Field of the Invention:

The present invention relates to an improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-la, represented by the following structure:

The present invention also relates to novel acid addition salts of compound of general formula-5a, which are useful in the preparation of (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-la.

Background of the Invention:

Ruxolitinib, (R)-3-(4-(7H-pyrrolo[233-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropane- nitrile which is useful in the treatment of janus kinase-associated disease such as myeloproliferative disorders. Ruxolitinib is the first FDA approved janus kinase (JAK) inhibitor and is the only drug currently approved for the treatment of myelofibrosis.

US pat. No. 7,598,257 B2 first discloses (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile, its pharmaceutical^ acceptable salts and process for the preparation thereof.

US pat. No. 8,722,693 B2 discloses the phosphate salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile.

US pat. No. 7,598,257 B2 discloses process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-1. The said patented process involves the separation of isomers of intermediates as well as final compound of formula-1 using preparative HPLC method. Further, the obtained intermediate compounds as well as the final compound of formula-1 were purified by column chromatography, which is a laborious and time consuming process and also the said process suffers from low yields and purities.

In view of the foregoing, there still remains an unmet need for a process for
preparation—of (R}-^3-(4:-(7H-pyr^

propanenitrile with high chemical and enantiomerical purity and also applicable for multi-kilogram production. The process of the present invention is inexpensive, environmental-friendly, rendering it amenable to the large-scale production of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y 1)-1 H-pyrazol-1 -yl)-3-cyclopentyl propanenitrile and its phosphate salt compound of formula-1 with high yield and purity.

Brief description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (R)-3^(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la.

The second aspect of the present invention is to provide acid addition salts of general formula-5(a) and process for its preparation thereof.

The third aspect of the present invention relates to novel crystalline oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5a(i), herein after designated as form-N.

The fourth aspect of the present invention relates to novel crystalline 3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-8a(i), herein after designated as form-M.

The fifth aspect of the present invention relates to novel crystalline (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-lb(i),. herein after designated as form-R.

Brief description of the Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate.

Figure 2: Illustrates the DSC thermogram of crystalline form-M of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile phosphate.

Figure 3: Illustrates the PXRP pattern of crystalline form-S of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanamide.

Figure-4: Illustrates the DSC thermogram of crystalline form-S of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanamide.

Figure 5: Illustrates the PXRD pattern of crystalline oxalate salt form-N of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine.

Figure 6: Illustrates the DSC thermogram of crystalline oxalate salt form-N of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine.

Figure 7: Illustrates the PXRD pattern of crystalline form-R (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile.

Figure-8: Illustrates the DSC thermogram of crystalline form-R (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile. Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, n-pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the "iike; "polar solvents" suclras wateror mixtures thereof:

The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo (4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, . diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

The first aspect of the present invention provides an improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la, comprising of the following steps:

a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with (2-(chloromethoxy)ethyl)trimethylsilane in presence of a suitable base in a suitable solvent to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-3,

b) reacting the compound of formula-3 with lH-pyrazol-4-ylboronic acid hydrochloride compound of formula-4 in presence of tetrakis(triphenylphosphine)palladium(0) and a

suitable base and in a suitable solvent to provide 4-( 1 H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[253-d]pyrimidine compound of formula-5,

c) treating the compound of formula-5 with a suitable acid in a suitable solvent to provide acid addition salts of compound of general formula-5(a),

d) neutralizing the acid addition salt of compound of general formula-5(a) with a suitable base in a suitable solvent to provide pure 4-(lH-pyrazol-4-yl)-7-((2-trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine compound of formula-5,

e) reacting the compound of formula-5 with (E)-3-cyclopentylacrylonitrile compound of . formula-6 in presence of a suitable base in a suitable solvent to provide 3-cyclopentyl-3- (4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile compound of formula-7,

f) treating the compound of formula-7 with phosphoric acid in a suitable solvent and then treating with a suitable base in a suitable solvent and followed by reacting with a suitable dehydrating agent in a suitable solvent to provide 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile compound of formula-8,

