DESC:Field of the invention
The present invention relates to an improved and industrially viable process for the preparation of high pure Palbociclib of formula-1. The present invention involves simple crystallization techniques avoiding column chromatographic techniques and the process conditions can be easily adopted for scale-up studies.

Background of the Invention:
Palbociclib is a potent and selective inhibitor of CDK4 and 6. The chemical name of palbociclib is 6-Acetyl-8-cyclopentyl-5-methyl-2{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib is marketed under the brand name IBRANCE® and it is used for the treatment of ER-positive and HER2-negative breast cancer.

Palbociclib is first disclosed as Palbociclib hydrochloride salt of formula-1a in US 6936612.

In the above mentioned patent, palbociclib hydrochloride was synthesized by the following synthetic scheme (scheme-1).

Scheme-1
4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester of formula-2 was subjected to catalytic hydrogenation in the presence of Raney Ni to give 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester of formula-3 which is reacted with 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-Pyrido[2,3-d]pyrimidin-7-one of formula-4 to yield 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester of formula-5. Compound of formula-5 was directly filtered from the reaction mass.

The resulting compound of formula-5 was reacted with tributyl(1-ethoxyvinyl)tin of formula-6 in the presence of tetrakis(triphenylphosphine)palladium(0) in toluene at reflux temperature to yield 4-{6-(8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester of formula-7. Compound of formula-7 was isolated by column chromatography. Hydrogen gas was bubbled into the solution of compound of formula-7 in methylene chloride to afford palbociclib hydrochloride of formula-1a. The process of hydrogen gas bubbling into the reaction mass is not suitable for plant scale operations.

US 7781583 patent disclosed a process to isolate palbociclib as isethionic acid of formula-1b. 6-Bromo-2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of formula-13 is used as the key starting material of the process. Synthetic scheme (scheme-2) is depicted below.

Scheme-2
6-Bromo-2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of formula-13 was reacted with 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester of formula-3 in the presence of lithiumhexamethyl disilazane to give compound of formula-3. The resulting compound of formula-3 was reacted with butyl vinyl ether in the presence of Pd(dppf)2Cl2 in n-butanol to afford required compound of formula-15. Compound was isolated by column chromatography. Finally the Boc-moiety of compound of formula-15 is deprotected by treating with isethionic acid of formula-16 to afford palbociclib isethionate of frmula-1b.

PCT application WO2014128588A1 describes crystalline form –A and form-B of Palbociclib. Palbociclib of formula-1 is synthesized by treating compound of formula-15 with acid then basified to afford Palbociclib. Acids chose for deprotection from methane sulfonic acid and hydrochloric acid. Synthetic scheme is depicted below (scheme-3). Palbociclib of formula-1 was recrystallized from the solvent mixture of anisole and n-butanol to obtain polymorphic form-A of palbociclib.

Scheme-3
Specific surface area, powder X-ray diffraction pattern, 13C solid state NMR and primary particle size distribution of palbociclib form-A were disclosed in this application.

Summary of the Invention:
One aspect of the present invention is to prepare a Palbociclib having surface area more than 2m2/g.

One aspect of the present invention is to provide a process for the Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5) with tributyl (1-ethoxyvinyl) tin (6) in presence of Tetrakis (triphenylphosphine) palladium to get 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7),
b) converting 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) to palbociclib.

Another aspect of the present invention is recrystallization of Palbociclib from the solvent system comprising methanol, n-propanol, n-butanol, n-pentanol, toluene, xylene anisole or the mixturtes thereof.

Yet another aspect of the present invention is to provide a process for the process for the preparation of Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (4) with butyl vinyl ether (5) in presence of base to give 4-[6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6), wherein the base is selected from potassium acetate, sodium acetate, potassium carbonate or sodium carbonate,
b) converting 4-[6-(6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6) to palbociclib HCl (1a) in presence of and 1, 4-dioxane and HCl,
c) converting palbociclib HCl (1a) to Palbociclib.

Yet another aspect of the present invention is to provide a process for the preparation of Palbociclib form A comprising the steps of:
a) dissolving Palbociclib in alcohol solvent and
b) isolating crystalline form A of Palbociclib.

Detailed description of the Invention:
The present invention is related to an improved process for the preparation of Palbociclib. The present invention also related to process for the preparation of Palbociclib form A.

One embodiment of the present invention is to prepare a Palbociclib having surface area more than 2m2/g.

