4-HYDROXY-L-PROLINE

Field of the Invention

The present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.

Formula IV

Background of the Invention

Tenelegliptin hydrobromide hydrate, chemically {(2S,4S)-4-[4-(3-Methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate of Formula I, is marketed in Japan for the treatment of type 2 diabetes mellitus.

Formula I

U.S. Patent Nos. 7,074,794 and 8,003,790 disclose processes for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof, comprising the steps of condensing (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV with thiazolidine to obtain fert-butyl (2S,4R)-4-hydroxy-2-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate, followed by its oxidation using a pyridine-sulfur trioxide complex in dimethylsulfoxide to obtain fert-butyl (2S)-4-oxo-2-(l,3-thiazolidin-3- ylcarbonyl)pyrroli

Formula II

(4R)-l-(fert-Butoxycarbonyl)-4-hydroxy-L-proline of Formula IV is a key raw material for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof. The prior art process for the preparation of the compound of Formula IV involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in the presence of a base in a mixture of water and an organic solvent. The insolubility of di-fert-butyl dicarbonate in water necessitates the use of an organic solvent in the reaction.

In a step towards green chemistry, the present invention involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in water alone. The present inventors have found that eliminating the organic solvent reduces the time taken for the reaction without compromising the purity of the product.

Summary of the Invention

The present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.

Formula IV A first aspect of the present invention provides a process for the preparation of (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV

Formula IV

wherein the process comprises reacting a compound of Formula III

Formula III

with di-fert-butyl dicarbonate in water.

A second aspect of the present invention provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof,

Formula II

wherein the process comprises the steps of:

a) reacting a compound of Formula III

Formula III with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV; and

Formula IV

b) converting the compound of Formula IV to {(2S,4S)-4-[4-(3-methyl- l-phenyl- lH-pyrazol-5 -yl) piperazin- 1 -yl] pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl) methanone of Formula II, or salts thereof.

A third aspect of the present invention provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl- l-phenyl- lH-pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3 -yl) methanone of Formula II, or salts thereof,

Formula II

wherein the process comprises the steps of:

a) reacting a compound of Formula III

Formula III

with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV;

Formula IV

b) oxidizing the compound of Formula IV to obtain a compound of Formula V;

Formula V

c) condensing the compound of Formula V with thiazolidine to obtain a

compound of Formula VI;

Formula VI

d) reacting the compound of Formula VI with a compound of Formula VII or salts thereof

Formula VII

to obtain a compound of Formula VIII; and

Formula VIII

e) deprotecting the compound of Formula VIII to obtain {(2S,4S)-4-[4-(3-methyl- 1 -phenyl- lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3- yl) methanone of Formula II, or salts thereof.

The following abbreviations are used in the present invention:

Boc tert-Butyloxycarbonyl

CDI Ι,Γ-Carbodiimidazole

DCC N,N'-Dicyclohexylcarbodiimide

DIC N,N'-Diisopropylcarbodiimide

DMAP 4-Dimethylaminopyridine

DEPC Diethyl phosphoryl cyanide

DMSO Dimethyl sulfoxide

DPPA Diphenylphosphoryl azide

EEDQ 2-Ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline

EDCI N-(3-Dimethylaminopropyl)-N'-etliylcarbodiimide

NHS N-Hydroxysuccinimide

HOBt Hydroxybenzotriazole

HOOBT 3-Hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine

PyBOP Benzotriazol-l-yl-ox rispyrrolidinophosphonium

hexafluorophosphate

KMn0 ₄ Potassium permanganate NaCIO Sodium hypochlorite

TCCA Trichloroisocyanuric acid

TEMPO (2,2,6,6-Tetramethylpiperidin- 1 -yl)oxyl

Detailed Description of the Invention

Various embodiments and variants of the present invention are described herein.

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

In the context of the present invention, "salts" refers to inorganic acid addition salts, organic acid addition salts, and salts formed with amino acids. Examples of inorganic acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acid addition salts include salts formed with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, and methylsulfuric acid. Examples of amino acid salts include salts formed with glutamic acid and aspartic acid.

The reaction of the compound of Formula III with di-fert-butyl dicarbonate is carried out in the presence of a base in water to obtain a compound of Formula IV. The base is selected from organic or inorganic bases. Examples of organic bases include methylamine, ethylamine, diethylamine, triethylamine, diisopropylamine, and

diisopropylethylamine. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

In general, the compound of Formula III is reacted with di-fert-butyl dicarbonate using sodium hydroxide in water to obtain the compound of Formula IV.

The oxidation of the compound of Formula IV to obtain a compound of Formula V is carried out using an oxidizing agent. Examples of oxidizing agents include a pyridine- sulfur trioxide complex in DMSO, an alkaline solution of KMnO/t, oxalyl chloride in DMSO and triethylamine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, NaCIO, a mixture of NaCIO and TEMPO, and a mixture of TCCA and TEMPO. The condensation of the compound of Formula V with thiazolidine to obtain a compound of Formula VI is carried out using a condensing agent. The condensing agent is selected from the group comprising of DCC, EDCI, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride. The condensation reaction is carried out in the presence of an additive. Examples of additives include NHS, HOBT, HOOBT, and DMAP.

