WO2016063294A2

WO2016063294A2 - Process for the preparation of (r)-3-(4-(7h-pyrrolo[2,3-d], pyrimidin-4-yl)-1 h-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and its polymorphs thereof

Info

Publication number: WO2016063294A2
Application number: PCT/IN2015/000398
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Gogulapati VENKATA PANAKALA RAI
Original assignee: Msn Laboratories Private Limited
Priority date: 2014-10-20
Filing date: 2015-10-20
Publication date: 2016-04-28
Also published as: WO2016063294A3

Abstract

The present invention provides an improved process for the preparation of (R)-3-(4-(7H- pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la and its novel polymorphs thereof, which is represented by the following structural formula:

Description

Process for the preparation of (R)-3-(4-(7H-pyrrolof2,3-dlpyrimidin-4-yl)-lH-pyrazol- l-yl)-3-cvclopentylpropanenitrile phosphate and its polymorphs thereof

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 5225/CHE/2014 filed on 20^th Oct. 2014, 270/CHE/2015 filed on 19^th Jan. 2015 and 2369/CHE/2015 filed on 11^th May 2015 which are incorporated herein by reference.

Field of the Invention:

The present invention provides an improved process for the preparation of (R)-3-(4- (7H-pyrrolo[2,3d-]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, represented by the following structural formula:

Formula- l a

The present invention also provides a novel polymorphs of (R)-3-(4-(7H-pyrrolo [2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la and its process for the preparation.

Further, the present invention provides hydrochloric acid salt of (R)-3-(4-(7H- pyrrolo[2, 3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile.

Further, the present invention provides an amorphous form of (R)-3-(4-(7H-pyrrolo [2,3d-]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la and its process for the preparation.

Further, the present invention provides 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:

The (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile commonly known as Ruxloitinib which is useful in the treatment of janus kinase-associated disease such as myeloproliferative disorders. The first FDA approved janus kinase (JAK) inhibitor such as Ruxloitinib, which is the only drug currently approved for the treatment of myelofibrosis.

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

US pat. No. 8,722,693 discloses the phosphate salt of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile.

US pat. No. 7,598,257 discloses process for the preparation of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile compound of formula- 1. The said patented process involves the separation of isomer intermediate compounds 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 poor yields and low purities.

In view of the foregoing, there is still remains an unmet need for a process for preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 -yl)-3-cyclopentyl propanenitrile with high chemical and enantiomerical purity and also applicable for multi- kilogram production. The process of the present invention is inexpensive, environmental- friendly having straight forward workups, rendering it amenable to the large-scale production of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile and its phosphate salt compound of formula- la with high yield and purity.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ( GA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.

The difference in the physical ^"properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. Pharmaceutical compounds having different crystalline forms or polymorphs have different dissolution property. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Pharmaceutical formulation is affected by the rate of delivery or the bioavailability of the pharmaceutically active substance is the crystalline forms or polymorphs. This relationship between crystalline forms or polymorphs and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products.

Many pharmaceutical actives are known to exist in different crystalline forms. Different polymorphic forms of the same compound may have completely different properties, especially when compared with an amorphous form of the same active. Amorphous materials have properties that can be of advantage in the preparation of solid dosage forms, such as solubility/dissolution rate, bioavailability, functional mechanics and adhesivity.

The discovery of new amorphous and crystalline polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

The present invention provides new amorphous and crystalline forms of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- 1 a and its process for the preparation.

Brief description of the Invention: The first aspect of the present invention is to provide a novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la.

The second aspect of the present invention is to provide an improved process for the preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-3.

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

The fourth aspect of the present invention is to provide another novel 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 fifth 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 sixth 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 seventh aspect of the present invention relates to novel crystalline (+)-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), herein after designated as form-R. The eighth aspect of the present invention is to provide another novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la.

The ninth aspect of the present invention relates to novel N-protected 4-(l H-pyrazol- 4-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 15 and its preparation.

The tenth aspect of the present invention is to provide a process for the preparation of compound of general formula- 16, comprising of reacting N-protected 4-(l H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine compound of general formula-15 with tosyl chloride in presence of a suitable base and a suitable catalyst in a suitable solvent to provide compound of general formula- 16.

The eleventh aspect of the present invention is to provide an improved process for the preparation of compound of formula- 1, comprising of resolution of compound of formula-8 in presence of a suitable resolving agent in a suitable solvent to provide compound formula- 1.

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

The thirteenth aspect of the present invention is to provide a process for the preparation of (R)-3-cyclopentyl-3-(4-halo-substituted- 1 H-pyrazol- 1 -yl)propanenitrile compound of general formula-1 1 , comprising of resolution of 3-cyclopentyl-3-(4-halo- substituted-1 H-pyrazol- 1 -yl)propanenitrile compound of general formula- 10 in presence of a suitable resolving agent in a suitable solvent to provide compound of general formula- 1 1.

The fourteenth aspect of the present invention is to provide a novel process for the preparation of (R)-3-(4-(N-protected-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l -yl)-3- cyclopentyl propanenitrile compound of general formula- 13, comprising of reacting (R)-3- cyclopentyl-3-(4-halo-substituted-l H-pyrazol- l-yl)propanenitrile compound of general formula-1 1 with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-N-protected-7H-pyrrolo [2,3-d]pyrimidine compound of general formula- 12 in presence of tetrakis(triphenyl phosphine)palladium in a suitable base in a suitable solvent to provide compound of general formula- 13. The fifteenth aspect of the present invention is to provide a novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula- 1, comprising of reacting (R)-3-cyclopentyl-3-(4-halo- substituted-1 H-pyrazol- l-yl)propanenitrile compound of general formula-1 1 with 4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-19 in presence of tetrakis(triphenylphosphine)palladium in a suitable base in a suitable solvent to provide compound of formula- 1.

The sixteenth aspect of the present invention is to provide an amorphous form of (R)- 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- 1 a and it process for the preparation.

The seventeenth aspect of the present invention is to provide an amorphous form of 3- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile compound of formula-8 and its preparation.

The eighteenth aspect of the present invention is to provide an amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la and its process for the preparation.

The nineteenth aspect of the present invention is to provide a novel crystalline form of (R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopenty lpropanenitri le phosphate compound of formula- la herein after designated as form-M and its process for the preparation.

The twentieth aspect of the present invention is to provide a novel crystalline form of (R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -y l)-3 -cyclopenty lpropanenitri le phosphate compound of formula- la herein after designated as form-S and its process for the preparation.

The twenty-first aspect of the present invention is to provide a novel crystalline form 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 herein after designated as form-N and its process for the preparation. The twenty-second aspect of the present invention relates to (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile hydrochloric acid compound of formula- lc.

The twenty-third aspect of the present invention is to provide a novel crystalline form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile hydrochloric acid compound of formula- lc herein after designated as form-R and its process for the preparation.

The twenty-fourth aspect of the present invention is to provide a novel crystalline form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentyl propanenitrile phosphate compound of formula- la herein after designated as form-I and its process for the preparation.

The twenty-fifth aspect of the present invention is to provide a pharmaceutical composition comprising the amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate and a pharmaceutically acceptable excipient.

The twenty-sixth aspect of the present invention is to provide a process for the preparation of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la. Brief description of Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-8a(i).

Figure 2: Illustrates the DSC thermogram of crystalline form-M of 3-(4-(7H-pyrrolo[2,3ⁱ-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-8a(i).

Figure 3: Illustrates the PXRD pattern of crystalline form-S of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l 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 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(i).

Figure 6: Illustrates the DSC thermogram of crystalline oxalate salt fprm-N of 4-(l H- pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5a(i).

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 compound of formula- lb(i).

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 compound of formula- lb(i).

Figure 9: Illustrates the PXRD pattern of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Figure 10: Illustrates the PXRD pattern of amorphous form of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile free base compound of formula- 8.

Figure 11: Illustrates the PXRD pattern of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Figure 12: Illustrates the PXRD pattern of crystalline form-M of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Figure 13: Illustrates the DSC thermogram of crystalline form-M of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- 1 a.

Figure 14: Illustrates the PXRD pattern of crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula- la. Figure 15: Illustrates the PXRD pattern of crystalline form-N of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Figure 16: Illustrates the PXRD pattern of crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile hydrochloric acid compound of formula- lc.

