DESC:“A NOVEL PROCESS FOR THE PREPARATION OF RUXOLITINIB PHOSPHATE”
FIELD OF THE INVENTION:
The present invention relates to a novel and economic industrial process for the preparation of Ruxolitinib phosphate with high yield, reduced steps and high stability. The present invention also relates to process for the preparation of Ruxolitinib phosphate wherein the process is simple with easily available solvents and reagents.

BACKGROUND OF THE INVENTION:
Ruxolitinib is an orally bioavailable Janus-associated kinase (JAK) inhibitor with potential antineoplastic and immunomodulating activities. Ruxolitinib specifically binds to adenosine triphosphate–binding pocket of JAK2 and inhibits protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The JAK-STAT (signal transducer and activator of transcription) pathway plays a key role in the signaling of many cytokines and growth factors and is involved in cellular proliferation, growth, hematopoiesis, and the immune response.
Ruxolitinib is chemically known as (R)-3-(4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile and is structurally represented as below:

Ruxolitinib

Ruxolitinib phosphate is a phosphate salt obtained by reaction of Ruxolitinib free base with phosphoric acid. Ruxolitinib phosphate is indicated for the treatment in patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. The BCR-ABL1–negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains.
The myeloproliferative neoplasms (MPN) are a group of clonal hematological malignancies that originate at the level of pluripotent hematopoietic stem cells (HSC) and include chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). PV and ET can both progress to myelofibrosis (termed post-ET/PV MF), which is clinically indistinguishable from PMF. Collectively, PMF and post- ET/PV MF are referred to simply as MF.
Ruxolitinib is first disclosed in US7598257 and is marketed by Incyte corporation as tablets are for oral administration. Each tablet contains Ruxolitinib phosphate together with microcrystalline cellulose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, sodium starch glycolate, povidone and hydroxypropyl cellulose. Initially, Ruxolitinib was approved by USFDA during 2011 as JAKAFI® tablet 5, 10, 15 and 20 mg. However, recommended daily dose of Ruxolitinib is 20 mg given orally twice daily for patients with a platelet count greater than 200 X 109/L, and 15 mg twice daily for patients with a platelet count between 100 X 109/L and 200 X 109/L and increase dose based on response and as recommended to a maximum of 25 mg twice daily. It is recommended to discontinue the drug after 6 months if no spleen reduction or symptom improvement is taken place.
US8722693 discloses phosphoric acid salt of Ruxolitinib, and process for preparation thereof. The said patent application discloses preparation of Ruxolitinib phosphoric acid where Ruxolitinib free base is reacted with phosphoric acid in the presence of solvents such as isopropyl alcohol (IPA) and acetonitrile.
WO2007/070514 discloses process for the preparation of Ruxolitinib which was prepared by reacting potassium tert-butoxide in tetrahydrofuran (THF). These solutions were added dropwise to a solution of diethyl cyanomethyl phosphonate in round bottom flask. The cold bath was removed and the reaction was warmed to room temperature followed by re-cooling to 0°C at which time a solution of cyclopentane in THF was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate which was washed with brine, then dried over sodium sulfate, to afford Ruxolitinib.
WO2010/083283 discloses process for the preparation of Ruxolitinib which was prepared by addition of 3R-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl]propane nitrile with 3-cyclopentylacrylonitrile which is further coupled with 4-chloropyrrolo[2,3- d]pyrimidine to yield Ruxolitinib.
The inventors of the present invention have developed an alternative improved process which is novel for the preparation of Ruxolitinib phosphate with reduced processing steps, high yield and stability. The present invention also represents the process for the preparation of Ruxolitinib wherein the process is simple with easily available solvents and reagents. Hence, it is less costly alternative compare to processes as disclosed in prior arts for preparation of Ruxolitinib.

OBJECT OF THE INVENTION:
The main object of the present invention is to provide a novel process for the preparation of Ruxolitinib phosphate with high yield and stability.
Another object of the present invention is to provide an economical industrial process for the preparation of Ruxolitinib phosphate with the reduced processing steps.
Another object of the present invention is to provide the preparation process of Ruxolitinib phosphate with the easily available solvents and reagents.
Another object of the present invention is to provide the preparation of Ruxolitinib phosphate that has excellent physicochemical properties.