In an embodiment of the present invention, the oxidation of the compound of Formula IV is carried out using a mixture of NaClO and TEMPO to obtain the compound of Formula V, followed by condensation of the compound of Formula V with thiazolidine in the presence of DCC and DMAP to obtain the compound of Formula VI.

The reaction of the compound of Formula VI with the compound of Formula VII to obtain a compound of Formula VIII is carried out in the presence of an acid catalyst. Examples of acid catalysts include acetic acid, p-toluenesulfonic acid, and borotriflouride etherate.

The deprotection of the compound of Formula VIII is carried out using conventional methods, such as those disclosed in Greene and Wuts, 2006. Greene 's Protective Groups in Organic Synthesis, 4th Edition.

The preparation and conversion of the compound of Formula VII into {(2S,4S)-4- [4-(3-methyl- 1 -phenyl- lH-pyrazol-5 -yl) piperazin- 1 -yl] pyrrolidin-2-yl} ( 1 ,3 -thiazolidin- 3-yl) methanone of Formula II, or salts thereof, is carried out by following the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790 or our co-pending Indian Patent Application Nos. 2347/DEL/2013, 3229/DEL/2013, and 2350/DEL/2013, which are incorporated herein by reference.

Method

The High Performance Liquid Chromatography (HPLC) purity was determined using an Agilent ^® Atlantis ^® T3 (250 x 4.6 mm), 5 μιη column with a flow rate of 1.0 mL/minute with gradient elution; Column oven temperature: 35°C; Sample tray temperature: 25°C to 30°C; Detector UV: 215 nm; Injection volume: 10 μί; Run time: 65 minutes.

The examples are set forth to aid the understanding of the invention but are not intended to and should not be construed to limit its scope in any way. Examples

Comparative Example 1 : Preparation of (4R)-l-(fer -butoxycarbonyl)-4-hvdroxy-L- proline (Formula IV) according to Example 1 of WO 2006/038119

Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in tetrahydrofuran (500 mL) to obtain a reaction mixture. The reaction mixture was cooled to 5°C to 10°C. A solution of sodium hydroxide (30.5 g sodium hydroxide in 305 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes. The reaction mixture was allowed to warm to 20°C to 25 °C, and then stirred at the same temperature for 20 hours to 24 hours. The reaction mixture was cooled to 5°C to 10°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (290 mL; 3M). The reaction mixture was stirred for 10 minutes, then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure. The residue obtained was again dissolved in ethyl acetate (200 mL) to obtain a solution. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes. The reaction mixture was stirred at 20°C to 25°C for 60 minutes to obtain a solid. Hexanes (700 mL) were again slowly added to the slurry over a period of 60 minutes. The slurry was cooled to 0°C to 5°C, and then stirred at the same temperature for 2 hours. The solid obtained was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, mixture of 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45°C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)- 4-hydroxy-L-proline .

Yield: 95.4 %

HPLC purity: 99.53 %

Comparative Example 2: Preparation of (4R)-l-(ferZ-butoxycarbonyl)-4-hvdroxy-L- proline (Formula IV) according to J Ors. Chem., 61(10):3534-3541 (1996)

Di-fert-butyl dicarbonate (332.6 g) and triethylamine (92.5 g) were added to a solution of trans-4-hydroxy-L-proline (100 g) in methanol (1000 mL) to obtain a reaction mixture. The reaction mixture was allowed to warm to 65°C to 68°C, then stirred at the same temperature for 2 hours to 3 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (1000 mL) and water (300 mL) were added to the residue and then the mixture was cooled to 0°C to 5°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (200 mL; 2.5 M). The solution was stirred for 10 minutes, then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) to obtain a solution. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes. The reaction mixture was stirred at 20°C to 25°C for 60 minutes to obtain a solid. Hexanes (700 mL) were again slowly added to the solid to obtain a slurry, which was then stirred for 60 minutes. The slurry was cooled to 0°C to 5°C, then stirred at the same temperature for 2 hours. The solid was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45°C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)- 4-hydroxy-L-proline.

Yield: 88.5 %

HPLC Purity: 99.24 %

Example 1 : Preparation of (4R)-l-(fer^-butoxycarbonyl)-4-hvdroxy-L-proline (Formula IV]

Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in water (200 mL). A solution of sodium hydroxide (33.6 g sodium hydroxide in 100 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes. The reaction mixture was allowed to warm to 40°C to 45 °C, then was stirred at the same temperature for 3 hours to 4 hours. The reaction mixture was cooled to 25°C to 30°C. Ethyl acetate (1000 mL) was added to the reaction mixture, and then the mixture was cooled to 0°C to 5°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (275 mL; 3M). The reaction mixture was stirred for 10 minutes, and then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 200 mL) at 15°C to 20°C. The combined organic layers were washed with an aqueous solution of sodium chloride (100 mL; 20 g sodium chloride in 100 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (200 mL), then stirred at 40°C to 45°C for 20 minutes. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes at 25 °C to 30°C, and then the mixture was stirred at the same temperature for 60 minutes to obtain a solid. Hexanes (700 mL) were slowly added to the solid to obtain a slurry, and then the mixture was stirred over a period of 60 minutes. The slurry was cooled to 0°C to 5°C, then stirred at the same temperature for 2 hours. The solid was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, a mixture of 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45 °C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L- proline.