g) optionally, purifying the compound of formula-8 by treating it with a suitable acid in a suitable solvent to provide acid addition salts of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of general formula-8(a), which is further converted into free base by treating the compound of general formula-8(a) with a suitable base in a suitable solvent to provide pure 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

h) resolving the compound of formula-8 obtained in step-(f) or step-(g) by treating it with a suitable resolving agent in a suitable solvent to provide chiral acid salt compound of general formula-1(b), i) treating the acid addition salt compound of general formula-1(b) with a suitable base in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1-yl)- 3-cyclo pentylpropanenitrile compound of formula-1, j) treating compound of formula-1 with phosphoric acid in a suitable solvent to provide (R)-
3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propane- nitrile phosphate compound of formula-la.

Wherein, in step-a), b), d), e), f), g) and i) the suitable base is selected from organic or inorganic base;
in step-c) and g) the suitable acid is selected from "organic acids" such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid7_benzoic acid7 benzenesulfonic acid7~citric acid; camphorsulfoic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid.

in step-f) the suitable dehydrating agent is selected from P2O5, POCI3, SOCI2, TiCU, NaBPLj, DBU-POCl2OEt, P4Q10, CuCl/MSTFA (N-Methyl-N-(trimethylsilyl)trifluoro acetamide), silazanes, aminosilanes, alkoxysilanes, chlorosilanes, TBAF, Cyunaric chloride/DMF, ZnCl2, (COCl)2-DMSO/ET3N, AlCl3/NaI, PdCl2, A1C13. 6H20/ KI, POCb-Py/Imidazole;

in step-h) the suitable resolving agent is optically active forms of mandelic acid, 2- chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, acertyl mandelic acid, 3 -bromocamphor- 8 -sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyl tartaric acid, (+)-di-p-' toluoyltartaric acid, (-)-di-p-toluoyltartaric acid, (-)-DBTA and (+)-DBTA; in step-a) to step-(j) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof. The preferred embodiment of the present invention provides an improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentyl propanenitrile phosphate compound of formula-la, comprising of the following steps:
-
a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with (2-(chloromethoxy)ethyl)trimethylsilane in presence of sodium tertiary butoxide in dimethyl formamide to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-djpyrimidine compound of formula-3,

b) reacting the compound of formula-3 with lH-pyrazol-4-ylboronic acid hydrochloride compound of formula-4 in presence of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate in water to provide 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5,

c) treating the compound of formula-5 with oxalic acid in isopropanol to provide oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine compound of formula-5a(i),

d) neutralizing the compound of formula-5a(i) with aqueous sodium carbonate solution in water to provide pure 4-( 1 H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5,

e) reacting the compound of formula-5 with (E)-3-cyclopentylacrylonitrile compound of formula-6 in presence of l,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile to provide 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile compound of formula-7,

f) reacting the compound of formula-7 with phosphoric acid in dichloromethane and then treating with aqueous ammonia in a mixture of water and acetonitrile and followed by reacting with thionyl chloride in dimethyl formamide to provide 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

g) optionally, purifying the compound of formula-8 by treating it with phosphoric acid in toluene to provide 3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula-8a(i),- which is further converted into free base by neutralizing compound of formula-8a(i) with aqueous sodium carbonate solution in a mixture of ethyl acetate and water to provide pure 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

h) resolving the compound of formula-8 obtained in step-(f) or step-(g) by treating it with (+)-dibenzoyl tartaric acid in a mixture of isopropanol and acetonitrile to provide (+)-dibenzoyl tartaric acid salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-lb(i),

i) treating the compound of formula-lb(i) with aqueous sodium carbonate solution in a mixture of dichloromethane and water to provide (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanenitrile compound of formula-1, j) treating compound of formula-12 with phosphoric acid in isopropanol to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4^ phosphate compound of formula-la.