Figure 17: Illustrates the PXRD pattern of crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Figure 18: Illustrates the PXRD pattern of amorphous of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile obtained according to US 7,598,257 B2.

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 like; "polar solvents" such as water or 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, l ,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

As used herein, the term suitable "acid" is selected from "organic acids" such as formic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, trifluoroacetic acid, 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.

The term "suitable resolving agent" used herein the present invention is selected from optically active forms of 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, (-)-dibenzoyl tartaric acid (-)-DBTA, 2-amino-7,7-dimethylbicyclo [2,2, l]heptan-l -methylene sulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo [2,2,1] heptan-1 -methylene sulfonic acid, (+)-di- p-toluoyltartaric acid, (-)-di-p-toluoyltartaric acid.

As used herein the term "suitable dehydrating agent" is selected from P₂0₅, POCI3, SOCl₂, TiCl₄, NaBH₄, DBU/POCl₂OEt, P4O10, CuCl/MSTFA (N-Methyl-N- (trimethylsilyl)trifluoroacetamide), silazanes, aminosilanes, alkoxysilanes, chlorosilanes, TBAF, Cyunaric chloride DMF, ZnCl₂, (COCl)₂-DMSO/ET₃N, AlCl₃ NaI, PdCl₂, AICI3. 6H₂0/ KI, POCl_3-Py/Imidazole.

The suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.

The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety.

In some embodiments, "Amino protecting group (Pg)" is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxy carbonyl(Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4- trifluoromethylphenylsulfonyl) ethoxycarbonyl (Tsc), t-butoxycarbonyl (BOC), 1 - adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl(2-Adoc), 2,4-dimethylpent-3- yloxycarbonyl (Doc), cyclohexyloxy carbonyl(Hoc), l ,l -dimethyl-2,2,2- trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, Ν',Ν'-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), l-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, and t-butyldimethylsilylmethyl, N-pivaloyloxymethyl (POM), 1 ,1 - diethoxymethyl, tri(Cl-4-alkyl)silyl, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, 9- Fluorenylmethyloxycarbonyl (FMOC) group, Acetyl (Ac) group, Benzoyl (Bz) group, Benzyl (Bn) group, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM) and vinylethyl ether;

According to some embodiments, the amino protecting group (Pg) is selected from - C(0)OC!-C6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxycarbonyl; optionally substituted -C(0)OCi-C₆ aryl, such as, for example, benzyloxy- carbonyl and p- methoxybenzyloxycarbonyl; optionally substituted -C1-C12 aryl(Ci-C3)alkyl such as, for example, benzyl, phenethyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted C -Cn aryl carbonyl, such as, for example, benzoyl; Ci-C₆ alkanoyl, such as, for example, formyl, acetyl, and propionyl; Ci-C₆ alkylsulfonyl, such as, for example, mesyl;

According to some embodiments, the amino protecting group (Pg) is selected from optionally substituted phenylsulfonyl, such as, for example, benzenesulfonyl, toluenesulfonyl (tosyl) and 3-nitrobenzenesulfonyl; -Ci-C₆ alkylcarbamoyl, such as for example-dimethyl carbamoyl; and optionally substituted -C -C|₀ arylalkyl carbamoyl, such as, for example, benzyl carbamoyl.

The first aspect of the present invention provides a novel 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, 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 1 H-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-(l H-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) neutralizing the acid addition salt of compound of general formula-5a 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)-lH-pyrazol-l-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)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of general formula-8a, which is further converted into its free base by treating the 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)- 1 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)-l H-pyrazol- l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- l a.

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 P₂0₅, P0C1₃, S0C1₂, TiCl₄, NaBH₄, DBU-POCl₂OEt, P₄Oio, 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/ I, POCl_3-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, 3- bromocamphor-8-sulfonic acid, 3-bromocamphor-lO-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 a novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-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-d]pyrimidine compound of formula-3,

b) reacting the compound of formula-3 with 1 H-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-(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 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)-lH-pyrazol-l-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)-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)-l H-pyrazol-l -yl)-3- cyclopentylpropanenitrile phosphate compound of formula-8a(i), which is further converted into its 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)-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)-l H- 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] pyramidin-4-yl)- 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)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitri le phosphate compound of formula- la.

US7,598,257 B2 discloses a process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l H-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 wsfs 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[2,3-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.

"Amide compound" 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 ^lH 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.

In another aspect of the present invention provides the amide compound as well as its crystalline form-S are useful in the preparation of pure compound of formula- 1.

The second aspect of the present invention provides an improved process for the preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-3, comprising of 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 compound of formula-3.

Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in the first aspect of the present invention. The preferred embodiment of the present invention provides an improved process for the preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine compound of formula-3, comprising of 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 compound of formula-3.

The prior known process 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.

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

Formula-5a

Wherein, the suitable acid is selected from "organic acids" such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, oxalic 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 another aspect of the present invention, provides a process for the preparation of acid addition salts of compound of general formula-5a, comprising of treating 4-(l H-pyrazol- 4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5 with a suitable acid in a suitable solvent to provide compound of general formula-5a.

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-5a(i), comprising of treating 4-(l H-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 fourth aspect of the present invention provides a 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, comprising of the following steps:

a) Treating 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-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 reacting 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,

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)-lH-pyrazol-l-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)-l H- 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)-lH-pyrazol-l -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- 1 a.

Wherein, in step-a), b) and (d) the suitable base is selected from organic or inorganic base; in step-a) the suitable dehydrating agent is same as defined in step-(f) of the first aspect of the present invention;

in step-c) the suitable acid is same as defined in step-(c) of the first aspect of the present invention;

in step-d) the suitable resolving agent is same as defined in the step-(h) of the first aspect of the present invention;

in step-a) to (e) 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.

The preferred embodiment of the present invention provides a 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- l 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)-l H-pyrazol-l-yl)propanenitrile compound of formula-7 with phosphoric acid in dichloromethane and then treating with aqueous ammonia in a mixture of acetonitrile and water and then followed by treating 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,

b) 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)-l H-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula-8a(i), which is further converted into free base by treating it 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,

c) resolving the compound of formula-8 obtained in step-(a) or step-(b) by treating it with (+)-DBTA in a mixture of isopropanol and acetonitrile to provide (+)-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), d) 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)- 1 H-pyrazol-1 -yl)-3-cyclopentylpropanenitrile compound of formula- 1 ,

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

The fifth 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[2,3-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 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(i) of the present invention is useful in the preparation of pure compound of formula-5 as well as compound of formula- 1.

The sixth aspect of the present invention relates to novel crystalline form-M of 3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -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 28.0 ± 0.2 degrees of two-theta and P- XRD pattern as depicted in figure- 1 ,

b) its DSC thermogram as shown figure-2. The seventh 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. Use of oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d] pyrimidine compound of formula-5a(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[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentyl propanenitrile compound of formula- lb(i) in the preparation of pure (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropane nitrile phosphate compound of formula- la.

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- l a obtained according to the present invention is having purity greater than 99.9%; preferably 99.95%; more preferably 99.98% as measured by HPLC.

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

a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with N- protected 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of general formula- 14 in presence of tetrakis(triphenylphosphine)palladium and a suitable base in a suitable solvent to provide N-protected 4-(lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine compound of general formula- 15,

b) reacting the compound of general formula- 15 with tosyl chloride in presence of a suitable base and a suitable catalyst in a suitable solvent to provide compound of general formula- 16,

c) deprotecting the amine protection of pyrazole ring compound of general formula- 16 in presence of a suitable deprotecting agent in a suitable solvent to provide 4-(lH- pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine compound of formula- 17, d) reacting the compound of formula- 17 with (E)-3-cyclopentylacrylonitrile compound of formula-6 in the presence of a suitable base in a suitable solvent to provide 3- cyclopentyl-3-(4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl) propanenitrile compound of formula- 18,

e) deprotecting the tosyl group of compound of formula- 18 in presence of a suitable base in a suitable solvent to provide 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- l H- pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8,

f) resolving the compound of formula-8 in presence of a suitable resolving agent in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 - yl)-3-cyclopentyl propanenitrile compound of formula- 1 ,

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

Wherein,

in step-a), b), d) and e) the suitable base is selected from organic or inorganic base, in step-b) the suitable catalyst is dimethyl amino pyridine;

in step-c) the suitable hydrochloric acid source is selected from HCl gas, aqueous HCl, dry HCl, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;

in step-f) the suitable resolving agents is selected from mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8- sulfonic acid, 3-bromocamphor-lO-sulfonic acid, 10-camphorsulfonic acid, dibenzoyl tartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclop[2,2, l ]heptan-l - methylene sulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo [2,2,1 ] heptan-1 - methylene sulfonic acid,

in step-a) to step-g) the suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

The ninth aspect of the present invention relates to novel N-protected 4-(l H-pyrazol- 4-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of general formula-15.

