DESC:FIELD OF THE INVENTION:
The present invention relates to the process for the preparation of highly pure crystalline Palbociclib (I).
BACKGROUND OF THE INVENTION:
Palbociclib (I) is chemically named as 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl) amino] -8H pyrido [2, 3-d] pyrimidin-7-one. The molecular formula for Palbociclib is C24H29N7O2 and its structural formula is:

Palbociclib, sold under the brand name of “IBRANCE”. IBRANCE capsules and tablet for oral administration contain 125mg, 100mg, or 75mg of Palbociclib, a kinase inhibitor. It is developed by Pfizer for the treatment of hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.
Barvian et al in US6936612B2 first disclosed Palbociclib and pharmaceutically acceptable salt thereof and this patent specifically exemplifies the preparation of Palbociclib hydrochloride salt, which follows the synthetic pathway as given in the Scheme-1:
Scheme -1: Process as per US6936612B2
WO2017076288A1 discloses a process for the preparation of crystalline Form A of Palbociclib, which comprises treating the Palbociclib free base and/or Palbociclib salts with an inorganic base in a water or water and a mixed solvent of an organic solvent miscible with water at 35-100°C to obtain Palbociclib free base Form A, as per the scheme:

Scheme -2: Process as per WO2017076288A1
Chekal et al in US10723730B2 discloses crystalline free base Form of Palbociclib having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 8.0±0.2, 10.1±0.2, 11.5±0.2°2? and this patent specifically exemplifies the preparation of Palbociclib and the polymorphic Forms A, B, C of its intermediate (2).
Polymorph Form-A of intermediate (2) having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 4.3±0.2, 4.8±0.2, 6.2±0.2°2?, Polymorph Form-B of intermediate (2) having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 5.5±0.2, 7.5±0.2, 9.7±0.2, 11.1±0.2, 14.8±0.2, 16.7±0.2, 17.5±0.2, 20.1±0.2°2? and Form-C of intermediate (2) having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 5.4±0.2, 9.7±0.2, 10.8±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 16.1±0.2, 16.6±0.2, 17.0±0.2, 17.5±0.2, 18.1±0.2, 18.8±0.2, 19.6±0.2, 20.6±0.2, 21.7±0.2, 22.9±0.2, 23.8±0.2, 24.4±0.2, 25.0±0.2°2? which follows the reaction pathway as given in the Scheme-3:

Scheme -3: Process as per US10723730B2
Mitas et al in US2021206761A1 discloses solid crystalline Form of tert-butyl 4-(6-(6-(1-butoxyvinyl) -8-cyclopentyl- 5-methyl- 7-oxo7, 8-dihydropyrido [2,3-d] pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate intermediate (2), which is characterized by XRPD pattern having 2? values 5.5°, 7.5°, 9.7°, 10.1°, 14.5°, 15.9°, 18.1°, 20.2° and 21.5° degrees 2 theta (±0.2 degrees 2 theta). This publication also discloses a process for the preparation of Palbociclib free base which follows the pathway as given in the Scheme-4:

