Process for Preparing Brivaracetam

FIELD OF THE DISCLOSURE

The present invention relates to a novel compound, (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, which can be used as an intermediate in the preparation of brivaracetam. The invention is also directed to processes for preparing intermediates used in the preparation of brivaracetam. Brivaracetam has the following structure:

BACKGROUND OF THE DISCLOSURE

Brivaracetam is marketed in the United States under the trade name BRIVIACT®. It is available in tablet form, as an oral solution, and as an injection. The chemical name of BRIVIACT® (brivaracetam) is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide. Its molecular formula is C11H20N2O2 and its molecular weight is 212.29. BRIVIACT® is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

Various patents disclose processes for the preparation of brivaracetam, such as U.S. Patent Nos. 7,629,474; 8,076,493; and 8,957,226. Various publications also disclose processes for the preparation of brivaracetam, such as Kenda et al, J. Med. Chem. 2004, 47, 530, “Discovery of 4- substituted pyrrolidone butanamides as new agents with significant antiepileptic activity.” However, these published syntheses describe the use of chiral or conventional chromatography or low yielding diastereomeric crystallizations to synthesize brivaracetam with the correct chirality of the two contained chiral centers, and thus are unattractive for scale-up.

SUMMARY OF THE DISCLOSURE

The present invention is directed to a novel compound, (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, which can be used as an intermediate in the preparation of brivaracetam. The invention is also directed to a process of preparing (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid. Further, the invention is directed to P100183W001 a process of preparing (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid from (4R)-1-((S)-

1-carboxypropyl)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid. (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid can also be used in a process of preparing brivaracetam.

DETAILED DESCRIPTION OF THE DISCLOSURE

The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples Various modifications to the examples described herein will be clear to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the examples described herein and shown but are to be accorded the scope consistent with the claims.

As used herein and unless otherwise specified, the following terms in quotes have the definitions as noted below.

As used herein and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a reaction, reactant, or conditions, e.g., a specific temperature or temperature range, including, e.g., melting, or evaporation, may deviate to an extent deemed reasonable to one of ordinary skill in the art. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3 or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

The term “ambient temperature” or “room temperature” means between about 15 °C to about 30 °C, such as about 15 °C to about 25 °C.

As used herein and unless otherwise specified, the following abbreviations are defined as follows:

2-MeTHF - 2-Methyltetrahydrofuran

MTBE - Methyl tert-butyl ether P100183W001

DMSO - Dimethyl sulfoxide

THF - Tetrahydrofuran

DCM - Dichloromethane

DMF - Dimethylformamide

EA - Ethyl acetate

ACN - Acetonitrile

IPA - Isopropyl alcohol

PE - Petroleum Ether

One embodiment of the invention is directed to (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, as depicted in Formula I:

Formula I

Another embodiment of the invention is directed to use of a compound of Formula I in preparing brivaracetam.

Another embodiment of the invention is directed to a process for preparing a compound of

Formula I comprising reacting a suspension of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid with a solution of (R)-2-bromobutanoic acid as depicted below.

