Claims:We Claim:

1. A process for preparing (R) - 2- (2, 5-difluorophenyl) -pyrolidine comprising the steps of:
(a) condensing the compound of Formula (III) with compound of Formula (II) in presence of suitable lithiating agent and suitable solvent to obtain compound of Formula (IV) ;

(b) cyclizing and deprotecting compound of Formula (IV) in presence of suitable acid and suitable solvent to obtain compound of Formula (V);

(c) reducing compound of Formula (V) in suitable reducing agent and suitable solvent to obtain compound of Formula (I);

(d) resolving compound of Formula (I) with a suitable resolving agent in presence of suitable solvent to obtain compound of Formula (Ia); and

(e) neutralizing compound of Formula (Ia) in presence of suitable base and suitable solvent to obtain (R) - 2- (2, 5-difluorophenyl)-pyrolidine.

2. The process as claimed in claim 1, wherein the term X in compound of Formula (III) is selected from halogen or H and the term R in compound of Formula (X) is selected from suitable acid labile nitrogen protecting groups selected from tert-butyloxycarbonyl, carbamate, triphenylmethyl, tert-butyl, 2-trimethylsilylethoxycarbonyl and 4-methoxybenzyloxycarbonyl.

3. The process as claimed in claim 1, wherein suitable lithiating agent in step (a) is selected from alkyl lithium such as n-buLi, hexyl lithium and sec-butyl lithium and suitable solvent is selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, hexane and 2-methyltetrahydrofuran.

4. The process as claimed in claim 1, wherein step (a) is carried out the temperature range of -95 °C to -65 °C.

5. The process as claimed in claim 1, wherein suitable acid in step (b) is selected from HCl and H2SO4 and suitable solvent is selected from water, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene.

6. The process as claimed in claim 1, wherein suitable reducing agent in step (c) is selected from reducing agent is selected from sodium cyanoborohydride, sodium triacetoxy boron hydride, lithium aluminium hydride and sodium borohydride and suitable solvent is selected from water, methanol, isopropanol, 2-propanol and 1-butanol.

7. The process as claimed in claim 1, wherein suitable resolving agent in step (d) is selected from S-(+)-mandelic acid, D-(-)-mandelic acid, L-(+) tartaric acid, D-(-) tartaric acid, D-(+)-camphor sulfonic acid, D-pyroglutamic acid, L-(-)-camphor sulfonic acid, (-)-DPT-L-tartaric acid and D-malic acid and suitable solvent is selected from water, methanol, isopropanol, 2-propanol, and 1-butanol.

8. The process as claimed in claim 1, wherein suitable base in step (e) is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate and potassium carbonate and suitable solvent is selected from water, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene.

Dated this 08 th December 2021

Dr. S.Ganesan
, Description:FIELD
The present invention relates to process for the preparation of (R)-2-(2, 5-difluorophenyl) pyrrolidine, a key intermediate used for the preparation of API in pharmaceutical filed.

BACKGROUND
(R)-2-(2, 5-difluorophenyl) pyrrolidine, a key intermediate used for the preparation of active pharmaceutical ingredient such as (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1-pyrrolidine carboxamide sulfate.

US 8,513,263 B2 (IN 2011KN02064) patent application discloses the process for the preparation of (R)-2-(2, 5-difluorophenyl) pyrrolidine as shown below in Scheme-1. This route uses 2-bromo-1, 4-difluorobenzene as a raw material, (-)-spartine base as a chiral induction reagent to synthesize (R)-2-(2, 5-difluorophenyl) pyrrolidine. It is necessary to use sec-butyl lithium which is too sensitive to air, and expensive palladium acetate and (-)-spartine, which are harsh in reaction conditions and high in cost, and are not suitable for industrial production.

Scheme-1
US 10,172,861 (IN 201737018868) discloses process for the preparation of malate salt of (R)-2-(2, 5-difluorophenyl) pyrrolidine as outlined in scheme 2.The process involves grignard reaction of 2-bromo-1, 4-difluorobenzene with tert-butyl 2-oxopyrrolidine-1-carboxylate in presence of iPrMgCl in THF; followed by cyclization, deprotection, reduction and resolution to obtain malate salt of (R)-2-(2, 5-difluorophenyl) pyrrolidine.

