Description:FIELD OF THE INVENTION:
The present invention is related to a process for preparing a crystalline Form-A of succinic acid salt 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-2-(5-piperazin-l-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxylic acid dimethylamide.
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.
Butanedioic acid -7-cyclopentyl-N, N-dimethyl-2- {[5-(piperazin1-yl) pyridine -2-yl] amino}-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide (1:1) (i.e. Ribociclib succinate) is a light yellow to yellowish brown crystalline powder. It is represented by the following structure of Formula I:

(Ribociclib Succinate)
WO2010/020675 discloses a compound 7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6- carboxamide (Ribociclib succinate) and its synthetic process (in example-74).

WO2012/064805 discloses crystalline forms of ribociclib succinate and process for the preparation of Ribociclib succinate using Isopropyl alcohol as solvent and describes that the Ribociclib succinate is yellow crystalline solid having the melting point at 202-203°C.
According to the European Committee for Medicinal Products for Human Use (CHMP) assessment Report for KISQALI (EMA/CHMP/506968/2017), the drug substance Ribociclib succinate is a slightly hygroscopic yellow to brown crystalline powder. It describes that the ribociclib succinate form A has been demonstrated to be stable and not to convert into other polymorphic forms under long term and accelerated stability studies when stored in the proposed packaging.
US10336763B1 discloses crystal forms B, C and D of Ribociclib succinate salt. Also, teaches that ribociclib succinate Crystalline-Form-A, as prepared in comparative example, having characteristic XRPD peaks at 2? values of 7.8°, 10.0°, 14.5°, 20.0°, and 21.5° (± 0.2 2?), is the same as the crystalline structure of the ribociclib succinate in WO2012/064805A1.
WO2020152629A1 discloses new crystalline forms of a succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d] pyrimidine -6-carboxylic acid dimethylamide in the form of Modification E, F, HA, or HB.
As per the above prior-art, crystalline ribociclib succinate Form-A is the approved marketed form, and manufacturing Form-A having chemical purity greater than 99.8% by HPLC is a critical step as it requires controlling formation of impurities in each stage of preparation of ribociclib prior to achieving ribociclib succinate Form-A.
The inventors of the present invention have developed an improved process for the preparation of crystalline Ribociclib succinate Form-A that is cost effective and industrially viable.

The crystalline Ribociclib succinate Form-A of present invention has a content of Ribociclib Impurity-D less than about 0.05% by HPLC and content of IPA less than 5000 ppm.

(Ribociclib Impurity-D)
BRIEF DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of crystalline Form-A of ribociclib succinate comprising:
a) dissolving succinic acid in isopropyl alcohol at a temperature of 70oC to 75oC.
b) adding Ribociclib to the clear solution obtained in the step-(a) and heating the reaction mixture up to a temperature of 85oC.
c) cooling the reaction mass up to a temperature of 40oC.
d) adding drop-wise a second solvent to the reaction mass in step-(c) at a temperature of about 40oC, then heating the reaction mixture up to a temperature of 85oC.
e) cooling to room temperature, and
f) recovering the Form-A of ribociclib succinate.
The crystalline form-A of Ribociclib succinate obtained by the present invention is characterized by an XRPD pattern is same as shown in figure 1 and having peaks at 2? values about 7.8° (±0.2° 2?), 10.0° (±0.2° 2?), 14.5° (±0.2° 2?), 20.0° (±0.2° 2?), and 21.5° (±0.2° 2?).
The crystalline form-A of Ribociclib succinate 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 204°C (± 3.0°C).
The second solvent in step-d of present invention is a C3-C6 alkyl ester solvent and is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate. Preferably, the second solvent is ethyl acetate.
The present invention provides an improved process for the preparation of ribociclib succinate Form-A, which has a content of Impurity-D less than about 0.05% by HPLC and content of IPA less than 5000 ppm.

(Ribociclib Impurity-D)
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-A of Ribociclib succinate obtained by the present invention.
Figure-2 is the characteristic differential scanning calorimetry (DSC) thermogram of crystalline Form-A of Ribociclib succinate 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-A of succinate salt of Ribociclib. Specifically, the present invention relates to a processes for the preparation of substantially pure Ribociclib succinate Form-A and reducing the content of Impurity-D and the structure of Impurity-D as depicted below.