In one embodiment, a solution of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is added to a suspension of base in an organic solvent to yield the suspension of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid. In one embodiment, the organic solvent is P100183W001 selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, CH3OH, and THF. In a particular embodiment, the organic solvent is THF. The organic solvent in the solution of (4R)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid and in the suspension of base can be the same or different. In a particular embodiment, the organic solvent is the same. In one embodiment, about 8-10 volumes (mL), particularly about 8.5 volumes, of organic solvent are used per weight (g) of base in the suspension of base. In one embodiment, the base is selected from t-BuOK, CHsONa, CS2CO3, K2CO3, NaOH, and LiOH. In a particular embodiment, the base is NaOH. In one embodiment, about 15-25 volumes (mL), particularly about 20 volumes, of organic solvent are used per weight (g) of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid in the solution of (4R)- 2-oxo-4-propylpyrrolidine-3 -carboxylic acid. In one embodiment, the molar ratio of (4R)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid to base is about l:4.5-6.5, particularly, about 1:5. In one embodiment, the solution of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid is added dropwise to the suspension of base for about 10-20 minutes, particularly for about 15 minutes. In one embodiment, the resulting suspension is stirred at about 35-45 °C, particularly at about 40 °C, for about 20-40 minutes, particularly for about 30 minutes. In one embodiment, the solution of (R)-2-bromobutanoic acid comprises (R)-2-bromobutanoic acid in an organic solvent. In one embodiment, the organic solvent is selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, CH3OH, and THF. In a particular embodiment, the organic solvent is THF. In one embodiment, about 8-12 volumes (mL), particularly about 10 volumes, of organic solvent are used per weight (g) of (R)-2-bromobutanoic acid in the solution of (R)-2-bromobutanoic acid. In one embodiment, the solution of (R)-2-bromobutanoic acid is added to the suspension of (4R)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid. In a particular embodiment, the solution of (R)-2- bromobutanoic acid is added dropwise over about 1.5-2.5 hours, particularly over about 2 hours. In one embodiment, the molar ratio of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid to (R)- 2-bromobutanoic acid is about 1 :2. In one embodiment, the reaction mixture containing the suspension of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid and solution of (R)-2- bromobutanoic acid is stirred at about 35-45 °C, particularly at about 40 °C, for about 12-22 hours, particularly for about 15 hours. If the reaction mixture does not stir easily, additional organic solvent may be added to facilitate stirring. In one embodiment, the reaction mixture is cooled to room temperature. In one embodiment, the reaction mixture is concentrated to remove the organic solvent. In one embodiment, water is added after concentration. In one embodiment, P100183W001 about 25-35 volumes (mL), particularly about 30 volumes, of water are added per weight (g) of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid starting material. In one embodiment, the resulting mixture after addition of water is washed with DCM. In one embodiment, the mixture is washed 2 or 3 times, particularly 3 times. In one embodiment, about 9-11 volumes (mL), particularly about 10 volumes, of DCM are used per weight (g) of (4R)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid starting material. In one embodiment, the pH of the aqueous solution is adjusted to about 1-2. In one embodiment, the pH is adjusted with aqueous HC1. In a particular embodiment, the pH is adjusted with 4 M aqueous HC1. In one embodiment, the mixture is extracted with EA, resulting in aqueous and organic phases. In one embodiment, the mixture is extracted 2-4 times, particularly 4 times. In one embodiment, about 9-11 volumes (mL), particularly about 10 volumes, of EA are used per weight (g) of (4R)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid starting material for each extraction. In one embodiment, the organic phases are combined. In a further embodiment, the organic phases are dried over MgSCh and concentrated to yield an oil. In one embodiment, the oil is dissolved is an organic solvent selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, and CH3OH. In one embodiment the solvent is MTBE. In one embodiment, about 1.5-2 volumes (mL) of organic solvent are used per weight (g) of oil. In one embodiment, an antisolvent is added to the dissolved oil. In one embodiment, the anti-solvent is heptane. In one embodiment, about 8-12 volumes (mL) of antisolvent are added per weight (g) of oil. In one embodiment, the anti-solvent is added dropwise over about 30 minutes. In one embodiment, the mixture is stirred at room temperature for about 2-5 hours, particularly for about 3.5 hours. In one embodiment, the precipitate is collected by filtration. In one embodiment, the precipitated solid is recrystallized. In one embodiment, the precipitated solid is dissolved in an organic solvent selected from in 2-MeTHF, 1,4-dioxane, MTBE, DMSO, and CH3OH. In one embodiment, the solvent is MTBE. In one embodiment, about 2-4 volumes (mL), particularly about 3 volumes, of organic solvent are used per weight (g) of precipitated solid. In one embodiment, an antisolvent is added to the dissolved solid. In one embodiment, the anti-solvent is heptane. In one embodiment, about 14-18 volumes (mL), particularly about 16 volumes, of anti-solvent are added per weight (g) of dissolved solid. In one embodiment, the anti-solvent is added dropwise over about 30 minutes. In one embodiment, the mixture is stirred at RT for about 12-24 hours, particularly for about 17 hours, to yield a P100183W001 compound of Formula I. The compound of Formula I may be isolated by any means known to one of skill in the art. In one embodiment, the compound of Formula I is isolated by filtration.

Another embodiment of the invention is directed to a process of preparing (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid by heating a mixture of (4R)-l-((S)-l-carboxypropyl)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid in an organic solvent as depicted below.