Yield: 95.8 %

HPLC Purity: 99.93 %

Example 2: Preparation of l-(ferf-butoxycarbonyl)-4-oxo-L-proline (Formula V)

Trichloroisocyanuric acid (75.6 g) was added to a solution of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to Example 1; 100 g) in ethyl acetate (1000 mL). The solution was cooled to -5°C to 0°C. A solution of TEMPO in ethyl acetate (3.38 g in 50 mL ethyl acetate) was slowly added to the reaction mixture at -5°C to 10°C, then the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to 25 °C to 30°C, then stirred at the same temperature for 60 minutes. After completion of the reaction, the reaction mixture was quenched with deionized water (200 mL), then stirred for 60 minutes at 25°C to 30°C. The reaction mixture was filtered through a Hyflo ^® bed. The filtrate was washed with deionized water (2 x 200 mL). The layers were separated. The organic layer was washed with an aqueous solution of sodium chloride (40 g sodium hydroxide in 200 mL deionized water). The organic layer was concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (100 mL). Hexanes (400 mL) were slowly added to the solution. The reaction mixture was stirred at 25°C to 30°C for 30 minutes. The reaction mixture was filtered to obtain a solid. The solid was washed with a mixture of ethyl acetate (20 mL) and hexanes (80 mL), then dried at 40°C to 45°C under reduced pressure to obtain l-(fert-butoxycarbonyl)-4-oxo-L-proline.

Yield: 95.9 %

Example 3: Preparation of fert-butyl (2S)-4-oxo-2-(1.3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate (Formula VI)

A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1- (fert-butoxycarbonyl)-4-oxo-L-proline (Formula V, prepared according to Example 2; 100 g) in toluene (900 mL) at -10°C to -5°C. The reaction mixture was stirred for 30 minutes at -10°C to -5°C. 4-Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at -6°C to -2°C over a period of 15 minutes to 20 minutes. The reaction mixture was allowed to warm to 0°C to 5°C, then stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), then stirred at 20°C to 25°C for 30 minutes. The resulting mixture was filtered through a Hyflo ^® bed. The filtrate was washed with an aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated, then washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, then the reaction mixture was stirred at 25 °C to 30°C for 30 minutes. The reaction mixture was filtered through a Hyflo ^® bed, then concentrated at 50°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50°C to 55°C. Hexanes (800 mL) were added at 50°C to 55°C over a period of one hour to 2 hours. The reaction mixture was further cooled to 0°C to 5°C, then stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solid was washed with a precooled (0°C to 5°C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), then dried at 40°C to 45°C under reduced pressure to obtain fert-butyl (2S)-4- oxo-2-( 1 ,3 -thiazolidin-3 -ylcarbonyl)pyrrolidine- 1 -carboxylate .

Yield: 81.7 %

HPLC Purity: 98.97 % Example 4: Preparation of fert-butyl (2S.4S)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yll-2-(1.3-thiazolidin-3-ylcarbonyl) pyrrolidine- 1-carboxylate (Formula VIII)

A solution of sodium triacetoxy borohydride (98.8 g) in toluene (300 mL) was added to a mixture of fert-butyl (2S)-4-oxo-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l- carboxylate (Formula VI, prepared according to Example 3; 100 g) and 1 -(3 -methyl- 1- phenyl-lH-pyrazol-5-yl)piperazine acetate (Formula VII; 100.7 g) in toluene (800 mL) at 5°C to 10°C. The reaction mixture was stirred at 20°C to 25°C for 3 hours. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mixture was quenched with deionized water (600 mL), and then stirred for 10 minutes. The reaction mixture was allowed to settle for 15 minutes. The organic layer was separated, then washed with aqueous sodium bicarbonate (60 g sodium bicarbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), then concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in isopropyl alcohol (500 mL) to obtain a solution. The solution was concentrated at 50°C under reduced pressure, and used as such in the next step.

Example 5: Preparation of {(2S.4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1-vH pyrrolidin-2-yl}(1.3-thiazolidin-3-yl)methanone hemipentahydrobromide hydrate (Formula I)

Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo ^® bed. The filtrate was heated to 70°C to 75°C. Hydrobromic acid (48 %; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), then dried at 50°C under reduced pressure for 15 hours to obtain crude {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate.

Yield: 90 % Example 6: Purification of {(2S.4S)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1-vH pyrrolidin-2-yl}(1.3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate (Formula I)

A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl) methanone hemipentahydrobromide hydrate (100 g; prepared according to Example 5) in ethanol (700 mL) was heated to 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to 65°C to 68°C, then deionized water (10 mL) was added at the same temperature. The solution was cooled to 55°C to 60°C, and then stirred at the same temperature for 2 hours. The solution was further cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, then washed with ethanol (100 mL), and then dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl} (1,3 -thiazolidin-3 -yl) methanone hemipentahydrobromide hydrate.

Yield: 90 %

HPLC Purity: 99.93 %