Description:FIELD OF THE INVENTION:
The present invention relates to a process for preparing crystalline Form-I of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide.

BACKGROUND OF THE INVENTION:
Ribociclib is a kinase inhibitor and designated chemically as 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide.
Ribociclib mono succinate salt was approved by USFDA in March 13, 2017 and is marketed under the brand name KISQALI and is indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
The IUPAC name of Ribociclib is 7-cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. It is represented by the following structure of Formula.

(Ribociclib)
Ribociclib was disclosed in WO2010/020675 for use in the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

This PCT disclosed synthesis of Ribociclib but did not describe polymorphs of Ribociclib and its other physicochemical properties.
A new process for the preparation of Ribociclib was disclosed in WO2012/064805. The document described a process scheme for making the compound of Formula (I) (Ribociclib) and the compound of Formula (II) (Ribociclib succinate), as shown below.

Example 3.2 of WO2012/064805 described a process for the preparation of Ribociclib free base (Compound A4/Formula-I) as a tan solid with a melting point of 194-195°C.
EP3156406A1 described crystalline Form-I of Ribociclib free base, characterized by PXRD 2θ values at 12.5°, 12.6°, 13.3°, 14.8°, 18.3°, 13.6°, 18.1°, 21.8°, 22.9°, and 26.9°, and a DSC peak temperature of 198.84°C.
Inventive Example 1a of EP3156406A1 described a process for the preparation of crystalline Form-I of Ribociclib free base as a white solid by slurrying amorphous Ribociclib free base in acetone at room temperature for 24 hours. Inventive Example 1b of EP3156406A1 described a process for the preparation of crystalline Form-I of Ribociclib free base by slurrying Form-6 of Ribociclib free base in acetone at room temperature for 24 hours.