In one embodiment, the organic solvent is DMF or 1,4-di oxane. In a particular embodiment, the organic solvent is DMF. In one embodiment, about 8-12 volumes (mL), particularly about 10 volumes, of organic solvent are used per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid. In one embodiment, the mixture of (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is heated to at least about 75 °C, particularly greater than about 100 °C. In one embodiment, the mixture of (4R)- l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxyl ic acid in an organic solvent is heated to about 105 °C in an oil bath. In one embodiment, the mixture of (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is stirred while heating. In a particular embodiment, the heating is for about 20-50 hours. The heating time can be adjusted based on the yield of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid. In one embodiment, the reaction mixture is cooled to RT. In one embodiment, aqueous HC1 is added to the reaction mixture. In a particular embodiment, 1 M aqueous HC1 is added. In one embodiment, about 25-35 volumes (mL), particularly about 30 volumes, of 1 M HC1 aqueous solution is added per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid starting material. In one embodiment, the mixture is extracted with EA, resulting in aqueous and organic phases. In one embodiment, the mixture is extracted 2-4 times, particularly 3 times, with EA. In one embodiment, about 8-12 volumes (mL), particularly about 10 volumes, of EA are used per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid starting material. In one embodiment, the organic phases are combined and washed with a LiCl aqueous solution. In one embodiment, the LiCl aqueous solution is 5% LiCl. In one embodiment, the combined organic phase is washed more than one time, particularly 5 times. In one P100183W001 embodiment, about 2-4 volumes (mL), particularly about 3 volumes, of aqueous LiCl is used per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-car boxylic acid starting material. In one embodiment, the organic phase is dried over MgSCh and concentrated to yield a solid. In one embodiment, the solid is optionally recrystallized. In one embodiment, the solid is dissolved in an organic solvent, such as EA, MTBE, toluene, 2-MeTHF, and THF. In a particular embodiment, the solvent is EA. In one embodiment, about 2 volumes of solvent (mL) are used per weight (g) of solid. In one embodiment, an antisolvent is added to the dissolved solid. In one embodiment, the anti-solvent is heptane. In one embodiment, about 1-14 volumes (mL), particularly about 12 volumes, of anti-solvent are added per weight (g) of solid. In one embodiment, the anti-solvent is added dropwise. In one embodiment, the mixture is stirred. In a particular embodiment, the mixture is stirred at RT for about 12-24 hours, particularly for about 17 hours, and at 0-5 °C for about 1-3 hours, particularly for about 2 hours, to yield (S)-2-((R)-2- oxo-4-propylpyrrolidin-l-yl)butanoic acid as a precipitate. The (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid may be isolated by any means known to one of skill in the art. In one embodiment, the (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid is isolated by filtration.

In one embodiment, the (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid is optionally recrystallized with an organic amine. In one embodiment, the organic amine is propan-2-amine or cyclohexylamine. In a particular embodiment, the organic amine is cyclohexylamine. In one embodiment, crude (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid is dissolved in an organic solvent such as EA, MTBE, and ACN. In a particular embodiment, the solvent is EA. In one embodiment, about 4-6 volumes, particularly about 5 volumes, of organic solvent are used per weight (g) of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid. In one embodiment, the organic amine is added to the dissolved (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid. In one embodiment, the molar ratio of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid to the organic amine is about 1: 1.5. In one embodiment, the organic amine is added drop wise. In one embodiment, the resulting mixture is stirred at RT for about 6-8 hours, particularly for about 6.5 hours, to yield the amine salt of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid as a precipitate. The precipitate may be isolated by any means known to one of skill in the art. In one embodiment, the precipitate is isolated by filtration. P100183W001

The above-described intermediates and processes therefore can be incorporated into a process for preparing brivaracetam. One embodiment of a process for preparing brivaracetam is set forth below.

