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1. WO2020222256 - POLYMORPHS OF 7-CYCLOPENTYL-N,N-DIMETHYL-2-{[5-(PIPERAZIN-1-YL) PYRIDIN-2-YL]-AMINO}-7H-PYRROLO[2,3-D]PYRIMIDINE-6-CARBOXAMIDE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS AND PROCESS FOR THE PREPARATION THEREOF

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[ EN ]

Claims:

1. Crystalline form-Nl of Ribociclib Succinate of formula- la


characterized by one or more of the following characteristics:

a) PXRD (powder X-Ray diffractogram) pattern having peaks at about 5.1°, 11.5°, 13.9°, 17.5° and 31.7°± 0.2° 2Q; or

b) PXRD pattern as illustrated in Figure 15; or

c) Differential Scanning Calorimetry (DSC) having endotherm peak at about 237° ± 3°C; or

d) Differential Scanning Calorimetry (DSC) as illustrated in figure-22.

2. A process for the preparation of crystalline form-Nl of Ribociclib succinate of claim 1, comprising:

a) dissolving succinic acid in a solvent,

b) adding Ribociclib of formula- 1,

c) isolating crystalline form-Nl of Ribociclib succinate.

3. The process according to claim 2, wherein dissolving succinic acid in step-a) can be carried out by heating the mixture to a temperature ranging from about 35°C to reflux temperature of the solvent used; the solvent in step-a) is selected from alcohol solvents, ether solvent, ketone solvents, ester solvents or mixtures thereof; isolating crystalline form-Nl in step-c) is carried out by removal of solvent using techniques selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by adding an anti-solvent.

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4. A process for preparation of Ribocicbb of formula- 1 or pharmaceutically acceptable salts thereof comprising:

a) reacting 5-(4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6


Formula-6

with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-7


to provide 7-cyclopentyl-N,N-dimethyl-2-((5-(4-tritylpiperazin-l-yl)pyridin-2-yl) amino)- 7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-8,


Formula- 8

b) converting 7-cyclopentyl-N,N-dimethyl-2-((5-(4-tritylpiperazin-l-yl)pyridin-2-yl)

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amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-8 to Ribociclib of formula- 1 or its pharmaceutically acceptable salts.


Formula- 1 or Ribociclib

5. The process according to claim 4, wherein the reaction in step-a) is carried out in presence of a coupling agent is selected from the group comprising of palladium catalysts that may be employed in this reaction include Pd(OAc)2, Pd2(dba)3, or Pd(PPh3)4, and PdCl2(PPh3)2, (Pd(dppf)2Cl2), [(CeHsCNbPdCh]; these catalysts are typically employed with a suitable ligand, such as BINAP, Xantphos or a related phosphine-based Pd ligand bis(dibenzylideneacetone) palladium (0) [(dba)2Pd], palladium chloride (PdCb), bis(benzonitrile)dichloropalladium and (Bis-(diphenylphosphinoferrocene) palladium dichloride dichloromethane complex, and the phospine compound is selected from 2,2'- bis(diphenylphosphino)-l,l '-binaphthalene (BINAP), 1,3 bis(diphenyl phosphino)propane, triphenylphosphine (Ph3P), triorthotolylphosphine [(o-CFbPlfbP] and tri-t-butylphosphine] or bis(trimethylsilyl)amide salt of sodium, potassium and lithium base or Grignard reagent such as Ci-6 alkyl magnesium halides or cycloalkyl magnesium halides or in the presence of bases selected from an inorganic or organic bases.

6. The process according to claim 4, wherein the conversion in step-b) is carried out in presence of an acid selected from “inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid;“organic acids” such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid,

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trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.

7. The process according to claim 4, wherein step-a) and/or step-b) is carried out in a solvent selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof.

8. A compound selected from the group consisting of:

5-(4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6,


Formula-6

7-cyclopentyl-N,N-dimethyl-2-((5-(4-tritylpiperazin-l-yl)pyridine-2-yl)amino)-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-8


Fromula-8

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9. Use of compounds according to claim 8 for the preparation of Ribociclib or its pharmaceutically acceptable salts.

10. A process for the preparation of 5-(4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6 of claim 8, comprising:

a) reacting the compound of formula-4 with trityl chloride in a solvent in presence of a base to provide l-(6-nitropyridin-3-yl)-4-tritylpiperazine of formula-5,

b) reduction of compound of formula-5 using a reducing agent in a solvent to provide 5- (4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6.

11. The process according claim 10, wherein the reducing agent in step-b) is selected from a group comprising of Fe, Fe in acidic media like U Cl or HC1 or acetic acid, Sn in acidic media like HC1, Zn, Zn in acidic media like HC1 or MLCl or acetic acid, sodium borohydride with catalytic NiCh^FhO or C0CI2.6H2O, Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd/C or combined with borohydrides, cyclohexene, acidic media like formic acid, H3PO2 etc., Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum oxide, borane-tetrahydrofuran complex and the like in combination with hydrogen, trialkyl silane and the like; base used in step-a) is selected from organic or inorganic bases; solvent used in steps-a) to b) is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof.