Scheme -4: Process as per US2021206761A1
Gadakar et al in US10710999B2 discloses Polymorphic Form-M of Palbociclib Intermediate (2) tert-butyl 4-(6-(6-(1-butoxyvinyl) -8-cyclopentyl- 5-methyl- 7-oxo7, 8-dihydropyrido [2,3-d] pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate which is characterized by a powder X-ray diffraction pattern having peaks at 6.0, 6.3, 8.7, 12.0, 15.3, 19.1, and 22.6±0.2°2?.
CN108864078B discloses Preparation method of Palbociclib crystal Form-B characterized by X-ray powder diffraction pattern having peaks at 5.898, 6.484, 10.822, 11.913, 12.697, 16.234, 19.647, 22.437, 26.549±0.2°2?.
Beylin et al in US7345171B2 discloses preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido [2,3-d] pyrimidin-7-one and its different salts comprising of hydrochloride salt and isethionate salt and their polymorphs.
WO2017145054A1 publication discloses a process for preparing crystalline Form A of palbociclib having specific surface area in the range from 7 to 15 m2 /g, which comprises dissolving palbociclib dihydrochloride trihydrate or palbociclib hydrochloride in acetone/water solvent system.
Other than the aforementioned patents/publications, following are additional disclosures relating to Palbociclib and its processes - CN105085517B (monohydrate), WO2016024249A1 (crystalline Form I to Form VIII & crystalline Form VA), WO2016090257 (crystalline Form I and Form II), CN 106065016A (type I crystals), CN106397431A (Form C), WO2017067506 A1 (Form IX, Form X and Form XII), WO2017115315 (crystalline Form M1 to Form M6 and amorphous form), WO2017197904 (Crystal Form I to Form XII and Form XIV), WO2017211788 (non-crystalline form) discloses different crystalline forms of palbociclib and process for their preparation. US10597393B2 disclosed solid state forms of palbociclib dimesylate Form-E, Form-F, Form-G and WO2016066420A1 publication disclosed Polymorphic Forms of Palbociclib monohydrochloride (Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Amorphous Form)
Despite various disclosures on the process and polymorphs, still there exists need for robust improvised process which is not only amenable to scale up but also providing consistent quality of high purity material considering the safety of patients consumers. The present inventors have developed a unique novel and impurity free process with a novel polymorph of intermediate (2) as represented compound of formula (V) in the present invention for the preparation of Palbociclib (I).
SUMMARY OF THE INVENTION
Particular aspects of the present invention relates to a process for the preparation of pure crystalline Palbociclib of Formula (I).
Different aspects of the present application are summarized herein below individually.
In one aspect of the present application, the present invention relates to a process for preparation of compound of formula (I) or a salt thereof,

(I)
comprising:
a). reacting the compound of formula (II) with compound of formula (III), in an organic solvent in the presence of isopropyl magnesium chloride to get the compound of formula (IV);

b). reacting the compound of formula (IV) as obtained in step a) with butyl vinyl ether in an alcoholic solvent (C1 – C4) using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C to get the pure thermodynamically stable crystalline form of compound of formula (V) characterized by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?;

c). reacting the crystalline compound of formula (V) in an aqueous medium with an inorganic acid at a temperature ranging between 40-55°C;
d). isolating the compound of formula (VI) in a ketone solvent as crystalline dihydrochloride hemipentahydate;

e). reacting the compound of formula (VI) in an aqueous medium with alkali metal hydroxide or carbonate to isolate compound of formula (I) having purity greater than 99.8% (Area % by HPLC) as crystalline form designated as Form SB.
In another aspect, the present invention relates to crystalline Form SD of compound formula (V) characterised by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?, DSC thermogram having three endothermic peaks ranging between 140 to 150°C, 190 to 198°C and 245 to 260°C and IR absorption spectrum having characteristic peaks at about 3425, 3236, 2959, 2870, 1433, 1378,1315, 1264, 1170, 1046, 1000, 916, 863, 821 ± 2 cm-1,
In yet another aspect according to the present invention, it relates to highly pure crystalline form SD of Palbociclib intermediate of compound of formula (V), having purity greater than 99.0 % (area % by HPLC) and TGA thermogram percentage weight loss upto less than 1% at temperature range below 200°C.
In yet another aspect of the present application, the present invention relates to a process for preparation of pure Crystalline form SD of compound formula (V), comprising the steps of-
a). reacting the compound of formula (IV) with butyl vinyl ether in n-butanol solvent using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C for 6 hours;
b). charging n-butanol;
c). stirring the reaction mass for 15-30 min at 80-90°C;
d). charging water and 1, 2-diaminopropane at 70-80°C to the filtrate;
e). removing the solvent from the organic layer;
f). isolating the solid;
g). adding a mixture of n-butanol and methanol in a molar ration of 30-50:50-70 (v/v);
h). isolating crystalline Form SD of formula V.
Further specific aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS:
FIG 1: is an illustration of High Performance Liquid Chromatography (HPLC) graph of the pure crystalline form SD of compound of formula (V).
FIG 2: is an illustration of X-Ray power Diffraction (XRPD) pattern of the pure crystalline form SD of compound of formula (V).
FIG 3: is an illustration of an IR Spectrum of the pure crystalline form SD of compound of formula (V).
FIG 4: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of the pure crystalline form SD of compound of formula (V).
FIG 5: is an illustration of a TGA thermogram of the pure crystalline Form SD of the compound of formula (V).
FIG 6: is an illustration of High Performance Liquid Chromatography (HPLC) graph of the compound of formula (VI).
FIG 7: is an illustration of a TGA thermogram of the compound of formula (VI).
FIG 8: is an illustration of a High Performance Liquid Chromatography (HPLC) of compound Palbociclib polymorphic form SB.
FIG 9: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of compound Palbociclib polymorphic form SB.
FIG 10: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of compound Palbociclib polymorphic form SB after 6 months stability.
FIG 11: is an illustration of X-Ray power Diffraction (XRPD) pattern of the Palbociclib polymorphic form SB of compound of formula (I).
FIG 12: is an illustration of X-Ray power Diffraction (XRPD) pattern of the Palbociclib polymorphic form SB of compound of formula (I) after 6 months stability.

