DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR PREPARATION OF RIBOCICLIB SUCCINATE AND ITS INTERMEDIATES

INTRODUCTION
The present application relates to a process for the preparation Ribocilcib of formula (II) and its succinate salt of formula (I). The present application also related to a process for preparation of key intermediate (VII) of Ribociclib and its application for preparation of Ribociclib succinate of formula (I).

Ribociclib succinate is a cylcin-dependent kinase-4/6 inhibitor 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. Ribociclib succinate is chemically known as Butanedioic acid-7-Cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-l-yl)pyridin-2-yl]amino}-7Hpyrrolo[2,3- d]pyrimidine-6-carboxamide (1:1) and has following structural formula:

(I)
Ribociclib is specifically disclosed in PCT patent application, WO2010020675Al (hereinafter referred as the WO’675 application) assigned to Novartis Pharmaceuticals. The polymorphic forms of Ribociclib succinate were disclosed in US9193732B2 (hereinafter referred as the US’732 patent) assigned to Novartis Pharmaceuticals/Astex Pharma, which are characterized by XRD, DSC, TGA, post-DVS XRD, post-DVS DSC and post-DVS TGA figures. US’ 732 patent also discloses a process for preparation of ribociclib and its interemediates. Numerous synthetic routes for preparation of Ribociclib and its succinate salt have been reported in the literature including process disclosed in CN106478641B, CN106749259B, CN106928236B, CN107936029B, CN108314686A, CN108586356B, CN108623599A, WO 2019142206A1, WO2019150181A, CN 109400612A, CN 109553621A, US10723739B, WO2020084389A1, IN201821020528A, CN 111100128A and IN201841004425A.

However, still there remains a need for an improved process for the commercial production of Ribociclib of formula (II) or pharmaceutically acceptable salts thereof, particularly Ribociclib succinate of formula (I).

SUMMARY
First aspect of the present application relates to the process for the preparation of compound of formula (VII), comprising the following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
.
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms.

Second aspect of the present application relates to one-pot process for the preparation of compound of formula (VII), comprising the following steps:
a) reacting cyclopentylamine (XI) with a-haloalkylacetate to form compound of formula (IX)
;
b) reacting compound of formula (IX) with compound of formula (X) in presence of a suitable base to obtain compound of formula (VII)
.
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms.

Third aspect of the present application relates to a process for preparation of Ribociclib (II) or its pharmaceutically acceptable salts thereof, comprising following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
;
c) converting compound of formula (VII) to compound of formula (VI) in presence of a suitable reducing agent
;
d) reacting compound of formula (VI) with compound of formula (XIII) to form compound of formula (V)
;
e) hydrolyzing compound of formula (V) to compound of formula (IV)

;
f) converting compound of formula (IV) to compound of formula (III)

;
g) converting compound of formula (III) to Ribociclib (II)

;
h) converting Ribociclib (II) to its pharmaceutically acceptable salt, in particular, succinate salt of formula (I).
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amine protecting group.

Fourth aspect of the present application relates to a process for preparation of Ribociclib or pharmaceutically acceptable salt thereof comprising the step of reacting compound of formula (XIV) with compound of formula (XIII) in presence of a suitable base to form compound of formula (IV)

wherein P is an amine protecting group.

Fifth aspect of the present application relates to a process for preparing crystalline form of Ribociclib succinate (I); the process comprising;
a) reacting Ribociclib (II) with succinic acid in a suitable solvent or mixture thereof;
b) isolating crystalline form of Ribociclib succinate (I);
c) optionally, drying the isolated product at suitable temperature.

Sixth aspect of the present application relates to a process for preparation of Ribociclib of formula (II) or its succinate salt of formula (I) comprising converting compound of formula (VII) and/or compound of formula (IV) prepared by any of the aspects of this application to Ribociclib of formula (II) or its succinate salt of formula (I).

DETAILED DESCRIPTION
First aspect of the present application relates to the process for the preparation of compound of formula (VII), comprising the following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
.
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms.