Formula- 15

Wherein, Pg = Amine protecting group;

Further, the present aspect of the present invention provides a process for the preparation of N-protected 4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 15, comprising of reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with N-protected 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of general formula- 14 in presence of tetrakis(triphenyl phosphine)palladium in a suitable base in a suitable solvent to provide compound of general formula-15.

Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

The tenth aspect of the present invention provides a process for the preparation of compound of general formula- 16, comprising, of reacting N-protected 4-(l H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 15 with tosyl chloride in presence of a suitable base and a suitable catalyst in a suitable solvent to provide compound of general formula-16. Wherein, the suitable base is selected from organic or inorganic bases and suitable catalyst is dimethyl amino pyridine; and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

The eleventh aspect of the present invention provides an improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentyl propanenitrile compound of formula- 1 , comprising of resolution of 3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of formula-8 in presence of a suitable resolving agent in a suitable solvent to provide compound formula- 1.

Wherein, the suitable resolving agent is same as defined in step-f) of the eighth aspect of the present invention and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

According to the prior known processes, the separation of isomers from the racemic mixture compound of formula-8 was carried out using preparative HPLC method and further the obtained compounds were purified using column chromatrography. Since the said process is quite tedious, time consuming and not suitable on commercial scale up.

In order to overcome the problem associated with prior known processes, the inventors of the present invention has carried out the resolution of compound of formula-8 using suitable chiral resolving agents. They have observed that, the desired enantiomeric excess compound was obtained with high yield and purity. Hence the present process is more advantageous over the prior reported process.

The (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentyl propanenitrile free base compound of formula- 1 obtained according to any one of the process of the present invention having HPLC purity greater than 99.95 % and chiral purity greater than 99.93 %. The twelth aspect of the present invention provides an improved process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la.

a) Reacting the 4-halo-substituted pyrazole compound of general formula-9 with (E)-3- cyclopentyl acrylonitrile compound of formula-6 in presence of a suitable base in a suitable solvent to provide 3-cyclopentyl-3-(4-halo-substituted- 1 H-pyrazol- 1 -yl) propanenitrile compound of general formula- 10,

b) resolution of compound of general formula- 10 in presence of a suitable resolving agent in a suitable solvent to provide (R)-3-cyclopentyl-3-(4-halo-substituted-l H- pyrazol- 1 -yl)propanenitrile compound of general formula- 1 1 ,

c) reacting compound of general formula-1 1 with 4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-N-protected-7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 12 in presence of tetrakis(triphenylphosphine)palladium and a suitable base in a suitable solvent to provide (R)-3-(4-(N-protected-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of general formula- 13, d) deprotecting the amine protecting group of compound of general formula- 13 in presence of a suitable base in a suitable solvent to provide (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of formula- 1,

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

Wherein,

in step-a), c) and d) the suitable base is selected from organic base or inorganic base;

in step-b) the suitable resolving agent is same as defined in step-f) of the eighth aspect of the present invention;

in step-a) to step-e) the suitable solvent is selected from alcohol solvent, chloro solvent,

ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof. The thirteenth aspect of the present invention provides a process for the preparation of (R)-3-cyclopentyl-3-(4-halo-substituted-lH-pyrazol-l-yl)propanenitrile compound of general formula-1 1, comprising of resolution of 3-cyclopentyl-3-(4-halo-substituted-l H- pyrazol-l-yl)propanenitrile compound of general formula- 10 in presence of a suitable resolving agent in a suitable solvent to provide compound of general formula- 1 1.

Wherein, the suitable resolving agents are same as defined in step-f) of the eighth aspect of the present invention and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

The fourteenth aspect of the present invention provides a novel process for the preparation of (R)-3-(4-(N-protected-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3- cyclopentyl propanenitrile compound of general formula- 13, comprising of reacting (R)-3- cyclopentyl-3-(4-halo-substituted-lH-pyrazol-l-yl)propanenitrile compound of general formula-1 1 with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-protected-7H-pyrrolo [2,3-d]pyrimidine compound of general formula- 12 in presence of tetrakis(triphenyl phosphine) palladium in a suitable base in a suitable solvent to provide compound of general formula-13.

Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in twelth aspect of the present invention.

The fifteenth aspect of the present invention provides a novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl)-3-cyclopentyl propanenitrile compound of formula- 1 , comprising of reacting (R)-3-cyclopentyl-3-(4-halo- substituted- lH-pyrazol-l-yl)propanenitrile compound of general formula-1 1 with 4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula- 19 in presence of tetrakis(triphenylphosphine)palladium in a suitable base in a suitable solvent to provide compound of formula-1.

Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in twelth aspect of the present invention. The sixteenth aspect of the present invention relates to an amorphous form of (R)-3- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, which is characterized by its powder X-ray diffractogram as depicted in figure-9.

Further, the present aspect of the invention provides a process for the preparation of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a suitable solvent to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-l a,

b) stirring the reaction mixture,

c) filtering the reacting reaction mixture through hy-flow bed,

d) spray-drying to get amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- l a.

Wherein, the suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent and ether solvents or mixture thereof; preferably alcohol solvents.

The term "spray drying" broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture. In a typical spray drying apparatus, there is a strong driving force for evaporation of acetone from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described, for example, in Perry's Chemical Engineer's Handbook, pages. 20-54 to 20-57 (Sixth Edition 1984).

A preferred method to remove the solvent involves spray-drying, in which a solution of (R)-Ruxolitinib phosphate is sprayed with spray drier at the flow rate ranging from about 1 to about 30 ml/min, and preferably about 5 to about 20 ml/min. The air inlet temperature to the spray drier used may range from about 25°C to about 150°C, and preferably from about 60°C to about 65°C and the outlet air temperature used may range from about 30° C. to about 90° C. Of course, specific conditions will vary somewhat for spray drying using different equipment configurations. The solid residue obtained after the solvent removal is isolated and, if desired, can be dried further using conventional methods. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use.

The substantially pure amorphous (R)-Ruxolitinib phosphate obtained according to the present invention may be further dried in, for example, Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor, to further lower residual solvents.

Drying techniques includes spray drying, vacuum drying, freeze drying or agitated thin film drying.

In another aspect of the present invention provides substantially amorphous (R)- Ruxolitinib phosphate, having a chemical purity of at least about 96% or more as measure by HPLC, preferably at least about 99% or more, and more preferably at least about 99.5% or more.

By way of non- limiting example only, a typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber.

Examples of such apparatuses include Niro Models PSD-I, PSD-2 and PSD-4 (Niro AJS, Soeborg, Denmark).

Typically, the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying. Spray-drying may be performed in a conventional manner in the processes of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 19th ed., vol. II, pg. 1627, herein incorporated by reference). The drying gas used in the invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen gas is a particularly preferred drying gas for use in the process of the invention. The (R)-Ruxolitinib phosphate produced by spray-drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter. The seventeenth aspect of the present invention relates to amorphous form of 3-(4-

(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3-cyclopentylpropanenitrile compound of formula-8, which is characterized by P-XRD pattern as depicted in figure- 10.

Further, the present aspect of the invention provides a process for the preparation of amorphous form of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8, comprising of the following steps:

a) Adding a suitable solvent to 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)propanenitrile,

b) cooling the reaction mixture,

c) adding a suitable acid to the reaction mixture,

d) stirring the reaction mixture,

e) distilling off the solvent from the reaction mixture,

f) adding a suitable base and a suitable solvent to the obtained compound,

g) stirring the reaction mixture,

h) distilling off the solvent from the reaction mixture,

i) extracting the reaction mixture from a suitable solvent and washed the organic layer with water and sodium chloride solution,

j) distilling off the solvent from the organic layer to get amorphous 3-(4-(7H-pyrrolo

[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile compound of formula-8.