DETAILED DESCRIPTION:
As set forth herein, embodiments of the present invention relate to a process for preparation of Palbociclib (I). The present invention provides an industrially amenable process for making the compound of formula (I), which exhibits various advantages over other processes known in the state of arts. The advantages are discussed on the relevant places of further description. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to the present application, it provides a process for preparation of compound of formula (I) or a salt thereof,

(I)
comprising the steps of:
a). reacting the compound of formula (II) with compound of formula (III), in an organic solvent in the presence of isopropyl magnesium chloride to get the compound of formula (IV);

b). reacting the compound of formula (IV) as obtained in step a) with butyl vinyl ether in an alcoholic solvent (C1 – C4) using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C to get the pure thermodynamically stable crystalline form of compound of formula (V) characterized by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?;

c). reacting the crystalline compound of formula (V) in an aqueous medium with an inorganic acid at a temperature ranging between 40-55°C;
d). isolating the compound of formula (VI) in a ketone solvent as crystalline dihydrochloride hemipentahydate;

e). reacting the compound of formula (VI) in an aqueous medium with alkali metal hydroxide or carbonate to isolate compound of formula (I) having purity greater than 99.8% (Area % by HPLC) as crystalline form designated as Form SB.
Individual steps of the process according to the present invention are detailed herein below.
In step a) the reaction of compound of formula (II) with compound of formula (III) is performed in the presence of isopropyl magnesium chloride in an organic solvent. The suitable organic solvent in step a) may be selected from tetrahydrofuran, acetic acid, dichloromethane or carbon tetra chloride, more preferably tetrahydrofuran was used in the present invention.
Inventors found that a 2M solution of isopropyl magnesium chloride in THF was significantly increase the robustness of the reaction at room temperature.
After completion of the reaction inventors of the present invention added freshly prepared acetic acid solution in tetrahydrofuran to isolate the compound of formula (IV).
Inventors of the present application found that the use the acetic acid solution in tertahydrofuran improvise the yield and purity of the compound of formula (IV). Acetic acid in tetrahydrofuran works as a quenching agent to quench isopropyl magnesium chloride from the reaction mixture.
For further purification of the compound of formula (IV) a ketone solvent is used to remove excess amount of water.
The suitable ketone solvent used in step b) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, or diethyl ketone. It is observed by the inventors that little amount of water in the compound of formula (IV) makes the reaction slow with palladium acetate.
In a particular embodiment, acetone was used as a ketone solvent for further purification.
In another embodiment, step b) involved reacting compound of formula (IV) as obtained in step a) with butyl vinyl ether in an alcoholic solvent (C1 – C4) using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C to get the compound of formula (V) which is characterized by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?.
Bis-diphenylphosphinophenyl ether is used as a chelating agent during the reaction to enhance the reactivity of the catalyst and improvise the yield of the product i.e. compound of formula (V).
During the reaction monitoring applicants surprisingly observed that in the absence of Bis-diphenylphosphinophenyl ether reaction does not go very well. It takes much higher time with low quality and yield.
The suitable alcoholic solvent (C1 – C4) in step b) is selected from ethanol, isopropyl alcohol, n-butanol.
After completion of the reaction in step b); 1,2-diamino propane was added to remove the metallic impurity of the palladium catalyst in order to obtain the high purity material.
The isolated product of Step b) of the present invention is highly pure crystalline intermediate tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo- 7, 8 dihydropyrido [2, 3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (V) having purity exceeding 99% (by HPLC).
