DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

PREPARATION OF RUXOLITINIB AND ITS INTERMEDIATES

INTRODUCTION
Aspects of the present invention relate to process for preparation of Ruxolitinib intermediate and their use in preparation of Ruxolitinib and its pharmaceutically acceptable salts.

BACKGROUND
Ruxolitinib is useful as inhibitor of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases and is represented by structure of formula (I).

I
Pyrazolylpyrrolo [2,3-d]pyrimidines of formula (II) is one of the key intermediates useful in the preparation of ruxolitinib.

II
Processes for the preparation of ruxolitinib and its intermediates have been disclosed in US7598257B2 and WO2010083283A1.
In view of the importance of JAKs inhibitors, new, cost-effective, novel methods of making such drugs and their intermediates are always of interest.

SUMMARY
The first embodiment of the present invention provides a process for preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II), which comprises:
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent;

wherein X= halogen, tosylate, triflate, nosylate, brosylate and P=nitrogen protecting group
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal;

wherein Y= halogen, MgX (X=halogen), SnR3 (R=C1-C6 alkyl) and P1=amine protecting group
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
The second embodiment of the present invention provides a process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent;

wherein X=halogen, tosylate, triflate, nosylate, brosylate and P= amine protecting group
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal;

wherein Y= halogen, MgX (X=halogen), SnR3 (R=C1-C6 alkyl) and P1 is amine protecting group
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
e) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
Third embodiment of the of the present invention provides process for a preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II), which comprises:
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent;

wherein X=halogen, tosylate, triflate, nosylate, brosylate, P=amine protecting group, excluding tosyl group and P2=amine protecting group
Ra and Rb are each independently H or C1-6 alkyl; or Ra and Rb, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted withC1-4 alkyl groups
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
The fourth embodiment of the present invention provides a process for preparation of Ruxolitinib of formula (I) which comprises;
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent;

wherein X=halogen, tosylate, triflate, nosylate, brosylate, P=amine protecting group, excluding tosyl group and P2=amine protecting group
Ra and Rb are each independently H or C1-6 alkyl; or Ra and Rb, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with C1-4 alkyl groups
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
d) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
The fifth embodiment of the present invention provides a process for preparation of ruxolitinib of formula (I) which comprises;
a) esterifying cyclopentyl acid of formula (VII) in presence of a suitable solvent;

wherein R=C1-C5 alkyl, C1-C5 cycloakyl, aryl group
b) converting the ester of formula (VIII) to a compound of formula (IX) in a suitable solvent;

wherein L= leaving group
c) reacting compound of formula (IX) with pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II) in the presence of suitable base and a suitable solvent;

d) reducing pyrazolylpyrrolo[2,3-d]pyrimidine of formula (X) in the presence of a suitable reducing agent and a suitable solvent;

e) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;

wherein L1= leaving group
f) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent;

g) converting the cyano compound of formula (XIII) to ruxolitinib;
h) optionally purifying ruxolitinib of formula (I);
i) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
The sixth embodiment of the present invention provides a process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting compound of formula (IX) with pyrazole of formula (XIV) in presence of a base in a suitable solvent;

wherein X=halogen, tosylate, triflate, nosylate, brosylate
b) reducing the ester of formula (XV) in presence of suitable reducing agents and suitable solvent ;

c) reacting alcohol of formula (XVI) with a suitable protecting agent in the presence of suitable base and a suitable solvent;

wherein P3= alcohol protecting groups
d) reacting protected alcohol of formula (XVII) with borate of formula (XVIII) in the presence of a suitable metal catalyst and a suitable base in a suitable solvent;

wherein Rc and Rd have same meaning to that of Ra and Rb
e) reacting pyrazole of formula (XIX) with pyrrolo[2,3-d]pyrimidine of formula (IV) in presence of suitable metal catalyst and a suitable base in suitable solvent;

wherein X=halogen, tosylate, triflate, nosylate, brosylate and P=amine protecting group
f) deprotecting pyrazolylpyrrolo[2,3-d]pyrimidines of formula (XX) with a suitable deprotecting agent in presence of suitable solvent;

g) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;

wherein L1 = leaving group
h) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent;

i) converting the cyano compound of formula (XIII) to ruxolitinib;
j) optionally purifying ruxolitinib of formula (I);
k) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
Seventh embodiment of the present invention provides the novel compounds as shown below:

Eighth embodiment of the present invention provides a pharmaceutical composition comprising ruxolitinib of formula (I) or its pharmaceutically acceptable salts prepared according to processes of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

