Palbociclib, Sun Pharmaceutical Industries Ltd, New patent, WO 2016016769

Palbociclib

WO2016016769,  A PROCESS FOR THE PREPARATION OF PALBOCICLIB

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

TYAGI, Vipin; (IN).
MOHAMMAD, Kallimulla; (IN).
RAI, Bishwa Prakash; (IN).
PRASAD, Mohan; (IN)

The present invention relates to a 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 compound the piperazine intermediate to produce 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one which is then converted to palbociclib.

Sun Pharma managing director Dilip Shanghvi.

Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2-pyridinyl]amino]pyrido 2,3-d]pyrimidin-7(8H)-one, represented by the Formula I.

Formula I

U.S. Patent No. 6,936,612 discloses palbociclib and a process for the preparation of its hydrochloride salt.

U.S. Patent No. 7,781,583 discloses a process for the preparation of palbociclib, wherein 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Formula II

Formula II

prepared by reacting 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine of Formula III

Formula III

with crotonic acid.

U.S. Patent No. 7,863,278 discloses polymorphs of various salts of palbociclib and processes for their preparation.

A first aspect of the present invention provides a process for the preparation of a compound of Formula IV,

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl

comprising reacting a crotonic acid derivative of Formula V

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl

with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV.

A second aspect of the present invention provides a process for the preparation of palbociclib of Formula I,

Formula I

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) converting the compound of Formula IV to palbociclib of Formula I.

A third aspect of the present invention provides a process for the preparation of a compound of Formula II

Formula II

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV,

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) intramolecular cyclization of the compound of Formula IV to give a

compound of Formula II.

A fourth aspect of the present invention provides a process for the preparation of palbociclib of Formula I

Formula I

comprising:

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl;

intramolecular cyclization of the compound of Formula IV to give a compound of Formula II; and

Formula II

converting the compound of Formula II to palbociclib of Formula I.

EXAMPLES

Preparation of 2-chloro-8 -cyclopentyl-5 -methyl-8H-pyrido Γ2.3 – lpyrimidin-7-one (Formula II)

Step a: Preparation of trimethylsilyl (2£)-but-2-enoate (Formula V, when R is trimethylsilyl)

Crotonic acid (18.68 g) was taken in dichloromethane (80 mL) at room

temperature to obtain a solution. Hexamethyldisilazane (HMDS) (21 g) followed by imidazole (0.4 g) was added to the solution at room temperature under stirring. The reaction mixture was refluxed for 2 hours. Dichloromethane was recovered completely under vacuum at 45°C. Dichloromethane (200 mL) was again added to the reaction mixture, and then recovered completely under vacuum at 45°C. The colorless liquid obtained was taken as such for next step.

Step b: Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-i/|pyrimidin-7-one (Formula II)

Method A

Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (52 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20 g, Formula III) in tetrahydrofuran (100 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans-dichlorobis(acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-o-tolylphosphine (0.770 g) was added to the reaction mixture under a nitrogen atmosphere.

The reaction system was again degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75°C to 80°C overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) (60% ethyl acetate/toluene). Trans-dichlorobis(acetonitrile) palladium (II) (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) to the reaction mixture at 75°C to 80°C. The reaction mixture was heated at 75°C to 80°C for 4 hours. After completion of the reaction, acetic anhydride (17 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) and IN hydrochloric acid (100 mL) were added and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (40 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (2 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo^® bed and then washed with dichloromethane (40 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (80 mL) was added to the residue and the solvent was evaporated under reduced pressure until 40 mL of isopropyl alcohol remained. Isopropyl alcohol (40 mL) was again added to the mixture, and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered, thenwashed with isopropyl alcohol (20 mL), and then dried under vacuum at 45°C to obtain the title compound.

Yield: 0.535% w/w

Chromatographic purity: 99.51%

Method B

Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (26.5 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (Formula III, 10 g) in tetrahydrofuran (50 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans-dichlorobis(acetonitrile) palladium (II) (1.39 g) followed by the addition of tri-o- tolylphosphine (1.1 g) was added to the reaction mixture under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75 °C to 80°C overnight. After completion of the reaction, acetic anhydride (20 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were added, and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (20 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (1 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo^® bed and then washed with dichloromethane (20 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (40 mL) was added to the residue and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. Isopropyl alcohol (20 mL) was again added to the mixture and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered and washed with isopropyl alcohol (10 mL), and then dried under vacuum at 45°C to obtain the title compound.

Yield: 0.46% w/w

Chromatographic purity: 98.1%

/////Palbociclib, Sun Pharmaceutical Industries Ltd, New patent, WO 2016016769