In embodiments of step a) reaction of compound of formula (X) with compound of formula (IX) or salt thereof is carried out in presence of a suitable base in a suitable solvent. Suitable base may be an organic base or in organic base. Inorganic base of step a) including but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; Specifically, inorganic base is sodium bicarbonate. Organic base of step a) including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), tetrabutylammonium (TBAF), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like. Specifically organic base is 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or triethyl amine. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent is toluene.
In embodiments of step b) cyclization of compound of formula (VIII) is carried out in presence of a suitable base in suitable solvent to form compound of formula (IX). Suitable base of step b) including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), tetrabutylammonium (TBAF), 1, 8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like. Specifically base is 1, 8-Diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; amide solvents such as Diethylformamide, Dimethylacetamide, Dimethylformamide and the like; water; and mixtures thereof. Specifically, the solvent may be toluene or dimethylformamide.

Second aspect of the present application relates to one-pot process for the preparation of compound of formula (VII), comprising the following steps:
a) reacting cyclopentylamine (XI) with a-haloalkylacetate to form compound of formula (IX)
;
b) reacting compound of formula (IX) with compound of formula (X) in presence of a suitable base to obtain compound of formula (VII)
.
In one embodiment, step a) and step b) are carried out in one pot without isolation/purification of intermediates.
In embodiments of step a) reaction of cyclopentylamine of formula (XI) with a-haloalkylacetate is carried out in presence of a suitable solvent.
In embodiments of step b) reaction of compound of formula (X) with compound of formula (IX) or salt thereof is carried out in presence of a suitable base in a suitable solvent to form compound of formula (VII). Suitable base of step b) including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), tetrabutylammonium (TBAF), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like. Specifically base is 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
Suitable solvent of step a) and b) including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent is toluene.
Another aspect of the present application relates to a preparation of compound of formula (VII), comprising the following steps:
a) reacting compound of formula (IX) or its salt thereof with compound of formula (X) in presence of a suitable base in a suitable solvent to obtain compound of formula (VIII)
b) cyclizing compound of formula (VIII) in presence of a suitable base in a suitable solvent
to obtain compound of formula (VII)

.
In one embodiment, step a) and step b) are carried out in one pot without isolation/purification of intermediates.
In embodiments of step a) reaction of compound of formula (X) with compound of formula (IX) or salt thereof is carried out in presence of a suitable base in a suitable solvent to form compound of formula (VIII). Suitable base of step b) including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), tetrabutylammonium (TBAF), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like. Specifically base is triethylamine. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent is toluene.
In embodiments of step b) cyclization of compound of formula (VIII) is carried out in presence of a suitable base in a suitable solvent to obtain compound of formula (VII).
Suitable base of step b) including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), tetrabutylammonium (TBAF), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like. Specifically base is Diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent is DMF. Further in embodiments of step b) cyclization is carried out in presence of silyl reagent such as trimethylsilyl chloride.

Third aspect of the present application relates to a process for preparation of Ribociclib (II) or its pharmaceutically acceptable salts thereof, comprising following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
;
c) converting compound of formula (VII) to compound of formula (VI) in presence of a suitable reducing agent
;
d) reacting compound of formula (VI) with compound of formula (XIII) to form compound of formula (V)
;
e) hydrolyzing compound of formula (V) to compound of formula (IV)

;
f) converting compound of formula (IV) to compound of formula (III)

;
g) converting compound of formula (III) to Ribociclib (II)

;
h) converting Ribociclib (II) to its pharmaceutically acceptable salt, in particular, succinate salt of formula (I).
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amine protecting group.

Fourth aspect of the present application relates to a process for preparation of ribiciclib or pharmaceutically acceptable salt thereof comprising the step of reacting compound of formula (XIV) with compound of formula (XIII) in presence of a suitable base to form compound of formula (IV)

wherein P is an amine protecting group.

In an embodiment reaction of compound of formula (XIV) with compound of formula (XIII) is carried out in presence of a suitable base in a suitable solvent to form compound of formula (IV). Suitable base including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), Lithium bis(trimethylsilyl)amide (LiHMDS) , Potassium bis(trimethylsilyl)amide (KHMDS), sodium hydride, sodium tert-butoxide, potassium tert-butoxide, and the like. Specifically, base is LiHMDS. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an ether solvent. More specifically, tetrahydrofuran.

Fifth aspect of the present application relates to a process for preparing crystalline form of Ribociclib succinate (I); the process comprising;
a) reacting Ribociclib (II) with succinic acid in a suitable solvent or mixture thereof;
b) isolating crystalline form of Ribociclib succinate (I);
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a) suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent is an alcohol solvent. More preferably, solvent is 1-propanol or 2-propanol. The reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent.
In embodiments of Step (b), further involves the removal of solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, freeze -drying or any other technique known in the art.
The resulting compound obtained in step (b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Sixth aspect of the present application relates to a process for preparation of Ribociclib of formula (II) or its succinate salt of formula (I) comprising converting compound of formula (VII) prepared by any of the aspects of this application to Ribociclib of formula (II) or its succinate salt of formula (I).