DETAILED DESCRIPTION
The first embodiment of the present invention provides a process for preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II), which comprises:
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent to form amine protected pyrrolo pyrimidine of formula (IV);
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal to form a compound of formula (II);
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
The step (b) of the first embodiment may be performed optionally in the presence of metal ligand and zero valent metal.
Suitable base that may be used in step (b) include, but are not limited to pyridine, 4,6-collidine, 2,6-ditert-butyl-4-methylpyridine, 1-diethylamino-2-propanol, N-ethylamino-2-propanol, N-ethyldiisopropylamine, 4-ethylmorpholine, 1-ethylpiperidine, 2,6-lutidine, N-methylmorpholine, 1-methylpiperidine, tribenzylamine, triethylamine, and the like.
Suitable additional zero valent metal that may be used in step (b) include, but are not limited to zinc, magnesium, manganese and the like.
Suitable metal ligands that may be used in step (b) include, but are not limited to triphenylphosphine, diglyme, dppe, dppf, BINAP and the like.
The pyrazole intermediate of formula (V) can be prepared according to methods known in the art. Any suitable amino protecting group may be used.
The temperature at which the steps described in the first embodiment may be carried out in between about -5 °C and about 100 °C, preferably at about -5 °C and about 60°C, based on the solvent or mixture of solvent used in particular step.
The second embodiment of the present invention provides a process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent to form amine protected pyrrolo pyrimidine of formula (IV);
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal to form a compound of formula (II);
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
e) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
The same reagents and solvents described for the first embodiment of the invention may be used for the second embodiment of the invention.
The temperature at which the steps mentioned in this embodiment may be carried out in between about -10 °C and about 100 °C, preferably at about -5 °C and about 60 °C, based on the solvent or mixture of solvent used in particular step.
The obtained compound of formula (II) may be converted to ruxolitinib by following any of the methods known in the art.
Optionally, the ruxolitinib obtained in this embodiment may be further subjected to conventional purification methods. Thus resulted freebase of ruxolitinib may be taken further to prepare the desired pharmaceutically acceptable salt.
Third embodiment of the of the present invention provides a process for preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II) which comprises:
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent to form a compound of formula (II);
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
The resulted compound of formula (II) may be converted ruxolitinib by following any of the methods known in the art.
Step (c) which involves the isolation and purification of compound of formula (II) or its pharmaceutically acceptable salt can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The pyrazole of formula (VI) can be prepared according to methods known in the art and any suitable amino protecting groups may be used.
The temperature at which the above steps may be carried out in between about 10 °C and about 150 °C, preferably at about 25 °C and about 105 °C, based on the solvent or mixture of solvent used in particular step.
The fourth embodiment of the present invention provides a process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent to form a compound of formula (II);
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
d) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
The same reagents and solvents described for the third embodiment of the invention may be used for the fourth embodiment of the invention.
The temperature at which the above steps may be carried out in between about 10 °C and about 150 °C, preferably at about 25 °C and about 105 °C, based on the solvent or mixture of solvent used in particular step.
The obtained compound of formula (II) may be converted to ruxolitinib by following any of the methods known in the art.
Optionally, the ruxolitinib obtained in the fourth embodiment of the invention may be further subjected to conventional purification methods. The resulted ruxolitinib may be converted to the desired pharmaceutically acceptable salt.
The fifth embodiment of the present invention provides a process for preparation of Ruxolitinib of formula (I) which comprises;
a) esterifying cyclopentyl acid of formula (VII) in presence of a suitable solvent to form ester of formula (VIII);
b) converting the ester of formula (VIII) to a compound of formula (IX) in a suitable solvent;
c) reacting compound of formula (IX) with pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II) in the presence of suitable base and a suitable solvent to form pyrazolylpyrrolo[2,3-d]pyrimidine of formula (X);