Example

Step 1

CH3OH (1 L) is added dropwise to butyraldehyde (288 g, 4.0 mol, 1.2 eq.) at -15 °C, and the temperature is raised to -2 °C, then nitromethane (200 g, 3.3 mol, 1.0 eq.) is added at -15 °C to -10 °C. 50% NaOH aqueous solution (320 g, 4 mol, 1.2 eq.) is added dropwise over 1.5 h, the resulting mixture is stirred at this temperature for another 2 h. The conversion is ~ 70.5% (by measuring the assay of the reaction mixture). Then H2O (1 L) is added into the reaction mixture P100183W001 and the resulting mixture is added into a 4.5 M HC1 aqueous solution (4.25 L). The resulting mixture is extracted with DCM (3 x 1.6 L) and the combined organic phase is dried over MgSCh and concentrated to give a light brown liquid. The crude liquid is distilled under vacuum (internal temperature, 22-26 °C; external temperature, 33-36 °C) to give light yellow oil in 95.3% purity and 49.6% yield (187 g, assay is 99.5%).

Step 2

To a solution of (E)-l -nitropent- 1-ene (65.4 g, 0.57 mol, 1.0 eq.) in THF (650 mL) at -20 to -15 °C under protection of Argon, pre-cooled (-20 to -15 °C) dimethyl malonate (225.1 g, 1.7 mol, 3.0 eq.) is added dropwise followed by the addition of a pre-cooled (-20 to -15 °C) solution of catalyst Q (8.8 g, 0.028 mol, 0.05 eq.) in THF (400 mL) at -20 to -15 °C. The reaction mixture is stirred at this temperature for 94 h. HPLC analysis shows 91.1% of dimethyl (R)-2-(l-nitropentan-2- yl)malonate and 2.8% of (E)-l -nitropent- 1-ene, ee value is 94.4%. The reaction mixture is concentrated to remove THF to give a light yellow oil along with some solid. DCM (100 mL) is added into the crude oil and the resulting mixture is stirred at RT for 2 h and some solid precipitates out. The mixture is filtered to yield an off-white solid (catalyst Q, ~ 4.5 g). The filtrate is washed with 1 M HC1 aqueous solution (3 x 80 mL), H2O (80 mL), dried over MgSCU and concentrated to give a light yellow oil in 92.0% purity along with 5.0% of dimethyl malonate (260 g), assay 48.7%, ee value is 94.0%, no catalyst Q is detected in the crude oil by LC-MS, the yield is 90.1%.

In order to recover catalyst Q, the above combined HC1 aqueous solution is adjusted to pH 8 - 9. Some solid precipitates out and the solid is collected by filtration and the crude solid is re-slurried in IPA (20 mL) and an off-white solid is collected by filtration (~ 2.4 g). The aqueous filtrate is extracted with DCM (4 x 30 mL), dried over MgSCh and concentrated to give a brown oil. A mixture of the crude oil in IPA (15 mL) is stirred at RT for 1.5 h and some amount of solid precipitates out. The mixture is filtered to yield an off-white solid (~ 0.9 g). The above batches of P100183W001 crude catalyst Q (~ 7.8 g) are re-slurred in IPA (40 mL) at 50 °C for 1 h and at RT for 1 h. An off- white solid is collected to provide catalyst Q in 96.9% purity and 69.3% yield (6.1 g).

Step 3

A mixture of dimethyl (R)-2-(l-nitropentan-2-yl)malonate (195 g, assay 48.7%, the amount of pure dimethyl (R)-2-(l-nitropentan-2-yl)mal onate is 95 g), iron powder (2.0 g) and Pd/C (10% palladium on carbon with 57% H2O, 9.5 g) in CH3OH (665 mL) is hydrogenated at 45 °C and 0.5 MPa of H2 in a 1 L autoclave for 10 h. LC-MS analysis shows 18.4% of methyl (4R)-2-oxo-4- propylpyrrolidine-3-carboxylate, 61.9% of methyl (4R)-l-hydroxy-2-oxo-4-propylpyrrolidine-3- carboxylate, no dimethyl (R)-2-(l-nitropentan-2-yl)mal onate, and 7.9% of dimethyl malonate. The reaction is hydrogenated at this condition for another 7 h. LC-MS analysis shows 21.6% of methyl (4R)-2-oxo-4-propylpyrrolidine-3-carboxylate, 53.2% of methyl (4R)-l-hydroxy-2-oxo- 4-propylpyrrolidine-3-carboxylate, no dimethyl (R)-2-(l-nitropentan-2-yl)mal onate, and 11.7% of dimethyl malonate. Then additional Pd/C (10% palladium on carbon with 57% H2O, 9.5 g) and iron powder (2.0 g) is added and the reaction mixture is hydrogenated at this condition for another 7 h. LC-MS analysis shows 66.6% of methyl (4R)-2-oxo-4-propylpyrrolidine-3- carboxylate, 1.5% of methyl (4R)-l-hydroxy-2-oxo-4-propylpyrrolidine-3 -carboxylate, no dimethyl (R)-2-(l-nitropentan-2-yl)mal onate and 14.2% of dimethyl malonate. The reaction mixture is filtered through a celite pad and the cake is washed with CH3OH (3 x 30 mL). The filtrate is concentrated to give a brown oil (~ 160 g). The oil is combined with another two batches of crude methyl (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylate (~ 45 g) and purified by column (1.5 Kg silica), and eluted with 16.7% - 50% EA in PE to give three crops of product. After purifying by column, methyl (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylate is a light yellow oil initially and becomes an off-white waxy solid as it is stored at RT.