One embodiment of the present invention is to provide a process for the Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5) with tributyl (1-ethoxyvinyl) tin (6) in presence of Tetrakis (triphenylphosphine) palladium to get 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7),
b) converting 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) to palbociclib.

Another embodiment of the present invention is recrystallization of Palbociclib from the solvent system comprising methanol, n-propanol, n-butanol, n-pentanol, toluene, xylene anisole or the mixturtes thereof.
The invention according to above embodiments is shown in below scheme:

Yet another embodiment of the present invention is to provide a process for the process for the preparation of Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (4) with butyl vinyl ether (5) in presence of base to give 4-[6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6), wherein the base is selected from potassium acetate, sodium acetate, potassium carbonate or sodium carbonate,
b) converting 4-[6-(6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6) to palbociclib HCl (1a) in presence of and 1, 4-dioxane and HCl,
c) converting palbociclib HCl (1a) to Palbociclib.
The invention according to above embodiments is shown in below scheme:
Yet another embodiment of the present invention is to provide a process for the preparation of Palbociclib form A comprising the steps of:
a) dissolving Palbociclib in alcohol solvent and
b) isolating crystalline form A of Palbociclib.
According to the present embodiment alcohol solvent is selected from methanol, ethanol, n-propanol and n-butanol.

Advantages of the present invention:
1. Less expensive chemicals were used in the process.
2. Potassium acetate is used as base instead of N,N-diisopropylethyl amine in the preparation
of compound of formula-6.
3. Usage of minimum quantities of expensive catalyst palladium acetate and the ligand bis (1- diphenylphosphinophenyl) ether were used in the preparation of compound of formula-6.
4. Minimized the palladium content in compound of formula-7 treating with resin by avoiding column chromatography technique.

The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention in anyway.

Example-1: 4-(6-Amino-pyridine-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3)
4-(6-nitro-pyridin-3-yl)-piperazine -1-carboxylic acid tert-butyl ester (2) 100g (0.32 moles), 5% Pd/C (50% wet) 2.0g and ethyl acetate (400 ml) were charged into the hydrogenation kettle and maintained under hydrogen pressure of 50 psi at 42-470C for about 10h. After completion of reaction (By TLC), reaction mass was cooled to 25-350C and catalyst was filtered. Solvent was removed from the filtrate under vacuum at 50.00C to obtain white to off-white colored solid. The resulting solid was triturated with n-heptane (450 ml) at 25-350C and product is filtered off to get 4-(6-Amino-pyridine-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3). Yield of the product: 86.0g (95.3%), purity: 98.8% by HPLC. H1 NMR (DMSO-D6): d 7.610-7.617 (d, 1 H), d 7.156-7.188 (dd, 1 H), d 6.389-6.411 (d, 1 H), d 5.462 (S, 2 H), d 3.412-3.436 (m, 4 H), d 2.837-2.862 (m, 4 H), d 1.411 (S, 9 H). Mass (M+H): 279.3

Example-2: 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5)
6-Bromo-8-Cyclopentyl-5-methyl-2-methylsulfinyl-8H-pyrido [2, 3-d] pyrimidin-7-one (4) 20g (0.054 moles), 4-(6-Amino-pyridine-3-yl)-piperazine-1-carboxylic tert-butyl ester (3) 16.5g (0.059 moles) and toluene (200 ml) were charged into the 4N RB flask under nitrogen. Then mass was heated to 110-1150C for 25 hours. After completion of reaction (by HPLC), mass was cooled to 25-350C and stirred for 1 h, then product was filtered off. Yield of the product: 12.0g (38.0%), purity: 99.15% by HPLC. H1 NMR (CDCl3): d 8.815 (S, 1 H), d 8.820 (S, 1 H), d 8.174-8.196 (d, 1 H), d 8.050-8.056 (d, 1 H), d 7.325-7.355 (dd, 1 H), d 5.947-6.034 (m, 1 H), d 3.606-3.632 (m, 4 H), d 3.116-3.141 (m, 4H), d 2.616 (S, 3 H), d 2.297-2.346 (m, 2 H), d 2.098-2.132 (m, 2H), d 1.866-1.905 (m, 2H), d 1.668-1.707 (m, 2 H), d 1.494 (S, 9 H); Mass (M+2): 586.2