Wherein,

in step-a), f and step-i) the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof;

in step-b) the reaction temperature is ranging from 0°C to 35°C.

in step-c) the suitable acid is selected from hydrochloric acid, methane sulfonic acid, trifluoroacetic acid and acetic acid;

in step-f) the suitable base is selected from organic or inorganic base.

In another aspect, there are provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous (R)-Ruxolitinib phosphate substantially free from crystalline form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

The invention also encompasses pharmaceutical compositions comprising (R)- Ruxolitinib or salts thereof of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the (R)-Ruxolitinib phosphate of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The eighteenth aspect of the present invention relates to amorphous form of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, which is characterized by P-XRD pattern as depicted in figure- 11. Further, the present aspect of the invention provides a process for the preparation of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a suitable solvent to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) distilling off the solvent completely from the reaction mixture,

d) adding a suitable solvent to the compound obtained in step-(c), - e) stirring the reaction mixture,

f) filtering the solid and drying to provide amorphous form of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Wherein,

in step a) the suitable solvent is selected from alcohol solvents and chloro solvents or mixture thereof;

in step-d) the suitable solvent is selected from hydrocarbon solvents. The preferred embodiment of the present invention provides a process for the preparation of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3- cyclopentylpropanenitrile phosphate compound of formula- l a, comprising of the following steps:

a) Adding a mixture of methanol and dichloromethane to (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate, b) stirring the reaction mixture,

c) distilling off the solvent completely from the reaction mixture,

d) adding cyclohexane to the obtained compound in step-(c),

e) stirring the reaction mixture,

f) filtering the solid and drying to provide amorphous of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

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

a) its powder X-ray diffractogram having peaks at 4.0, 12.3, 14.0, 15.2, 15.8, 16.4, 17.8, 20.6, 22.0 and 26.0 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 12.

b) its DSC thermogram as depicted in figure- 13.

Further, the present aspect of the invention provides a process for the preparation of crystalline form-M of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- l H-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a suitable solvent to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) filtering the reaction mixture through hi-flow bed,

d) adding a suitable anti-solvent to the filtrate obtained in step-(c),

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- 1 a.

Wherein,

in step-a) the suitable solvent is selected from alcohol solvents;

in step-d) the suitable anti-solvent is selected from chloro solvents.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding methanol to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) filtering the reaction mixture through hi-flow bed,

d) adding dichloromethane to the filtrate obtained in step-(c),

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

The twentieth aspect of the present invention relates to novel crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, characterized by its powder X-ray diffractogram having peaks at 3.7, 7.5, 11.4, 13.7, 15.2, 15.5, 18.0, 18.8, 19.0, 20.1, 23.5, 23.8, 24.8, 25.3 and 27.4 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 14.

Further, the present aspect of the invention provides a process for the preparation of crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate compound of formula- l a, comprising of the following steps:

a) Adding a suitable solvent to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-

1 -yl)-3 -cyclopentylpropanenitnle phosphate,

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) cooling the reaction mixture,

e) adding a suitable anti-solvent to the reaction mixture,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide crystalline form-S of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

Wherein,

in step-a) the suitable solvent is selected from alcohol solvents or mixtures thereof, in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction;

in step-e) the suitable anti-solvent is selected from hydrocarbon solvents.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3 -cyclopentylpropanenitnle phosphate compound of formula- la, comprising of the following steps:

a) Adding a mixture of methanol and isopropanol to (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate, b) heating the reaction mixture to 50-55°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C,

e) adding n-heptane to the reaction mixture,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide crystalline form-S of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la. The twenty-first aspect of the present invention relates to novel crystalline form-N of

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, characterized by its powder X-ray diffractogram having peaks at 4.1, 4.8, 12.3, 14.1, 15.0, 15.2, 15.9, 16.0, 16.4, 17.4, 17.9, 18.7, 19.6, 20.6, 21.1, 21.9, 22.1 and 23.1 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-15.

Further, the present aspect of the invention provides a process for the preparation of crystalline form-N of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3- cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

1 -yl)-3-cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) adding a suitable solvent to the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide crystalline form-N of (R)-3-(4-

(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

Wherein,

in step-a) the suitable solvent is selected from alcohol solvents and hydrocarbon solvents or mixture thereof;

in step-c) the suitable solvent is selected from hydrocarbon solvents. The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a mixture of methanol and cyclohexane to (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate, b) stirring the reaction mixture,

c) adding cyclohexane to the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide crystalline form-N of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

The amorphous and crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate obtained according to the present invention having phosphate content about 22.0 weight-% to 24.0 weight-%.

The twenty-second aspect of the present invention relates to (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile hydrochloric acid.

Formula- lc

The twenty-third aspect of the present invention relates to novel crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile hydrochloric acid compound of formula- lc, characterized by its powder X-ray diffractogram having peaks at 8.2, 9.6, 11.7, 12.0, 13.7, 14.7, 15.2, 15.6, 16.5, 17.9, 18.7, 19.3, 19.8, 20.4, 20.8, 22.0, 22.4, 22.8, 23.5, 24.8, 25.4, 26.4, 27.7, 28.1 , 30.4, 33.3 and 37.6 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 16. The crystalline form-R obtained according to the present invention is having chloride content about 8.5 wt-% to 10.0 wt-%.

Further, the present aspect of the invention provides a process for the preparation of crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentylpropanenitrile hydrochloric acid compound of formula- lc, comprising of the following steps:

a) Adding a suitable solvent to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile,

b) stirring the reaction mixture,

c) filtering the reaction mixture through hy-flow bed,

d) heating the filtrate obtained in step-(c),

e) adding a suitable hydrochloric acid source to the reaction mixture,

f) stirring the reaction mixture,¹

g) cooling the reaction mixture,

h) adding a suitable solvent to the reaction mixture,

i) filtering the precipitated solid and drying to provide crystalline form-R of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile hydrochloric acid compound of formula- lc.

Wherein,

in step-a) the suitable solvent is selected from ester solvents;

in step-d) the suitable temperature is ranging from 25°C°C to the reflux temperature of the solvent used in the reaction;

in step-e) suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;

in step-h) the suitable solvent is selected from alcohol solvents.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3 -cyclopentylpropanenitrile hydrochloric acid compound of formula- lc, comprising of the following steps: a) Adding ethyl acetate to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl 3 -cyclopentylpropanenitrile,

b) stirring the reaction mixture,

c) filtering the reaction mixture through hy-flow bed,

d) heating the filtrate obtained in step-(c) to 50-55 °C,

e) adding ethyl acetate-hydrochloric acid to the reaction mixture,

f) stirring the reaction mixture,

g) cooling the reaction mixture,

h) adding isopropanol to the reaction mixture,

i) filtering the precipitated solid and drying to provide crystalline form-R of (R)-3-(4-

(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3 -cyclopentylpropanenitrile hydrochloric acid compound of formula- lc.

The crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 - yl)-3 -cyclopentylpropanenitrile hydrochloric acid compound of formula- lc of the present invention is useful in the preparation of pure amorphous and crystalline forms of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

The twenty-fourth aspect of the present invention relates to novel crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l -yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, characterized by its powder X-ray diffractogram having peaks at 3.9, 7.5, 8.2, 9.4, 12.0, 14.4, 14.7, 15.8, 16.6, 17.5, 18.7, 18.9, 20.1 , 21.6, 22.7, 23.1 , 23.4, 23.7, 24.8, 25.1 and 26.2 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 17.