The prior known process for the preparation of the compound of formula-3 involved the use of strong base like sodium hydride, which is pyrophoric in nature, hence difficult to store and use in large scale process. The present invention uses milder bases like alkali metal alkoxides preferably sodium tertiary butoxide, making the process more easy to be performed on commercial scale. Further the cost of the bases like metal alkoxides, alkali metal hydroxides, carbonates etc., are very cheaper rendering the process cost effective and viable at industrial scale. Hence the present process is advantageous when compared with the prior art process.

US7,598,257 B2 discloses a process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-1 by reacting 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimid -in-4-yl)-lH-pyrazol-l-yl)propanenitrile compound of formula-7 in the presence of TFA, EDA, dichloromethane and methanol to provide compound of formula-8. Compound of formula-8 was further subjected to flash column and preparative-HPLC to provide compound of formula-1. Moreover the said process also suffers from drawbacks like usage of highly corrosive TFA which cannot be easily handled in the laboratory as well as on commercial scale.

It was observed that when the same reactions were performed in-toto by the inventors of the present invention, it was found that the reactions were either incomplete or took longer period of time for the completion, resulting in the formation of number of impurities and by¬products affecting the purity of the final product. Hence in order to get the desired compound of formula-1, more no of purifications were required which are laborious, time consuming and making the process more difficult to perform in the laboratory as well as on industrial scale.

In the present invention the compound of formula-7 was deprotected using simple acid such as phosphoric acid, followed by resolution using a chiral acid to provide compound of formula-1. This overcame all the disadvantages of the prior art.

During the conversion of compound of formula-7 to compound of formula-8, when the reaction was stopped midway after the treatment of compound of formula-7 with phosphoric acid and then aqueous ammonia, it was observed that the reaction mixture consisted of a mixture of 80-85% 3-(4-(7H-pyrrolo[253-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8 and an intermediate compound 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanamide in a concentration of about 15-20% which herein after is designated as "Amide compound", represented by the following structural formula.

The "amide compound", when treated with a suitable dehydrating agent provided the compound of formula-8.

The "amide compound" was isolated from the reaction mixture as a crystalline solid and characterized by 'H NMR and Mass spectrometry. The P-XRD and DSC also were recorded which are depicted in figure-3 and 4 respectively

The crystalline 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanamide herein after referred to as form-S, is characterized by:

a) Its powder X-ray diffractogram having peaks at 6.9, 7.6, 8.0, 8.2, 9.1, 10.3, 12.2, 12.7, 13.9, 16.1, 16.6, 17.2, 17.8, 18.6, 18.9, 19.2, 19.5, 20.2, 21.0, 22.2, 23.0, 24.0, 25.1, 25.9, 26.9, 28.0, 28.3, 30.7, 31.7, 32.7, 33.9, 34.5 and 41.2 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-3,

b) its DSC thermogram as shown in figure-4.

The second aspect of the present invention provides acid addition salts of compound of general formula-5a.

Wherein, the suitable acid is selected from acid defined in step-(c)" of the first aspect.
In another aspect of the present invention, provides a process for the preparation of acid addition salt of compound of general formula-5a, comprising of treating 4-(lH-pyrazol-4-yl)-7-((2-(trimethyl silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5 with a suitable acid in presence of a suitable solvent to provide compound of general formula-5 a.

Wherein, the suitable acid is same as defined above and suitable solvent is same as defined in the first aspect of the present invention.

The preferred embodiment of the present invention provides a process for the preparation of oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5 a(i), comprising of treating 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidine compound of formula-5 with oxalic acid in isopropanol to provide compound of formula-5a(i).

The third aspect of the present invention relates to novel crystalline form-N of oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[253-d] pyrimidine compound of formula-5a(i), characterized by:

a) Its powder X-ray diffractogram having peaks at 5.5, 7.7, 10.8, 11.7, 15.0, 15.5, 16.8, 18.5, 18.7, 20.4, 20.7, 21.9, 22.6, 23.2, 25.5, 26.5, 27.7, 29.9, 30.7, 21.5, 32.2, 34.3, 36.0, 38.4, 41.3, 42.1, 44.2, 46.0 and 47.1 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-5,

b) its DSC thermogram as shown in figure-6.