Example-3: 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7).
Toluene (200 ml) was charged into 2L 4N RB flask and degassed by nitrogen purging. Then, 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5), 50.0g (0.086 moles),tributyl (1-ethoxyvinyl) tin (6) 37.0g (0.103 moles)) were charged into above reaction mass and degassed by nitrogen purging. Tetrakis (triphenylphosphine) palladium (0) 11.8g (0.01 moles) and toluene (50 ml) were added to the reaction and degassed for 20 min. Then reaction mass was heated to reflux for 9 h under nitrogen atmosphere. After completion of reaction (By HPLC), the mass was cooled to 25-35°C and solid was filtered and washed with toluene (150 ml). The resulting solid was dissolved in methylene dichloride (500 ml) and washed with DM Water (3x 250.0 ml) and layers were separated. Organic layer was dried over sodium sulphate and filtered. MPTMT resin (13.75g) and activated carbon (5g) were added to the filtrate and stirred for 2h 25-35°C. Reaction mass was filtered and the filtrate was washed with DM water (2x 250 ml), layers were separated. Organic layer was dried over sodium sulphate and solvent was distilled off under vacuum below 40°C to obtain a yellow coloured solid. The resulting solid was recrystallized from the toluene (200 ml) at 25-35°C to yield 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) as a yellow colored solid. Yield of the product: 38.4g (78.05%), purity: 99.4% by HPLC.
H1 NMR (DMSO-D6): d 10.009 (S, 1 H), d 8.872 (S, 1 H), d 8.062-8.069 (d, 1 H), d 7.895-7.918 (d, 1 H), d 7.474-7.504 (dd, 1 H), d 5.785-5.874 (m, 1 H), d 4.457-4.462 (d, 1 H), d 4.048-4.053 (d, 1 H), d 3.796-3.848 (m, 2 H), d 3.470-3.493 (m, 4 H), d 3.097-3.122 (m, 4 H), d 2.312 (S, 3 H), d 2.179-2.224 (m, 2 H), d 1.859-1.890 (m, 2 H), d 1.734-1.782 (m, 2 H), d 1.539-1.626 (m, 2 H), d 1.142 (S, 9 H), d 1.233-1.268 (m, 3 H).
Mass (M+H): 576.11

Example-4: Preparation of Palbociclib (1) using ethyl acetate/HCl
4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) 36.0g (0.0625 moles) and methylene chloride (360 ml) were charged into the 500 ml 3N RB flask. Then EtOAc. HCl (207.3g, assay 11.0% w/w, 0.625 moles) was added slowly to the above reaction mass by maintain below 35°C. The resulting suspension was stirred at 25-35°C for 5 hours. After reaction completion, solid was filtered from the reaction mass, washed with methylene chloride (110 ml) and dried. Then solid was taken into DM water (650 ml) and pH was adjusted to 9.0-10.0 using 5% aq.NaOH solution. The resulting suspension was stirred for 30 min, solid was filtered off and washed with water. Finally, the solid was leached with acetone (360 ml) to get technical grade of palbociclib (1). Yield of the product: 21.9g (78.2% by theory), purity: 99.74% by HPLC.

Example-5: Preparation of Palbociclib (1) using aq. hydrochloric acid and 1,4-dioxane
4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) 2.0g (0.0035 moles) and 1,4-dioxane (20 ml) were charged into the RB flask and stirred to get clear solution. Then 7.0 ml of dilute hydrochloric acid (7.0 ml, prepared from 3.5 ml of Conc. hydrochloric acid and 3.5 ml of DM water, 0.035 moles) was added during 10 min at 25-35°C under stirring. The resulting suspension was heated to 55-55°C for 3 h. After reaction completion, mass was cooled to 25-35°C, stirred for 30 min and solid was filtered off and washed with 1, 4-dioxane (16 ml). Solid was suck dried for 30 min. Wet material (1.4 g) was again leached with 1, 4-dioxane (20 ml) at 25-35°C and solid filtered, then dried. Wt. of the solid 1.35 g. From the above solid, 1.2 g was taken into 20 ml of DM water, pH was adjusted to 9.0-10.0 using 5.0% aq.NaOH solution. The resulting suspension was stirred for h and solid was filtered off. The wet material was leached with acetone (20 ml) at 25-35°C, solid was filtered off and dried to afford Palbociclib as yellow solid.
Dry weight: 0.95 g; purity by HPLC: 99.9%.