Further the present aspect of the invention provides a process for the preparation of crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

b) stirring the reaction mixture, c) heating the reaction mixture to a suitable temperature,

d) adding a mixture of isopropanol and phosphoric acid to the reaction mixture at a suitable temperature,

e) stirring the reaction mixture,

f) cooling the reaction mixture,

g) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

Wherein,

in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, polar solvent like water or mixture thereof;

in step-c) and d) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction;

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-l H-pyrazol- l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding isopropanol to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)- 3 -cyclopentylpropanenitrile,

b) stirring the reaction mixture,

c) heating the reaction mixture to 50-55°C,

d) adding a mixture of isopropanol and phosphoric acid to the reaction mixture at 50- 55°C,

e) stirring the reaction mixture,

f) cooling the reaction mixture,

g) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate. Further, the aspect of the present invention provides an alternate process for the for the preparation of crystalline form-l of (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- l a, comprising of,

a) Dissolving (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentyl propanenitrile compound of formula- 1 in a suitable first solvent, b) heating the reaction mixture to a suitable temperature,

c) adding a suitable second solvent and phosphoric acid to the reaction mixture, d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4-

(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

Wherein,

in step-a) the suitable first solvent is selected from alcohol solvents;

in step-b) the suitable temperature is ranging from 0°C to the reflux temperature of solvent used in the reaction;

in step-c) the suitable second solvent is selected from alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-l of (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H-pyrazol- l -yl)-3-cyclopentyl propanenitrile phosphate compound of formula- la, comprising of,

a) Dissolving (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentyl propanenitrile compound of formula- 1 in methanol,

b) heating the reaction mixture to 45-50°C,

c) adding isopropanol and phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate. The present invention provides the pharmaceutical composition comprising the amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate.

The twenty-fifth aspect of the present invention provides the pharmaceutical composition comprising the amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate and a pharmaceutically acceptable excipient.

The oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof. Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxylpropyl methyl cellulose, hydroxylethyl cellulose and pre-gelatinized starch.

Exemplary disintegrants are selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.

Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide. A specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal silicon dioxide. In one embodiment, the pharmaceutical composition is prepared by wet granulation.

In a specific embodiment, the process includes wet granulation of amorphous (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate with at least one excipient, followed by compression.

In another embodiment, the pharmaceutical composition is prepared by compaction. In a specific embodiment, the compaction process includes compaction of amorphous (R)-3- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate with at least One excipient, followed by compression. In yet another embodiment, the pharmaceutical composition is prepared by direct compression. In a specific embodiment, the direct compression process includes blending amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate with at least one excipient, followed by compression. The preferred embodiment of the present invention provides a process for the preparation of pharmaceutical composition of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate comprising of following steps:

a) Blending of amorphous R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l -yl)- 3-cyclopentylpropanenitrile phosphate, diluent & disintegrant.

b) lubricating the obtained blend.

c) compressing the lubricated blend of step (ii) into tablets.

d) optionally coating the compressed tablets. Alternative process for the preparation of pharmaceutical composition of amorphous

(R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile phosphate comprising of following steps:

a) Granulation of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 - yl)-3 -cyclopentylpropanenitrile phosphate, diluent, binder, disintegrant & optionally with a suitable solvent.

b) lubricating the obtained blend.

c) compressing the lubricated blend of step (ii) into tablets.

d) Optionally, coating the compressed tablets.

The present inventors have repeated the process disclosed in US pat. No. US 7,598,257 B2 and characterized the obtained (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H- pyrazol-l-yl)-3 -cyclopentylpropanenitrile free base using P-XRD which was depicted in figure-18.

The twenty-sixth aspect of the present invention provides a process for the preparation of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 - yl)-3-cyclopentylpropanenitrile phosphate compound of formula- l a, comprising the following steps of:

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) filtering the reaction mixture,

e) isolating the amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la from the filtrate obtained in step-(d).

Wherein,

in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, polar aprotic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, nitrile solvents and polar solvents like water or mixture thereof.

in step-b) the suitable temperature is selected from ambient temperature to the reflux

temperature of the solvent used in the reaction.

in step-e) the isolation of amorphous compound of formula- 1 involves removal of solvent by the techniques such as lyophilization, spray drying, recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation and the like.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising the following steps of:

a) Adding a mixture of methanol and water to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate,

b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture for 30-45 minutes,

d) filtering the reaction mixture,

e) lyophilizing the amorphous (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)- 1 H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- l a from the filtrate obtained in step-(d).

Freeze-drying (or) lyophilization has been widely used for a number of decades in pharmaceutical, food, and chemical industries. Freeze-drying is particularly desirable in situations where a pharmaceutical or other material is required to be dried or dehydrated or desolvated, but is sensitive to the application of heat for the purpose of drying. Many compounds, when exposed to the typically employed drying temperatures of non-freeze drying techniques, decompose, degrade, or volatilize away, resulting in an undesirable product.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

Freeze drying (lyophilization) may be carried out by freezing a solution of Ruxolitinib phosphate at low temperatures and reducing the pressure as required for removing the solvent from the frozen solution of Ruxolitinib phosphate. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of Ruxolitinib phosphate, may range from about -80°C to about 0°C, or up to about 20°C.

The invention also encompasses pharmaceutical compositions comprising (R)- Ruxolitinib phosphate of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the amorphous (R)-Ruxolitinib phosphate of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. The crystalline Form-I of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l- yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la produced by the present invention is stable at room temperature as well stable at 40±2°c.

Amorphous and crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la produced by the present invention can be further micronized or milled 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 starting material for the preparation of amorphous (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate can be selected from the novel crystalline forms obtained from the present invention (or) also selected from the (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropane nitrile phosphate salt prepared from the processes known in the art. Novel crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l- yl)-3-cyclopentylpropanenitrile phosphate of the present invention can be prepared using crystalline form-I of the present invention (or) (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate salt known in the art. The novel amorphous and crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-

4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate obtained according to the present invention can be useful in the preparation of pharmaceutical composition.

HPLC Method of Analysis:

4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (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 μηι (or) equivalent; Wavelength: 220 run; Column Temperature: 15°C; Injection volume: 1Q μί; 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 0.22μπι Nylon membrane filter paper.

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

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Symmetry C 18 150 x 4.6mm, 3.5 μιη (or) equivalent; Wavelength: 225 nm; Column Temperature: 40°C; Injection volume: 5 μί;

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 0.22μπι Nylon membrane filter paper.

(R)-3-(4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yI)-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 μιη (or) equivalent; Wavelength: 225 nm; Column Temperature: 15°C; Injection volume: 5 μί; 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 0.45μηι nylon membrane filter paper and transfer accurately 1.0 ml of perchloric acid (70%). Mix well and conicate to degas.

(R)-RuxoIitinib free base and (R)-Ruxolitinib Phosphate salt:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: X-Terra RP 18 250 x 4.6 mm, 5 μπι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 225 nm; Column Temperature: 25°C; Injection volume: 10 μΐ,; Run time: 35 minutes; Diluent: Water : Methanol: Acetonitrile: Buffer (25:25:50) v/v; Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water: Methanol (90:5:5) v/v; Buffer: 1.1 grams of ortho phosphoric acid in water and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it. Chiral Method of Analysis:

(R)-Ruxolitinib free base and (R)-Ruxolitinib Phosphate salt:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector; Column: Chiral Pack IC, 250 X 4.6 mm, 3μ (or) equivalent; Flow rate: 1.0 mL/min; Wavelength: 310 nm; Column Temperature: 25°C; Injection volume: 5 μί; Needle wash: Diluent; Run time: 30 minutes; Diluent: Methanol; Elution: Isocratic; Mobile phase: Solution-A: Solution-B (75:25) v/v; Solution-A: n-Hexane; Solution-B: Ethanol: Methanol (80:20) v/v; Concentration: 4.0 mg/mL.

P-XRD Method of Analysis:

PXRD analyses of compounds produced by the present invention were 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 Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

The process of the present invention can be represented schematically as follows:

Scheme-I:

Formula-!

Formula-la

Scheme-II:

Formula-la

Scheme-Ill:

Formula-la Formula-1 Formula-13

Scheme-IV:

Formula-11 Formula-19 Formula-1

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example-1: Preparation of Oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) 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 10-15°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 1 15-120°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)

A mixture of water (600 ml) and 20% aqueous sodium carbonate solution (500 ml) was added to the compound obtained in example-1 at 25-30°C and stirred for 15 minutes 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-(trimethylsiIyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (Formula-5)

A mixture of toluene (250 ml) and 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (50 gms) was stirred for 1 ½ 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-cycIopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)propanenitriIe (FormuIa-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 (Formula-8)

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 at 25-30°C. 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 at the same temperature. 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 extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane to get the title compound. Yield: 45 gms; Amide compound: 15-20%; Hydroxy methyl compound: 10-15%. Example-6: Preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate (Formula-8a(i))

Dimethyl formamide (140 ml) was added to 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile compound of formula-7 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. Adjusted the pH of the reaction mixture to 8-9 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 aqueous layer was extracted with ethyl acetate. Combined the organic layers and 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.