d) reducing pyrazolylpyrrolo[2,3-d]pyrimidine of formula (X) in the presence of a suitable reducing agent and a suitable solvent to form alcohol of formula (XI);
e) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;
f) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent to form cyano compound of formula (XIII);
g) converting the cyano compound of formula (XIII) to ruxolitinib;
h) optionally purifying ruxolitinib of formula (I);
i) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
Step (a) is typically carried out under Fischer–Speier esterification conditions in the presence of excess alcohol and a suitable catalyst. Suitable catalysts that may be used in step (a) include, but are not limited to, Bronsted acids, such as sulfuric acid, tosic acid, boric acid, hydrogen chloride (used directly or generated in situ from AcCl or SOCl2 and sulfamic acid; Lewis acids, such as MgCl2, Mg(OMe)2, SnCl4, Al(OTf)3, FeCl3, BF3.Et2O and AlCl3; and solid acids, such as DOWEX 50W and Amberlyst 15.
Optionally, step (a) may be carried out in presence of a co-solvent such as toluene and the like or a reagent such as 2, 2-dimethoxypropane and the like that facilitates the removal of water produced during the course of reaction. Optionally, step (a) may be carried out in presence of a suitable base and alkylating agents like alkyl halides, preferably methyl iodide, ethyl bromide and the like or dialkylcarbonates such as dimethyl carbonate and the like.
Suitable leaving groups that may be used in steps (b) and (e) include, but are not limited to halogen such as chlorine, bromine, fluorine, iodine; mesylate, tosylate, triflate, nosylate, brosylate and the like.
Suitable reducing reagents that may be used in step (d) include, but not limited to lithium aluminium hydride, lithium borohydride, diisobutylaluminium hydride, sodium borohydride, diborane, diborane generated in situ like NaBH4 with BF3 etherate, sodium borohydride with BF3.THF complex, sodium borohydride and iodine, sodium borohydride in presence of acids like sulfuric acid, phosphoric acid, methane sulfonic acid and the like.
Step (f) may be carried out in one or more suitable cyanating agents. Suitable cyanating agents that may be used in step (e) include, but are not limited to, sodium cyanide, potassium cyanide, hydrogen cyanide, copper cyanide, lithium cyanide or the like.
The cyano compound of formula (XIII) may be converted to ruxolitinib by the processes disclosed in the prior art.
Optionally, the alcohol of compound of formula (XI) may be converted to (XIII) under Mitsunobu-Wilk conditions by adopting the suitable process conditions reported in the literature. For example, the process conditions are, but not limited to, involving the use of acetone cyanohydrin or lithium cyanide in a suitable solvent in the presence of suitable Mitsunobu mediators such as DEAD-TPP, DIAD-TPP, N,N, N’,N’-Tetramethylazodicarboxamide (TMAD)-tributylphosphine, cyanomethylene- tributylphosphorane (CMBP) and cyanomethylenetrimethylphosphorane (CMMP). The suitable solvents that may be employed but are not limited to ethers such as THF and diethyl ether and hydrocarbons such as toluene or the like.
The temperature at which the above steps may be carried out in between about
-10 °C and about 100 °C, preferably at about -10 °C and about 70 °C, based on the solvent or mixture of solvent used in particular step.
The sixth embodiment of the present invention provides the process for preparation of Ruxolitinib of formula (I) which comprises;
a) reacting compound of formula (IX) with pyrazole of formula (XIV) in presence of a base in a suitable solvent to form ester of formula (XV);
b) reducing the ester of formula (XV) in presence of suitable reducing agents and suitable solvent to form alcohol of formula (XVI);
c) reacting alcohol of formula (XVI) with a suitable protecting agent in the presence of suitable base and a suitable solvent to form protected alcoholof formula (XVII);
d) reacting protected alcohol of formula (XVII) with borate of formula (XVIII) in the presence of a suitable metal catalyst and a suitable base in a suitable solvent to form pyrazole of formula (XIX);
e) reacting pyrazole of formula (XIX) with pyrrolo[2,3-d]pyrimidine of formula (IV) in presence of suitable metal catalyst and a suitable base in suitable solvent to form pyrazolylpyrrolo[2,3-d]pyrimidines of formula (XX);
f) deprotecting pyrazolylpyrrolo[2,3-d]pyrimidines of formula (XX) with a suitable deprotecting agent in presence of suitable solvent to form alcohol f formula (XI);
g) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;
h) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent to form cyano compound of formula (XIII);
i) converting the cyano compound of formula (XIII) to ruxolitinib;
j) optionally purifying ruxolitinib of formula (I);
k) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
The reducing agents that may be used in step (b) may be same as described for step (d) of the fifth embodiment of the present invention.