In another embodiment the suitable inorganic acid used for the inorganic salt formation of the compound of formula (VI) in step c) is selected from concentrated hydrochloric acid.
In another embodiment, step d) proceeds with the isolation of the crystalline dihydrochloride hemipentahydate of Palbociclib of formula (VI) in a ketone solvent.
Chloride content in the compound of formula (VI) i.e crystalline dihydrochloride hemipentahydate of Palbociclib is in the range of 12.9 % to 15.36%.
In a particular embodiment, chloride content was 14.2% in the compound of formula (VI) i.e crystalline dihydrochloride hemipentahydate of Palbociclib.
In yet another embodiment water content ranging between 7.8 to 9.0% w/w in the compound of formula (VI) and having the purity greater than 99.8% (Area % by HPLC).
The suitable ketone solvent used in step d) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, or diethyl ketone.
In a particular embodiment, acetone was used as a ketone solvent in step d).
In step e) reacting the compound of formula (VI) in an aqueous medium with alkali metal hydroxide or carbonate to isolate compound of formula (I).
The isolated product of Step e) of the present invention is highly pure crystalline Palbociclib (I) having purity exceeding 99.5% (Area % by HPLC) as crystalline form designated as Form SB.
The said crystalline Palbociclib (I) is designated as crystalline form SB which is characterized by its DSC melting point having peak ranging between 270-280°C. In a particular embodiment the DSC melting point peak was observed at 274.36°C. The crystalline form SB having purity exceeding 99.5% and moisture content ranging between 0.96-1.16% (w/w) in three consecutive batches which is not more than 2.0% (w/w) shows the anhydrous nature of the final product. The crystalline form SB was observed for a 6 months stability duration with no deviation in its XRPD and DSC melting point. This indicates its thermodynamically stable nature. Its robust stability makes this crystalline form to be suitable for making the doses form. Inventors of the present application observed that this crystalline form remains stable in the solid oral dosages form derived from this API for exceeding 6 months.
In another aspect, the present invention provides a process for the preparation of crystalline form SD of compound formula (V).
In one embodiment, crystalline form SD of compound formula (V) may be prepared by a process that includes the steps of-
a). reacting the compound of formula (IV) with butyl vinyl ether in n-butanol solvent using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C for 6 hours;
b). charging n-butanol;
c). stirring the reaction mass for 15-30 min at 80-90°C;
d). charging water and 1, 2-diaminopropane at 70-80°C to the filtrate;
e). removing the solvent from the organic layer;
f). isolating the solid;
g). adding a mixture of n-butanol and methanol in a molar ration of 30-50:50-
70 (v/v);
h). isolating crystalline Form SD of formula V.
In an embodiment the reaction of the compound of formula (IV) with butyl vinyl ether in n-butanol solvent using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C for 6 hours;
According to the present embodiment the inventors of the present invention found that the reaction time of 6 hours is controlling the impurity of compound of formula (IV) in the final API. Inventors of the present invention found that reaction time drastically affects the purity of the final API w.r.t impurity in the form of compound of formula (IV).
Another embodiment of the present invention is crystallization of the compound of formula (V) from the solvent system comprising particularly n-butanol and methanol.
In another embodiment the molar ratio of n-butanol and methanol is in the range between 30-50:50-70 (v/v).
In a particular embodiment, inventors of the present invention found that the most preferred range of ratio of n-butanol and methanol is 50:50 to achieve the desired polymorphic form of SD of the compound of formula (V) consistently and without involving any seeding.
In one aspect, the present invention provides crystalline Form SD of compound of formula (V).

