A PROCESS FOR THE PREPARATION OF PALBOCICLIB
Field of the Invention
The present invention relates to a process for the preparation of palbociclib.
Background of the Invention
Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2-
pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8 H)-one, represented by t e 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.
Summary of the Invention
The present invention relates to a process for the preparation of palbociclib.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within t e range
defined by a number up to ±10% of the value.
The term "room temperature," as used herein, refers to a temperature in the range
of25°C to 35°C.
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 t e 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 t e 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 t e 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 .
The compound of Formula V may be prepared by any method known in t e art, for
example, the method described in U.S. Patent No. 7,126,025, or by the method as
described herein.
The compound of Formula III may be prepared by any method known in the art,
for example, the method described in U.S. Patent No. 7,781,583.
The compound of Formula III is reacted with the compound of Formula V in the
presence of the palladium catalyst, the base, and optionally the ligand to give the
compound of Formula IV in a solvent.
The compound of Formula V may be reacted with the compound of Formula III
after isolation from the reaction mixture in which it is formed. Alternatively, the reaction
mixture containing the compound of Formula V may be used for the reaction with the
compound of Formula III.
The base is an organic base or an inorganic base. Examples of organic bases
include triethylamine, diisopropylethylamine, and tributylamine. Examples of inorganic
bases include potassium carbonate, sodium carbonate, and lithium carbonate.
The palladium catalyst is selected from the group consisting of
tetrakis(triphenylphosphine)palladium (0), palladium acetate, palladium chloride, and
trans-dichlorobis(acetonitrile)palladium (II) .
The ligand is selected from the group consisting of tri-o-tolylphosphine,
triphenylphosphine, and tri-i-butylphosphine.
The solvent is selected from the group consisting of ethers, halogenated
hydrocarbons, alcohols, and esters. Examples of ether solvents include tetrahydrofuran,
1,4-dioxane, diisopropylether, and methyl -butyl ether. Examples of halogenated
hydrocarbon solvents include dichloromethane, dichloroethane, chloroform, and carbon
tetrachloride. Examples of alcohol solvents include methanol, ethanol, n-propanol,
isopropanol, and n-butanol. Examples of ester solvents include ethyl acetate and butyl
acetate.
The reaction of the compound of Formula III with the compound of Formula V is
carried out for from about 15 hours to about 30 hours, for example, from about 18 hours to
about 24 hours.
The reaction of the compound of Formula III with the compound of Formula V is
carried out at a temperature of from about 50°C to about 90°C, for example, from about
70°C to about 80°C.
The compound of Formula IV may optionally be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. The compound of Formula IV may be
dried using conventional techniques, for example, drying, drying under vacuum, spray
drying, air drying, or agitated thin film drying.
The intramolecular cyclization of t e compound of Formula IV to give the
compound of Formula II is carried out in the presence of an acid anhydride or an acid
chloride.
Examples of acid anhydrides include acetic anhydride, propionic anhydride,
butyric anhydride, trifluoroacetic anhydride, and trifluoromethanesulfonic anhydride.
Examples of acid chlorides include acetyl chloride and ethanoyl chloride.
The intramolecular cyclization of the compound of Formula IV may be carried out
after isolation from the reaction mixture in which it is formed. Alternatively, the reaction
mixture containing the compound of Formula IV may be used for this step.
The intramolecular cyclization of the compound of Formula IV is carried out for
from about 1hour to about 6 hours, for example, from about 2 hours to about 3 hours.
The intramolecular cyclization of the compound of Formula IV is carried out at a
temperature of from about 50°C to about 90°C, for example, from about 70°C to about
80°C.
The compound of Formula II may optionally be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. The compound of Formula II may be
dried using conventional techniques, for example, drying, drying under vacuum, spray
drying, air drying, or agitated thin film drying.
The compound of Formula II is converted to palbociclib of Formula I by processes
known in the art, for example, as disclosed in U.S. Patent No. 7,781,583.
While the present invention has been described in terms of its specific aspects and
embodiments, certain modifications and equivalents will be apparent to those skilled in t e
art, and are intended to be included within the scope of the present invention.
Method
Chromatographic purity was determined by HPLC using an Agilent® Model 1200;
the column used was an ACE® C18-PFP (150 x 4.6 nm).
The following examples are for illustrative purposes only and should not be
construed as limiting the scope of the invention in any way.
EXAMPLES
Preparation of 2-chloro-8 -cyclopentyl-5 -methyl-8H-pyrido 2.3 -Jlpyrimidin-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. Transdichlorobis(
acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-otolylphosphine
(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. Transdichlorobis(
acetonitrile) palladium (II) (1.39 g) followed by the addition of tri-otolylphosphine
(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 t e 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%

We Claim:
1. 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 t e presence of a palladium catalyst, a base, and optionally a ligand to give a compound
of Formula IV.
A process for the reparation 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 t e 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 t e compound of Formula IV to palbociclib of Formula I .
A process for the preparation of a compound of Formula II
Formula II
comprising:
a) reacting a crotonic acid derivative of Formula V
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or ferf-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 process for t e reparation 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;
b) intramolecular cyclization of the compound of Formula IV to give a
compound of Formula II; and
Formula II
c) converting the compound of Formula II to palbociclib of Formula I .
5. The process according to claim 1, 2, 3, or 4, wherein the compound of Formula III
is reacted with the compound of Formula V to give t e compound of Formula IV in a
solvent.
6. The process according to claim 1, 2, 3, or 4, wherein the palladium catalyst is
selected from the group consisting of tetrakis(triphenylphosphine) palladium (0),
palladium acetate, palladium chloride, and trans-dichlorobis(acetonitrile) palladium (II).
7. The process according to claim 1, 2, 3, or 4, wherein the base is an organic base or
an inorganic base.
8. The process according to claim 7, wherein the organic base is selected from the
group consisting of triethylamine, diisopropylethylamine, and tributylamine, and the
inorganic base is selected from the group consisting of potassium carbonate, sodium