Example-6: Preparation of Palbociclib (1) using aq. hydrochloric acid and tetrahydrofuran
4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) 2.0g (0.0035 moles) and tetrahydrofuran (20 ml) were charged into the RB flask and stirred to get clear solution. Then 7.0 ml of dilute hydrochloric acid (7.0 ml, prepared from 3.5 ml of Conc. hydrochloric acid and 3.5 ml of DM water, 0.035 moles) was added during 10 min at 25-35°C under stirring. The resulting suspension was heated to 55-55°C for 4.5 h. After reaction completion, mass was cooled to 25-35°C, stirred for 30 min and solid was filtered off and washed with tetrahydrofuran (16 ml). Solid was suck dried for 30 min. Wet material (1.9 g) was again leached with tetrahydrofuran (10 ml) at 25-35°C and solid filtered, then dried. Wt. of the solid 1.5g. From the above solid, 1.2g was taken into 20 ml of DM water, pH was adjusted to 9.0-10.0 using 5.0% aq.NaOH solution. The resulting suspension was stirred for 1h and solid was filtered off. The wet material was leached with acetone (20 ml) at 25-35°C, solid was filtered off and dried to afford palbociclib as yellow solid.
Dry weight: 0.85 g; purity by HPLC: 99.84%

Example-7: Recrystallization of palbociclib from the solvent mixture of toluene and methanol.
Palbociclib (19.0 g), toluene (1045 ml) and methanol (475 ml) were charged into RB flask and heated to 60-65°C to get clear solution. Then carbon (1.9g) was charged to the above reaction mass and stirred for 15 min and filtered on hyflow bed and washed with solvent mixture of toluene and methanol (95 ml, toluene 66.5 ml and methanol 28.5 ml). Filtrate was taken and distilled off the solvent under atmospheric pressure at 90°C till crystallization was initiated. Then the reaction mass was cooled to 25-35°C, stirred for 1 h and product was filtered off to afford pure Palbociclib as yellow colored solid. Yield of the product: 17.1g, purity by HPLC: 99.88%.
BET Surface area: 2.3m2/g
PSD: D90 = 37 ?m, D50= 11?m, D10= 3?m

Example-8: Recrystallization of palbociclib from the solvent mixture of n-butanol: anisole
Palbociclib (2.0 g), n-butanol (32.0 ml) and anisole (49.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, crystallization was initiated when the mass temperature reached to 53°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of n-butanol (8.0 ml) and anisole (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.42g. Purity by HPLC: 99.84%.

Example-9: Recrystallization of palbociclib from the solvent mixture of n-butanol: toluene
Palbociclib (1) (2.0 g), n-butanol (56.0 ml) and toluene (84.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, solid formation was observed at mass temperature reached to 60°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of n-butanol (8.0 ml) and toluene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.60g. Purity by HPLC: 99.84%.

Example-10: Recrystallization of palbociclib from the solvent mixture of n-butanol: o-xylene
Palbociclib (1) (2.0 g), n-butanol (56.0 ml) and o-xylene (84.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get clear solution. The resulting solution is cooled to 25-35°C, and material formation was observed at mass temperature reached to 61°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of n-butanol (8.0 ml) and o-xylene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.50g. Purity by HPLC: 99.85%.

Example-11: Recrystallization of palbociclib (1) from the solvent mixture of 1-pentanol: anisole
Palbociclib (1) (2.0 g), 1-pentanol (32.0 ml) and anisole (48.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, crystallization was initiated when the mass temperature reached to 56°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-pentanol (8.0 ml) and anisole (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.45g. Purity by HPLC: 99.88%.

Example-12: Recrystallization of palbociclib (1) from the solvent mixture of 1-pentanol: toluene
Palbociclib (2.0 g), 1-pentanol (32.0 ml) and toluene (48.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, material was formed when the mass temperature reached to 55°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-pentanol (8.0 ml) and toluene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.45g. Purity by HPLC: 99.85%.

Example-13: Recrystallization of palbociclib (1) from the solvent mixture of 1-pentanol: o-xylene
Palbociclib (1) (2.0 g), 1-pentanol (32.0 ml) and o-xylene (48.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to clear solution. The resulting solution is cooled to 25-35°C, crystallization was initiated when the mass temperature reached to 55°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-pentanol (8.0 ml) and o-xylene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.48g. Purity by HPLC: 99.86%.