DEFINITION
The following definitions are used in connection with the present disclosure unless the context indicates otherwise.
“Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like. preferably, the amino protecting group is tert-Butyloxycarbonyl (Boc).
Certain specific aspects and embodiments of the present application will be explained in greater 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 disclosure in any manner.
EXAMPLES
Example 1: Preparation of 2,4,6-Trichloropyrimidine-5-carbaldehyde (X)

A mixture of Barbituric acid (XII) (50 g, 390 mmol) and POCl3 (500 mL) in DMF (37.8 mL) was refluxed for 12 hours at 100 °C. Half of the reaction mixture was distilled under vacuum at 90 °C. The above reaction mass was added to chilled water (2 L) at 15 °C and stirred for 2 hours at the 25-35 °C. The reaction mixture is then filtered and suck dried. The resulting solid was washed with water twice (2 X 1 L) and dried at 50-55 °C for 12 hours to get the title compound (55 g), which was proceeded to the next step without further purification.
Example 2: Preparation of Methyl cyclopentylglycinate hydrochloride (IXa)

To a solution of cyclopentylamine (XI) (58.4 g) in toluene (500 mL) was added a solution of Methyl-2-bromoacetate (50 g) in toluene (100 mL) at 30-40 °C. The reaction mixture is stirred for 8 hours at the same temperature. A solution of 10% aqueous ammonium chloride (200 mL) was added to the above reaction mixture and stirred for 0.5-1 hour. After one hour, organic and aqueous layers were separated from the reaction mixture. Organic layer was again mixed with 10%aqueous ammonium chloride solution (200 mL) and stirred for 0.5-1 hour. Organic and aqueous layers were separated from the reaction mixture. Combined aqueous layers were extracted with toluene (2 X 150 mL). To the combined organic layers was added IPA.HCl (39.25 g) and stirred for about 15-30 minutes. The reaction mixture is then cooled to -5 °C and maintained at the same temperature for 2-4 hours. The resulting solid was then filtered and washed with toluene (100 mL). The wet solid was dried at 50-55°C under vacuum for 12 hours to obtain the title compound (IXa) (49.6 g), which was proceeded to the next step without further purification.
Example 3: Preparation of Methyl N-cyclopentyl-N-(2,6-dichloro-5-formylpyrimidin-4-yl)glycinate (VIIIa)

To a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (X) (100 g) and methyl cyclopentylglycinate hydrochloride (IXa) (88 g) in Toluene (1.5 L) was added sodium bicarbonate (120 g) slowly at 25-30 °C and stirred for 6 hours at the same temperature. The reaction mixture was then filtered and washed with toluene (200 mL). Filtrate was evaporated under reduced pressure to obtain the crude residue. The resulting crude residue was mixed with ethyl acetate (100 mL) and hexane (400 mL), stirred for 1.5 hour. Filter the above reaction mixture to remove the solid impurities. The obtained filtrate was diluted with hexane (400 mL) and cooled to 0 °C under stirring. The reaction mixture was maintained for 2-4 hours at the same temperature to precipitate the solid, which was then filtered and washed with hexane (50 mL). The resulting wet solid was dried under vacuum at 50-55 °C for 12 hours to obtain the title compound (VIIIa) (103 g).
Example 4: Preparation of Methyl 2,4-dichloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIIa)

To a solution of Methyl-N-cyclopentyl-N-(2,6-dichloro-5-formylpyrimidin-4-yl)glycinate (VIIIa) (10 g) in toluene (100 mL) was added DBU (8.87 g) at -5 °C and stirred for 4 hours at the same temperature. The reaction mixture was brought up to room temperature and mixed with water (50 mL). After 30 minutes, organic layer was separated from the reaction mixture and evaporated under reduced pressure to obtain crude residue. The crude residue mixed with IPA (12 mL), water (8 mL) and stirred for 1.5 hour. The resulting solid was then filtered and washed with IPA (8 mL). The wet solid was dried at 50-55 °C under vacuum for 10 hours to obtain the title compound (VIIa) (3.8 g).
Example 5: Preparation of Methyl 2,4-dichloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIIa)