(Ribociclib Impurity-D)
The present invention relates to a process for the preparation of crystalline Form-A of Ribociclib succinate. The process comprises:
a) dissolving succinic acid in isopropyl alcohol at a temperature of 70oC to 75oC.
b) adding Ribociclib to the clear solution obtained in the step-(a) and heating the reaction mixture up to a temperature of 85oC.
c) cooling the reaction mass up to a temperature of 40oC.
d) adding drop-wise a second solvent to the reaction mass in step-(c) at a temperature of about 40oC, then heating the reaction mixture up to a temperature of 85oC.
e) cooling to room temperature, and
f) recovering the Form-A of ribociclib succinate.
According to the present invention, prepare a clear solution by dissolving Succinic acid in Isopropyl alcohol and heat the reaction mixture to 70°C to 75°C.
According to the present invention, add Ribociclib base to the solution containing Succinic acid and Isopropyl alcohol under nitrogen atmosphere at 70°C to 75°C and then heating the reaction mixture to 80°C to 85°C with slow RPM for 6 hours.
According to the present invention, add the second solvent drop-wise to the reaction mixture containing Ribociclib base, succinic acid and Isopropyl alcohol with slow agitation i.e. at low RPM at a temperature of about 40oC and then heating the reaction mixture to 70°C to 75°C with slow RPM. The obtained reaction mass stirred for 6 hours at the same temperature with slow agitation.
According to the present invention, the reaction mass is cooling to room temperature with slow RPM and filter the reaction mass to obtain Ribociclib succinate and drying the material to obtain crystalline Form-A of Ribociclib succinate.
According to the present invention, crystalline Form-A of Ribociclib succinate characterized by an X-ray powder diffraction (XRPD) pattern in accordance with figure-1.
According to the present invention, crystalline Form-A of Ribociclib succinate characterized by an XRPD pattern having peaks at 2? values about 7.8° (±0.2° 2?), 10.0° (±0.2° 2?), 14.5° (±0.2° 2?), 20.0° (±0.2° 2?), and 21.5° (±0.2° 2?).
According to the present invention, crystalline Form-A of Ribociclib succinate characterized by a differential scanning calorimetry (DSC) thermogram in accordance with figure-2.
According to the present invention, DSC thermogram of crystalline Form-A of Ribociclib succinate has an endothermic peak at 204°C (± 3.0°C).
According to the present invention, ribociclib succinate Form-A has content of Iso-propyl alcohol (IPA) less than 5000 ppm.
According to the present invention, ribociclib succinate Form-A has a content of Impurity-D less than about 0.05% by HPLC.

(Ribociclib Impurity-D)
According to the present invention, the second solvent in step-(d) is a C3-C6 alkyl ester solvent.
According to the present invention, C3-C6 alkyl ester solvent is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate. Preferably, the C3-C6 alkyl ester is ethyl acetate.
According to the present invention, a process for the preparation of crystalline Form-A of Ribociclib succinate comprises:
a) dissolving succinic acid in isopropyl alcohol at a temperature of 70oC to 75oC.
b) adding Ribociclib to the clear solution obtained in the step-(a) and heating the reaction mixture up to a temperature of 85oC.
c) cooling the reaction mass up to a temperature of 40oC.
d) adding drop-wise ethyl acetate to the reaction mass in step-(c) at a temperature of about 40oC, then heating the reaction mixture up to a temperature of 85oC.
e) cooling to room temperature, and
f) recovering the Form-A of ribociclib succinate.

According to the present invention, the process for the preparation of Ribociclib free base comprises:
a) treating “2-Chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide” with “tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate” in presence of LiHMDS, Tetrahydrofuran, methanol and water to obtain “tert-butyl 4-(6-((7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate” (t-boc-protected ribociclib).
b) adding “t-boc-protected ribociclib” to a mixture of Ethyl acetate and Isopropyl alcohol, then heating the reaction mass to 70°C to 75°C.
c) cooling the reaction mass to room temperature and filter and dry the material to obtain pure “t-boc-protected ribociclib”.
d) treating a solution containing “t-boc-protected ribociclib” in toluene with aqueous HCl and Liq. Ammonia to obtain ribociclib free base.
The details of the present 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” (t-boc protected ribociclib).
2-Chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide was reacted with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate in the presence of LiHMDS and tetrahydrofuran, and the reaction mass was stirred at room temperature. After the reaction completed, a solution of acetic acid in tetrahydrofuran was added dropwise. The precipitated material was filtered and washed with chilled methanol. The obtained solid was charged into a round bottom flask with purified water and stirred for one hour at room temperature. The material was filtered and washed with purified water.

