Claims:1. A process for preparation of Palbociclib (I) comprising synthesizing 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), a key intermediate by a process which comprises;
a) reacting 1-(2,4-dichloropyrimidin-5-yl)ethanone (II) with Cyclopentylamine in presence of base in solvent to obtain1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl) ethanone (III);

b) reacting the 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III) with Ethyl acetate in presence of Lithium bis(trimethylsilyl)amide in a solvent to obtain 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV);

c) brominating the 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV) with 1,3-Dibromo-5,5-dimethylhydantoin in a solvent to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V).

2. The process according to claim 1, wherein the solvent in step a) is selected from hydrocarbon or halogenated hydrocarbons such as Dichloromethane, Dichloroethane, Chloroform etc.
3. The process according to claim 1, wherein the base in step a) is selected from alkali hydroxides, carbonates or bicarbonates.
4. The process according to claim 1, wherein the addition of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one to the mixture of Ethyl acetate and Lithium bis(trimethylsilyl)amide (LiHMDS) in step b) is conducted under N2 atmosphere at a temperature of -70 to -75oC.
5. The process according to claim 1, wherein the solvent in step b) and step c) is selected from THF or Toluene.
6. The process for preparation of Palbociclib (I) according to claim 1, which comprises;
a) preparing 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), in accordance with claim 1;
b) reacting the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V) with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) in presence of base in a solvent or bromotris(triphenylphosphine)copper(I) and a base in a solvent to obtain 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 (VII);
c) reacting the 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 (VII) with a novel reagent, vinyloxy ethylene glycol, in presence of [1,1’-Bis (diphenylphosphino)ferrocene]palladium(II)chloride complex and a base to obtain tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate(VIII);
d) converting the tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate(VIII) into 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) by treatment with Conc. HCl; and
e) deprotecting the 4-[6-(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride by acid catalyzed hydrolysis into 2-(5-(piperazin-1-yl)pyridin-2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib).
7. The process according to claim 6, wherein the base and solvent in step (b) is selected from the group consisting of sodium tert. pentoxide in THF or Toluene, p-Tolylmagnesium bromide in THF or Cyclopentyl methyl ether; and bromotris(triphenylphosphine)copper(I) along with a base selected from the group consisting of Cesium carbonate; Potassium tert.butoxide, Sodium tert. pentoxide in a solvent selected from Toluene, THF and DMF.
8. The process according to claim 6, wherein the base in step (c) is an organic base.
9. A process for synthesis 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 (VII), comprising reacting 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V) with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) in presence of base and in a solvent or bromotris(triphenylphosphine)copper (I) and a base in a solvent.
10. The process according to claim 9, wherein the base and solvent is selected from the group consisting of sodium tert. pentoxide in THF or Toluene; p-Tolylmagnesium bromide in THF or Cyclopentyl methyl ether; and bromotris(triphenylphosphine)copper (I) along with a base selected from the group consisting of Cesium carbonate, Potassium tert.butoxide, Sodium tert. pentoxide in a solvent selected from Toluene, THF and DMF.
11. A process for preparation of Palbociclib (I) comprising;
a) reacting the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V) with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) in presence of a base in a solvent or bromotris(triphenylphosphine)copper(I) and a base in a solvent to obtain 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 (VII);

b) reacting the 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 (VII) with vinyloxy ethylene glycol or N-Vinylpyrrolidone in presence of [1,1’-Bis (diphenylphosphino)ferrocene]palladium(II)chloride. DCM complex and a base in a solvent to obtain tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate(VIII);

c) converting the tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate(VIII) into 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) by treatment with Conc. HCl and

d) deprotecting the 4-[6-(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride by acid catalyzed hydrolysis to obtain 2-(5-(piperazin-1-yl)pyridin-2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib).

12. The process according to claim 11, wherein the base and solvent used in step (a) is selected from the group consisting of sodium tert. pentoxide in THF or Toluene; p-Tolylmagnesium bromide in THF or Cyclopentyl methyl ether; and bromotris(triphenylphosphine)copper (I) along with a base selected from the group consisting of Cesium carbonate, Potassium tert.butoxide, Sodium tert. pentoxide in a solvent selected from Toluene, THF and DMF.
13. The process according to claim 11, wherein the base in step (b) is an organic base and the solvent is selected from DMF, n-Butanol, Ethylene glycol, DMSO, DMAc and NMP.
14. Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII),
.
15. 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX),
.
, Description:Technical filed:
The present invention relates to synthesis of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), useful as a key intermediate in the synthesis of Palbociclib (I) and further conversion of the same into Palbociclib (I) via a novel reagent to novel intermediates, tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (VIII) and 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX), with good yields and purity.