ExampIe-7: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl)-3-cyclopentyIpropane 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]pyrimidin-4-yl)-lH-pyrazol-l- yl)-3-cyclopentyIpropanenitriIe 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: D₉₀ = 33.49 μιη; D[4,3] = 14.37 μηι.

Example-9: Preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanam.de (Amide Compound)

Dichloromethane (280 ml) was added to 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-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 ½ 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.

Example-10: Preparation of Amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yI)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (Formula-la)

Methanol (120 ml) was added to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (3 gms) at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed. The obtained filtrate was spray dried at below mentioned parameters to obtain amorphous (R)-3- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentylpropanenitrile phosphate.

Operation parameters:

Labultima Instrument.

Aspirator: 70%

Feed Rate: 5 ml/min

Inlet temperature: 55°C to 60°C.

Gas flow N₂: 2kg/ cm².

Yield: 1.0 gms; Phosphate content: 22.3% w/w; Melting point: 185°C-190°C; HPLC purity: 99.70 %; Chiral purity: 99.94 %.

The P-XRD pattern of the obtained compound was shown in figure- 1 1.

Example-11: Preparation of Amorphous form of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazoI-l-yI)-3-cycIopentylpropanenitrile (Formula-8) Trifluoroacetic acid (83.69 gms) was added to a pre-cooled solution of 3-cyclopentyl- 3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl) propanenitrile (34 gms) in dichloromethane (210 ml) at 0-5°C and stirred for 6 hours at the same temperature. Distilled off the solvent completely from the reaction mixture and co- distilled twice with dichloromethane. To the obtained compound, methanol (157 ml) was added at 0-5°C and stirred for 20 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. Ethylenediamine (21 ml) was added to the reaction mixture at 25-30°C and stirred for 13 hours at the same temperature. Distilled off the solvent completely from the reaction mixture. Ethyl acetate (100 ml) followed by water (80 ml) was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and organic layer was washed with water and followed by with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 18 gms; M.R: 52°C-54°C;

The P-XRD pattern of the obtained compound was shown in figure- 10.

Reference Example-12: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl)-3-cyclopentylpropanenitrile according to US 7,598,257 B2

Dichloromethane (210 ml) was added to (R)-3-cyclopentyl-3-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)propane nitrile (34 gms) at 25-30°C. Trifluoroacetic acid (83.69 gms) was added to the reaction mixture at 25-30°C and stirred for 5-6 hours at the same temperature. Distilled off the solvent from the reaction mixture and the co-distilled with dichloromethane. Methanol (157 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 20 minutes at the same temperature. Ethylenediamine (21 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 13 hours at the same temperature. Distilled off the solvent from the reaction mixture under vacuum below 55-60°C. Ethyl acetate (100 ml) and water (80 ml) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with water and then followed by sodium chloride solution. Distilled off the solvent completely from the reaction mixture to get the title compound. Yield: 29 gms;

The P-XRD pattern was shown in figure- 18.

Example-13: Preparation of crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazoI-l-yI)-3-cyclopentylpropanenitrile phosphate (Formula-la)

A mixture of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l -yl)-3- cyclopentylpropanenitrile obtained according to reference example- 12 (2.0 gms) and isopropanol (22 ml) was stirred for 15 minutes at 25-30°C. Slowly raised the temperature of the reaction mixture to 50-55°C and stirred for 15 minutes at the same temperature. A solution containing phosphoric acid (0.54 gms) and isopropanol (6 ml) was added to the above reaction mixture at 50-55°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture 25-30°C and stirred for 15 minutes at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 1.9 gms; Phosphate content: 21.9% w/w; HPLC purity: 99.88%; Chiral purity: 99.85%. PSD: D₉₀ = 17.57 μιη; D[4,3] = 8.91 μιη.

The P-XRD pattern was shown in figure- 17.

Example-14: Preparation of Amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (Formula-la)

Methanol (35 ml) and dichloromethane (35 ml) were added to (R)-3-(4-(7H- pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3 -cyclopentylpropanenitrile phosphate (2.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure at 50-55°C To the obtained foamy solid, cyclohexane (10 ml) was added at 25-30°C and stirred for 145 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound. Yield: 1.8 gms; Phosphate content: 22.3% w/w; HPLC purity: 99.75%; Chiral purity: 99.83%.

The P-XRD pattern was shown in figure-9.

Example-15: Preparation of crystalline form-M of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cycIopentylpropanenitrile phosphate (Formula-la) Methanol (75 ml) was added to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (2.5 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with methanol. Slowly dichloromethane (90 ml) was added to the obtained filtrate at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. Yield: 2.0 gms; Phosphate content: 23.7 % w/w. HPLC purity: 99.75 %; Chiral purity: 99.96 %.

The P-XRD pattern was shown in figure- 12.

Example-16: Preparation of crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitriIe phosphate (Formula-la)

A mixture of methanol (26 ml) and isopropanol (16 ml) were added to (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate (2.0 gms) at 25-30°C. Raised the temperature of the reaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. Slowly cooled the reaction mixture to 25-30°C. n- heptane (50 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 1.8 gms; Phosphate content: 23.2 % w/w. HPLC purity: 99.86 %; Chiral purity: 99.95 %.

The P-XRD pattern was shown in figure- 14.

Example-17: Preparation of crystalline form-N of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cycIopentylpropanenitrile phosphate (Formula-la)

A mixture of methanol (80 ml) and cyclohexane (80 ml) was added to (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (2.0 gms) at 25-30°C and stirred for 20 minutes at the same temperature. Cyclohexane (20 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 1.49 gms; Phosphate content: 22.6 % w/w.

The P-XRD pattern was shown in figure- 15. Example-18: Preparation of crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitriIe hydrochloric acid (Formula- lc)

Ethyl acetate (3 ml) was added to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl)-3-cyclopentylpropanenitrile (0.5 gms) at 25-30°C and stirred for 10_^1 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with ethyl acetate. The filtrate was taken in another RB flask and heated to 50-55°C and then stirred for 10-15 minutes at the same temperature. Slowly ethyl acetate-hydrochloric acid (0.7 ml) was added to the reaction mixture at 50-55°C and stirred for 10-15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Isopropanol (1 ml) to the reaction mixture at 25-30°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 0.4 gms; M.R: 83-85°C; Chloride content: 10 % w/w.

The P-XRD pattern was shown in figure- 16.

Example-19: Preparation of Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (Formula-la)

A mixture of methanol (30 ml) and water (180 ml) was added to (R)-3-(4-(7H- pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopenty lpropanenitrile phosphate ( 10 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and immediately freezed the obtained filtrate at -70°C for 45 minutes and then lyophilized to get the title compound.

Yield: 9.5 gms; Chiral Purity: 99.96%.

The PXRD of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 - yl)-3 -cyclopenty lpropanenitrile phosphate is depicted in figure-l l .

Example-20: Preparation of crystalline form-I of (R)-3-(4-(7H-pyrroIo[2,3d-]pyrimidin- 4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (Formula-la)

Methanol (15 ml) was added to (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentylpropanenitrile (2.5 gms) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 1 hour at the same temperature. Phosphoric acid (0.80 gms) and isopropanol (3.8 ml) was added to the reaction mixture at 45-50°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound.

Yield: 1.2 gms.

The P-XRD pattern was shown in figure- 17.