The wet material was charged into a round bottom flask and methanol and purified water were added. The mixture was heated to 45 to 50°C for 2 hours. Then, the reaction mass was cooled to 0°C to 5°C, and the material was filtered and washed with purified water to obtain 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" (t-boc protected ribociclib).
Subsequently, the crude material was suspended in methanol and stirred for one hour at room temperature. The material was filtered and washed with methanol. The wet cake was dried under vacuum at 45 to 50°C for 10 hours to obtain t-boc protected ribociclib with a purity of 99.59%.
Example-1 (a): Purification of 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 (t-boc protected ribociclib)”:
The "t-boc protected ribociclib", ethyl acetate, and isopropyl alcohol were charged into a round bottom flask at room temperature. The reaction mass was heated to 70 to 75°C and stirred for one hour. Subsequently, the reaction mass was cooled to 0°C to 5°C and stirred for one hour. The material was then filtered and washed with ethyl acetate, followed by methanol. Finally, the material was dried under vacuum at 45 to 50°C for 10 hours to obtain pure "t-boc protected ribociclib" with a purity of 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-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate and toluene. The suspension was stirred at room temperature for 2 hours. After the reaction was completed, the layers were separated, and the organic layer was extracted with purified water. The combined aqueous layer was treated with activated charcoal for one hour at room temperature, filtered through a Hyflo bed, and washed with purified water.
The pH of the filtrate was adjusted to 8 to 10 by adding liquor ammonia dropwise at room temperature. The precipitated solid was filtered and washed with purified water. The wet material obtained was suspended in purified water until the pH reached 7 to 9, and then the material was washed with methanol. The resulting material was further dried under vacuum at 45 to 50°C for 10 hours to obtain Ribociclib base with a purity of 99.50%.
Example-3: Preparation of Butanedioic acid -7-cyclopentyl-N, N-dimethyl-2- {[5-(piperazin1-yl) pyridine -2-yl] amino}-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide (1:1). (Ribociclib succinate form-A).
Example-3 (a): The mixture of succinic acid (11.52g, 0.098 moles) and isopropyl alcohol (120mL) was heated to 70°C to 75°C until a clear solution formed. Ribociclib free base (7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide) was added to the clear solution, and the reaction mixture was stirred for 6 hours at 80°C to 85°C with slow RPM. The reaction mixture was then cooled to 40°C to 45°C, and ethyl acetate (1200 mL, 30 volumes) was added drop-wise. The reaction mixture was heated to 70°C to 75°C and stirred for 6 hours. After cooling the reaction mass to room temperature, it was filtered and washed with ethyl acetate. The wet material obtained was suspended in ethyl acetate and heated to 70°C to 75°C for 2 hours. The reaction mass was then cooled to room temperature, filtered, and washed with ethyl acetate. The material obtained was dried under vacuum at 65°C to 70°C for 10 hours to obtain Ribociclib succinate Form-A.
Example-3 (b): The mixture of succinic acid (11.52g, 0.098 moles) and isopropyl alcohol (200mL) was heated to 70°C to 75°C until a clear solution formed. Ribociclib free base (7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide) was added to the clear solution, and the reaction mixture was stirred for 6 hours at 80°C to 85°C with slow RPM. The reaction mixture was then cooled to 40°C to 45°C, and ethyl acetate (1200 mL, 30 volumes) was added drop-wise. The reaction mixture was heated to 70°C to 75°C and stirred for 6 hours. After cooling the reaction mass to room temperature, it was filtered and washed with ethyl acetate. The wet material obtained was suspended in ethyl acetate and heated to 70°C to 75°C for 2 hours. The reaction mass was then cooled to room temperature, filtered, and washed with ethyl acetate. The material obtained was dried under vacuum at 65°C to 70°C for 10 hours to obtain Ribociclib succinate Form-A.