SUMMARY OF THE INVENTION:
The present invention relates to a novel process to synthesize Ruxolitinib phosphate (IX) wherein 3-Cyclopentyl-3-oxopropanenitrile is converted to (3S)-3 cyclopentyl-3-hydroxypropanenitrile. Further (3S)-3-cyclopentyl-3-hydroxypropanenitrile is converted to 2-Cyano-1-cyclopentylethyl methane sulfonate in the presence of Triethyl amine and methane sulfonyl chloride. Also, 2-Cyano-1-cyclopentylethyl methanesulfonate and 4-(4,4,5,5-tetramethyl-1,3, dioxaborolan-2-yl)-1H-pyrazole were added to yield (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane nitrile.
On the other side 4a,7-dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one is converted to 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate.
Further, 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate and (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane nitrile which is synthesized in the earlier step are coupled to form Ruxolitinib phosphate.
One aspect of the present invention relates to preparation of Ruxolitinib phosphate (IX) comprising the reaction steps as below:
a) Converting 3-Cyclopentyl-3-oxopropanenitrile (I) via a two-step reaction to 2-Cyano-1-cyclopentylethyl methane sulfonate (III);
b) Adding 2-Cyano-1-cyclopentylethyl methane sulfonate (III) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (IV) to form and get (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V);
c) 4a,7-dihydro -4H-pyrrolo [2,3-d] pyrimidin-4-one (VI) is converted to 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII);
d) 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) is coupled with (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) (V) propane nitrile to form Ruxolitinib phosphate (IX).

The present invention is depicted as below in Scheme-1:

Scheme -1
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a novel process for preparation of Ruxolitinib Phosphate (IX), wherein 3-Cyclopentyl-3-oxopropanenitrile (I) is converted to 2-cyano-1-cyclopentylethyl methanesulfonate (III) via a 2-step reaction, adding 2-Cyano-1-cyclopentylethyl methanesulfonate (III) with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to get (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (V).

On the other hand, 7-dihydro -4H-pyrrolo [2,3-d] pyrimidin-4-one (VI) is converted to 7H-pyrrolo[2,3-d]pyrimidin-4-yl-trifluoromethanesulfonate (VII). 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) is coupled with (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V) to form Ruxolitinib phosphate (IX).

One embodiment of the present invention relates to novel process of Ruxolitinib phosphate (IX):
a) Converting 3-Cyclopentyl-3-oxopropanenitrile (I) via a two-step reaction to 2-Cyano-1-cyclopentylethyl methane sulfonate (III);
b) adding 2-Cyano-1-cyclopentylethyl methane sulfonate (III) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to form and get (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V);
c) 4a, 7-dihydro -4H-pyrrolo [2,3-d] pyrimidin-4-one (VI) is converted to 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII);
d) 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) is coupled with (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V) to get Ruxolitinib base (VIII) and further addition of Phosphoric acid to get Ruxolitinib phosphate (IX)to form Ruxolitinib phosphate (IX).

The present invention follows as depicted below:

Scheme -1
Organic solvents used in the present invention may be selected from methanol, ethanol and isopropyl alcohol. Sulphonyl chloride used in the present invention may be selected from mesyl chloride and tosyl chloride. Catalysts used in the present invention may be selected from R-CBS (Corey–Bakshi–Shibata) catalyst, Borane-THF complex, palladium on carbon and [1,1'-Bis(diphenylphosphino)ferrocene] palladium (II) dichloride.
One embodiment of the present invention relates to conversion of 3-Cyclopentyl-3-oxopropanenitrile (I), where it is reacted in presence of R-CBS (Corey–Bakshi–Shibata) catalyst, Borane-THF complex into Tetrahydrofuran to get (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II).

Another embodiment of the present invention relates to conversion of (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II), which was taken in methylene dichloride. Triethyl amine and methane sulfonyl chloride are added to get 2-cyano-1-cyclopentylethyl methanesulfonate (III).
The inventors of the present invention developed such a novel process wherein new intermediate 2-cyano-1-cyclopentylethyl methanesulfonate (III) is obtained. This intermediate is reported first time in this patent application. This unique intermediate helps inventors of the present invention to develop a novel process having very few numbers of stages to yield Ruxolitinib.

Another embodiment of the present invention relates to addition of 2-cyano-1-cyclopentylethyl methanesulfonate (III) with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (IV) in the presence of Triethyl amine and anhydrous MDC to get (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)propane nitrile (V).
During development of Ruxolitinib from novel intermediate, 2-cyano-1-cyclopentylethyl methanesulfonate (III), the inventors of the present invention again developed one more novel intermediate (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)propane nitrile (V). Similar to the stage-1 of the present invention, stage-2 also helps to reduce the production stages at the commercial scale. Thereby making the present invention novel with technical advancement.