Background and prior art:
Palbociclib is chemically described as 6-acetyl-8-cyclopentyl-5- methyl-2-[[5-( l-piperazin l)-2-pyridinyl]amino]pyrido[2, 3-d]pyrimidin-7(8H)-one, having the following structure.

Palbociclib is first disclosed in US6936612, which is approved by the USFDA for use in combination with Letrozole for the treatment of postmenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy.

US6936612 provides processes for the preparation of Palbociclib hydrochloride.

U.S. Patent No. 7,781,583 provides a process for the preparation of Palbociclib isoethionate.
WO2016016769 provides process for the preparation of Palbociclib utilizing a silyl-protected crotonic acid derivative to produce a silyl-protected 5-(1-methyl-3 carboxy-prop-1-en-1-yl)-2-chloro-piperazine followed by intramolecular cyclization of the piperazine intermediate to produce 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, which is further converted to Palbociclib.

6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one is one of the key intermediates of Palbociclib. WO2016030439 proposes a process for preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one as per the following below (scheme I).
Scheme I

WO2016082605 discloses another synthetic route for the production of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one and further conversion into Palbociclib, as shown in scheme II below.

Scheme II

In the light of the limited methods available in the prior art for the production of the key intermediate of Palbociclib and also efficient processes for the production of Palbociclib there is a need in the art to provide an alternate and efficient method for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), a key intermediate and its further conversion into Palbociclib.

Accordingly, it is an objective of the present invention to provide an efficient process for preparation of the key intermediate of Palbociclib viz., 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V).

Another objective of the invention is to provide a process for preparation of Palbociclib via novel reagent and novel intermediates, viz., Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate(VIII) and 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX), with good yields and purity.

Summary of the invention
In line with the above objective, in an aspect, the present invention provides a process for preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), a key intermediate for the synthesis of Palbociclib (I) which comprises;
a) reacting 1-(2,4-dichloropyrimidin-5-yl)ethanone (II) with cyclopentylamine in presence of base in solvent to obtain 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III);
b) reacting the 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III) with ethyl acetate in presence of Lithium bis(trimethylsilyl)amide in a solvent to obtain 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV);
c) brominating the 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV) with 1,3-Dibromo-5,5-dimethylhydantoin in a solvent to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V).

The solvent in step a) is selected from hydrocarbon or halogenated hydrocarbons such as Dichloromethane, Dichloroethane, Chloroform, etc.

The base in step a) is selected from alkali hydroxides, carbonates or bicarbonates.
The addition of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one to the mixture of Ethyl acetate and Lithium bis(trimethylsilyl)amide (LiHMDS) in step b) is conducted under N2 atmosphere at a temperature of -70 to -75oC.

The solvent used in step b) and step (c) is selected from THF or Toluene.

The process for preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one is shown in scheme III below:

Scheme III

In another aspect, the invention provides process for preparation of Palbociclib (I) which comprises;
a) reacting the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V) with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) in presence of a base in a solvent or bromotris(triphenylphosphine)copper (I) and a base in a solvent to obtain 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 (VII);

b) reacting the 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 (VII) with vinyloxy ethylene glycol in presence of [1,1’-Bis (diphenylphosphino)ferrocene]palladium(II)chloride. DCM complex and a base to obtain tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII);

c) converting the tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) into 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) by treatment with Conc. HCl; and

d) deprotecting the 4-[6-(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride by acid catalyzed hydrolysis to obtain 2-(5-(piperazin-1-yl)pyridin-2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib).

The base and solvent used in step (a) is selected from the group consisting of Sodium tert. pentoxide in THF or toluene; p-Tolylmagnesium bromide in THF or Cyclopentyl methyl ether; or bromotris(triphenylphosphine)copper (I) [Cu[pph3]3Br] along with a base selected from the group consisting of Cesium carbonate , Potassium tert.butoxide , Sodium tert. pentoxide in a solvent selected from Toluene, THF and DMF.
The base in step (b) is an organic base.
The process for preparation of Palbociclib is shown in scheme IV.
Scheme IV

Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present invention provides a novel process for preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V), a key intermediate for the synthesis of Palbociclib (I) which comprises;
a) reacting 1-(2,4-dichloropyrimidin-5-yl)ethanone (II) with cyclopentylamine in presence of base in solvent to obtain1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl) ethanone (III);
b) reacting the 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III) with Ethyl acetate in presence of Lithium bis(trimethylsilyl)amide in a solvent to obtain 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV);
c) brominating the 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV) with 1,3-Dibromo-5,5-dimethylhydantoin in a solvent to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V).