Example-3 (c): Succinic acid (11.52 g, 0.098 moles) was added to a mixture of isopropyl alcohol (60 mL) and ethyl acetate (60 mL), and the reaction mixture was heated to 70°C to 75°C until a clear solution formed. Ribociclib free base (7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide) was added to the clear solution, and the reaction mixture was stirred for 6 hours at 80°C to 85°C with slow RPM. Afterwards, the reaction mixture was cooled to 40°C to 45°C, and ethyl acetate (1200 mL, 30 volumes) was added drop-wise. The reaction mixture was then heated to 70°C to 75°C and stirred for 6 hours. Subsequently, the reaction mass was cooled to room temperature, filtered, and washed with ethyl acetate. The wet material was suspended in ethyl acetate and heated to 70°C to 75°C for 2 hours. The reaction mass was cooled to room temperature, filtered, and washed again with ethyl acetate. The material obtained was dried under vacuum at 65°C to 70°C for 10 hours to obtain Ribociclib succinate Form-A.
Example-3 (d): The mixture of succinic acid (11.52g, 0.098 moles) and isopropyl alcohol (200mL) was heated to 70°C to 75°C until a clear solution formed. Ribociclib free base (7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide) was added to the clear solution, and the reaction mixture was stirred for 6 hours at 80°C to 85°C with slow RPM. The reaction mixture was then cooled to 40°C to 45°C, and isopropyl acetate (1200 mL, 30 volumes) was added drop-wise. The reaction mixture was heated to 70°C to 75°C and stirred for 6 hours. After cooling the reaction mass to room temperature, it was filtered and washed with isopropyl acetate. The wet material obtained was suspended in isopropyl acetate and heated to 70°C to 75°C for 2 hours. The reaction mass was then cooled to room temperature, filtered, and washed with isopropyl acetate. The material obtained was dried under vacuum at 65°C to 70°C for 10 hours to obtain Ribociclib succinate Form-A.
Example-3 (e): Succinic acid (11.52 g, 0.098 moles) was added to a mixture of isopropyl alcohol (60 mL) and isopropyl acetate (60 mL), and the reaction mixture was heated to 70°C to 75°C until a clear solution formed. Ribociclib free base (7-Cyclopentyl-N, N-dimethyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide) was added to the clear solution, and the reaction mixture was stirred for 6 hours at 80°C to 85°C with slow RPM. Afterwards, the reaction mixture was cooled to 40°C to 45°C, and isopropyl acetate (1200 mL, 30 volumes) was added drop-wise. The reaction mixture was then heated to 70°C to 75°C and stirred for 6 hours. Subsequently, the reaction mass was cooled to room temperature, filtered, and washed with isopropyl acetate. The wet material was suspended in isopropyl acetate and heated to 70°C to 75°C for 2 hours. The reaction mass was cooled to room temperature, filtered, and washed again with isopropyl acetate. The material obtained was dried under vacuum at 65°C to 70°C for 10 hours to obtain Ribociclib succinate Form-A.
,
Claims:We Claim:
1. A process for the preparation of crystalline Form-A of ribociclib succinate comprising:
a) dissolving succinic acid in isopropyl alcohol at a temperature of 70oC to 75oC.
b) Adding Ribociclib to the clear solution obtained in the step-(a) and heating the reaction mixture up to a temperature of 85oC.
c) cooling the reaction mass up to a temperature of 40oC.
d) adding drop-wise a second solvent to the reaction mass in step-(c) at a temperature of about 40oC, then heating the reaction mixture up to a temperature of 85oC.
e) cooling to room temperature, and
f) recovering the Form-A of ribociclib succinate.
2. The ribociclib succinate Form-A according to claim 1, characterized by an X-ray powder diffraction (XRPD) pattern in accordance with figure-1.
3. The ribociclib succinate Form-A according to claim 2, characterized by an XRPD pattern having peaks at 2? values about 7.8° (±0.2° 2?), 10.0° (±0.2° 2?), 14.5° (±0.2° 2?), 20.0° (±0.2° 2?), and 21.5° (±0.2° 2?).
4. The ribociclib succinate Form-A according to any of preceding claims, characterized by a differential scanning calorimetry (DSC) thermogram in accordance with figure-2.
5. The ribociclib succinate Form-A according to claim-4, DSC thermogram has an endothermic peak at 204°C (± 3.0°C)
6. The process of ribociclib succinate Form-A according to claim 1, wherein the second solvent in step-(d) is a C3-C6 alkyl ester solvent.
7. The process of ribociclib succinate Form-A according to claim 6, wherein C3-C6 alkyl ester is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate.
8. The process of ribociclib succinate Form-A according to claim 7, the C3-C6 alkyl ester is ethyl acetate.
9. The process according to any of preceding claims, wherein ribociclib succinate Form-A has content of Impurity-D less than about 0.05% by HPLC.

(Ribociclib Impurity-D)
10. The process of ribociclib succinate Form-A according to any of preceding claims, wherein ribociclib succinate Form-A has content of Iso-propyl alcohol (IPA) less than 5000 ppm.