Scheme-2
CN111138333A discloses process for the preparation of L- (-) -di-p-toluoyl tartrate salt of (R)-2-(2, 5-difluorophenyl) pyrrolidine by carrying out reduction of (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrolidine to obtain 2- (2, 5-difluorophenyl) –pyrrolidine and further resolution by using resolving agent L- (-) -di-p-toluoyl tartaric acid.

The acute hazards of the Grignard reaction make it one of the more challenging processes to develop and bring to commercial scale. These hazards include: (1) strongly exothermic magnesium metal activation and reaction steps; (2) heterogeneous reactions with potential difficulties in suspending and mixing; and (3) operational hazards posed by solvents with low vapor pressures. Therefore, it would be desirable to provide a simplified and straightforward process such as carrying out lithiation reaction of difluoro compound which is environment friendly, carried out advantageously on an industrial scale and supports an active compound in high yield.
SUMMARY
In one aspect, present invention provides a process for preparing (R) - 2- (2, 5-difluorophenyl) -pyrolidine comprising the steps of:
(a) condensing the compound of Formula (III) with compound of Formula (II) in presence of suitable lithiating agent and suitable solvent to obtain compound of Formula (IV);
(b) cyclizing and deprotecting compound of Formula (IV) in presence of suitable acid and suitable solvent to obtain compound of Formula (V);
(c) reducing compound of Formula (V) in suitable reducing agent and suitable solvent to obtain compound of Formula (I);
(d) resolving compound of Formula (I) with a suitable resolving agent in presence of suitable solvent to obtain compound of Formula (Ia); and
(e) neutralizing compound of Formula (Ia) in presence of suitable base and suitable solvent to obtain (R) - 2- (2, 5-difluorophenyl) –pyrolidine.
The present invention is shown schematically in Scheme-3:

Scheme-3

DETAILED DESCRIPTION
In one embodiment of the present invention, the step (a) is carried out by reacting the compound of Formula (III) with an suitable lithiating agent at the temperature range of -95 °C to -65 °C followed by reacting the ensuing lithiated compound of Formula (III) with compound of Formula (II). The reaction is preferably carried out in presence of suitable solvent and at the temperature range of -95 °C to -65 °C to obtain compound of Formula (IV).
The term X in compound of Formula (III) is selected from halogen or H; more preferably H and the term R in compound of Formula (II) is selected from suitable acid labile nitrogen protecting groups such as tert-butyloxycarbonyl, carbamate, triphenylmethyl, tert-butyl, 2-trimethylsilylethoxycarbonyl, or 4-methoxybenzyloxycarbonyl; more preferably tert-butyloxycarbonyl.

Suitable lithiating is selected from alkyl lithium such as n-buLi, hexyl lithium, sec-butyl lithium, more preferably n-buLi. Suitable solvent is selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, hexane and 2-methyltetrahydrofuran. More preferably, tetrahydrofuran.

In yet another embodiment of the present invention, compound of Formula (IV) in step (b) is cyclized and deprotected in presence of suitable acid and suitable solvent at the temperature range of 50 °C to 60 °C to obtain compound of Formula (V); wherein suitable acid is selected from HCl, H2SO4, more preferably H2SO4. Suitable solvent is selected from water, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene, more preferably water.

In still another embodiment of the present invention, compound of Formula (V) in step (c) is reduced in presence of suitable reducing agent and suitable solvent at temperature range of -5 °C to 5 °C to obtain compound of Formula (I); wherein reducing agent is selected from sodium cyanoborohydride, sodium triacetoxy boron hydride, lithium aluminium hydride and sodium borohydride, more preferably sodium borohydride. Suitable solvent is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, more preferably methanol.

In yet another embodiment of the present invention, compound of Formula (I) in step (d) is resolved with suitable resolving agent in presence of suitable solvent at temperature range of -5 °C to 5 °C to obtain compound of Formula (Ia); wherein suitable resolving agent is selected from S-(+)-mandelic acid, D-(-)-mandelic acid, L-(+) tartaric acid, D-(-) tartaric acid, D-(+)-camphor sulfonic acid, D-pyroglutamic acid, L-(-)-camphor sulfonic acid, (-)-DPT-L-tartaric acid and D-malic acid, more preferably (-)-DPT-L-tartaric acid and suitable solvent is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, more preferably methanol.