A solution of Methyl 2-bromoacetate (40 g) in toluene (80 mL) was slowly added to a solution of Cyclopentanamine (XI) (46.8 g) in toluene (420 mL) at 30-40 °C and stirred for 8 hours at the same temperature. 10% aqueous ammonium chloride solution (400 mL) was added to the above reaction mixture and stirred for 1 hour. Organic and aqueous layers were separated. Aqueous layer is then extracted with toluene (2 X 120 mL). The combined organic layers were proceeded to the next step. A solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (X) (46.4 g) was added to the above organic layer at room temperature and cooled to 0 °C. DBU (71.7 g) was added to the above reaction mixture at 0 °C and stirred for 2 hours at the same temperature. Water (200 mL) was added to the above reaction mixture and stirred for 30 minutes. After 30 minutes, Organic and aqueous layers were separated. Organic layer was washed with water (2 X 200). Combined aqueous layers were extracted with toluene (140 mL). Combined organic layers were evaporated under reduced pressure, the resulting crude residue was mixed with IPA (60 mL) and water (20 mL). The reaction mixture was then cooled to 5 °C and stirred for 1 hour at the same temperature. The reaction mixture then filtered and washed with IPA (10 mL). The obtained wet solid was dried at 50-55 °C under vacuum for 8 hours to obtain the title compound (VIIa) (15 g).
Example 5A: Preparation of Methyl 2,4-dichloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIIa)

A solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (X) (50 g) in toluene (500 mL) was cooled to 5 °C and stirred for 10 minutes. A solution of triethyl amine (36.5 g) in toluene (50 mL) was added to the above reaction mixture at 5-10 °C and stirred for 2 h at the same temperature. Water (100 mL) was added to the reaction mixture and stirred for 30 minutes. Layers were separated. Aqueous layer was mixed with toluene (50 mL) at room temperature. The mixture was heated to 40 °C and stirred for 20 minutes. Layers were separated. Combined organic layers were mixed with water (100 mL) and stirred for 20 minutes at room temperature. Layers were separated. Organic layer was distilled under vacuum at 50 °C to obtain crude compound (VIIIa) (75 g), which was then mixed with DMF (125 mL) and proceed to the next step.
Above solution was further diluted with DMF (180 mL) and stirred for 10 minutes. The reaction mixture was cooled to -15 °C and added TMS-Cl (68.7 g) under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature. DBU (151 g) was slowly added to the above reaction mixture at the same temperature and stirred for 3 h. IPA.HCl (120 mL) followed by IPA (120 mL) were added to the above reaction mixture at -15 °C and stirred for 30 minutes at the same temperature. Chilled water (900 mL) was added to the above reaction mixture at -15 °C and stirred for 1.5 h. The reaction mixture was then filtered and washed with water (300 mL) followed by IPA (60 mL). The resulting wet material was mixed with methanol (240 mL) and heated to 60 °C, stirred for 2 h at the same temperature. The reaction mixture was then cooled to room temperature and maintained for 1 h. The resulting solid was the filtered and washed with methanol (30 mL). The filtrate was distilled completely and the resulting wet material was dried under vacuum at 45 °C to obtain the tilte compound (VIIa) (31.8 g).
Example 6: Preparation of Methyl 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIa)

To a solution of Methyl 2,4-dichloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIIa) (10 g) in methanol (250 mL) was added Zinc (9.36 g) and acetic acid (8.6 g) at room temperature. The reaction mixture was heated to 65 °C and stirred at the same temperature for 6 hours. The reaction mixture was filtered through celite bed followed by washed with methanol (20 mL). The filtrate was distilled up to 6 volumes under reduced pressure to obtain crude residue. The obtained residue was cooled to -5 °C and mixed with MTBE (10 mL). The reaction mixture was stirred for 2 h and then filtered, washed with methanol (10 mL). The wet cake was mixed with 80% water in methanol (50 mL) and stirred for 2 h than filtered and wash with water (30 mL). The resulting wet solid was dried under vacuum at 50-55 °C for 12 hours to obtain the title compound (VIa) (7 g).
Example 7: Preparation of Methyl 2-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Va)