Additional embodiment of the present invention relates to coupling of (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V) with 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII), to get Ruxolitinib (VIII).
The inventors of the present invention became successful in developing a novel and high yield stage to prepare Ruxolitinib base (VIII) from the novel intermediate V. This base was then further converted phosphate salt using phosphoric acid to afford Ruxolitinib Phosphate (IX).
One more embodiment of the present invention relates to preparation of 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) from 4a,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (VI) using triflic acid, triethyl amine and methylene dichloride.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

Example-1: Preparation of (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II):
A dry 3000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with 3-Cyclopentyl-3-oxopropanenitrile (100g, 0.729 mole) (I) into 300ml tetrahydrofuran at 25-30°C and reacted in presence of R-CBS catalyst (10.1g, 0.036 mole, 0.05eq) at RT. Slowly added 1M Borane-THF complex (1093.5ml, 1.093mole, 1.5eq) into reaction mass at 20-30°C. Maintain the reaction mass for 30mins at 20-30°C. Check TLC for completion of reaction. If reaction complies charge purify water 500ml and ethyl acetate 500ml, stir settle and separate the organic layer. Take organic layer and wash with 300ml ethyl acetate. Organic layer dry with sodium sulphate, distilled out solvent under vacuum to get (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II) having yield 73.5gm.

Example-2: Preparation of (2-cyano-1-cyclopentylethyl methanesulfonate (III)
A dry 2000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with (3S)-3-cyclopentyl-3-hydroxypropanenitrile ( 100g, 0.718 mole) (II) is taken in 500ml methylene dichloride at 25-30°C and addition of triethyl amine (101.7g, 01.005mole, 1.4eq) at same temperature and cool to 0-5°C. Slowly added methane sulfonyl chloride (98.76g, 0.862mole, 1.2eq) into the reaction mass at 0-5°C. Maintain the reaction mass for 1hr. Check TLC for completion of reaction. If reaction complies charge 500ml chilled purify water stir settle and separate the organic layer. Take organic layer and wash with 300ml 5% brine solution. Organic layer dry with sodium sulphate, distilled out solvent under vacuum to get 2-cyano-1-cyclopentylethyl methanesulfonate (III) having yield 136.5gm.

Example-3: Preparation of R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V)
A dry 2000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with 2-Cyano-1-cyclopentylethyl methanesulfonate (100g, 0.46mole) (III) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (98.22g, 0.506mole, 1.1eq) is taken in 500ml methylene dichloride at 25-30°C. Addition of triethyl amine (60.5g, 0.598mole, 1.3eq) into the reaction mass at 25-30°C. Temperature raised to 65-70°C. Maintain the reaction mass for 5-6hrs at 65-70°C Check TLC for completion of reaction. If reaction complies charge 500ml purify water stir settle and separate the organic layer. Take organic layer and wash with 300ml 5% brine solution. Organic layer dry with sodium sulphate, distilled out solvent under vacuum to get (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) propane nitrile (V) having yield 105.2gm.

Example-4: Preparation of 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII)
A dry 2000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with 4a, 7-dihydro -4H-pyrrolo[2,3-d] pyrimidin-4-one (100g, 0.74mole) (VI) in presence of 300ml THF at 25-30°C and slowly added Triflic anhydride (219.25g, 0.777mole, 1.05eq) in to reaction mass at 25-30°C, addition of TEA (97.3g, 0.962mole, 1.3eq) in 100ml MDC mixture into reaction mass at 25-30°C . Maintain the reaction mass for 3-4hrs at 35-40°C Check TLC of the reaction mass if TLC complies cool the reaction mas to 25-30°C and charge 400ml purify water and 500ml MDC in to reaction mass, stir settle and separate the organic layer. Take organic layer and wash with 300ml 5% brine solution. Organic layer dry with sodium sulphate, distilled out solvent under vacuum to get 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) having yield 155.92gm.

Example-5: Preparation of Ruxolitinib
A dry 2000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with 7H-pyrrolo[2,3-d]pyrimidin-4-yl trifluoro methanesulfonate (100g, 0.64mole) (VII) into 300ml 1, 4 Dioxane at 25-30°C was reacted with (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (86.5g, 0.64mole, 1eq) (V) in presence of [1,1' Bis(diphenylphosphino)ferrocene]palladium(II) dichloride [Pd(dppf)Cl2] (4.69g 0.0064mole, 0.01eq) and reaction mass warm to 35°C. Maintain the reaction mass for 2-3hrs at 30-35°C Check TLC of the reaction mass if TLC complies cool the reaction mas to 25-30°C and charge 400ml purify water and 500ml Ethyl acetate in to reaction mass, stir settle and separate the organic layer. Take organic layer and wash with 300ml 5% brine solution. Organic layer dry with sodium sulphate, distilled out solvent under vacuum reaction mass to get Ruxolitinib base (crude-VIII) having yield 90.0 gm.