The fourth aspect of the present invention relates to novel crystalline form-M of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-8a(i), characterized by:

a) Its powder X-ray diffractogram having peaks at 4.8, 5.1, 5.6, 7.9, 9.8, 12.9, 13.6, 14.1, 14.3, 14.7, 15.1, 15.9, 16.4, 17.1, 17.4, 18.6, 18.6, 19.2, 18.2, 20.4, 21.2, 21.5, 27.9, 22.9, 23.7, 24.0, 24.9, 25.7, 26.5, 27.1 and 28.Q ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-1,
b) its DSC thermogram as shown figure-2.

The fifth aspect of the present invention relates to novel crystalline form-R of (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-lb(i), characterized by:

a) Its powder X-ray diffractogram having peaks at 5.7, 7.5, 8.6, 11.5, 12.1, 12.9, 13.8, 14.5, 14.9, 15.8, 16.3, 16.8, 17.4, 17.8, 18.4, 19.0, 19.5, 20.1, 21.0, 21.3, 22.3, 23.0, 23.2, 23.6, 24.0, 24.5, 24.9, 26.0, 26.4, 27.1, 27.4, 27.9, 28.3, 28.8, 29.2, 30.3, 31.4, 35.6 and 35.7 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-7,

b) its DSC thermogram as shown in figure-8.

In another aspect of the present invention provided pharmaceutical compositions comprising a therapeutically effective amount of (R)-Ruxolitinib phosphate with one or more pharmaceutical^ acceptable carriers, excipients or diluents.

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la produced by the present invention can be further micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The process of the present invention can be represented schematically as follows:

HPLC Method of Analysis:

4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)m

(Formula-5).
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: X-Terra RP18 250 x 4.6mm, 5 |im (or) equivalent; Wavelength: 220 nm; Column Temperature: 15°C; Injection volume: 10 |iL; Diluent: Buffer: Methanol: Acetonitrile (50:25:25) v/v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Methanol: Water (90:05:05) v/v/v; Concentration: 1.0 mg/ml; Buffer: Transfer accurately 1.0 ml orthophosphoric acid (85%) in 1000 ml of milli-Q-water then filter through 0.22|im Nylon membrane filter paper.

3«(4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yI)-3-cyclopentylpropanenitrile phosphate (Formula-lOa) and (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yI)-3-cyclopentylpropanenitrile (+)-DBTA salt (formula-lb(i))

Apparatus: A liquid chromatographic system is to be equipped with variable ■■■ wavelength" UV^detector and integrator; Column: Symmetry~C18 150 x 4.6mmr3.5"|im (or) equivalent; Wavelength: 225 nm; Column Temperature: 40°C; Injection volume: 5 \xL; Diluent: Buffer: Methanol: Acetonitrile (50:25:25) v/v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Methanol: Water (90:05:05) v/v/v; Concentration: 0.6 mg/ml; Buffer: Transfer accurately 1.0 ml orthophosphoric acid (85%) in 1000 ml of Milli-Q-water then filter through 0.22jam Nylon membrane filter paper. (R)-3-(4-(7H-pyrrolo[2,3-d)pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate (formula-la)

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength PDA-detector; Column: Symmetry shield RP18, 250 x 4.6mm, 5 nm (or) equivalent; Wavelength: 225 nm; Column Temperature: 15°C; Injection volume: 5 |iL; Diluent: Buffer: Methanol: Acetonitrile (50:25:25) v/v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water (90:10) v/v; Buffer: First filter 1000 ml of Milli-Q-water through 0.45p,m nylon membrane filter paper and transfer accurately 1.0 ml of perchloric acid (70%). Mix well and sonicate to degas. P-XRD Method of Analysis:

PXRD analysis of compounds of present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0. DSC Method of Analysis:

Differential scanning calorimetric (DSC) analysis was performed with TA Instruments. Samples of about 2 to.3 milligrams were analyzed.
The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Example-l: Preparation of Oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsiIyl)

ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [Formula-5a(i)]