Example-21: Preparation of (Formula-15)

l-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of formula-14 (13.8 gm) was added to a mixture of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine compound of formula-2 (10 gm) and N,N-dimethylformamide (60 ml). Aq. potassium carbonate solution (26.9 gm in 30 ml water) was added to the reaction mixture at 25-30°C and stirring the reaction mixture for 10 min at the same temperature. Heated the reaction mixture at 50-55°C under nitrogen atmosphere. Palladium tetrakistriphenyl phosphine(3.76 gm) was added to the reaction mixture. Heating the reaction mixture to 120°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water and dichloromethane were added to the reaction mixture. Filtered the reaction mixture through hyflow and washed with water. Both the organic layer and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 12.5 gm

ExampIe-22: Preparation of (Formula-16)

4-Dimethylaminopyridine (1.70 gm) and triethylamaine (7.07 gm) were added to a solution of compound of formula-15 (12 gm) in dichloromethane (36 ml). P-toluene sulfonyl chloride (13.32 gm) in dichloromethane (48 ml) was added to the reaction mixture at 25- 30°C and stirred for 2 and a half hrs at the same temperature. Water was added to the reaction mixture. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and distilled off the solvent completely from the organic layer and dried to get the title compound. Yield: 8.35 gm

Exaraple-23: Preparation of (Formula-17)

Compound of formula-16 (13 gm) was dissolved in tetrahydrofuran ( 13 ml) at 25- 30°C and water (26 ml) was added to the reaction mixture. Hydrochloric acid (4 ml) dissolved in water (26 ml) and was slowly added to the reaction mixture at 25-30°C Stirred the reaction mixture for 3 hrs at the same temperature. Cooled the reaction mixture to Q-5°C and stirred the reaction mixture for 1 hr at the same temperature. The solid formed was filtered and washed with water. Water (30 ml) was added to the above obtained compound. Basify the reaction mixture using aq.potassium carbonate solution at 25-30°C. The solid formed was filtered, washed with water and dried to the title compound. Yield: 1 gm

Example-24: Preparation of (Formula-18)

1,8-Diazabicyclo (5,4,0)undec-7-ene (4.7 gm) and (E)-3-cyclopentylacrylonitrile compound of formula-6 (2.99 gm) were added to a solution of the compound of formula- 17 (7 gm) in acetonitrile (35 ml) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 5 hrs at the same temperature. Distilled off the solvent from the reaction mixture. Water and dichloromethane were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and dried to get the title compound. Yield: 8.35 gms

Example-25: Preparation of HCl salt of compound of formula-8 (Formula-8)

Dissolved the Compound of formula-18 (8 gm) in methanol (40 ml) at 25-30°C. Potassium carbonate (3.6 gm) was added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture. Water and dichloromethane were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and distilled off the solvent completely from the organic layer. Isopropyl alcohol (16 ml) was added to the obtained compound at 25-30°C. Isopropanolic HCl (16 ml) was slowly added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C. The solid formed was filtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 4 gms.

Claims

We Claim:

1. 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- l 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)-lH-pyrazol-l-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)-l H-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)-l H-pyrazol- l-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,

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)- 1 H-pyrazol- 1 -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.

2. The process according to claim- 1, wherein:

in step-a), b) and d) the suitable base is selected from organic or inorganic base;

in step-a) the suitable dehydrating agent is selected from P₂0₅, P0C1₃, SOCl₂, T1CI4, NaBH₄, DBU-POCl₂OEt, P₄O₁₀, CuCl/MSTFA (N-methyl-N-(trimethylsilyl) trifluoroacetamide), silazanes, aminosilanes, alkoxysilanes, chlorosilanes, TBAF, Cyunaric chloride/DMF, ZnCl₂, (C0C1)₂-DMSQ/ET₃N, AlCl₃/NaI, PdCl₂, A1C1₃. 6H₂0/ KI, POCl₃.Py/Imidazole;

in step-b) 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-c) the suitable resolving agent is optically active forms of 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 (e) 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)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- l 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)-lH-pyrazol-l-yl)propanenitrile compound of formula-7 with phosphoric acid in dichloromethane and then treating with aqueous ammonia in a mixture of acetonitrile and water and followed by treating with thionyl chloride in dimethyl formamide to provide 3-(4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of formula-8,

b) 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-pyrazol-l -yl)-3-cyclopentyl propanenitrile phosphate compound of formula-8a(i), which is further converted into free base by treating it with aqueous sodium carbonate solution in a mixture of ethyl acetate and water to provide pure 3-(4-(7H-pyirolo[2,3-d]pyrimidin-4-yl lH- pyrazol- 1 -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 (+)-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),

d) 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-cyclopentylpropanenitrile compound of formula- 1,

e) treating the 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-cyclopentyl propanenitrile phosphate compound of formula- la.

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.

Formula- 5 a

Wherein, 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;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanamide (Amide compound).

A novel process for the preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentylpropanenitrile 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 1 H-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) optionally, 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-(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 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)-lH-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)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile compound of general formula-8a, which is further converted into its 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)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile compound of formula-8,

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)-l H-pyrazol- 1 -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)-l H-pyrazol- l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- 1 a.

7. The process according to claim-6, 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 same as defined in step-b) of claim- 1 ;

in step-f) the suitable dehydrating agent is selected from P₂0₅, POCI3, SOCl₂, TiCl₄, NaBH₄,

DBU-POCl₂OEt, P₄O₁₀, CuCl/MSTFA (N-Methyl-N-(trimethylsilyl)trifluoroacetamide), silazanes, aminosilanes, alkoxysilanes, chlorosilanes, TBAF, Cyunaric chloride/DMF,

ZnCl₂, (COCl)2-DMSO/ET₃N, AlCl₃/NaI, PdCl₂, A1C1₃. 6H₂0/ I, POCl_3-Py/Imidazole; step-h) the suitable resolving agent is same as defined in step-c) of claim- 1 ; 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.

b) reacting the compound of formula-3 with l H-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-(l 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 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[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- l -yl)-3-cyclopentyl propanenitrile compound of formula-8, g) 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-cyclopentyl propanenitrile 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)- 1 H-pyrazol- 1 -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)-l H- 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)- 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.

Crystalline forms of the following compounds:

Crystalline form-M of 3-(4-(7H-pyrrolo[2,3-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.

Crystalline form-S of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l -yl)-3- cyclopentylpropanamide, 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(i), characterized by: i. Its powder X-ray diffractogram having peaks at 5.5, 7.7, 10.8, 1 1.7, 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)-l H- 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 DSC thermogram as shown in figure-8.

10. 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 formula-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 1 H-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-(l H-pyrazol- 4-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine compound of formula-5.

1 1. Amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate.

12. A process for the preparation of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a mixture of methanol and dichloromethane to (R)-3-(4-(7H-pyrrolo[2,3- dJpyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate, b) stirring the reaction mixture,

c) distilling off the solvent completely from the reaction mixture,

d) adding cyclohexane to the obtained compound in step-(c),

e) stirring the reaction mixture,

13. Novel crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1-yl)- 3-cyclopentylpropanenitrile phosphate compound of formula- la, wherein;

a) Crystalline form-M is characterized by its powder X-ray diffractogram having peaks at 4.0, 12.3, 14.0, 15.2, 15.8, 16.4, 17.8, 20.6, 22.0 and 26.0 ± 0.2 degrees of two- theta and P-XRD pattern as depicted in figure- 12.

b) Crystalline form-S is characterized by its powder X-ray diffractogram having peaks at 3.7, 7.5, 11.4, 13.7, 15.2, 15.5, 18.0, 18.8, 19.0, 20.1 , 23.5, 23.8, 24.8, 25.3 and 27.4 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-14.

c) Crystalline form-N is characterized by its powder X-ray diffractogram having peaks at 4.1, 4.8, 12.3, 14.1 , 15.0, 15.2, 15.9, 16.0, 16.4, 17.4, 17.9, 18.7, 19.6, 20.6, 21.1 , 21.9, 22.1 and 23.1 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 15.

d) Crystalline form-I is characterized by its powder X-ray diffractogram having peaks at 3.9, 7.5, 8.2, 9.4, 12.0, 14.4, 14.7, 15.8, 16.6, 17.5, 18.7, 18.9, 20.1 , 21.6, 22.7, 23.1 , 23.4, 23.7, 24.8, 25.1 and 26.2 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure-17.

14. Crystalline (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile hydrochloric acid.

15. Crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3- cyclopentylpropanenitrile hydrochloric acid compound of formula- lc, characterized by its powder X-ray diffractogram having peaks at 8.2, 9.6, 1 1.7, 12.0, 13.7, 14.7, 15.2, 15.6, 16.5, 17.9, 18.7, 19.3, 19.8, 20.4, 20.8, 22.0, 22.4, 22.8, 23.5, 24.8, 25.4, 26.4, 27.7, 28.1 , 30.4, 33.3 and 37.6 ± 0.2 degrees of two-theta and P-XRD pattern as depicted in figure- 16.

16. A process for the preparation of crystalline form-M of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding methanol to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) filtering the reaction mixture through hi-flow bed,,

d) adding dichloromethane to the filtrate obtained in step-(c),

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M 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.