In accordance with the above, 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one, is prepared by reacting 1-(2,4-dichloropyrimidin-5-yl)ethanone with Cyclopentylamine in presence of base in solvent to obtain 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone. The reaction is carried out at ambient temperature. The solvent may be selected from hydrocarbon or halogenated hydrocarbons such as Dichloromethane, Dichloroethane, Chloroform etc. The preferred solvent is Dichloromethane or Dichloroethane. The base may be selected from alkali hydroxides, carbonates or bicarbonates. The preferred base is bicarbonate such as Sodium bicarbonate or Potassium bicarbonate. After the completion of the reaction, the reaction mixture is quenched with water and the product is extracted in to solvent, followed by concentration, and isolated by making a slurry using a hydrocarbon solvent to obtain pure product, 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III).

1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III) thus obtained is further reacted with Ethyl acetate in presence of a base, Lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent such as THF or Toluene to obtain 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV). The addition of 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III) to the mixture of Ethyl acetate and Lithium bis(trimethylsilyl)amide (LiHMDS) in THF or Toluene is conducted under N2 atmosphere at a temperature of -70 to -75°C. The reaction is performed at room temperature and after the completion of the reaction, the reaction mass is diluted with water and the product, 2-chloro-8-cyclopentyl-5-methyl pyrido[2,3-d]pyrimidin-7(8H)-one (IV) is isolated as a solid.
2-chloro-8-cyclopentyl-5-methyl pyrido[2,3-d]pyrimidin-7(8H)-one (IV) thus obtained is brominated with 1,3-Dibromo-5,5-dimethylhydantoin in a polar aprotic solvent such as DMF, DMSO, acetonitrile etc. to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one (V). The bromination reaction may be performed at a temperature of 50 to 100°C for 5 to 10 hrs. After the completion of the reaction, the reaction mass is diluted with water, stirred with 10% NaHSO3, and the product, 6-bromo-2-chloro-8-cyclopentyl-5-methyl pyrido[2,3-d]pyrimidin-7(8H)-one (V) is isolated as a solid.
In another embodiment, the invention provides process for preparation of Palbociclib (I) which comprises;
a) reacting the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d] pyrimidin-7(8H)-one (V) with tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) in presence of a base in a solvent or bromotris(triphenylphosphine)copper (I) along with a base in a solvent to obtain 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 (VII);

b) reacting the 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 (VII) with vinyloxy ethylene glycol in presence of [1,1’-Bis (diphenylphosphino)ferrocene]palladium(II)chloride. DCM complex and a base to obtain tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII);

c) converting the tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) into 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) by treatment with Conc. HCl; and

d) deprotecting the 4-[6-(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) by acid catalyzed hydrolysis to obtain 2-(5-(piperazin-1-yl)pyridin-2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib (I)).

According to this aspect, the synthesis 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 (VII) comprises the reaction of tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) with 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) in presence of a base such as Sodium tert-pentoxide in a solvent such as THF or Toluene or mixture of THF and Toluene under stirring at room temperature. Alternately, p-Tolylmagnesium bromide in THF or Cyclopentyl methyl ether may be added at 10-25°C and stirred at the same temperature for 4 hrs. After the completion, the reaction mixture is cooled to 10°C, diluted with water and stirred for 30 min at RT to obtain crude 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, which is filtered and dried. The crude is further purified by stirring in IPA for 30min.

In another process variant, the synthesis 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 (VII) includes the reaction of tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) with 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) in presence of bromotris(triphenylphosphine)copper (I), Cesium carbonate in Toluene under stirring at 100oC for 6 hrs. After completion of the reaction, the reaction mass is cooled to 10oC, NH3 solution is added and stirred at RT for 1hr. The product is extracted with DCM and concentrated. The crude product thus obtained is purified by stirring in Ethyl acetate to get pure product, 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 (VII).

