DESC:
BACKGROUND OF THE INVENTION
Ruxolitinib phosphate was approved by U.S. Food and Drug Administration and European Medicine Agency. It was co-developed by Incyte and Novartis and marketed as Jakafi® by Incyte in the US, and as Jakavi® by Novartis in Europe. Ruxolitinib is a kinase inhibitor that inhibits Janus associated kinases (JAK1/JAK2). This is indicated for the treatment of patients with certain types of myelofibrosis. Ruxolitinib phosphate which is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate has the following structural formula:

US Patent No. 7,598,257 discloses (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH- pyrazol-l-yl)-3-cyclopentylpropanenitrile, its pharmaceutically acceptable salts thereof. Also, it discloses a process for the preparation of Ruxolitinib which involves using HPLC methods to separate intermediates, also, involves in the use of column chromatography purification methods for the final product, which is laborious and time consuming and suffers from poor yield and low purity.
US Patent 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 Patent No. 8,410,265 discloses a process for the preparation of (R)-3-(4-(7Hpyrrolo [2,3-d] pyrimidin-4-yl)- 1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, which involves in the resolution of the intermediate compound(s) with (+)-2,3-dibenzoyl-D-tartaric acid to obtain high chiral purity of the final product i.e. Ruxolitinib phosphate.
US Patent No. 9,908,888 discloses a process for the preparation of (R)-3-(4-(7Hpyrrolo [2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile. However, the patent discloses the use of hazardous and costly chiral reagents in the process for the preparation of Ruxolitinib.
US10562904, WO201039939A1, WO2016035014A1, WO2016063294A2 discloses a process for the preparation of Ruxolitinib and its intermediates.
Above prior-art methods involve chiral resolution reactions, chromatographic purification methods and the use of costly chiral and hazardous reagents. Using complex chiral agents increases the cost of production. Usage of chromatographic purification methods not suitable for industrial production.
In view of the above review, still there is a great need to develop a novel process for the preparation of Ruxolitinib phosphate with high purity and suitable for industrial production. The inventors of the current invention focused more on resolving the shortcomings of the prior-art processes and developed a novel method for the preparation of Ruxolitinib phosphate which is more useful for industrial production.

SUMMARY OF THE INVENTION
First embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, which comprises reacting N-protected compound of formula II

With compound of formula III

in presence base and solvent Or alky azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IV

Compound of formula IV on deprotection will give Ruxolitinib of Formula I

Optionally, compound of formula I can be converted to its pharmaceutically acceptable salts.
Second embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, which comprises reacting compound of formula IIa

With compound of formula IIIa or IIIb

in presence base and solvent or alky azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IVa

Compound of formula IVa on deprotection will give Ruxolitinib of Formula I

Optionally, compound of formula I can be converted to its pharmaceutically acceptable salts.
Third embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, which comprises reacting compound of formula IIb

With compound of formula IIIa or IIIb

in presence base and solvent or alky azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IVb

Compound of formula IVb on deprotection will give Ruxolitinib of Formula I

Optionally, compound of formula I can be converted to its pharmaceutically acceptable salts.
Fourth embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, which comprises reacting compound of formula IIc

With compound of formula IIIa or IIIb

in presence base and solvent or alky azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IVc

Compound of formula IVc on deprotection will give Ruxolitinib of Formula I

Optionally, compound of formula I can be converted to its pharmaceutically acceptable salts.
Fifth embodiment of the present invention provides a novel process for the preparation of Ruxolitinib formula I, which comprises reacting compound of formula II

With compound of formula V

in presence base and solvent to form protected Ruxolitinib for formula IV

Compound of formula IV on deprotection will give Ruxolitinib of Formula I

Optionally, compound of formula I can be converted to its pharmaceutically acceptable salts.
Sixth embodiment of the invention is the novel compound of formula III’

Wherein leaving group may be selected from alkyl sulfonyls e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.