Step 4 P100183W001

To a solution of methyl (4R)-2-oxo-4-propylpyrrolidine-3-carboxylate (41.3 g, 223 mmol, 1.0 eq.) in CH3OH (200 mL), a 3 M NaOH aqueous solution (223 mL, 669 mmol, 3.0 eq.) is added drop wise and the resulting mixture is stirred at RT for 2 h. HPLC analysis shows 99.4% of (4R)- 2-oxo-4-propylpyrrolidine-3 -carboxylic acid. The reaction is concentrated to remove CH3OH and the residual is washed with DCM (2 x 100 mL), then the pH of the aqueous solution is adjusted to 1-2 by 4 M HC1 aqueous solution. The resulting aqueous solution is extracted with EA (4 x 100 mL). The combined organic phase is dried over Na2SO4 and concentrated to give a light yellow oil in 99.0% purity and 99% yield (38 g).

Step 5

A 3 L jacketed flask is equipped with a mechanical stirrer. To a suspension of NaOH (47.9 g, 1.2 mol, 5.0 eq.) in THF (410 mL), a solution of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid (41 g, 0.24 mol, 1.0 eq., purity 96.1%) in THF (820 mL) is added dropwise for 15 min and the resulting suspension is stirred at 40 °C for 30 min. Then a solution of (R)-2-bromobutanoic acid (80 g, 0.48 mol, 2.0 eq.) in THF (820 mL) is added dropwise for 2 h. After addition, a sample is taken and LC-MS analysis shows 11.9% of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, 38.2% of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid, and 25.2% of (R)-2-bromobutanoic acid, along with some impurities. The reaction mixture is intended to be stirred at this temperature overnight (~ 15 h), but the mechanical stirrer became stuck, possibly due to the stickiness of the reaction mixture. LC-MS analysis shows 40.1% of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-car boxylic acid, 5.5% of (4R)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid, and 3.7% of (R)-2-bromobutanoic acid, along with some impurities. Then THF (300 mL) is added and the resulting mixture is stirred at this temperature for another 7 h. LC-MS analysis shows 42.1% of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, 1.5% of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid, and 1.5% of (R)-2-bromobutanoic acid, along with some impurities. The reaction mixture is cooled to RT and concentrated to remove THF. H2O (1.2 L) is added into the residual and the resulting mixture is washed with DCM (3 x 400 mL). Then the pH of the aqueous solution is P100183W001 adjusted to 1-2 by 4 M HC1 aqueous solution. The resulting mixture is extracted with EA (4 x 400 mL). The combined organic phase is dried over MgSCh and concentrated to give a light yellow oil (84 g). The crude oil is dissolved in MTBE (168 mL) and heptane (840 mL) is added dropwise over 0.5 h and some amount of oily product is observed during the addition process of heptane. The mixture is stirred at RT and some amount of solid is precipitated out after about 1.5 h. The suspension is stirred at RT for another 2 h and an off-white solid is collected by filtration (53 g wet weight). The solid is dissolved in MTBE (168 mL) and heptane (840 mL) is added dropwise over 0.5 h. The mixture is stirred at RT for 17 h and filtered to yield an off-white solid in 86.4% purity and 74.4% yield (45.8 g).