17. A process for the preparation of crystalline form-S of (R)-3-(4-(7H-pyrrolo[2,3-d]

pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula- la, comprising of the following steps:

a) Adding a mixture of methanol and isopropanol to (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate, b) heating the reaction mixture to 50-55°C,

c) stirring the reaction mixture, d) cooling the reaction mixture to 25-30°C,

e) adding n-heptane to the reaction mixture,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide crystalline form-S of (R)-3-(4- (7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -y l)-3 -cyclopenty lpropanenitri le phosphate compound of formula- 1.

18. A process for the preparation of crystalline form-N of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- 1, comprising of the following steps:

a) Adding methanol and cyclohexane to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol- 1 -yl)-3-cyclopentylpropanenitrile phosphate,

b) stirring the reaction mixture,

c) adding cyclohexane to the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide crystalline form-N of (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate.

19. A process for the preparation of crystalline form-I of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3 -cyclopenty lpropanenitrile phosphate compound of formula- 1 , comprising of the following steps:

a) Adding isopropanol to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1-yl)- 3 -cyclopentylpropanenitrile,

b) stirring the reaction mixture,

c) heating the reaction mixture to 50-55°C,

e) stirring the reaction mixture,

f) cooling the reaction mixture, g) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo [2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile phosphate.

20. A pharmaceutical composition comprising an amorphous (R)-3-(4-(7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-l H-pyrazoI-l -yl)-3-cyclopentylpropanenitrile phosphate and at least one pharmaceutically acceptable excipient.

21. A pharmaceutical composition comprising (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- l -yl)-3-cyclopentylpropanenitrile phosphate obtained in any of the preceding claims and atleast one pharmaceutically acceptable excipient for inhibiting JAK1 and/or JAK2 diseases such as myeloproliferative disorders.

22. Use of crystalline form-R of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- l H-pyrazol- 1 - yl)-3 -cyclopentylpropanenitrile hydrochloride in the preparation of amorphous and other crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l -yl)-3- cyclopentylpropanenitrile phosphate.

23. A process for preparation of amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- l H- pyrazol-l-yl)-3 -cyclopentylpropanenitrile phosphate, comprising the steps of:

a) Dissolving (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l -yl)-3-cyclo pentylpropanenitrile phosphate in a suitable solvent,

b) isolating the amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl)-3 -cyclopentylpropanenitrile phosphate compound of formula- 1 from the solution of step-(a).

24. The process according to claim-23, wherein,

in step-(a) the solvent used is selected from methanol, ethanol, n-propanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, water or mixture thereof;

in step-(b) the isolation of compound of formula- 1 involves removal of solvent by the techniques such as lyophilization, recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation and the like. 25. The process according to claim 23, wherein the solvent is methanol.

26. The process according to claim 23, wherein the solvent is a mixture of water and methanol. 27. The process according to claim 23, wherein the isolation of compound of formula-1 involves the removal of solvent by lyophilization.

28. A process for the preparation of crystalline form-1 of (R)-3-(4-(7H-pyrrolo[2,3d-] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- 1 a, comprising of:

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

b) isolating crystalline form-1 of (R)-3-(4-(7H-pyirolo[2,3d-]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate compound of formula- l a from the solution of step-(a).

29. A process for the preparation of crystalline form-1 of (R)-3-(4-(7H-pyrrolo[2,3d- ]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising of,

a) Dissolving (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)-l H-pyrazol-1 -yl)-3- cyclopentyl propanenitrile compound of formula-1 in a suitable first solvent, b) heating the reaction mixture to a suitable temperature,

c) adding a suitable second solvent and phosphoric acid to the reaction mixture, d) stirring the reaction mixture, e) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

30. The process according to claim-28, wherein,

in step-a) the suitable first solvent is selected from alcohol solvents;

in step-b) the suitable temperature is ranging from 0°C to the reflux temperature of

solvent used in the reaction;

31. A process for the preparation of crystalline form- 1 of (R)-3-(4-(7H-pyrrolo[2,3d- ]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising of,

a) Dissolving (R)-3-(4-(7H-pyrrolo[2,3d-]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3- cyclopentyl propanenitrile compound of formula- 1 in methanol,

b) heating the reaction mixture to 45-50°C,

c) adding isopropanol and phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to provide the crystalline form-I of (R)-3-(4- (7H-pyrrolo[2,3d-]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

32. A process for the preparation of amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la, comprising the following steps of:

a) Adding a mixture of methanol and water to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopentylpropanenitrile phosphate,

b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture, d) filtering the reaction mixture,

e) removing the solvent by lyophilization to get amorphous (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula- la.

33. A novel process for the preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8, comprising of:

a) Reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula-2 with N- protected 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of general formula- 14 in presence of tetrakis(triphenylphosphine)palladium and a suitable base in a suitable solvent to provide N-protected 4-(l H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine compound of general formula- 15,

c) deprotecting the amine protection of pyrazole ring compound of general formula- 16 in presence of a suitable deprotecting agent in a suitable solvent to provide 4-(l H- pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine compound of formula- 17, d) reacting the compound of formula- 17 with (E)-3-cyclopentylacrylonitrile compound of formula-6 in the presence of a suitable base in a suitable solvent to provide 3- cyclopentyl-3-(4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl) propanenitrile compound of formula- 18,

e) deprotecting the tosyl group of compound of formula- 18 in presence of a suitable base in a suitable solvent to provide 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-l-yl)-3-cyclopentyl propanenitrile compound of formula-8.

34. The process according to claim-33, wherein,

in step-c) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl; in step-a) to step-e) the suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

35. N-protected 4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 15.

Formula- 15

wherein, Pg is amine protecting group;

36. A process for the preparation of N-protected 4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- djpyrimidine compound of general formula- 15, comprising of reacting 4-chloro-7H- pyrrolo[2,3-d]pyrimidine compound of formula-2 with N-protected 4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of general formula- 14 in presence of tetrakis(triphenyl phosphine)palladium in a suitable base in a suitable solvent to provide compound of general formula- 15, wherein, the suitable base is selected from organic or inorganic base and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

37. A process for the preparation of compound of general formula-16, comprising, of reacting N-protected 4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine compound of general formula- 15 with tosyl chloride in presence of a suitable base and a suitable catalyst in a suitable solvent to provide compound of general formula-16, wherein, the suitable base is selected from organic or inorganic bases and suitable catalyst is dimethyl amino pyridine; and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

38. 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 compound of formula- 1 , comprising of resolution of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl)-3-cyclopentyl propanenitrile compound of formula-8 in presence of a suitable resolving agent in a suitable solvent to provide compound formula- 1, wherein, the suitable resolving agent is same as defined in step-f) of the eighth aspect of the present invention and suitable solvent is selected from alcohol solvent, chloro solvent, ketone solvent, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof.

39. Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate.

40. Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate obtained according to any of the preceding claims having chiral purity greater than 99.95 % by HPLC.

41. Use of oxalate salt of 4-(lH-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d] pyrimidine compound of formula-5a(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[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl)-3-cyclopentyl propanenitrile compound of formula- lb(i) in the preparation of pure

(R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3 -cyclopenty 1

propanenitrile phosphate compound of formula- la.

42. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-yclopentylpropanenitrile phosphate compound of formula- la obtained according to the preceding claims having

"Hydroxy methyl compound" not more than 1.5%, preferably not more than 1.0%; more preferably not more than 0.05%.

43. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-yclopentylpropanenitrile phosphate compound of formula- la obtained according to the preceding claims having "Amide compound" not more than 0.15%, preferably not more than 0.1%; more preferably not more than 0.05%.

44. 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 μπι, preferably less than 50 μηι.

45. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-yclopentylpropanenitrile phosphate compound of formula- la obtained according to the preceding claims having purity greater than 99.9%; preferably 99.95%; more preferably 99.98% as measured by HPLC.

46. Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl)-3-cyclopentyl propaneitrile phosphate obtained according to any of the preceding claims useful for the preparation of pharmaceutical composition. 47. Novel crystalline forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol- 1 -yl)- 3-cyclopentylpropaneitrile phosphate obtained according to any of the preceding claims are useful for the preparation of pharmaceutical composition.

48. A pharmaceutical composition comprising amorphous (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate and a pharmaceutically acceptable carrier or diluent.