In another aspect, the 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 (VII) thus obtained is reacted with a novel reagent, viz., vinyloxy ethylene glycol in presence of [1,1’-Bis (diphenylphosphino)ferrocene]palladium(II) chloride complex with DCM, viz., [Pd(dppf)Cl2].DCM in an organic base such as N,N-di isopropyl ethyl amine in presence of an aprotic solvents such as DMF, DMSO, DMAc, NMP and protic solvents such as n-Butanol and Ethylene glycol under inert atmosphere at a temperature of 100-105oC for a period of about 12 hrs. After completion of the reaction, the reaction mass is cooled to RT, poured over ice cold water (20mL) and stirred for 30 min to obtain crude tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII), which is slurried in MTBE (Methyl tert-butyl ether) for 30min, to get the product with acceptable purity.

Thus the invention provides a novel reagent viz., vinyloxy ethylene glycol to synthesize novel intermediates viz., Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) and 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) for the preparation of Palbociclib, which becomes another novel feature of the invention.
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Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) thus obtained is taken in n-butanol and added con. HCl and stirred at room temperature for 2hrs. After completion of the reaction, the reaction mixture is diluted with MTBE, stirred for 30 min and filtered to get the product 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX).

Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) and 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) thus obtained are hitherto unreported novel intermediates, which are further characterised using 1HNMR and Mass etc.

Finally, Palbociclib is obtained by bubbling hydrogen chloride gas into an ice bath cooled solution of 4-[6-(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) in dichloromethane and the resulting suspension is stirred at room temperature overnight, and then diluted with MTBE. The solid was collected by filtration, washed with MTBE and dried to give the hydrochloride salt of Palbociclib, which is treated with a solution of sodium hydroxide at 25-300C , to obtain Palbociclib with 90% yield.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1
Preparation of 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethanone (III):
To a suspension of 1-(2,4-dichloropyrimidin-5-yl)ethanone (20g, 0.104mol) in DCM (200mL) and Sodium bicarbonate (14g, 0.166mol), Cyclopentylamine (9.8g, 0.115mol) dissolved in DCM (60mL) was added. The reaction mixture was stirred for 5 hrs. It was diluted with water (100mL), stirred for 15min. The organic layer was washed with water (100mL) and concentrated. The product was isolated by making slurry of the crude product in Heptane (60 mL). 22.5g of pure product with 90% yield was isolated after filtration.

Preparation of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV):
To a solution of LiHMDS (1M in THF) (7.54g, 0.045mol) in THF (70mL), Ethyl acetate (3.3g, 0.0375mol), dissolved in THF (2mL) was added dropwise under N2 atmosphere at -70 to -75oC. 1-(2-chloro-4-(cyclopentylamino) pyrimidin-5-yl)ethanone (III) (3.6g, 0.015mol) was added to the reaction mixture at -70oC and slowly allowed to warm and to room temperature. Reaction mixture was diluted with ice water (36mL), obtained solid was filtered, washed with water and dried, to get 2.9g of compound with 73.23% yield.

Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V):
1,3-Dibromo-5,5-dimethylhydantoin (11.4g, 0. 0398mol), dissolved in DMF (23mL) was added drop wise to a solution of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IV) ( 4.2g, 0.0159mol) in DMF (40mL) at 10-15oC. The reaction mixture was heated to 50oC for 7hrs, cooled to 10oC and diluted with water (42mL). 10% NaHSO3 sol (42mL) was added slowly and stirred for 30min, obtained solid was collected by filtration and dried to get 4.92 g of the product with 90.3% yield.

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 (VII):
Method-1
Tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) (0.42g, 0.0015mol) was taken in THF (4mL) and cooled to 10-15oC. Sodium tert-pentoxide (0.26g, 0.0023mol) was added at the same temperature and stirred for 30min at RT. 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) (0.4g, 0.00116mol) in THF (4mL) was added to the reaction mixture and stirred for 2hrs at RT. Reaction mixture was cooled to 10oC and diluted with water (2mL), stirred for 30 min at RT. Obtained crude solid was filtered and dried. Crude was taken in IPA (2mL), stirred for 30 min filtered and dried to get 0.3g of pure product with 44.1% yield.

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 (VII):
Method-2
6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) (0.5g, 0.0014mol) and tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) (0.52g, 0.0018mol) were taken in THF (2.5mL) and cooled to 15-20oC. 1M solution of p-Tolylmagnesium bromide in THF (5mL, 0.0058mol) was added at 15-20°C and stirred at 20°C for 4hrs. Reaction mixture was quenched with Acetic acid (1mL) at 20°C, diluted with water (10mL) and stirred at RT for 30 min .Obtained solid was filtered and dried to get 0.52g of product with 61.17% yield.