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (25 gms) compound of formula-2 was slowly added to a pre-cooled mixture of sodium tertiary butoxide (23.9 gms) and dimethyl formamide (125 ml) at 10-1£°C under nitrogen atmosphere and stirred for 3 hours at the same temperature. Trimethylsilyloxymethyl chloride (33.9 gms) was added to the reaction mixture at 10-15°C and stirred for 3 hours. Water was added to the reaction mixture at 10-15°C and stirred for 20 minutes at the same temperature. Potassium carbonate (33.7 gms) was added to the reaction mixture at 15-20°C and stirred for 20 minutes at the same temperature. lH-pyrazol-4-ylboronic acid hydrochloric acid (36.2 gms) compound of formula-4 was added to the reaction mixture at 15-20°C and stirred for 20 minutes. Tetrakis(triphenylphosphine)palladium (0) (5.6 gms ) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 115-120°C and stirred for 3 hours. Cooled the reaction mixture to 25-30°C. Carbon (2.5 gms) was added to the reaction mixture at 25-30°C and stirred for 30 minutes. Dichloromethane and water were added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Both the organic and aqueous layers of the filtrate were separated and the organic layer was washed twice with chilled water. Distilled off the solvent completely from the organic layer and co-distilled with isopropanol. Oxalic acid (25.6 gms) and Isopropanol (50 ml) were added to obtained compound at 25-30°C and stirred for 30 minutes. Cooled the reaction mixture to 0-5°C and stirred for 3 hours. Filtered the solid and washed with isopropanol to get the title compound. Yield: 160 gms; Melting point: 155-160°C.

The P-XRD pattern of the obtained compound was depicted in figure-5. Example-2: Preparation of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Formula-5)
Water (600 ml) was added to the compound obtained in example-l at 25-30°C and basify the reaction mixture using aqueous sodium carbonate solution at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 140 gms; M.R: 168-172°C; Purity by HPLC: 93.94%.

Example-3: Purification of 4-(lH-pyrazol-4-yl)-7-((2-(trimethyIsiIyl)ethoxy)methyl)-7H-

pyrrolo[2,3-d]pyrimidine (Formula-5)

A mixture of toluene (250 ml) and compound of formula-5 (50 gms) was stirred for 1 !/2 hour at 25-30°C. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 44 gms; M.R: 172-175°C.

Example-4: Preparation of 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)propanenitrile (Formula-7)

3-Cyclopentylacrylonitrile (23.04 gms) was added to a mixture of acetonitrile (250 ml), l,8-diazabicyclo[5.4.0]undec-7-ene (28.94 gms) and the compound of formula-5 (50 gms) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 9 hours at the same temperature. Distilled off the solvent completely from the reaction mixture. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Both the organic and aqueous layers were separated and the organic layer was washed with 10% hydrochloric acid solution and then washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 67 gms.

Example-5: Preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate [Formula-8a(i)]

Dichloromethane (200 ml) was added to the compound obtained in example-4 at 25-30°C and stirred for 15 minutes at the same temperature. Phosphoric acid (140 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. Distilled off the solvent under reduced pressure. Acetonitrile (100 ml) and water (65 ml) were added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C. Aqueous ammonia solution (200 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hours. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with ethyl acetate. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer and then co-distilled with cyclohexane. Dimethyl formamide (140 ml) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C. Thionyl chloride (18.86 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 3 hours at the same temperature. Water and then followed by ethyl acetate were slowly added to the reaction mixture at 10-15 °C. Basify the reaction mixture using aqueous sodium carbonate solution. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent from the organic layer and co-distilled with toluene. To the obtained compound, toluene (250 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. Phosphoric acid (15.55 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 45 gms; M.R: 160-165°C; Purity by HPLC: 93.94%; SEM pyrimidine impurity: Not detected; Acrylo pyrimidine impurity: 0.02%; Amide compound: 1.0%; Hydroxy methyl compound: Not detected; HIUS impurity: 0.91%. The P-XRD pattern of the obtained compound was depicted in figure-1. Example-7: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yI)-3-cyclopentylpropane nitrile (+)-dibenzoyl tartaric acid [Formula-lb(i)].