To a mixture of Methyl 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (VIa) (5 g), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (4.97 g) (XIIIa), BINAP (0.22 g) and Pd(OAc)2 (0.04 g) in methyl isobutyl ketone (45 mL) was added Cesium carbonate (9.0 g) at 40 °C. The reaction mixture was then heated to 100-105 °C and stirred for 4 hours at the same temperature. The reaction mixture was then cooled to room temperature and water (50 mL) followed by heptane (60 mL) was added under stirring. After 30 minutes of maintenance, the reaction mixture was filtered and the obtained solid was washed with heptane (10 mL). The resulting wet solid was dried under vacuum at 50-55 °C for 12 hours to obtain the title compound (Va) (8.1 g).
Example 8: Preparation of 2-((5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (IVa):

To a solution of Methyl 2-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Va) (5 g) in THF (100 mL) and methanol (50 mL) was added a solution of lithium hydroxide (0.4 g) in water (10 mL) at room temperature. The reaction mixture was heated to 45 °C and stirred for 6 hours at the same temperature. Solvents were evaporated from the reaction mixture under vacuum. The resulting residue was mixed with water (100 mL) and stirred for 2 hours at room temperature. The resulting solid was filtered and washed with water (10 mL), dried under vacuum at 50-55 °C to obtain the title compound (IVa) (4 g).
Example 8A: Preparation of 2-((5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (IV):

To a solution of Methyl 2-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Va) (5 g) in THF (50 mL) and methanol (20 mL) was added a solution of Sodium hydroxide (1.15 g) in water (15 mL) at room temperature. Stirred for 6 hours at the same temperature. Solvents were evaporated from the reaction mixture under vacuum. The resulting residue was mixed with water (50 mL) and netralize with HCl solution stirred for 1-2 hours at room temperature. The resulting solid was filtered and washed with water (10 mL), dried under vacuum at 50-55 °C to obtain the title compound (IVa) (4 g).
Example 8B: Preparation of 2-((5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (IVa):

To a solution of compound (XIV) (5 g) and compound (XIIIa) (5.76 g) in THF (85 mL) was added LiHMDS (70 mL, 1M in THF) in dropwise manner at -25 °C for about 30 minutes. The reaction mixture was slowly brought to 0 °C and stirred for 4 h at the same temperature. The reaction mixture was quenched with acetic acid (10 mL) followed by water (5 mL) at the same temperature. The reaction mixture was warmed to room temperature and layers were separated. Organic layer was distilled up to 70% and the remaining residue was treated with aqueous hydrochloric acid (25 mL, 10%). The reaction mixture was stirred for 1 h and the resulting solid precipitate was filtered. The solid precipitate was further mixed with water (50 mL) and stirred for 30 minutes. The mixture was then filtered and dried under VTD dryer at 50 °C to obtain the title compound (IVa) (8.26 g).
Example 9: 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 (IIIa)

To a mixture of 2-((5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (IVa) (3.02 g), HBTU (2.35 g), DIPEA (2.29 g) in DMF was added a solution of dimethylamine hydrochloride (0.96 g) in THF (5 mL) at room temperature and stirred for 3 hours. Water (45 mL) and concentrated hydrochloric acid (0.43 g) were added to the above reaction mixture at room temperature and stirred for 1 hour. The resulting solid was filtered and washed with water (10 mL), dried under vacuum at 50-55 °C to obtain the title compound (IIIa) (2.7 g).
Example 10: Preparation of Ribociclib free base (II)

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 (IIIa) (1 g) in toluene (6 mL) and water (4 mL) was added hydrochloric acid (0.068 g, 6 N) at room temperature. After 1.5 hour stirring, aqueous layer was separated and treated with sodium hydroxide solution (0.09 g) to adjust its pH to 12.0 - 12.5. The resulting solid was then filtered and washed with water (2 mL), dried under vacuum at 50-55 °C to obtain the title compound (II) (0.6 g).
Example 11: Preparation of Ribociclib Succinate (I)