Suitable protecting agents that may be used in step (c) include, but are not limited to, silyl alkyl ethers such as, O-tert-butyldimethylsilylether, trimethylsilylether, triisopropylsilyl ether, O-tert-butyldiphenylsilylether and the like; esters such as acetic acid ester, pivalic acid ester, benzoic acid ester or the like; ether such as methoxymethyl ether, benzyl ether, allyl ether, tert-butyl ether, tetrahydropyranyl ether or the like.
The metal catalysts that may be used in steps (d) and (e) may be same as described for step (b) of the first embodiment of the instant application.
Step (f) may be carried out in the presence of one or more suitable hydroxy deprotecting agents. Suitable deprotecting agents that may be used in step (f) include, but are not limited to tetrabutyl ammonium fluoride or acid like citric acid, alkyl sulfonic acid, hydrofluoric acid, hydrochloric acid, hydro bromic acid, hydro iodic acid, periodic acid, sulphuric acid, phosphoric acid, poly phosphoric acid, phosphorous acid, nitric acid, nitrous acid, or the like or base like carbonates, alkali, bicarbonates or metal catalyst like palladium, nickel or like.
The reagents and solvents for steps (g) and (h) may be selected from one or more suitable reagents and solvents as described in steps (e) and (f) of the fifth aspect of the present invention.
The cyano compound of formula (XIII) may be converted to ruxolitinib by the methods known in the literature.
Optionally, the alcohol compound of formula (XVI) may be converted directly to compound of formula (XI) without subjecting to the protection of hydroxy group.
Optionally, the compound of formula (XVII) may be converted to compound of formula (XX) by following the conditions of Kumada or Stille coupling.
In case of Kumada coupling, the compound of formula (XVII) may be converted into a Grignard reagent (either with Mg or with the aid of Turbo Grignard), and which may be subsequently coupled with the compound of formula (IV) in presence of palladium or nickel catalyst. While in Stille coupling, the Grignard reagent, derived from compound of formula (XVII) may be reacted with a trialkyltin halide to obtain an organo stannate reagent, which may be subsequently coupled with the compound of formula (IV) in presence of palladium as catalyst.
The temperature at which the above steps may be carried out in between about
-10°C and about 100°C, preferably at about -10°C and about 80°C, based on the solvent or mixture of solvent used in particular step.
The isolation and purification of compounds of or their pharmaceutically acceptable salt of the present invention can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The suitable solvent that may be used in one or more steps of one or more embodiments as described above include, but are not limited to, ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; ketone solvents, such as, for example, acetone, dialkyl ketone or the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated solvents such as, for example, chloroform, dichloromethane or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol, butanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide or the like, water or mixtures thereof.
The suitable base that may be used in one or more steps of one or more embodiments as described above include, but are not limited to, organic bases such as, 2,4,6-collidine, 2,6-ditert-butyl-4-methylpyridine, 1-diethylamino-2-propanol, N-ethylamino-2-propanol, N-ethyldiisopropylamine, 4-ethylmorpholine, 1-ethylpiperidine, 2,6-lutidine, N-methylmorpholine, 1-methylpiperidine, tribenzylamine, triethylamine, pyridine, dimethylamino pyridine and the like. Suitable inorganic bases include, but are not limited to alkali hydrides, such as, for example, sodium hydride, potassium hydride or the like; alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide or the like; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; alkali metal acetates, such as, for example sodium acetate, potassium acetate or the like.
The suitable amino protecting group used in one or more steps of one or more embodiments as described above include, but are not limited to, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (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), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazinyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), tri(alkyl)silyl,1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), N-pivaloyloxymethyl (POM) or the like.
“Pharmaceutically acceptable salt" refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the phrase "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Suitable pharmaceutically acceptable salts that may be used include, but are not limited to, those derived from organic and inorganic acids such as, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methane sulfonic, ethane sulfonic, toluene sulfonic, salicylic, benzoic, and similarly known acceptable acids.
Seventh embodiment of the present invention provides the novel compounds as shown below:

The present invention also includes the use of novel compounds as described in the seventh embodiment for the preparation of ruxolitinib or its pharmaceutically acceptable salts.
Eighth embodiment of the present invention provides pharmaceutical compositions comprising ruxolitinib of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
The processes of the present invention are easy to handle, environment friendly, provides better yield and purity and these may also be practiced on industrial scale.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES:
Example 1: Preparation of tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (V)
4-bromo-1H-pyrazole (3g, 0.020 moles) was added to dichloromethane (30ml) and stirred at room temperature. Triethylamine (5.6ml, 0.040 moles) was added to the reaction mixture and cooled to 0-5°C. BOC-anhydride (4.6ml, 0.020 moles) was added at 0-5°C and the temperature of the reaction mixture was slowly raised to 20-25°C and maintained for 4 hours. Water (20 mL) was added to the reaction mixture and stirred at room temperature for 10-15 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (20ml). The combined organic layer was washed with brine solution (10ml). The layers were separated and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure at 40-45 °C to give the title compound as an off-white solid.
Yield: 4.75g (94.2%)
Example 2: Preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (IV)
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 0.065 moles) was added to dimethylacetamide (150 mL) at room temperature under inert atmosphere and cooled to 0-5°C. Sodium hydride (2.9 g, 0.071 moles) was added to the reaction mixture at 0-5°C and stirred for 10-15 minutes. 2-(Trimethylsilyl) ethoxymethylchloride (12.7 mL, 0.071 moles) was added to the reaction mixture at 0-5°C and stirred for 30-45 minutes. Water (100 mL) was added to the reaction mixture and stirred for 10-15 minutes at 0-5°C. At room temperature, ethyl acetate (100ml) was added to the reaction mixture and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine solution (100 mL). The layers were separated and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product as dark brown color liquid. The crude product was purified by column chromatography (5-10%ethyl acetate: hexane) to provide the title compound as pale yellow color syrup.
Yield: 15.8 g (85.5%)
Example 3: Preparation of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine (II)
4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2 g, 0.007 moles) and tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (1.74 g, 0.007 moles) was added to pyridine (10 mL) at room temperature under inert atmosphere. Triphenylphosphine (0.55 g, 0.002 moles) and Zinc dust (0.68 g, 0.010 moles) were added to the reaction mixture at room temperature and degassed with nitrogen for 10-15 minutes. Reaction mixture was heated to 50-55°C and maintained for 20-30 minutes. NiCl2(glyme) (76 mg, 0.0003 moles) was added to reaction mixture at 50-55°C and stirred for 20-22 hours. Water (100 mL) and dichloromethane (50ml) was added to the reaction mixture and stirred for 10-15 minutes at room temperature. The layers were separated and the organic layer was washed with water (50ml), 2N hydrochloric acid (100ml) and brine solution (20 mL). The layers were separated and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product as dark brown color semi solid. The crude product was purified by column chromatography (4-6% dichloromethane: methanol) to provide the title compound as pale brown color solid.
Yield: 0.63 g (28.3%)
Example 4: Preparation of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (VI)
N-Boc-Bromopyrrazole (2.5 g, 0.010 moles) was added to dioxane (25 mL) at room temperature. Bis (pinacolato) diboron (5.08 g, 0.02 moles) and potassium acetate (2.94g, 0.03 moles) was added to the reaction mixture at room temperature and stirred for 10-15 minutes under nitrogen atmosphere. Pd(dppf)Cl2.CH2Cl2 (408 mg, 0.0005 moles) was added to the reaction mixture at room temperature and stirred for 10 minutes. The reaction mixture was slowly heated to 80-85°C and maintained for three hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product. The crude product was purified by column chromatography (5-10% ethyl acetate: hexane) to provide the title compound as off-white color solid.
Yield: 2.9 g (97.4%)
Example 5: Preparation of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine (II)
4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1g, 0.0035 moles), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.34g, 0.0045 moles) and potassium carbonate (1.45g, 0.010 moles) were added to a mixture of 1-butanol (7.5 mL) and water (2.5 mL) at room temperature under nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (20 mg, 0.000017 moles)was added to the reaction mixture at room temperature and stirred for 10 minutes. The reaction mixture was slowly heated to 100-105°C and maintained for four hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product. Water (10mL) and ethyl acetate (10 mL) was added to the crude product and stirred for 10 minutes. Organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure at 40-45 °C. The product was taken in n-hexane (10 mL) and stirred at room temperature. The solid was filtered and dried under vacuum at room temperature to provide the title compound as white solid.
Yield: 0.5 g (45%)
Example 6: Preparation of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