A mixture of ethyl acetate (250 ml), water (200 ml) and the compound of formula-8a(i) (100 gms) were stirred for 15 minutes at 25-30°C. Basify the reaction mixture using aqueous sodium carbonate solution (35.7 gms) at 25-30°C and stirred for 30 minutes. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer. Isopropanol (70 ml) and acetonitrile (850 ml) were added to the obtained compound at 25-30°C. (+)-Dibenzoyl tartaric acid (65 gms) was added to it at 25-30°C and stirred for 6 hours. Heated the reaction mixture to 80-85°C and stirred for 45 minutes. Cooled the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Filtered the solid and washed with acetonitrile. The obtained compound was purified from the mixture of acetonitrile and isopropanol to get the pure title compound. Yield: 37.7 gms; Melting range: 154-157°C; Chiral Purity: 99.75%. The P-XRD pattern of the obtained compound was depicted in figure-7.

Example-8: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yI)-3-cyc!opentylpropane nitrile phosphate (Formula-la)

A mixture of water (300 ml), dichloromethane (800 ml) and the compound of formula-lb(i) (100 gms) was stirred for 15 minutes at 25-30°C. Basify the reaction mixture using aqueous sodium carbonate solution at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with water. Carbon (10 gms) was added to the organic layer at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and filtered through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the organic layer. Isopropanol (500 ml) was added to the obtained compound at 25-30°C and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed. A solution of Phosphoric acid (16.9 gms phosphoric acid in 50 ml isopropanol) was added to the filtrate at 25-30°C and stirred for 3 hrs. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 57.93 gms; M.R: 196-198°C; Purity by HPLC: 99.15%; Chiral HPLC Purity: 99.93%; Phosphate content: 23.93 %w/w. PSD: D9o= 33.49 (am; D[4,3] = 14.37 \xm. Example-9: Preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl)-3-cyclopentylpropanamide (Amide Compound)

Dichloromethane (280 ml) was added to 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[253-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)propanenitrile (86 gms) at 25-30°C and stirred for 15 minutes. Phosphoric acid (195.7 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 12 hours. Distilled off the solvent completely from the reaction mixture. Acetonitrile (70 ml) and water (91 ml) were added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C. Aqueous ammonia solution (490 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 lA hours. Filtered the compound and washed with water. To the obtained compound, water (70 ml) was added at 25-30°C and stirred for 2 hours. Toluene (210 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 53 gms; Melting point: 220.69 (by DSC). The P-XRD pattern of the obtained compound was depicted in figure-3.

We Claim:

1. An improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula-1, comprising of the following steps:
a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with (2-(chloromethoxy)ethyl)trimethylsilane in presence of a suitable base in a suitable solvent to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-djpyrimidine compound of formula-3,

b) reacting the compound of formula-3 with lH-pyrazol-4-ylboronic acid hydrochloride compound of formula-4 in presence of tetrakis(triphenylphosphine)palladium(0) and a suitable base and in a suitable solvent to provide 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5,

c) treating the compound of formula-5 with a suitable acid in a suitable solvent to provide acid addition salts of compound of general formula-5a,

d) treating the acid addition salt of compound of general formula-5a with a suitable base in a suitable solvent to provide pure 4-( 1 H-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine compound of formula-5,

e) reacting the compound of formula-5 with (E)-3-cyclopentylacrylonitrile compound of formula-7 in presence of a suitable base in a suitable solvent to provide 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2)3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile compound of formula-7,

f) treating the compound of formula-7 with phosphoric acid in a suitable solvent and then treating with a suitable base in a suitable solvent and then followed by treating with a suitable dehydrating agent in a suitable solvent to provide 3-(4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

g) optionally, purifying the compound of formula-8 by treating it with a suitable acid in a suitable solvent to provide acid addition salts of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-

' 4-yl)-1 H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of general formula-8a,

which is further converted into free base by neutralizing compound of general formula-8a with a suitable base in a suitable solvent to provide pure 3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8, h) resolving the compound of formula-8 obtained in step-(f) or step-(g) by treating it with a suitable resolving agent in a suitable solvent to provide compound of general formula-lb, i) treating the compound of general formula-lb with a suitable base in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanenitrile compound of formula-1, j) treating the compound of formula-1 with phosphoric acid in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la.