DETAIL DESCRIPTION OF THE INVENTION
First embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I,

The process comprises reacting N-protected compound of formula II

Wherein N-protecting group is selected from the group consisting of tert-Butyloxycarbonyl (BOC), pivaloyloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM) and the like.
With compound of formula III

Wherein R is H or leaving group selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.
in presence base and solvent to form protected Ruxolitinib for formula IV
Wherein Base can be selected from the group consisting of Inorganic base such as Sodium carbonate, potassium carbonate and the like
Solvent can be selected from group consisting of Acetone, Acetonitrile DMF and the like
Or
In presence of Alkyl azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IV.

Wherein alkyl azodicarboxylates can be selected from Diiisopropyl azodicarboxylate (DIAD), Diethyl azodicaroxylate (DEAD) and the like
Solvent can be selected form DCM, DMF and the like
Compound of formula IV on deprotection will give Ruxolitinib of Formula I

Deprotection can be done as per the process known in the art.
Compound of formula I can be converted to its salt form i.e. phosphate salt as per the method known in the art.
Second embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, as below:

The process comprises, reacting compound of formula IIa

With compound of formula III-a

Wherein R is H or leaving group selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.
in presence base and solvent to form protected Ruxolitinib for formula Iva
Wherein Base can be selected from the group consisting of inorganic bases like Sodium carbonate, Potassium carbonate and the like
Solvent can be selected from group consisting of Acetone, Acetonitrile, DMF and the like
Or
In presence of Alkyl azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IV.

Wherein alkyl azodicarboxylates can be selected from Diiisopropyl azodicarboxylate (DIAD), Diethyl azodicarboxylate (DEAD) and the like
Solvent can be selected form DCM, DMF and the like
Compound of formula IVa on deprotection will give Ruxolitinib of Formula I

Deprotection can be done using acids like HCl, H3PO4, TFA and etc
Compound of formula I can be converted to its salt form i.e. phosphate salt as per the method known in the art.
Third embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, as below:

Process comprises, reacting compound of formula IIb

With compound of formula III

Wherein R is H or leaving group selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.
in presence base and solvent to form protected Ruxolitinib for formula IVb
Wherein Base can be selected from the group consisting of inorganic bases like Sodium carbonate, Potassium carbonate and the like
Solvent can be selected from group consisting of Acetone, Acetonitrile, DMF and the like
Or
In presence of Alkyl azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IVb.

Wherein alkyl azodicarboxylates can be selected from Diiisopropyl azodicarboxylate (DIAD), Diethyl azodicarboxylate (DEAD) and the like
Solvent can be selected form DCM, DMF and the like
Compound of formula IVb on deprotection will give Ruxolitinib of Formula I

Deprotection can be done using acids like HCl, H3PO4, TFA and etc
Compound of formula I can be converted to its salt form i.e. phosphate salt as per the method known in the art.
Fourth embodiment of present invention provides a novel process for the preparation of Ruxolitinib formula I, as below:

The process comprises, reacting compound of formula IIc

With compound of formula III

Wherein R is H or leaving group selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like

in presence base and solvent to form protected Ruxolitinib for formula IVc.

Wherein Base can be selected from the group consisting of inorganic bases like Sodium carbonate, Potassium carbonate and the like

Solvent can be selected from group consisting of Acetone, Acetonitrile, DMF and the like
Or
In presence of Alkyl azodicarboxylates, triphenyl phosphine and solvent to form protected Ruxolitinib for formula IVc.

Wherein alkyl azodicarboxylates can be selected from Diiisopropyl azodicarboxylate (DIAD), Diethyl azodicarboxylate (DEAD) and the like
Solvent can be selected form DCM, DMF and the like

Compound of formula IVc on deprotection will give Ruxolitinib of Formula I

Deprotection can be done using Liq. Ammonia, Ammonium bifluoride and etc.
Compound of formula I can be converted to its salt form i.e. phosphate salt as per the method known in the art.

Fifth embodiment of the present invention provides a novel process for the preparation of Ruxolitinib formula I, as below:

The process comprises, reacting compound of formula II

Wherein N-protecting group is selected from the group consisting of tert-Butyloxycarbonyl (BOC), pivaloyloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM) and the like
With compound of formula V

in presence base and solvent to form protected Ruxolitinib for formula IV

Wherein Base can be selected from the group consisting of Inorganic base such as Sodium carbonate, potassium carbonate or Cesium carbonate and the like Solvent can be selected from group consisting of Acetone, Acetonitrile, DMF and the like Compound of formula IV on deprotection will give Ruxolitinib of Formula I

Deprotection can be done using acid in alcoholic solvents like MeOH, Ethanol and IPA
Compound of formula I can be converted to its salt form i.e. phosphate salt as per the method known in the art.