1-(tetrahydro-2H-pyran-2-yl)-Bromopyrrazole (2.5 g, 0.010 moles) was added to dioxane (25 mL) at room temperature. Bis (pinacolato) diboron (5.5 g, 0.02 moles) and potassium acetate (3,2 g, 0.032 moles was added to the reaction mixture at room temperature and stirred for 10-15 minutes under nitrogen atmosphere. Pd(dppf) Cl2.CH2Cl2 (440 mg, 0.0005 moles) was added to the reaction mixture at room temperature and stirred for 10 minutes. The reaction mixture was slowly heated to 80-85°C and maintained for three hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with ethyl acetate (20 mL). The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product. The crude product was purified by column chromatography (10-30% ethyl acetate: hexane) to provide the title compound as off-white color solid.
Yield: 1.5 g (49.4%)
Example 7: Preparation of4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine (II)
4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1g, 0.0035 moles), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 0.0038 moles) and potassium carbonate (1.2g, 0.0087 moles) were added to a mixture of 1-butanol (7.5 mL) and water (2.5 mL) at room temperature under nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (20 mg, 0.000017 moles)was added to the reaction mixture at room temperature and stirred for 10 minutes. The reaction mixture was slowly heated to 95-100°C and maintained for four hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure at 40-45 °C to give crude product. Water (5.7 mL), tetrahydrofuran (1.6 mL) and aqueous hydrochloric acid (9 mL) were added to the reaction mixture and stirred for twelve hours at room temperature. 30% aqueous sodium hydroxide (20 mL) was added to the reaction mass and stirred for three hours. Ethyl acetate (50 mL) was added to reaction mass and the layers were separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40-45 °C. The product was taken in n-hexane (10 mL) and stirred at room temperature. The solid was filtered and dried under vacuum at room temperature to provide the title compound as white solid.
Yield: 0.75 g (67.5%)
Example 8: Preparation of methyl (R)-2-cyclopentyl-2-hydroxyacetate (VIII)
(R)-2-cyclopentyl-2-hydroxyacetic acid (3.9 g, 0.027 moles) was added to methanol (39 mL) at room temperature. Concentrated sulfuric acid (0.2 mL, catalytic) was added to the reaction mixture drop wise at room temperature and stirred at 60-70 °C for six hours. The reaction mixture was cooled to room temperature, quenched with solid sodium bicarbonate and concentrated at 50 °C. The crude compound was dissolved in ethyl acetate (100 mL) and the resulted organic layer was washed with water (2x20 mL) and brine (20 mL). The organic layer was distilled off to get the crude product. The crude product was purified by column chromatography (10% ethyl acetate: hexane) to provide the title compound as pale yellow liquid.
Yield: 2.1 g (48.8%)
Example 9: Preparation of (R)-methyl 2-cyclopentyl-2-(trifluoromethylsulfonyloxy)acetate (IX)
Methyl (R)-2-cyclopentyl-2-hydroxyacetate (2 g, 0.0126 moles) was added to dichloromethane (20 mL) under nitrogen and cooled to 0 °C. Pyridine (2 mL) was added to the reaction mixture and stirred at 0 °C for 10 minutes. Triflic anhydride (3.2 mL, 0. 0189 mol) was added drop wise over a period of 10 minutes and was then stirred at 0 °C for one hour. Dichloromethane (30 mL) was added to the reaction mixture and the organic layer was washed with water (2x15 mL), saturated sodium bicarbonate (10 mL) and brine (15ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a pale brown liquid. Yield: 3.5 g
Example 10: Preparation of methyl (S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (X)
(R)-Methyl 2-cyclopentyl-2-(trifluoromethylsulfonyloxy)acetate (3.22 g, 11.098 mmol), 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.75 g, 5.547 mmol) was added to a mixture of dimethyl formamide (2.5 mL) and tetrahydrofuran (14 mL) at room temperature. Cesium carbonate (2.7 g, 8.321 mmol) was added to the reaction mixture and was stirred at room temperature for eighteen hours. The reaction mixture was concentrated under reduced pressure at 40-45 °C and the residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 20mL) and brine (20 mL).The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product as a pale brown liquid. The crude product was purified by column chromatography (30-40% ethyl acetate-hexane) to obtain the title compound as a pale yellow sticky liquid.
Yield: 2.25 g (89.28%)
Example 11: Preparation of(S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol (XI)
Methyl (S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (1.6 g, 3.511 mmol) was added to tetrahydrofuran (16 mL) and was cooled to -10 °C. Lithium aluminum hydride (293 mg, 7.725 mmol) was added in three portions at intervals of 3 minutes to the reaction mixture and was stirred at -10 °C for one hour. Ethyl acetate was added to the reaction mixture and quenched with saturated sodium sulfate (1 mL) at -10 °C and then stirred at -10 °C for 15 minutes. The resultant reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite pad and washed with ethyl acetate (20 mL). The combined filtrate was dried over sodium sulfate and concentrated under vacuum to obtain the crude product as a pale yellow brown liquid. The crude product was purified by column chromatography (40-50% Ethyl acetate-hexanes) to obtain the title compound as a pale yellow sticky liquid. Yield: 1.23 g (82%)
Example 12: Preparation of (S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (XII)