2. The process according to claim-1, wherein: in step-a), b), d), e), f), g) and i) the suitable base is selected from organic or inorganic base;

in step-c) and g) the suitable acid is selected from organic acids such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfoic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid;

in step-f) the suitable dehydrating agent is selected from P2O5, POCI3, SOCl2, TiCU, NaBHLj, DBU-POCl2OEt, P4O10, CuCl/MSTFA (N-Methyl-N-(trimethylsilyl)trifluoroacetamide), silazanes, aminosilanes, alkoxysilanes, chlorosilanes, TBAF, Cyunaric chloride/DMF, ZnCl2, (COCO2-DMSO/ET3N, AlCl3/NaI, PdCl2, A1C13. 6H20/ KI, POCl3-Py/Imidazole;

in step-h) the suitable resolving agent is optically active forms of mandelic acid, acetyl mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10- camphorsulfonic acid, dibenzoyl tartaric acid (+)-DBTA, (-)-DBTA, (+)-di-p-toluoyltartaric acid, (-)-di-p-toluoyltartaric acid; in step-a) to step-(j) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof 3. An improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula-1, comprising of the following steps:

a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with (2-(chloromethoxy)ethyl)trimethylsilane in presence of sodium tertiary butoxide in dimethyl formamide to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-3,

b) reacting the compound of formula-3 with lH-pyrazol-4-ylboronic acid hydrochloride compound of formula-4 in presence of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate in water to provide 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5,

c) treating the compound of formula-5 with oxalic acid in isopropanol to provide oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5a(i),

d) neutralizing the compound of formula-5a(i) with aqueous sodium carbonate solution in presence of water to provide pure 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5,

e) reacting the compound of formula-5 with (E)-3-cyclopentylacrylonitrile compound of formula-7 in presence of l,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile to provide 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol-l-yl)propanenitrile compound of formula-7,

f) reacting the compound of formula-7 with phosphoric acid in presence of dichloromethane and then treating with aqueous ammonia in a mixture of water and acetonitrile and followed.by treating with thionyl chloride in dimethyl formamide to provide 3-(4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8,

g) optionally, purifying the compound of formula-8 by treating it with phosphoric acid in toluene to provide 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl)-3-

—cyclopentylpropanenitrile-phosphate compound-of formula-8a(i), which is- further ■•-converted into free base by neutralizing compound of formula-8a(i) with aqueous sodium carbonate solution in a mixture of ethyl acetate and water to provide pure 3-(4-(7H-pyrrolo[253-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

h) resolving the compound of formula-8 obtained in step-(f) or step-(g) by treating it with (+)-dibenzoyl tartaric acid in a mixture of isopropanol and acetonitrile to provide (+)-dibenzoyl tartaric acid salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl)-3-cyclopentylpropanenitrile compound of formula-1 b(i),

i) treating the compound of formula-lb(i) with aqueous sodium carbonate solution in a mixture of dichloromethane and water to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y 1)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile compound of formula-1,

j) treating compound of formula-1 with phosphoric acid in isopropanol to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-1 a. 4. Acid addition salts of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-
pyrrolo[2,3-d] pyrimidine compound of general formula-5a.

Wherein, the term acid is same as defined in step-(c) of claim-2.