12. The process according to claim 10, wherein 5-(4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6 is further converting into Ribociclib of formula- 1 or its pharmaceutically acceptable salts.

13. Crystalline form-Ml of 5-(4-tritylpiperazin-l-yl)pyridin-2-amine of formula-6 which is

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characterized by one or more of the following characteristics:

a) PXRD pattern having peaks at about 9.2, 11.1, 13.1, 13.7, 16.5, 17.6 and 20.9° 2Q± 0.2° 2Q; or

b) PXRD pattern as depicted in Figure 19.

14. Crystalline form-Nl of 7-cyclopentyl-N,N-dimethyl-2-((5-(4-tritylpiperazin-l-yl) pyridine-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-8 which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 9.1 , 11.3, 15.6, 17.4 and 21.0° ± 0.2° 2Q; or ii) PXRD pattern as depicted in Figure-20.

15. A process for the preparation of an acid addition salt of Ribociclib wherein the acid is selected from a group of benzoic acid, fumaric acid, DL-mandelic acid, 4-hydroxybenzoic acid and salicylic acid comprising:

a) dissolving Ribociclib of formula- 1 in a solvent or mixture thereof,

b) adding an acid to the solution of step a),

c) isolating acid addition salt of formula- 1 from solution of step b).

16. The process according to claim 15, wherein solvent in step-a) and step-b) is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof; isolating acid addition salt of compound of formula- 1 in step-c) is done by removal of solvent using known techniques selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization.

17. The process according to claim 15, wherein an acid can be added to the solution of Ribociclib in a solvent or mixture thereof directly (or) a solution containing the acid in a solvent can be adding to the solution of Ribociclib in a solvent (or) the solution of Ribociclib in a solvent can be adding to the acid or a solution of acid in a suitable solvent.

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18. Crystalline form-Ml of Ribociclib benzoate, which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 10.0°, 19.3°, 20.4° and 21.5° ± 0.2° of 2-theta, or ii) PXRD pattern as illustrated in figure-6, or

iii)DSC thermogram as illustrated in figure-7.

19. Crystalline form-M2 of Ribociclib fumarate, which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 11.9°, 16.0°, 17.9°, 20.8° and 22.1°± 0.2° of 2- theta, or

ii) PXRD pattern as illustrated in figure-8, or

iii)DSC thermogram as illustrated in figure-9.

20. Crystalline form-M3 of Ribociclib DL-mandelate, which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 5.8°, 11.7°, 17.4°, and 18.2° ± 0.2° of 2-theta, or ii) PXRD pattern as illustrated in figure- 10.

21. Crystalline form-M4 of Ribociclib 4-hydroxybenzoate, which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 6.0°, 11.1°, 12.9°, 17.1° and 21.5° ± 0.2° of 2- theta, or

ii) PXRD pattern as illustrated in figure-11, or

iii)DSC thermogram as illustrated in figure-12.

22. Crystalline form-M5 of Ribociclib salicylate, which is characterized by one or more of the following characteristics:

i) PXRD pattern having peaks at about 11.0°, 12.7°, 19.4°, 20.8°, and 22.3° ± 0.2° of 2- theta, or

ii) PXRD pattern as illustrated in figure-13, or

iii) DSC thermogram as illustrated in figure- 14.

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23. Crystalline form-S of Ribociclib succinate of formula- la, which is characterized by one or more of the following characteristics:

a) PXRD pattern illustrated in figure-3, or

b) DSC thermogram as illustrated in figure-4.

24. A process for the preparation of crystalline form-S of Ribociclib Succinate of formula-la of claim 23; comprising:

a) combining Ribociclib succinate of formula- la with 1,4-dioxane or mixture of 1,4- dioxane and another solvent;

b) isolating the crystalline form-S of compound of formula- la.

25. Crystalline form-N of Ribociclib succinate of formula- la, which is characterized by one or more of the following characteristics:

a) PXRD pattern illustrated in figure-5, or

b) DSC thermogram as illustrated in figure-6.

26. A process for the preparation of crystalline form-N of Ribociclib succinate of formula- la of claim 25; comprising:

a) providing a solution of Ribociclib succinate in alcohol and optionally in mixture of ether solvent,

b) isolating crystalline form-N of Ribociclib succinate of formula- la.

27. The process according to any of preceding claims, wherein the purity of Ribociclib of formula- 1 or its pharmaceutically acceptable salts is greater than 99% by HPLC.

28. A pharmaceutical composition comprising Crystalline form-Nl of Ribociclib succinate of claim 1 and at least one pharmaceutically acceptable excipient.

29. A method of treating a mammal by administering a therapeutically effective amount of

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Crystalline form-Nl of Ribociclib succinate of claim 1 for treating postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.

30. Ribociclib or its pharmaceutically acceptable salts and their polymorphs of any of preceding claims used for preparation of pharmaceutical composition used for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.

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