Sixth embodiment of the invention is the novel compound of formula III’

Wherein R is H or leaving group selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.

The starting material used in the above process are prepared as per the process known in the art. For example, compound of Formula IX and formula X is prepared as per the scheme below:

Wherein reduction can be enantioselective reduction using catalyst or enzymatic route to give desired S-isomer of hydroxy intermediate of formula IX. e.g., reduction can be done in presence of (R)-CBS catalyst and the like
Activation of Formula X can be done using Alkyl sulfonyl chloride like Methane sulfonyl chloride, Ethane sulfonyl chloride, p-toluene sulfonyl chloride and the like.

Base can be triethylamine and the like
Solvent can be selected from group consisting of chlorinated solvents like DCM, Chloroform and the like.

Starting material II can be prepared as per the process known in the art. For example, compound of formula II is prepared as per the scheme below:

Base can be Sodium carbonate, potassium carbonate and the like.
Solvent can be selected from group consisting of DMF, DMAc and the like

,CLAIMS:
1. A process for the preparation of Ruxolitinib formula I, comprising,

a) reacting N-protected compound of formula II,

with compound of formula III to obtain protected Ruxolitinib of formula IV in presence base or an alkyl azodicarboxylate and triphenyl phosphine.
b) deprotection of compound of formula IV to obtain Ruxolitinib of Formula I.
c) Optionally, converting compound of formula I into its phosphate salt.

2. A process for the preparation of Ruxolitinib formula I, comprising,

a) reacting N-protected compound of formula IIa,

with compound of formula III to obtain protected Ruxolitinib of formula IVa in presence base or an alkyl azodicarboxylate and triphenyl phosphine.

b) deprotection of compound of formula IV to obtain Ruxolitinib of Formula I.
c) Optionally, converting compound of formula I into its phosphate salt.

3. A process for the preparation of Ruxolitinib formula I, comprising,

a) reacting N-protected compound of formula IIb,

with compound of formula III to obtain protected Ruxolitinib of formula IVb in presence base or an alkyl azodicarboxylate and triphenyl phosphine.

b) deprotection of compound of formula IVb to obtain Ruxolitinib of Formula I.
c) Optionally, converting compound of formula I into its phosphate salt.

4. A process for the preparation of Ruxolitinib formula I, comprising,

a) reacting N-protected compound of formula IIc,

with compound of formula III to obtain protected Ruxolitinib of formula IVb in presence base or an alkyl azodicarboxylate and triphenyl phosphine.

b) deprotection of compound of formula IVc to obtain Ruxolitinib of Formula I.
c) Optionally, converting compound of formula I into its phosphate salt.

5. A process for the preparation of Ruxolitinib formula I, comprising,

a)
b) reacting N-protected compound of formula II,

with compound of formula V to obtain protected Ruxolitinib of formula IV in presence base,
c) deprotection of compound of formula IVc to obtain Ruxolitinib of Formula I.
d) Optionally, converting compound of formula I into its phosphate salt.

6. The process according proceeding claims, wherein the N-protecting group of formula II and formula IV is selected from the group consisting of tert-Butyloxycarbonyl (BOC), pivaloyloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM) and the like.

7. The process according proceeding claims, wherein R is H or leaving group of formula III selected from alkyl sulfonyl e.g. methane sulfonyl, ethane sulfonyl, p-toluene sulfonyl, trifluoro methanesulfonate and the like.

8. The process according proceeding claims, wherein Base are selected from the group consisting of Inorganic base such as Sodium carbonate, potassium carbonate and the like.

9. The process according proceeding claims, wherein alkyl azodicarboxylates are selected from Diiisopropyl azodicarboxylate (DIAD), Diethyl azodicaroxylate (DEAD) and the like.