5. 3-(4-(7H-pyrrolo[2,3-d]pyrimi^

6. Crystalline forms of the following compounds:

a) Crystalline form-M of 3-(4-(7H-pyrrolo[2s3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentyl propanenitrile phosphate compound of formula-8a(i), characterized by:

i. Its powder X-ray diffractogram having peaks at 4.8, 5.1, 5.6, 7.9, 9.8, 12.9, 13.6, 14.1, 14.3, 14.7, 15.1, 15.9, 16.4, 17.1, 17.4, 18.6, 18.6, 19.2, 18.2, 20.4, 21.2, 21.5, 27.9, 22.9, 23.7, 24.0, 24.9, 25.7, 26.5, 27.1 and 28.0 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-1,

ii. its DSC thermogram as shown in figure-2
.
b) Crystalline form-S of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentyl propanamide, characterized by:

i. Its powder X-ray diffractogram having peaks at 6.9, 7.6, 8.0, 8.2, 9.1, 12.2, 12.7, 13.9, 16.1, 16.6, 17.2, 17.8, 18.6, 18.9, 19.2, 19.5,20.2,21.0,22.2,23.0,24.0,25.1,25.9, 26.9, 28.0, 28.3, 30.7, 31.7, 33.9, 34.5 and 41.2 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-3,

ii. its DSC thermogram as shown in figure-4.

c) Crystalline form-N of oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5a, characterized by:

i. Its powder X-ray diffractogram having peaks at 5.5, 7.7, 10.8, 11.7, 15.0, 15.5, 16.8, 18.5, 18.7, 20.4, 20.7, 21.9, 22.6, 23.2, 25.5, 26.5, 27.7, 29.9, 30.7, 21.5, 32.2, 34.3, 36.0, 38.4, 41.3, 42.1, 44.2, 46.0 and 47.1 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-5,

ii. its DSC thermogram as shown in figure-6.

d) Crystalline form-R of (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-lb(i), characterized by:

i. Its powder X-ray diffractogram having peaks at 5.7, 7.5, 8.6, 11.5, 12.1, 12.9, 13.8,
14.5, 14.9, 15.8, 16.3, 16.8, 17.4, 17.8, 18.4, 19.0, 19.5, 20.1, 21.0, 21.3, 22.3, 23.0,
23.2, 23.6, 24.0, 24.5, 24.9, 26.0, 26.4, 27.1, 27.4, 27.9, 28.3, 28.8, 29.2, 30.3, 31.4,
35.6 and 35.7 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-7,
ii. its-DSCthermogranras shown in figure-8".~~ " ~
7. An improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile phosphate compound of formula-1 a, comprising of the following steps:

a) Treating 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1 H-pyrazol-1 -yl)propanenitrile compound of formula-7 with phosphoric acid in a suitable solvent and then treating with a suitable base in a suitable solvent and followed by treating with a suitable dehydrating agent in a suitable solvent provides 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8,

b) optionally, purifying the compound of formula-8 by treating it with a suitable acid in a suitable solvent to provide acid addition salt of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile phosphate compound of general formula-8a, which is further converted into free base by treating it with a suitable base in a suitable solvent to provide pure 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

c) resolving the compound of formula-8 obtained in step-(a) or step-(b) by treating it with a suitable resolving agent in a suitable solvent to provide compound of general formula-lb,

d) treating the compound of general formula-lb with a suitable base in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanenitrile compound of formula-1,

e) treating the compound of formula-1 with phosphoric acid in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la.

8. An improved process for the preparation of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formuIa-5, comprising of:

a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with (2-(chloromethoxy)ethyl)trimethylsilane in presence of sodium tertiary butoxide in dimethyl formamide to provide 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-3,

b) reacting the obtained compound of formula-3 in-situ with lH-pyrazol-4-ylboronic acid hydrochloride compound of formula-4 in presence of tetrakis(triphenyl phosphine)palladium(O) and potassium carbonate in water to provide 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5.

9. The crystalline oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] . pyrimidine compound of formula-5 a(i), 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanenitrile phosphate compound of formula-8a(i) and (+)-DBTA salt of (R)-3-(4-(7H-pyrrolo[233-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-lb(i) are useful in the preparation of pure (R)-3-(4-(7H-pyrrolo[233-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la.

10. The (R)-3-(4-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-la obtained according to the preceding claims having particle size distribution of D90 less than 100 ^im, preferably less than 50 (im.