Example-14: Recrystallization of palbociclib (1) from the solvent mixture of 1-propanol: anisole
Palbociclib (1) (2.0 g), 1-propanol (40.0 ml) and anisole (60.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, material was formed when the mass temperature reached to 55°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-propanol (8.0 ml) and anisole (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.30g. Purity by HPLC: 99.89%.

Example-15: Recrystallization of palbociclib (1) from the solvent mixture of 1-propanol: toluene
Palbociclib (1) (2.0 g), 1-propanol (56.0 ml) and toluene (84.0 ml) were charged into the 250.0 ml 4N RB flask and heated to 95-100°C under stirring to get homogenous solution. The resulting solution is cooled to 25-35°C, crystallization was initiated when the mass temperature reached to 68°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-propanol (8.0 ml) and toluene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.30g. Purity by HPLC: 99.84%.
BET surface area: 1.73 m2/g
PSD: D90 = 23 ?m, D50= 7.91?m, D10= 2.37?m

Example-16: Recrystallization of palbociclib (1) from the solvent mixture of 1-propanol: o-xylene
Palbociclib (1) (2.0 g), 1-propanol (56.0 ml) and o-xylene (84.0 ml) were charged into the 250.0 ml 4NRBF and heated to 95-100°C under stirring to obtain clear solution. The resulting solution is cooled to 25-35°C, material formation was observed when the mass temperature reached to 62°C. Then the suspension was stirred for 1h at 25-35°C and product was filtered off under suction. Product was washed with the solvent mixture of 1-propanol (8.0 ml) and o-xylene (12.0 ml). Then the resulting product was dried in vacuum oven at 50-55°C to obtain palbociclib as yellow colour crystalline solid. Wt. of the product: 1.50g. Purity by HPLC: 99.82%.

Exampe-17: Preparation of 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (4)
4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3, 75.3g, 0.270 moles), toluene (586.0 ml) were charged into the 2.0 lit 4N RB flask and stirred to get brown coloured suspension. Reaction mass was cooled to 5-100C. Lithium bis (trimethylsilyl) amide (1.0 M in THF, 306.8 ml, 0.307 moles) was added dropwise to the above reaction mass under nitrogen atmosphere and then stirred for 10-15 min. A slurry of 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8h-pyrido [2, 3-d] pyrimidin-7-one (2, 50g, 0.146 moles) in toluene (400 ml) was added to the reaction mass during 10-15 min. reaction mass was allowed to 30±50C and stirred for 2 h. After completion of reaction (By TLC), reaction mass is quenched with 600.0 ml of saturated aq.NaHCO3 solution. After 1 h maintenance at 30±50C, solid was filtered from the reaction mass followed by leaching with water (500 ml) and toluene (500 ml). Product was dried in hot air oven at 70-75°C to afford title compound. Wt. of the product 75.8g (88.9% by theory). Purity by HPLC > 97.0%.
H1 NMR (CDCl3): d 8.847 (S, 1 H), d 8.534 (S, 1 H), d 8.178-8.201 (d, 1 H), d 8.072-8.079 (d, 1 H), d 7.328-7.358 (dd, 1 H), d 5.952-6.040 (m, 1 H), d 3.610-3.636 (m, 4 H), d 3.120-3.144 (m, 4H), d 2.620 (S, 3 H), d 2.298-2.356 (m, 2 H), d 2.100-2.132 (m, 2H), d 1.883-1.907 (m, 2H), d 1.651-1.707 (m, 2 H), d 1.495 (S, 9 H); Mass (M+2): 586.2

Example-18: Preparation of 4-[6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6)
n-Butanol (300 ml) was is charged into the 1.0 lit 4 necked round bottomed flask under nitrogen atmosphere. Then nitrogen purging was given for about 20 min. 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (4) (60.0 g, 0.103 moles), butyl vinyl ether (5) (30g, 0.30 moles) and potassium acetate (40.2g, 0.41 moles) were added to the reaction mass. Reaction mass was purged with nitrogen for about 20 min. of Palladium acetate (0.23g, 0.0010 moles) and bis (1-diphenyl phosphinophenyl) ether (0.83g, 0.0015 moles) were added to the above reaction mass and nitrogen was purged for 15 min. Reaction mass was heated to 95±2.50C and maintained for 2h. After completion of reaction (By TLC), reaction mass was cooled to 80-850C DM. Water (90 ml) and n-Butanol (180 ml) were is added to the reaction mass. Reaction mass was stirred for 15 min at same temperature and filtered with the help of n-butanol (60 ml).

