield comprising the steps of;a) subjecting methyl 2-(2-oxopyrrolidin-l-yl) butanoate to hydrolysis in presence of aqueous solution of strong base at elevated temperature for an hour;b) upon completion of reaction of step a) the reaction mixture is quenched by adjusting to acidic pH and precipitated at a lower temperature 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3);c) extracting 2-(2-oxopyrrolidin-l-yl) butanoic acid (rac-3) of step b) by a mixture of an organic solvent and water.

19. The process for the preparation of one of the key intermediates, 2-(2-oxopyrrolidin-l- yl) butanoic acid in higher purity and higher yield as claimed in claim 18 wherein in step a) the strong base is selected from alkali metal hydroxides and alkaline earth metal hydroxides, preferably the inorganic base is an alkali metal hydroxide.

20. The process for the preparation of one of the key intermediates, 2-(2-oxopyrrolidin-l- yl) butanoic acid in higher purity and higher yield as claimed in claim 18 wherein in step a) the strong base is selected from sodium hydroxide and potassium hydroxide.

21. The process for the preparation of one of the key intermediates, 2-(2-oxopyrrolidin-l- yl) butanoic acid in higher purity and higher yield as claimed in claim 18 wherein in step a) the strong base is present in 1.4 equivalents.

22. The process for the preparation of one of the key intermediates, 2-(2-oxopyrrolidin-l- yl) butanoic acid in higher purity and higher yield as claimed in claim 18 wherein in step c) the organic solvent and water mixture is preferably dichloromethane (DCM) and water mixture.

23. A process for the preparation of one of the key intermediates, the methyl ester of 2-(2- oxopyrrolidin-l-yl) butanoic acid comprising the steps of;a) esterifying 2-(2-oxopyrrolidin-l-yl) butanoic acid with 40% of methanol;b) stirring the reaction mixture of step a) at 0° C for 15 minutes in an inert gas; c) to the stirred mixture of step b) con.H2.SO4 is added and refluxed for an hour; d) upon completion of the reaction of step b) NaiCOs solution is added to maintain pH in between 8 and 10;e) concentrated the reaction mixture under reduced pressure;f) to the concentrated reaction mixture dichloromethane and distilled water is added; g) the organic layer is collected, dried over anhydrous NaiSCh;h) after concentrating the organic layer under reduced pressure, the titled compound rac- 4a was obtained as a pale-yellow liquid with >95% yield.

24. A process for the preparation of one of the key intermediates, the ethyl ester of 2-(2- oxopyrrolidin-l-yl) butanoic acid comprising the steps of;a) esterifying 2-(2-oxopyrrolidin- 1-yl) butanoic acid with excess amount of ethanol in the presence of the catalytic amount of organic base and stoichiometric amount of dehydrating agent in solvent;b) stirring the reaction mixture of step a) at room temperature for 24 hours;c) upon completion of the reaction of step b) a non-polar solvent is added to make precipitate, and it was filtered off;d) filtrate is concentrated in vacuum to afford colorless oily liquid;e) the oily liquid of step d) is washed with dichloromethane;f) solvent is passed through NaiSCk and concentrated in vacuo to obtain ethyl ester of 2-(2-oxopyrrohdin-l-yl) butanoic acid with >95% yield.25) The process for the preparation of one of the key intermediates, the ethyl ester of 2- (2-oxopyrrolidin-l-yl) butanoic acid as claimed in claim 23 wherein the organic base of step a) is N,N-dimethylaminopyridine.26) The process for the preparation of one of the key intermediates, the ethyl ester of 2- (2-oxopyrrolidin-l-yl) butanoic acid as claimed in claim 23 wherein the dehydrating agent of step a) is N,N’ -dicyclohexylcarbodiimide.27) The process for the preparation of one of the key intermediates, the ethyl ester of 2- (2-oxopyrrolidin-l-yl) butanoic acid as claimed in claim 23 wherein the solvent of step a) is tetrahydro furan (THF).28) The process for the preparation of one of the key intermediates, the ethyl ester of 2- (2-oxopyrrolidin-l-yl) butanoic acid as claimed in claim 23 wherein the non-polar solvent of step c) is hexane.

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