(S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol (1 g, 2.338 mmol) was added to dichloromethane (10 mL) under nitrogen atmosphere at room temperature and was cooled to 0 °C. Pyridine (1 mL) and 4-dimethylaminopyridine (29 mg, 0.233 mmol) were added in single lot to the resultant reaction mixture and stirred at 0 °C for 5 minutes. Mesyl chloride (0.36 mL, 4.677 mmol) was added drop wise to the reaction mixture over a period of 5 minutes and stirred at 0 °C for 30 minutes. The resultant reaction mixture was then stirred at room temperature for three hours. Dichloromethane (40 mL)was added to the reaction mixture, and successively washed with water (2 x 15 mL), saturated sodium bicarbonate (5 mL) and brine (15 mL). The combined organic layer was then dried over sodium sulfate and concentrated to obtain the title compound as a pale brown liquid.
Yield: 1.2 g
Example 13: Preparation of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (XIII)
(S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)ethyl methane sulfonate (1.2 g, 2.338 mmol) was added to dimethyl formamide(8 mL) under nitrogen at room temperature. Sodium cyanide (600 mg, 12.244 mmol) was added in a single lot to the reaction mixture and stirred at 60 °C for sixteen hours. The resultant reaction mixture was cooled to room temperature. Water (80 mL) was added to the reaction mixture and extracted with ethyl acetate (3x40 mL). The combined organic layer was washed with water (2x20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product as a light brown liquid. The crude product was purified by column chromatography (40-50% ethyl acetate-hexane) to obtain title compound as a pale yellow liquid.
Yield: 830 mg (81%)
Example 14: Preparation of methyl (S)-2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopentylacetate (XV)
(R)-Methyl 2-cyclopentyl-2-(trifluoromethylsulfonyloxy)acetate (482 mg, 1.65 mmol) and 4-bromo-1H-pyrazole (122 mg, 0.827 mmol) was added to a mixture of dimethyl formamide (0.24 mL) and THF (5 mL) at room temperature under nitrogen atmosphere. Cesium carbonate (322 mg, 0.992 mmol) was added in a single lot to the reaction mixture and stirred at room temperature for sixteen hours. The reaction mixture was concentrated under vacuum at 50°Cand the residue obtained was diluted with ethyl acetate (24 mL). The organic layer was washed with water (2 x 5mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product as a pale brown liquid. The crude product was purified by column chromatography (3-5% ethyl acetate-hexane) to obtain the title compound as an off-white solid.
Yield: 150 mg (63.5%)
Example 15: Preparation of(S)-2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopentylethan-1-ol (XVI)
Methyl (S)-2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopentylacetate (145 mg, 0.505 mmol), was added to tetrahydrofuran (3 mL) at room temperature and cooled to -10 °C under nitrogen. Lithium aluminum hydride (39 mg, 1.017 mmol) was added in three portions at intervals of 5 min to the reaction mixture. The resultant reaction mixture was stirred at -10 °C for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and stirred at -10 °C. Saturated sodium sulfate (0.5mL) was added to reaction mixture at -10 °C and stirred for 10 minutes. The reaction mixture was then stirred at room temperature for 15 minutes. The reaction mixture was filtered through celite pad and washed with ethyl acetate (10 mL). The combined filtrate was dried over anhydrous sodium sulfate and concentrated to obtain title compound as a pale yellow liquid.
Yield: 125 mg
Example 16: Preparation of (S)-4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)-1-cyclopentylethyl)-1H-pyrazole (XVII)
(S)-2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopentylethan-1-ol (125 g, 0.508 mmol) was added to dichloromethane (5 mL) at room temperature under nitrogen atmosphere. Imidazole (104 mg, 1.524 mmol) was added in a single portion to the reaction mixture and was cooled to 0°C. tert-Butyldimethylsilylchloride (153 mg, 1.016 mmol) was added in a single portion to the reaction mixture and stirred at 0°C for 30 minutes. The resultant reaction mixture was stirred at room temperature for 16 hours. Dichloromethane (20 mL) was added to the reaction mixture and washed successively with water (2 x 10 mL) and brine (10 mL).The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product as a pale brown liquid. The crude product was passed through a short pad of silica gel (100-200 mesh, eluent: 10% ethyl acetate-hexane) and distilled off the solvent to obtain the title compound as colorless liquid.
Yield: 120 mg
Example 17: Preparation of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-cyclopentyl ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (XIX)
(S)-4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)-1-cyclopentylethyl)-1H-pyrazole (120 mg, 0.237 mmoles), bis (pinacolato) diboron (121 mg, 0.475 mmoles) and potassium acetate (70 mg, 0.711 mmoles) was added to 1, 4-dioxane (4 mL) at room temperature under argon atmosphere. Pd(dppf)2Cl2.CH2Cl2 (10 mg, 0.0118 mmoles) was added to the reaction mixture at room temperature. The reaction mixture was heated at 70-80°C for 6 hours. The reaction mass was cooled to room temperature and concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (20 mL), filtered through a short Celite pad and washed with ethyl acetate (10 mL). The combined organic layer was washed with water (2 x 10 mL) and brine (10 mL).The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product as a pale brown liquid. The crude product was passed through a short silica gel pad (100-200 mesh, eluent: 20% ethylacetate-hexane) and distilled off the solvent to provide title compound as pale yellow liquid.
Yield: 100 mg
Example 18: Preparation of (S)-4-(1-(2-((tert-butyldimethylsilyl)oxy)-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (XX)