A solution of Succinic acid (0.257 g) in IPA (7.2 mL) was added to a solution of Ribociclib (II) (0.9 g) in IPA (10 mL) at 80 °C and stirred for 1 hour at the same temperature. The reaction mixture was then cooled to 20 °C and further stirred for 1 hour at the same temperature. The resulting solid was filtered and washed with water (9 mL), dried in hot air oven at 60-65 °C to obtain the title compound (I) (1.1 g).
Example 12: Preparation of Ribociclib Succinate (I):
Ribociclib (II) (15 g) was mixed with 1-propanol (300 mL) and stirred for 30 minutes at 70 °C to obtain the clear solution. The reaction mixture was the filtered to separate the undissolved particles. A clear particle free solution of Succinic acid (1.8 g) in 1-propanol (150 mL) was added to the above reaction mixture at 75 °C and stirred for 1 h at the same temperature. A slurry of Form X seed (75 mg, 0.5%) in 1-propanol was added to the above reaction mixture at 70 °C and stirred for 4 h at the same temperature. A clear particle free solution of Succinic acid (1.8 g) in 1-propanol (60 mL) was further added to the above reaction mixture at 70 °C and stirred for 20 minutes at the same temperature. The reaction mixture was slowly cooled to 0 °C in the duration of 16 and stirred at the same temperature for 2 h. The resulting solid was filtered and washed with 1-propanol (30 mL) at room temperature. The wet solid was then dried under vacuum for 2h at room temperature followed by 10 h at 60 °C to get the title compound as crystalline solid. PXRD pattern is shown in Figure 1.
Example 13: Preparation of Ribociclib Succinate (I):
Ribociclib (II) (5 g) was mixed with 2-Propanol (IPA) (300 mL) and stirred for 30 minutes at 80 °C to obtain the clear solution. The reaction mixture was the filtered to separate the undissolved particles. A clear particle free solution of Succinic acid (0.9 g) in IPA (30 mL) was added to the above reaction mixture at 80 °C and stirred for 1 h at the same temperature. A slurry of Form X seed (25 mg, 0.5%) in IPA was added to the above reaction mixture at 80 °C and stirred for 10 minutes at the same temperature. A clear particle free solution of Succinic acid (0.6 g) in IPA (20 mL) was further added to the above reaction mixture at 80 °C and stirred for 40 minutes at the same temperature. The reaction mixture was slowly cooled to 0 °C in the duration of 16 and stirred at the same temperature for 2 h. The resulting solid was filtered and washed with IPA (25 mL) at room temperature. The wet solid was then dried under vacuum for 2h at room temperature followed by 10 h at 60 °C to get the title compound as crystalline solid. PXRD pattern is shown in Figure 2.
,CLAIMS:We claim:
1. A preparation of compound of formula (VII), comprising the following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
.
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms.

2. Suitable base as claimed in step a) and b) of claim 1) is either same or different selected from triethylamine, diisopropylethylamine, pyridine, dimethyl aminopyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene.

2. One-pot process for the preparation of compound of formula (VII), comprising the following steps:
a) reacting cyclopentylamine (XI) with a-haloalkylacetate to form compound of formula (IX)
;
b) reacting compound of formula (IX) with compound of formula (X) in presence of a suitable base to obtain compound of formula (VII)
.
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms.

3. A process for preparation of Ribociclib (II) or its pharmaceutically acceptable salts thereof, comprising following steps:
a) reacting compound of formula (X) with compound of formula (IX) or salt thereof in presence of a suitable base to obtain compound of formula (VIII)
;
b) converting compound of formula (VIII) to compound of formula (VII) in presence of a suitable base
;
c) converting compound of formula (VII) to compound of formula (VI) in presence of a suitable reducing agent
;
d) reacting compound of formula (VI) with compound of formula (XIII) to form compound of formula (V)
;
e) hydrolyzing compound of formula (V) to compound of formula (IV)
;
f) converting compound of formula (IV) to compound of formula (III)
;
g) converting compound of formula (III) to Ribociclib (II)

;
h) converting Ribociclib (II) to its pharmaceutically acceptable salt, in particular, succinate salt of formula (I).
wherein, R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amine protecting group.

4. A process for preparation of Ribiciclib or pharmaceutically acceptable salt thereof comprising the step of reacting compound of formula (XIV) with compound of formula (XIII) in presence of a suitable base to form compound of formula (IV)

wherein P is an amino protecting group.

5. A process for preparing crystalline form of Ribociclib succinate (I); the process comprising;
a) reacting Ribociclib (II) with succinic acid in a suitable solvent or mixture thereof;
b) isolating crystalline form of Ribociclib succinate (I);
c) optionally, drying the isolated product at suitable temperature.

6. Suitable solvent as claimed in claim 5) is selected from methanol, ethanol, 1-propanl, 2-Propanol.