Crystalline Form SD is a unqiue thermodynamically stable crystalline form characterised by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?; DSC thermogram having three endothermic peaks ranging between 140 to 150°C, 190 to 198°C and 245 to 260°C and IR absorption spectrum having characteristic peaks at about 3425, 3236, 2959, 2870, 1433, 1378, 1315, 1264, 1170, 1046, 1000, 916, 863, 821 ± 2 cm-1.
In still another embodiment crystalline Form SD of compound of formula (V) having purity greater than 99% (Area % by HPLC) and TGA thermogram percentage weight loss upto less than 1% at temperature range below 200°C.
The compositions for parenteral administration can be suspensions, emulsions or an aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Palbociclib of the present application include, but are but not limited to diluents such as starch, pre-gelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pre-gelatinized starch, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Palbociclib of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the below best mode demonstrating working examples, which are provided by way for illustration purpose only and should not be construed as limiting the scope of the invention in any manner.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the present invention.
Example:
Step–01: Preparation of tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8- dihydropyrido [2, 3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (IV):

Charge 1000 ml of Tetrahydrofuran in RBF at 25-30°C under stirring. Charge 105.5 gm of tert-butyl 4-(6-aminopyridine-3-yl) piperazine-1-carboxylate (III) at 25-30°C under stirring. Add 2.0 M solution of Isopropyl magnesium chloride in tetrahydrofuran 156g (160 ml) in 30 min at 15-25°C. Stir the reaction mixture in 60 min at 15-25°C. Charge 100gm of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2, 3-d] pyrimidin-7(8H)one (II) in reaction mass at 15-25°C under stirring flush with tetrahydrofuran 100 ml. Add 2.0 M solution of Isopropyl magnesium chloride in tetrahydrofuran 156 g (160ml) in 60 min at 15-25°C. Stir for 90 minutes at 15-25°C. Prepared 24.65 gm Acetic acid solution in 300 ml THF and then add prepared acetic acid solution into the reaction mass in 30.0mins at 60-65°C. Stir reaction mixture for 60 minutes at 60-65°C. Cool the reaction mass to 15-20°C. Stir the reaction mixture for 4.0 hour at 15-20°C. Filter the solid and wash the cake with 500 ml of water. Suck dry the material for 25-30 minutes. Wash the cake with 200 ml of acetone.
Charge 1000 ml of acetone in the RBF at 20-25°C. Charge the wet cake into RBF at 20-25°C. Raise the temperature of reaction mass to reflux (55-60°C). Stir the reaction mass for 30mins at 55-60°C. Cool to 25-30°C. Stir for 60 mins at 25-30°C. Filter the solid and wash the wet cake with 200 ml of acetone. Suck dry for 25-30 minutes and unload the material for drying. Dry the material under vacuum for 8 hr. at 50-55°C.
Yield: 120 gm
Purity: 99% (Area % of HPLC)
Step-02: Preparation of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7, 8 dihydropyrido [2, 3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (V):