In yet another embodiment of the present invention, compound of Formula (Ia) in step (e) is neutralized in presence of suitable base at temperature range of 20 °C to 35 °C to obtain (R) - 2- (2, 5-difluorophenyl) –pyrolidine; wherein suitable base is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate and potassium carbonate, more preferably sodium hydroxide. Suitable solvent is selected from water, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene, more preferably water.

In another embodiment, present invention provides a process for preparing (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate comprising the steps of:
i) condensing (R)-2-(2,5-difluorophenyl)pyrrolidine with 5-chloropyrazolo [1,5-a] pyrimidine in presence of suitable base, suitable catalyst and suitable solvent to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo [1,5-a] pyrimidine;
ii) nitrating (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo [1,5-a] pyrimidine with nitric acid in presence of suitable activating agent and suitable solvent to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo [1,5-a] pyrimidine;
iii) reducing (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo [1,5-a] pyrimidine in presence of suitable reducing agent and suitable solvent to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-amine;
iv) condensing (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-amine with (S)-pyrrolidin-3-ol or its salt in presence of suitable coupling agent and suitable solvent to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide; and
v) treating (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide with sulphuric acid in presence of suitable solvent to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.
According to the present invention, the compound which is isolated from the reaction mass by techniques such as 1) addition of suitable anti solvent 2) cooling the reaction mass 3) distilling the solvent 4) evaporation 5) spray drying 6) lyophilization 7) freeze drying or by combination of any of the said method in any order. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In yet another embodiment, the present invention provides the product as isolated is having residual solvent limit according to ICH standard.

In still another embodiment, the present invention provides substantially pure (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate, which is substantially free of Impurity-I, Impurity-II, Impurity-III and Impurity-IV.
, ,
and
In an embodiment of the present invention provides substantially pure (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate having purity of greater than about 99.9%; preferably greater than about 99.95%; more preferably greater than about 99.99% as measure by HPLC.

In yet another embodiment, present invention provides a pharmaceutical composition comprising an admixture of a (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate drug substance and a pharmaceutically acceptable carrier, wherein the (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate drug substance is substantially free of Impurity-I, Impurity-II, Impurity-III and Impurity-IV.

In yet another embodiment, the present invention provides (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples
Example 1: Preparation of (R)-2-(2,5-difluorophenyl) pyrrolidine acid addition salt
To a solution of 2-pyrrolidinone (96.98 g, 1.14moles) and 4-dimethylaminopyridine (5.35 g, 0.044 moles) in toluene, di-tert-butyl dicarbonate (281.22g, 1.289moles) was added and reaction mixture was stirred for 2-3 hrs at room temperature. After completion of reaction, water was charged into the reaction mass and the pH of the reaction mixture was adjusted at 4.0 with 1N HCl solution. The layers were separated, organic layer was washed with brine solution and toluene was distilled to afford tert - butyl 2- oxopyrrolidine-1- carboxylate as residue. To the obtained residue, THF (75 mL) was added below 60°C under nitrogen atmosphere and cooled to 0-10°C. To a solution of n-butyllithium (300 g) (2.5 M in hexane 420 mL, 1.061 moles) in THF (400 ml) was added 1, 4-difluorobenzene (100.0 g, 0.877 moles) in THF (400 mL) under nitrogen atmosphere and stirred for 45 mins at -90 to -60°C.Tert - butyl 2- oxopyrrolidine-1-carboxylate was added was added into the reaction mixture and stirred for 1 hour at -90 to -60°C. After completion of reaction, ammonium acetate solution was added and layers were seperated at 0-5 °C. To the organic layer, water and sulfuric acid was added 30- 50°C. The reaction mixture was heated to 60-65°C and stirred for 3 hours. Reaction mixture was cooled, layers were separated and pH of the aqueous layer was adjusted to 11-12 by sodium hydroxide aq. solution. Organic layer was filtered through hyflobed and hyflobed was washed with toluene. The layers were seperated and solvent was distilled completely under vacuum below 50°C to obtain 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole as residue. To a residue, methanol was added at 40-55°C and reaction mixture was cooled to room temperature. Water was added at room temperature and reaction mixture was cooled to -5 to 5 °C. Sodium borohydride (60 g) was added at 0-5°C to the reaction mixture .The temperature of the reaction mixture was raised to room temperature and stirred for 2 hrs. After completion of reaction, layers were seperated. Organic layer was filtered through hyflobed and hyflobed was washed with DCM. The layers were seperated and solvent was distilled completely under vacuum below 50°C to obtain 2- (2, 5- difluorophenyl) pyrrolidine as residue. To a residue, methanol was added at 40-50°C and reaction mixture was cooled to 20-30°C.suitable resolving agent was added and reaction mixture was stirred for 30-50 mins at room temperature. Reaction mixture was refluxed at 60-70°C, gradually cooled and stirred for 10-12 hrs at 20-30°C. The solid was filtered, washed with methanol to obtain wet cake. To wet cake, methanol was added, stirred and temperature of reaction mixture was raised to 60-70°C. Reaction mixture was gradually cooled, stirred for 10-12 hrs at 20-30°C, solid was filtered and dried in VTD to obtain (R)-2-(2,5-difluorophenyl) pyrrolidine acid addition salt.
Same example can be followed by replacing 1, 4-difluorobenzene with 2-bromo-1, 4-difluorobenzene.