The above filtrate was transferred into 2.0 L 4 necked round bottomed flask along with DM water (210 ml) and 1, 2-diaminopropane (38.0g). Reaction mass was heated to 700C and stirred for 30 min. Layers were separated, organic layer was cooled to 5-100C under stirring. After 1h maintenance, product was filtered off under suction and washed with 120.0 ml of n-Butanol (120 ml). Product was dried in hot air oven at 70-75°C to give title compound. Dry weight is 48.0 g
(77.5% by theory). Purity by HPLC > 97.0%.

H1 NMR (DMSO-d6): d 9.970 (S, 1 H), d 8.866 (S, 1 H), d 8.058-8.066 (d, 1 H), d 7.891-7.914 (d, 1 H), d 7.471-7.501 (dd, 1 H), d 5.757-5.868 (m, 1 H), d 4.466-4.471 (d, 1 H), d 4.045-4.050 (d, 1H), d 3.749-3.781 (m, 2 H), d 3.469-3.493 (m, 4 H), d 3.097-3.123 (m, 4H), d 2.365 (s, 3H), d 2.198-2.225 (m, 2 H), d 1.889 (m, 2 H), d 1.733-1.756 (m, 2 H), d 1.583-1.619 (m, 4 H)d 1.351-1.407 (m, 11 H), d 0.885-0.922 (m, 3 H); Mass (M+1): 604.3

Example-19: preparation of Palbociclib hydrochloride (1a)
4-[6-(6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6) (40.0g, 0.066 moles) and 1, 4-dioxane (400 ml) were charged into the 1.0 L four necked round bottomed flask at 30±50C under Nitrogen atmosphere and stirred to dissolve.. Then dil.HCl (150 ml, prepared from 75 ml conc. hydrochloric acid and 75 ml of DM water) was added dropwise to the above reaction mass during 15 min. Reaction mass was turned to yellow coloured suspension. Reaction mass heated to 50-550C and maintained for 5 h. After reaction completion by TLC, reaction mass was cooled to 25-350C, stirred for 1h and filtered. Resulting solid was suck dried for 1h.

The wet cake obtained above was leached with the solvent mixture of 1,4-dioxane (600 ml) and DM water (200 ml) at 25-35°C for 60 -75 min. Solid was filtered off under suction then suck dried for 1h. Material was unloaded and dried in hot air oven at 70-75°C for 6h to afford the title compound as yellow coloured solid. Dry weight is 31.4 g (yield by theory 98.1%). Purity by HPLC > 99.8.0%.

Example-20: preparation of Palbociclib (1) Polymorph B
Palbociclib hydrochloride (1a) (20g) and DM Water (300 ml) were charged into the 500 ml four necked round bottomed flask and the reaction mass was heated to 65-700C under stirring to get clear solution. Activated carbon (2.0g) was added to the above reaction mass and stirred for 30-45 min. Reaction mass was filtered through hy-flow bed under suction and bed was washed with DM Water (40 ml). The resulting filtrate was transferred into 1.0 L four necked round bottomed flask and pH was adjusted to 9-11 with aq.sodium hydroxide solution to get yellow coloured suspension. The resulting suspension was stirred for 1h 25-350C and filtered under suction. Compound was suck dried for 1h. Then the wet cake was leached with DM water (200 ml) for 1h and filtered under suction. Then product was dried in vacuum oven at 70-75°C for 6h to afford pure palbociclib (1). Wt. of the product: 13.0g (70.3% by theory). Purity by HPLC > 99.8%.
PSD: D90 = 76.2 ?m, D50= 5.23?m, D10= 0.11?m

Example-21: preparation of Palbociclib (1) Polymorph A
Palbociclib hydrochloride (1a) (20g) and DM Water (300 ml) were charged into the 500 ml four necked round bottomed flask and the reaction mass was heated to 65-700C under stirring to get clear solution. Activated carbon (2.0g) was added to the above reaction mass and stirred for 30-45 min. Reaction mass was filtered through hy-flow bed under suction and bed was washed with DM Water (40 ml). The resulting filtrate was transferred into 1.0 L four necked round bottomed flask and pH was adjusted to 9-11 with aq.sodium hydroxide solution to get yellow coloured suspension. The resulting suspension was stirred for 1h 25-350C and filtered under suction. Compound was suck dried for 1h. Then the wet cake was leached with methanol (15 volumes) at 60-65°C for 55-70min then dried at 25-35°C for 1hr and filtered pure palbociclib (1).
Purity by HPLC > 99.8%.
BET surface area: 5.95 m2/g
PSD: D90 = 15.9 ?m, D50= 5.76?m, D10= 2.11?m