(S)-1-(2-(tert-butyldimethylsilyloxy)-1-cyclopentylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.237 mmoles), 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.176 mmoles) and potassium carbonate (61 mg, 0.440 mmoles) were added to mixture of 1, 4-dioxane-water (6:1; 7 mL) at room temperature under argon atmosphere. Tetrakis(triphenylphosphine)palladium (10 mg, 0.0088 moles) was added to the reaction mass at room temperature and heated at 50-55 °C for 16 hours. The reaction mass was cooled to room temperature and concentrated under reduced pressure. Water was removed by azeotropic distillation with toluene from the residual mass. The crude product was purified by column chromatography (10-15% ethyl acetate-hexane) to obtain title compound as a pale yellow liquid.
Yield: 15 mg
Example 19: Preparation of (S)-2-cyclopentyl-2-(4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol (XI)
(S)-4-(1-(2-((tert-butyldimethylsilyl)oxy)-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (45 mg, 0.083 mmol) was added to tetrahydrofuran (2 mL) at room temperature and cooled to 0 °C.
Tetrabutylammoniumfluoride (1M in THF) (0.12 mL, 0.124 mmol) was added in a single portion to the reaction mixture and stirred at 0 °C for 30 minutes. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (2% methanol-dichloromethane) to obtain the title compound as colorless liquid.
Yield: 30 mg (84.5%)
,CLAIMS:
1) A process for preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II), which comprises:
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent to form amine protected pyrrolo pyrimidine of formula (IV);
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal to form a compound of formula (II);
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
2) A process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting pyrrolo pyrimidine of formula (III) with an amine protecting reagent in presence of a base and a suitable solvent to form amine protected pyrrolo pyrimidine of formula (IV);
b) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (V) in presence of a metal catalyst in a suitable solvent, optionally in the presence of a base, metal ligand and a zero valent metal to form a compound of formula (II);
c) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
e) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
3) A process for preparation of pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II), which comprises:
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent to form a compound of formula (II);
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
4) A process for preparation of Ruxolitinib of formula (I) which comprises;
a) reacting amine protected pyrrolo pyrimidine of formula (IV) with pyrazole of formula (VI) in presence of a metal catalyst and a base in a suitable solvent to form a compound of formula (II);
b) optionally converting compound of formula (II) to its pharmaceutically acceptable salts;
c) optionally purifying compound of formula (II) or its pharmaceutically acceptable salts.
d) converting compound of formula (II) to ruxolitinib or its pharmaceutically acceptable salts.
5) A process for preparation of ruxolitinib of formula (I) which comprises;
a) esterifying cyclopentyl acid of formula (VII) in presence of a suitable solvent to form ester of formula (VIII);
b) converting the ester of formula (VIII) to a compound of formula (IX) in a suitable solvent;
c) reacting compound of formula (IX) with pyrazolylpyrrolo[2,3-d]pyrimidines of formula (II) in the presence of suitable base and a suitable solvent to form pyrazolylpyrrolo[2,3-d]pyrimidine of formula (X);
d) reducing pyrazolylpyrrolo[2,3-d]pyrimidine of formula (X) in the presence of a suitable reducing agent and a suitable solvent to form alcohol of formula (XI);
e) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;
f) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent to form cyano compound of formula (XIII);
g) converting the cyano compound of formula (XIII) to ruxolitinib;
h) optionally purifying ruxolitinib of formula (I);
i) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
6) A process for preparation of ruxolitinib of formula (I) which comprises;
a) reacting compound of formula (IX) with pyrazole of formula (XIV) in presence of a base in a suitable solvent to form ester of formula (XV);
b) reducing the ester of formula (XV) in presence of suitable reducing agents and suitable solvent to form alcohol of formula (XVI);
c) reacting alcohol of formula (XVI) with a suitable protecting agent in the presence of suitable base and a suitable solvent to form protected alcohol of formula (XVII);
d) reacting protected alcohol of formula (XVII) with borate of formula (XVIII) in the presence of a suitable metal catalyst and a suitable base in a suitable solvent to form pyrazole of formula (XIX);
e) reacting pyrazole of formula (XIX) with pyrrolo[2,3-d]pyrimidine of formula (IV) in presence of suitable metal catalyst and a suitable base in suitable solvent to form pyrazolylpyrrolo[2,3-d]pyrimidines of formula (XX);
f) deprotecting pyrazolylpyrrolo[2,3-d]pyrimidines of formula (XX) with a suitable deprotecting agent in presence of suitable solvent to form alcohol of formula (XI);
g) converting the alcohol of formula (XI) to a compound of formula (XII) in presence of a suitable solvent;
h) reacting compound of formula (XII) with a suitable cyanating agent in presence of suitable solvent to form cyano compound of formula (XIII);
i) converting the cyano compound of formula (XIII) to ruxolitinib;
j) optionally purifying ruxolitinib of formula (I);
k) optionally converting ruxolitinib of formula (I) to its pharmaceutically acceptable salts.
7) Novel compounds of formulae:

8) The compounds as claimed in claim 7, used in the preparation of ruxolitinib of formula (I) or its pharmaceutically acceptable salts thereof.