Example-6: Purification of Ruxolitinib base (VIII)
A dry 1000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with Ruxolitinib crude (100g, 0.326 mole) into 300ml THF at 25-30°C stirred to clear solution, slowly charge 700ml purify water at 25-30°C. The reaction mixture was concentrated under reduce pressure to remove most of THF. And the reaction mass is stirred at 25-30°C for 2-3hrs. The solids were collected by filtration and wash with (3*500ml) purify water at 25-30°C. Unloaded the material and dry under vacuum at below 50°C to get Ruxolitinib having yield 78.5gm.

Example7: Preparation of Ruxolitinib phosphate (IX)
A dry 2000ml three necked round bottomed flask equipped with a rubber septum a thermometer, and a magnetic stirrer was flushed with nitrogen and charged with Ruxolitinib base (VIII) (100g, 0.326mole) into 1400ml isopropanol and heat the reaction mass at 60-65°C was added a solution of phosphoric acid (35.18g, 0.359mole, 1.1eq) in 270ml isopropanol. No exotherm was observed while adding a solution of phosphoric acid, and a precipitate was formed almost immediately. The resulting mixture was then heated at 75-78°C for 2.0hrs, then cooled gradually to ambient temperature and stirred at 25-30°C for overnight. The mixture was filtered and the solids were washed with a mixture of heptane and isopropanol (1/1, v/v, 500ml) before being transferred back to the original flask and stirred 700ml heptane for 1hrs at 25-30°C. Unloaded the material and dry under vacuum at below 40°C to get Ruxolitinib phosphate (IX) having yield 108.9 gm.
The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described
,CLAIMS:We Claim:

1. A novel process for the preparation of following formula (IX) comprising the below stages:

a) conversion of (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II) to prepare 2-cyano-1-cyclopentylethyl methanesulfonate (III) in the presence of sulphonyl chloride and organic solvents;

b) coupling of 2-cyano-1-cyclopentylethyl methanesulfonate (III) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (IV) in the presence of organic solvents to yield (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)propane nitrile (V);

c) coupling of (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)propane nitrile (V) with 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) in the presence of a catalyst to prepare Ruxolitinib base (VIII);

d) converting Ruxolitinib base (VIII) to Ruxolitinib Phosphate in the presence of phosphoric acid and an alcohol selected from methanol, ethanol and isopropyl alcohol.

2. A novel process for the preparation of Ruxolitinib Phosphate (IX) as claimed in claim 1, wherein sulphonyl chloride is selected from mesyl chloride, tosyl chloride and organic solvents are selected from methylene dichloride and triethyl amine.

3. A novel process for the preparation of Ruxolitinib Phosphate (IX) as claimed in claim 1, wherein catalyst is derivative of palladium which is selected from palladium on carbon and [1,1'-Bis(diphenylphosphino)ferrocene] palladium (II) dichloride.

4. A novel intermediate of following formula (III):

5. A novel intermediate of following formula (V):

6. A novel intermediate of following formula (VII):

7. A novel process for the preparation of 7H-pyrrolo[2,3-d] pyrimidin-4-yl trifluoro methanesulfonate (VII) from 4a,7-dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one (VI) using triflic anhydride as followed:

8. A novel process for the preparation of 2-cyano-1-cyclopentylethyl methanesulfonate (III) from (3S)-3-cyclopentyl-3-hydroxypropanenitrile (II) in the presence of mesyl chloride, dichloromethane and triethyl amine as followed:

9. A novel process for the preparation of (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)propane nitrile (V) from coupling of 2-cyano-1-cyclopentylethyl methanesulfonate (III) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (IV) in the presence of dichloromethane and triethyl amine as followed:

10. A novel process for the preparation of Ruxolitinib base (VIII) from coupling (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl) propane nitrile (V) with 7H-pyrrolo[2,3-d]-pyrimidin-4-yl-trifluoro methanesulfonate (VII) in the presence of [1,1'-Bis(diphenyl phosphino)ferrocene]palladium(II) dichloride as followed:

Dated this 3rd day of February, 2021.