Example-22: preparation of Palbociclib (1) Polymorph A
Palbociclib hydrochloride (1a) (20g) and DM Water (300 ml) were charged into the 500 ml four necked round bottomed flask and the reaction mass was heated to 65-700C under stirring to get clear solution. Activated carbon (2.0g) was added to the above reaction mass and stirred for 30-45 min. Reaction mass was filtered through hy-flow bed under suction and bed was washed with DM Water (40 ml). The resulting filtrate was transferred into 1.0 L four necked round bottomed flask and pH was adjusted to 9-11 with aq.sodium hydroxide solution to get yellow coloured suspension. The resulting suspension was stirred for 1h 25-350C and filtered under suction. Compound was suck dried for 1h. Then the wet cake was leached with n-butanol (15 volumes) at 80-85°C for 55-70min then dried at 25-35°C for 1hr and filtered pure palbociclib (1).
Purity by HPLC > 99.8%.
BET surface area: 3.98 m2/g
PSD: D90 = 61.9 ?m, D50= 6.34?m, D10= 2.11?m

Example-23: preparation of Palbociclib (1) Polymorph A
Palbociclib hydrochloride (1a) (20g) and DM Water (300 ml) were charged into the 500 ml four necked round bottomed flask and the reaction mass was heated to 65-700C under stirring to get clear solution. Activated carbon (2.0g) was added to the above reaction mass and stirred for 30-45 min. Reaction mass was filtered through hy-flow bed under suction and bed was washed with DM Water (40 ml). The resulting filtrate was transferred into 1.0 L four necked round bottomed flask and pH was adjusted to 9-11 with aq.sodium hydroxide solution to get yellow coloured suspension. The resulting suspension was stirred for 1h 25-350C and filtered under suction. Compound was suck dried for 1h. Then the wet cake was leached with n-propanol (15 volumes) at 70-75°C for 55-70min then dried at 25-35°C for 1hr and filtered pure palbociclib (1).
Purity by HPLC > 99.8%.
BET surface area: 4.12 m2/g
PSD: D90 = 13.7 ?m, D50= 5.65?m, D10= 2.35?m
,CLAIMS:We Claim:
1. A crystalline Palbociclib form A having a specific surface area in the range of 4 to 7 m2/g.

2. A process for the preparation of crystalline Palbociclib form A having a specific surface area in the range of 4 to 7 m2/g comprising the steps of:
a) dissolving Palbociclib in alcohol solvent and
b) isolating crystalline form A of Palbociclib.

3. The process according to claim 2, wherein the alcohol solvent is selected from methanol, ethanol, n-propanol and n-butanol.

4. A process for the preparation of Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (4) with butyl vinyl ether (5) in presence of base to give 4-[6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6), converting 4-[6-(6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (6) to palbociclib HCl (1a) in presence of base and 1, 4-dioxane and HCl,
b) converting palbociclib HCl (1a) to Palbociclib.

5. A process according to claim 4, wherein the base is selected from potassium acetate, sodium acetate, potassium carbonate or sodium carbonate.

6. A process for the preparation of Palbociclib comprising the steps of:
a) reacting 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d] pyrimidin-2-yl amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5) with tributyl (1-ethoxyvinyl) tin (6) in presence of Tetrakis (triphenylphosphine) palladium to get 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7),
b) converting 4-{6-[8- cyclopentyl-6-(ethoxy-vinyl)-5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d] pyrimidin-2-yl amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (7) to Palbociclib in presence of HCl and solvent.

7. The process according to claim 6, wherein the solvent is selected from of ethyl acetate, 1, 4-dioxane and tetrahydrofuran.

8. A process for the recrystallization of Palbociclib comprising the steps of:
a) dissolving Palbociclib in a solvent or mixture thereof, and
b) isolating the Palbociclib.

9. A process according to claim 8, wherein the solvent system is selected from methanol, n-propanol, n-butanol, n-pentanol, toluene, xylene, anisole or mixturtes thereof.

Dated this the 21st day of August 2018