Example 2: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide

Step-I: preparation of (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine
To process water, sodium hydroxide (70g, 1.75 moles) was added below 50°C and cooled to 20-30°C to obtain sodium hydroxide solution. To a sodium hydroxide solution, (R)-2-(2, 5-difluorophenyl) pyrrolidine acid addition salt obtained above was added and reaction mixture was stirred for 20-30 mins at room temperature. Toluene was added to reaction mixture, stirred and layers were seperated and solvent was distilled to obtain (R)-2-(2,5-difluorophenyl) pyrrolidine as residue. To the residue, DMF (50 mL) and potassium carbonate (39.31g, 0.2845 moles) was added and reaction mixture was stirred for 1-2 hrs at 20-30°C. 5-chloro pyrazolo pyrimidine (26 g, 0.1703 moles) and KI (5.83g, 0.0351 moles) were added to reaction mixture at 20-30°C. The reaction mixture was gradually refluxed at110-130 °C and stirred for 4- 5 hrs. After completion of reaction, reaction mixture was cooled to 70-80 °C and water was added. The reaction mixture was further cooled gradually to 35-50 °C, stirred for 1 hr, filtered and washed with water and dried to obtain crude (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine .To crude (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine, MTBE was added and stirred for 20-35 minutes at room temperature. The temperature of reaction mixture was raised to 50-60°C and stirred for 1-2 hrs. The reaction mixture was cooled to 0-5°C and stirred for 1-2 hrs. The obtained solid was filtered, washed with MTBE and dried in VTD to obtain (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a]pyrimidine. (40 g).

Step-II: Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo [1,5-a] pyrimidine
To a solution of (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a]pyrimidine (100 g, 0.333 moles) in TFA , nitric acid (152.24 g) was added and reaction mixture was stirred for 1-2 hrs at -10 to 5°C.After completion of reaction, DCM and water was added and layers were seperated. To organic layer, sodium bicarbonate solution was added, stirred and layers were seperated. The organic layer was filtered through hyflobed, washed with DCM and layers were seperated. Solvent was distilled atmospherically below 50°C to obtain residue. Methanol was added to the residue and reaction mixture was refluxed to 60-70 °C. The reaction mixture was stirred for 1-2 hrs at 60-70 °C and cooled to 20-30°C.The obtained solid was filtered, washed with methanol and dried in VTD to obtain(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo [1,5-a] pyrimidine.80 g.

Step-III: Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-amine
To a stirring solution of R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo [1,5-a] pyrimidine(100g, 0.29 moles) in DCM and methanol , Zn dust powder (37.86 g) and ammonium acetate solution(143.98 g ammonium acetate in 350 ml process water) was added at -10 to 10°C.After completion of reaction, reaction mixture was filtered through hyflobed, washed with DCM and layers were seperated. A dilute HCl solution was added to organic layer, stirred and layers were seperated. To an aqueous layer, DCM and sodium hydroxide solution was added, stirred and layers were seperated. The organic layer was filtered through hyflobed, washed with DCM and layers were seperated. Solvent was distilled from organic layer atmospherically below 50°C, cooled and stirred for 1 hr at 0-2°C.Cyclohexane was added to reaction mixture at 0-10°C.The temperature of reaction mixture was raised to room temperature and stirred for 3 hrs. The obtained solid was filtered, washed with cyclohexane and dried in VTD to obtain (R)-5-(2-(2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1, 5-a] pyrimidin-3-amine.70 g.