Further, it has been found that Ribociclib crystallizes in several different solid forms, including both polymorphic crystalline and amorphous forms. Among the crystalline forms of Ribociclib free base in crystalline Form-I, as described in EP3156406, is particularly advantageous for preparing pharmaceutically acceptable acid addition salts of Ribociclib due to its ease of access and good solubility in organic solvents. The process described in the prior-art for preparing crystalline Ribociclib Form-I has certain disadvantages related to purity, also, the process for converting Ribociclib free base into crystalline Form-I requires a longer time.
Hence, there is a need for a process to prepare crystalline Form-I of Ribociclib free base on an industrial scale, ensuring sufficient yield and purity, and the residual solvents comply with ICH guidelines.
Surprisingly, the inventors of the present application have found a processes for the preparation of crystalline Form-I of Ribociclib with purity greater than 99.5% by HPLC that is cost effective and industrially viable and requires a lesser time for Form-I conversion.
BRIEF DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of crystalline Form-I of Ribociclib free base comprising:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC and stir for 2 to 3 hours.
b) adding a second solvent to the reaction mass in step-(a) at a temperature of about 20°C to 30°C and stir the reaction for 2 to 3 hour.
c) Isolating the crystalline Form-I of Ribociclib free base.
The crystalline Form-I of Ribociclib free base obtained by the present invention is characterized by an XRPD pattern is same as shown in figure 1 and having peaks at 2θ values about 12.5° (±0.2° 2θ), 12.6° (±0.2° 2θ), 13.3° (±0.2° 2θ), 13.6° (±0.2° 2θ), 14.8° (±0.2° 2θ), 18.1° (±0.2° 2θ), 18.3° (±0.2° 2θ), 21.8° (±0.2° 2θ), 22.9° (±0.2° 2θ), 26.9° (±0.2° 2θ).
The crystalline Form-I of Ribociclib free base obtained by the present invention is characterized by a differential scanning calorimetry (DSC) thermogram is same as shown in figure 2 and has an endothermic peak at 198.8°C (± 3.0°C).
The second solvent in step-(b) of present invention is a ketone solvent and is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone. Preferably, the second solvent is acetone.
The present invention provides a process for the preparation of crystalline Form-I of Ribociclib free base comprising:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC and stir for 2 to 3 hours.
b) adding acetone to the reaction mass in step-(a) at a temperature of about 20 to 30°C and stir the reaction for 2 to 3 hour.
c) isolating the crystalline Form-I of Ribociclib free base.
The Ribociclib free base obtained by the current invention having the purity greater than 99.5% by HPLC.
The crystalline Form-I of Ribociclib free base obtained by the present invention is further converting to pharmaceutically acceptable acid addition salts of Ribociclib.
BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate the present invention and together with the description.
Figure-1 is the characteristic XRPD pattern of crystalline Form-I of Ribociclib free base obtained by the present invention.
Figure-2 is the characteristic differential scanning calorimetry (DSC) thermogram of crystalline Form-I of Ribociclib free base obtained by the present invention.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention may be understood more readily by reference to the following detailed description and the examples included herein. It is to be understood that the terminology used herein is to describe specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.
The present disclosure relates to an improved process for the preparation of crystalline Form-I of Ribociclib free base that is cost effective and industrially viable and requires a lesser time for Form-I conversion.
The present invention relates to a process for the preparation of crystalline Form-I of Ribociclib free base. The process comprises:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC and stir for 2 to 3 hours.
b) adding second solvent to the reaction mass in step-(a) at a temperature of about 20 to 30°C and stir the reaction for 2 to 3 hour.
c) isolating the crystalline Form-I of Ribociclib free base.
According to the present invention, slurrying Ribociclib free base in 2-methyl-THF and stir the reaction mass at 20 to 30°C for 2 hours.
According to the present invention, add the second solvent to the reaction mixture containing Ribociclib base, and 2-methyl-THF at 20 to 30°C and stir the reaction mass.
According to the present invention, filter the reaction mass to obtain Ribociclib free base in crystalline Form-I and dry the material.
According to the present invention, crystalline Form-I of Ribociclib free base characterized by an X-ray powder diffraction (XRPD) pattern in accordance with figure-1.
According to the present invention, crystalline Form-I of Ribociclib free base characterized by an XRPD pattern having peaks at 2θ values about 12.5° (±0.2° 2θ), 12.6° (±0.2° 2θ), 13.3° (±0.2° 2θ), 13.6° (±0.2° 2θ), 14.8° (±0.2° 2θ), 18.1° (±0.2° 2θ), 18.3° (±0.2° 2θ), 21.8° (±0.2° 2θ), 22.9° (±0.2° 2θ), 26.9° (±0.2° 2θ).
According to the present invention, crystalline Form-I of Ribociclib free base characterized by a differential scanning calorimetry (DSC) thermogram in accordance with figure-2.
According to the present invention, DSC thermogram of crystalline Form-I of Ribociclib free base has an endothermic peak at 198.8°C (± 3.0°C).
According to the present invention, the second solvent in step-(b) is a ketone solvent, which is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone. Preferably, the second solvent is acetone.
According to the present invention, a process for the preparation of crystalline Form-I of Ribociclib free base comprises:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC and stir for 2 to 3 hours.
b) adding acetone to the reaction mass in step-(a) at a temperature of about 20 to 30°C and stir the reaction for 2 to 3 hour.
c) isolating the crystalline Form-I of Ribociclib free base.
The Ribociclib free base obtained by the current invention having the purity greater than 99.5% by HPLC.
The crystalline Form-I of Ribociclib free base obtained by the present invention is further converting to pharmaceutically acceptable acid addition salts of Ribociclib. Preferably, the crystalline Form-I of Ribociclib free base obtained by the present invention converts to succinic acid salt of Ribociclib.
The Ribociclib free base used in the preparation of crystalline Form-I of Ribociclib can be prepared by the methods disclosed in the prior-art. The details of the invention are given in the examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.