Charge 660 ml of n-Butanol at 25-35°C into a clean and dry multi neck RBF. Charge 110 gm of tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8- dihydropyrido [2, 3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (IV) at 25-35°C under stirring. Stir for 15-20 minutes at 25-35°C. Charge 113.75 gm of butyl vinyl ether in 10-15 min 25-35°C. Charge 58.75 gm diisopropyl ethylamine in 10-15 minutes 25-35°C. Stir for 15-20 minutes at 25-35°C. Charge 1.76 gm of palladium acetate and 9.9 gm of bis-diphenyl phosphino phenyl ether at 25-35°C.Raise the temperature of reaction mass to 90-100°C. Stir the reaction mass for upto 6 hour at 90-100°C. After completion of reaction cool to 80°C.Charge 330 ml n-Butanol into the reaction mass at 80°C under stirring. Charge 165 ml purified water in 10-15 minutes at 80°C.Stir the reaction mass for 15-20 min, at 80°C. Filter the reaction mass through 0.45-micron filter and wash the bed with 110 ml hot n-butanol (80°C).Charge clear filtrate into RBF at 80-85°C. Add 69.3 gm 1, 2-diaminopropane in 5-10 minutes and stir the reaction mass for 30 minutes at 70°C. Settle and separate the layer at 70°C. Collect upper organic layer and completely distilled the solvent under vacuum below 75°C. Charge 330 ml of methanol and distilled the solvent completely under vacuum below 60°C and degassed the mass for 1-2 hrs. Charge 550 ml of n - butanol and 550 ml of methanol then reflux for 30 mins to get the clear solution. Slowly cool the reaction mass to 25-30°C. Stir the solid reaction mass for 2 to 4 hours at 25-30°C. Filter the solid and wash the wet cake with 2x110 ml methanol. Suck dry the cake for 25-30 minutes. Dry the material under vacuum for 6 hour at 55-60°C. After complying the result of LOD, unload the material.
% Yield: 104.5 gm
Purity: 99% (Area % of HPLC)
Step 03: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino) pyridine [2, 3-d] pyrimidin-7(8H)-one di hydrochloride hemi pentahydrate (VI):

Charge water 300 ml at 25-35°C in the 5 lit RBF under stirring charge 300 ml Conc. HCl at 25-35°C in the 5 lit RBF under stirring. Cool the reaction mass to 10-20°C. Slowly charge 100 gm of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7, 8 dihydropyrido [2, 3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (V) in the above RBF at 10-20°C under stirring. Slowly add 400 ml Conc. HCl in 30-60 min. at 10-20°C under stirring. Stir the reaction mass for 10-15 min. at 10-20°C. Raise the temperature of reaction mass to 45-50°C. Stir the reaction mass for 30 minutes at 45-50°C. After completion of reaction add acetone 5000 ml in 60-90 minutes at 45-55°C. Stir for 30 minutes at reflux (55-60°C).Cool the reaction mass to 25-30°C. Stir for 2 hour at 25-30°C.Filter the solid and wash the wet cake with 2x150.0 ml of acetone. Suck dry for 20-30 min. Dry the material under vacuum for 8 hour at 50-55°C. After complying the result of moisture content, release the vacuum under nitrogen to unload the material.
Yield: 80 gm
Purity: 99.5 % (Area% of HPLC)
Step–04: Isolation of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl) pyridin-2- yl)amino) pyrido [2, 3-d] pyrimidin-7 (8H) - one (I).

Charge 5000 ml of water into 10 lit clean RBF at 25-30°C under stirring. Charge 100 gm of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino) pyridine [2, 3-d]pyrimidin-7(8H)-one di hydrochloride hemi pentahydrate (VI) into above RBF at 20-25°C under stirring. Stir the reaction mass for 1hr. at 25-35°C until dissolution. Filter the reaction mass through 0.45 micron and washed with water 200 ml. Charge the clear filtrate in to separate RBF at 25-35°C. Cool the reaction mass at 10-20°C. Prepared sodium hydroxide solution with 17.5 gm sodium hydroxide in 500 ml of water. Add prepared sodium hydroxide solution in the reaction mass in 45-60 min. at 10-20°C. Raise the temperature of reaction mass to 25-30°C after complete addition of sodium hydroxide solution. Stir the reaction mass for 12 hour at 25-30°C. Filter the solid and wash the wet cake with 500 ml of water. Suck dry for 60-90 min under vacuum. Dry the material under vacuum at for 8 hour at 55-60°C. After complying the result of moisture content, unload the material.
Yield: 75.0gm
Purity: 99.8% (Area % of HPLC)
The above mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities use etc.
,CLAIMS:We Claim:
1. A process for preparing of compound of Formula (I) or a salt thereof,