Step-IV: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide
To a solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-amine (100 gm, 0.3171 moles) in dichloromethane, 1,1'-Carbonyldiimidazole (CDI) (77.14 gm) and (S)-3-hydroxypyrrolidine hydrochloride (58.79 gm) was added at 20-30 °C. After completion of reaction, water was added to reaction mixture and stirred at room temperature. A dilute HCl solution was added to reaction mixture, stirred and layers were seperated. Dichloromethane and methanol were added to the aqueous layer, stirred and layers were seperated. A solution of sodium bicarbonate was added to reaction mixture, stirred and layers were seperated. Dichloromethane was added to the aqueous layer, stirred and layers were seperated. Solvents were distilled out under vacuum below 50°C from organic layer to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide.

Example 3: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate
To a solution of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide as obtained from Ex.2, Step-IV in methanol (approx. 6-7 v), a pre-cooled solution of sulphuric acid (27.47 g) in methanol (220 ml) was added at 30- 35°C. Reaction mixture was flushed with methanol and stirred at 30- 35°C. To the obtained reaction mixture, isopropyl ether was added at 30- 35°C and stirred. Alternatively ethyl acetate, cyclohexane can also be used in place of isopropyl ether. The solid was filtered; washed with isopropyl ether and dried under vacuum in VTD for 12 hrs at 40-50 °C to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.(>80% yield).
Precooled solution of sulphuric acid is prepared by slowly adding concentrated sulfuric acid (27.47 g) in methanol (220 ml) at temperature in the range of -20 to 0 °C.

Purity by HPLC: 99.95%; Impurity-I: Not detected; Impurity-II: Not detected; Impurity-III: 0.03%; and Amine impurity: Not detected.

Example 4: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate
To a solution of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide as obtained from Ex.2, Step-IV in methanol (600 mL), a pre-cooled solution of sulphuric acid (27.47 g) in methanol (220 ml) was added at 30- 35°C. Reaction mixture was flushed with methanol and stirred for long hours. The solid was filtered and dried under vacuum in VTD for 12 hrs at 40-50 °C to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.

Example 5: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate
To a solution of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide as obtained from Ex.2, Step-IV in methanol (600 mL), concentrated sulphuric acid (27.47 g) was added at 30- 35°C. Reaction mixture was flushed with methanol and stirred at 30- 35°C. To the obtained reaction mixture, isopropyl ether was added at 30- 35°C and stirred. The solid was filtered; washed with isopropyl ether and dried under vacuum in VTD for 12 hrs at 40-50 °C to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.(>80% yield).

Example 6: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate
To a solution of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide as obtained from Ex.2, Step-IV in methanol (230 ml), a pre-cooled solution of concentrated sulphuric acid (26.43 g) in methanol (200 ml) was added at 32-38 °C. Reaction mixture was flushed with methanol, stirred and seed crystal of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate (0.1 gm) was added at 32-38 °C. To the obtained reaction mixture, ethyl acetate was added at 30- 35°C and stirred. The solid was filtered, washed with ethyl acetate and dried under vacuum in VTD for 12 hrs at 40-50 °C to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.(>75% yield).

Example 7: Preparation of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate
To a solution of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide as obtained from Ex.2, Step-IV in ethanol a pre-cooled solution of concentrated sulphuric acid (26.43 g) in ethanol (200 ml) was added at 32-38 °C. Reaction mixture was flushed with ethanol, stirred and seed crystal of (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate (0.1 gm) was added at 32-38 °C. To the obtained reaction mixture, ethyl acetate was added at 30- 35°C and stirred. The solid was filtered, washed with ethyl acetate and dried under vacuum in VTD for 12 hrs at 40-50 °C to obtain (3S)-N-{5-[(2R)-2-(2, 5-difluorophenyl)-1-pyrrolidinyl] pyrazolo [1, 5-a] pyrimidin-3-yl}-3-hydroxy-1- pyrrolidine carboxamide sulfate.(>75% yield).