Example-1: Preparation of Tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate.
To a mixture of 2-Chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide, Tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate, and Tetrahydrofuran, LiHMDS solution in THF was added. The reaction mass was stirred until reaction completes at room temperature. After the reaction completion, a solution of acetic acid in tetrahydrofuran was added dropwise. The material precipitated was filtered and washed with chilled methanol. To the obtained solid, charged purified water and stirred at room temperature for 1 hour. The reaction mass was filtered and washed with purified water. Thus obtained wet material was further purified using methanol and purified water at 45 to 50°C. The reaction mass was cooled to 0 to 5°C filtered, and washed with purified water to get crude Tert-butyl 4-(6-((7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate material. The crude material was suspended in methanol and stirred for 1 hour at room temperature. The material was isolated by filtration by washing the cake with methanol. Finally, thus obtained material was dried under vacuum at 45 to 50°C for 10 hours to get the title compound. (Purity: 99.59%)
Example-1 (a): Purification of Tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate.:
To a mixture of Ethyl acetate and Isopropyl alcohol, tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate was added at room temperature. The reaction mass was heated to 70 to 75°C and stirred for 1 hour. Then, the reaction mass was cooled to 0 to 5°C and stirred for 1 hour. The material was isolated by filtration and washed with ethyl acetae followed by washing with methanol. Then, the material was dried under vacuum at 45 to 50°C for 10 hours to get pure Tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (Purity: 99.91%).
Example-2: Preparation of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide. (Ribociclib base)
Aqueous hydrochloric acid solution was added dropwise to a solution of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate in toluene. The suspension was stirred at room temperature for 2 hours. After the completion of reaction, the layers were separated, and organic layer was extracted with purified water. The combined aqueous layer was treated with activated charcoal for 1 hour at room temperature, filtered through Hyflo bed and washed with purified water. The pH of the filtrate was adjusted to 8 to 10 by adding dropwise liquor ammonia at room temperature. The precipitated solid was filtered and washed with purified water. Thus obtained wet material was suspended in purified water until the pH is 7 to 9 and the material washed with methanol. The obtained material was further dried under vacuum at 45 to 50°C for 10 hours to get Ribociclib base (Purity: 99.50%).
Example-3(a): Preparation of crystalline Form-I of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide. (Ribociclib base Form-I)
The mixture of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and 2-methyl THF was stirred for 2 hours at 20 to 30°C. After maintenance for 2 hours, added acetone solvent to the reaction mixture and stirred for 3 hours. The precipitated solid was filtered and washed with mixture of acetone and of 2-Methyl THF. Thus obtained material was dried under vacuum at 50 to 60°C for 10 hours to get crystalline Form-I of Ribociclib free base (Purity: 99.8%).
Example-3(b): Preparation of crystalline Form-I of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide. (Ribociclib base Form-I)
The mixture of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and 2-methyl THF was stirred for 2 hours at 20 to 30°C. After maintenance for 2 hours, added methyl ethyl ketone solvent to the reaction mixture and stirred for 3 hours. The precipitated solid was filtered and washed with mixture of methyl ethyl ketone and of 2-Methyl THF. Thus obtained material was dried under vacuum at 50 to 60°C for 10 hours to get crystalline Form-I of Ribociclib free base (Purity: 99.6%).
Example-3(c): Preparation of crystalline Form-I of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide. (Ribociclib base Form-I)
The mixture of 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and 2-methyl THF was stirred for 2 hours at 20 to 30°C. After maintenance for 2 hours, added methyl isobutyl ketone solvent to the reaction mixture and stirred for 3 hours. The precipitated solid was filtered and washed with mixture of methyl isobutyl ketone and of 2-Methyl THF. Thus obtained material was dried under vacuum at 50 to 60°C for 10 hours to get crystalline Form-I of Ribociclib free base (Purity: 99.6%). , Claims:We Claim:
1. A process for the preparation of crystalline Form-I of Ribociclib free base comprising:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC.
b) adding a second solvent to the reaction mass in step-(a) at a temperature of about 20 to 30°C.
c) stir the reaction mass in step-(b) and isolating the crystalline Form-I of Ribociclib free base.
2. The process of Ribociclib free base Form-I according to claim 1, wherein the second solvent in step-(b) is a ketone solvent.
3. The process of Ribociclib free base Form-I according to claim 2, wherein a ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone.
4. The process of Ribociclib Free Base Form-I according to claim 3, the ketone solvent is acetone.
5. The Ribociclib free base Form-I according to any one of the preceding claims, characterized by an x-ray powder diffraction (XRPD) pattern in accordance with figure-1.
6. The Ribociclib free base Form-I according to any one of the preceding claims, characterized by an XRPD pattern having peaks at 2θ values about 12.5° (±0.2° 2θ), 12.6° (±0.2° 2θ), 13.3° (±0.2° 2θ), 13.6° (±0.2° 2θ), 14.8° (±0.2° 2θ), 18.1° (±0.2° 2θ), 18.3° (±0.2° 2θ), 21.8° (±0.2° 2θ), 22.9° (±0.2° 2θ), 26.9° (±0.2° 2θ).
7. The Ribociclib free base Form-I according to any of preceding claims, characterized by a differential scanning calorimetry (DSC) thermogram in accordance with figure-2.
8. The Ribociclib free base Form-I according to any of preceding claims, DSC thermogram has an endothermic peak at 198.8°C (± 3.0°C).
9. A process for the preparation of crystalline Form-I of Ribociclib free base comprising:
a) slurrying Ribociclib free base in 2-methyl tetrahydrofuran solvent at a temperature of 20oC to 30oC.
b) adding acetone to the reaction mass in step-(a) at a temperature of about 20 to 30°C.
c) stir the reaction mass in step-(b) and isolating the crystalline Form-I of Ribociclib free base.
10. The Ribociclib free base Form-I obtained by any of the preceding claims converts to pharmaceutically acceptable acid addition salts of Ribociclib.