Field of the Invention:

The present invention relates to a process for the preparation of amorphous form of (R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate compound of formula-1, represented by the following structure:

Background of the Invention:

Ruxloitinib, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl)-3-cyclo pentylpropanenitrile which is useful in the treatment of janus kinase-associated disease such as myeloproliferative disorders is the first FDA appro ved janus kinase (JAK) inhibitor and is the only drug currently appro ved for the treatment of myelofibrosis.

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

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

Brief description of the Invention:

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

Brief description of the Drawings:

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

Detailed description of the Invention:

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

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

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

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

b)heating the reaction mixture to a suitable temperature,

c)stirring the reaction mixture,

d)filtering the reaction mixture,

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

Wherein,

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

in step-b) the suitable temperature is selected from ambient temperature to the reflux temperature of the solvent uséd in the reaction.

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

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

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

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

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

d)filtering the reaction mixture,

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

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

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

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

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

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

Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclo pentylpropanenitrile phosphate colnpound of formula-1 produced by the present invention can be further micronized or milled by the conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.

Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer milis, and jet milis. Milling or micronization may be performed before drying, or after the completion of drying of the product.

P-XRD Method of Analysis:

PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Gu Ka radiation of wavelength 1.5406 A° and continuous sean speed of 0.03°/min.

Amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate of the present invention can be prepared using crystalline form-I (or) (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate salt known in the art.

The amorphous form of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate obtained according to the present invention can be useful in the preparation of pharmaceutical composition.

These examples are provided a$ illustration only and therefpre should not be construed as limitation of the scope of the invention.

Examples:

Example-1:

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

A mixture of methanol (30 mi) and water (180 mi) was added to (R)-3-(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentylpropanenitrile phosphate (10 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and immediately freezed the obtained fíltrate at -70°C for 45 minutes and then lyophilized to get the title compound. Yield: 9.5 gms; Chiral Purity: 99.96%.

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

We Claim:

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

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

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

2.The process according to claim-1, wherein, in step-(a) the solvent used is selected from methanol, ethanol, n-propanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, water or mixture thereof; in step-(b) the isolation of compound of formula-1 involves removal of solvent by the techniques such as lyophilization, recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation and the like.

3.The process according to claim 1, wherein the solvent is methanol.

4.The process according to claim 1, wherein the solvent is a mixture of water and methanol.

5.The process according to claim 1, wherein the isolation of compound of formula-1 involves the removal of solvent by lyophilization.

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

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

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

c)stirring the reaction mixture,

d)filtering the reaction mixture,

e)removing the solvent by lyophilization to get amorphous (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-l H-pyrazol- l-yl)-3-cyclopentylpropanenitrile phosphate compound of formula-1.

7.Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentyl propanenitrile phosphate obtained according to preceding claims is depicted in figure-1.

8.Amorphous (R)-3 -(4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-3 -cyclopentyl propanenitrile phosphate obtained according to any of the preceding claims having chiral purity greater than 99.95 % by HPLC.

9.Amorphous (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazól-l-yl)-3-cyclopentyl propaneitrile phosphate obtained according to any of the preceding claims useful for the preparation of pharmaceutical composition.

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