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 (VII):
Method-3
6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) (0.2g, 0.58mmol) and tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) (0.21g, 0.75mmol) were taken in THF(2mL) cooled to 15-20°C. 1M solution of p-Tolylmagnesium bromide in Cyclopentyl methyl ether (3mL, 2.9mmol) was added at 15-20°C and stirred at 20°C for 6hrs. Reaction mixture was quenched with acetic acid (1mL) at 20oC, diluted with water (5mL) and stirred at RT for 30 min. Obtained solid was filtered and dried to get 0.2g of product with 60% yield.

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 (VII):
Method-4
6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (V) (0.2g, 0.58mmol), tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate (VI) (0.227g, 0.816mmol), bromotris (triphenylphosphine)copper (I) [Cu(pph3)3Br](0.29g,0.311mmol) and Cesium carbonate (0.38g,1.16mmol) were taken in N2 bubbled Toluene (2mL), stirred for 5 min . Heated the contents to 100oC for 6hrs. After completion of the reaction the reaction mass was cooled to 10oC, added 15% of NH3 solution (2mL) and stirred at RT for 1hr. Then the product was extracted with DCM (2X2ML) and concentrated. The crude product is slurried in Ethyl acetate (2mL) for 30min, Filtered and dried to get 0.2g of the product with 59% yield.
Preparation of tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII):
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 (VII) (1g, 0.00171mol), Vinyloxy ethylene glycol (0.60g, 0.00681mol), [1,1’-Bis (diphenylphosphino) ferrocene] palladium (II)chloride complex with DCM [Pd(dppf)Cl2].DCM (0.062g, 0.0000847mol), N,N-di isopropyl ethyl amine (0.553g, 0.00427mol ) were taken in N2 bubbled DMF (10mL). The reaction mixture was heated to 100-105°C for 12hrs. After completion of the reaction, RM was cooled to RT, poured over ice cold water(20mL) and stirred for 30 min. Obtained solid was filtered and dried to get crude product. Crude product was slurried in MTBE (10mL) for 30min, filtered and dried to get 0.96g of product with 95% yield.

1HNMR(300MHz,CDCl3) dppm:1.41(s,9H), 1.5-1.7 (m,2H), 1.8-1.9 (m,2H),2.0-2.1(m,2H),2.3-2.4 (m,2H), 2.5 (s,3H), 3.1-3.2 (m,4H), 3.6-3.7(m,4H),3.9-4.0 (m,2H),4.1-4.2 (m,2H),4.3 (d,1H), 4.6 (d,1H), 5.8-5.9 (m,1H),7.4(dd,1H),8.0 (d,1H),8.2(d,1H),8.8 (s,1H). Mass:C31H41N7O5 (M+H):592
4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX):

Tert-butyl 4-(6-(6-(1-(2-Hydroxy ethoxy)vinyl)-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (VIII) (1.00g, 0.00169mol) was taken in n-butanol (10mL). Con.HCl (0.25g,0.68ml,0.00684mol) was added at RT and stirred for 2hrs. After completion of the reaction the reaction mixture was diluted with MTBE (20mL), stirred for 30 min and filtered to get 0.8g of the product with 81.6% yield.

1HNMR(300MHz,DMSO-D6) dppm:1.41(s,9H), 1.5-1.7 (m,2H), 1.7-1.9 (m,2H),1.9-2.0 (m,2H),2.1-2.3 (m,2H), 2.33 (s,3H),2.4 (s,3H) 3.1-3.2 (m,4H), 3.4-3.5(m,4H), 5.8-5.9 (m,1H),7.7(d,1H),7.9-8.1(d,1H),8.2(d,1H), 9.0 (s,1H). Mass: C29H37N7O4 (M+H):547 (without HCl)

2-(5-(piperazin-1-yl)pyridin-2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (I)
Hydrogen chloride gas was bubbled into an ice bath cooled solution of 4-[6-(6-Acetyl-8-cyclopentyl -7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride (IX) (0.4g, 0.00068 mol,) in DCM (8 mL) at 0-5oC for 10min . The resulting suspension was stirred at RT overnight, and then diluted with MTBE (20 mL). The solid was collected by filtration, washed with MTBE (4mL) and dried to give the hydrochloride salt of (I). The salt was taken in water (4mL) and a solution of NaOH (0.16g, 0.0041mol) in water (4mL) was added. The reaction mixture was stirred at RT for 12hrs. Obtained solid was filtered, washed with water (8mL) and Acetone (4mL) to get 0.27 g of product with 90% yield.