(I)
comprising:
a). reacting the compound of formula (II) with compound of formula (III), in an organic solvent in the presence of isopropyl magnesium chloride to get the compound of formula (IV);

b). reacting the compound of formula (IV) as obtained in step a) with butyl vinyl ether in an alcoholic solvent (C1 – C4) using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C to get the pure thermodynamically stable crystalline form of compound of formula (V) characterized by XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?;

c). reacting the crystalline compound of formula (V) in an aqueous medium with an inorganic acid at a temperature ranging between 40-55°C;
d). isolating the compound of formula (VI) in a ketone solvent as crystalline dihydrochloride hemipentahydate;

e). reacting the compound of formula (VI) in an aqueous medium with alkali metal hydroxide or carbonate to isolate compound of formula (I) having purity greater than 99.8% (Area % by HPLC).
2. A process for preparing a compound of formula (I) or a salt thereof as claimed in claim 1 wherein organic solvent used in step a) is selected from tetrahydrofuran, acetic acid, dichloromethane or carbon tetrachloride.
3. A process for preparing a compound of formula (I) or a salt thereof as claimed in claim 1 wherein an alcoholic solvent (C1 – C4) in step b) is selected from ethanol, isopropyl alcohol, n-butanol.
4. A process for preparing a compound of formula (I) or a salt thereof as claimed in claim 1 wherein an inorganic acid in step c) is selected from hydrochloric acid.
5. A process for preparing a compound of formula (I) or a salt thereof as claimed in claim 1 wherein a ketone solvent in step d) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, or diethyl ketone.
6. A compound of formula (V) designated as Form SD characterised by –
i). XRPD diffraction angel peaks at 3.7, 4.9, 7.6, 11.0, 14.5, 15.4, 17.9, 21.9, 24.4 ± 0.2° 2?;
ii). DSC thermogram having three endothermic peaks ranging between 140 to 150°C, 190 to 198°C and 245 to 260°C;
iii). IR absorption spectrum having characteristic peaks at about 3425, 3236, 2959, 2870, 1433, 1378, 1315, 1264, 1170, 1046, 1000, 916, 863, 821 ± 2 cm-1.
7. A Crystalline compound of formula (V) designated as Form SD comprising purity greater than 99% (Area % by HPLC) and TGA Thermogram percentage weight loss upto less than 1% at temperature range below 200°C.
8. Process for preparing crystalline Form SD of compound formula (V), comprising the steps of-
a). reacting the compound of formula (IV) with butyl vinyl ether in n-butanol solvent using palladium acetate and bis-diphenylphosphinophenyl ether as catalyst at a temperature ranging between 85-110°C for 6 hours;
b). charging n-butanol;
c). stirring the reaction mass for 15-30 min at 80-90°C;
d). charging water and 1, 2-diaminopropane at 70-80°C to the filtrate;
e). removing the solvent from the organic layer;
f). isolating the solid;
g). adding a mixture of n-butanol and methanol in a molar ration of 30-50:50- 70 (v/v);
h). isolating crystalline Form SD of formula V.
9. A compound of formula (VI) as claimed in claim 1 comprising a purity greater than 99.5% (Area % by HPLC) and 2.5 hydrate having water content ranging between 7.8 to 9.0% w/w.
10. A thermodynamically stable anhydrous crystalline Form SB of formula (I) as claimed in claim 1 is characterized by
i). XRPD peaks according to the Fig-11;
ii). DSC thermogram having thermal peak at ranging between 270-280ºC;
iii). purity greater than 99.8% (% w/w by HPLC) and
iv). moisture content not exceeding than 2.0% (w/w).