Step 6

A mixture of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-car boxylic acid (37.5 g, 145.8 mmol, 1.0 eq.) in DMF (375 mL) is stirred in a 105 °C oil bath for 27 h. LC-MS analysis shows 85.6% of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid, 3.1% of (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid, and some impurities. The reaction mixture is stirred at this temperature for another 23 h. LC-MS analysis shows 85.7% of (S)-2- ((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid, 1.2% of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, and some impurities. The enantiomeric purity of (S)-2-((R)- 2-oxo-4-propylpyrrolidin-l-yl)butanoic acid by chiral HPLC (AUC purity) is 91.1%. The reaction mixture is cooled to RT and 1 M HC1 aqueous solution (1.125 L) is added and the resulting mixture is extracted with EA (3 x 375 mL). The combined organic phase is washed with 5% LiCl aqueous solution (5 x 110 mL), dried over MgSC and concentrated to give a light yellow solid in 85.3% purity along with 1.2% of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3- carboxylic acid and some impurities. The enantiomeric purity of (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid is 91.2%. The crude oil is dissolved in EA (60 mL). Heptane (360 mL) is added drop wise and the resulting mixture is stirred at RT for 17 h and stirred at 0-5 °C for 2 h. The mixture is filtered to yield an off-white solid in 94.5% purity and 52.6% yield (17 P100183W001 g). The enantiomeric purity of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid is 90.8%. There is some amount of DMF that remains in the product.

Recrystallization as cyclohexylamine salt: 8.0 g of crude (S)-2-((R)-2-oxo-4-propylpyrrolidin-l- yl)butanoic acid are dissolved in EA (40 m , 5 vol), then cyclohexylamine (5.4 g, 54.4 mmol, 1.5 eq.) is added dropwise. The resulting mixture is stirred at RT for 6.5 h and some solid precipitates out. The suspension is filtered to yield an off-white solid in 99% purity (~ 5.2 g). The enantiomeric purity is 98.1%.

Step 7

1 M HC1 aqueous solution (100 mL) and EA (100 mL) are added to about 11.2 g of the cyclohexylamine salt of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid and the resulting mixture is stirred at RT for 10 min followed by separation. The aqueous solution is extracted with EA (5 x 30 mL) and the combined organic phase is washed with brine (2 x 30 mL) and concentrated to yield an off-white solid in 98.9% purity (about 7.2 g). The enantiomeric purity of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid is 98.1%.

To a solution of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid (7.2 g, 33.7 mmol, 1.0 eq.) and E N (6.8 g, 67.4 mmol, 2.0 eq.) in THF (50 mL) at 0-5 °C under protection of Argon, a solution of pivaloyl chloride (6.1 g, 50.6 mmol, 1.5 eq.) in THF (20 mL) is added dropwise over 20 min and the resulting mixture is stirred at this temperature for 1 h. A sample is taken and quenched by 1.4 MNHa in THF. LC-MS analysis shows 88.6% of (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanamide (brivaracetam) and 8.7% of (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid. The enantiomeric purity of brivaracetam is 97.6%. Then 1.4 M NH3 in THF (110 mL, 155.4 mmol, 4.6 eq.) is added dropwise for about 1 h and the resulting mixture is stirred at RT for 1.5 h. LC-MS analysis shows 90.1% of (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanamide (brivaracetam) and 6.4% of (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid. The enantiomeric purity of brivaracetam is 97.5%. The reaction mixture is filtered and the cake is washed with THF (2 x 5 mL). The filtrate is P100183W001 concentrated, then a saturated NaHCCh solution (60 mL) is added. The mixture is extracted with DCM (3 x 60 mL). The combined organic phase is washed with brine (2 x 30 mL), dried over MgSO4 and concentrated to yield a light yellow oil in 97.0% purity (~ 7.2 g). The crude oil (~ 7.2 g) is dissolved in acetone (14 mL) and heptane (70 mL) is added and a large amount of solid precipitates out. The resulting mixture is stirred at 0-5 °C for 2 h and filtered to yield a white solid in 98.4% purity along with 1.6% of pivalamide (HPLC AUC, 210 nm) in 74.0% yield (5.3 g). ¹ HNMR assay is 85.6% along with 14.4% of pivalamide. The enantiomeric purity (chiral HPLC, AUC purity) of brivaracetam is 97.7%.