DESC:COGNATE APPLICATION:
The specification below is a cognate application of Indian Provisional Patent
Application No. 201721023027 filed on Jun. 30, 2017; Indian Provisional Patent
Application No. 201721043842 filed on Dec. 07, 2017.
5 FIELD OF THE INVENTION
The present invention relates to an improved method of producing
palbociclib and pharmaceutical compositions comprising the same.
BACKGROUND OF THE INVENTION
Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l10
piperazinyl)-2- pyridinyl] amino]pyrido 2,3-d]pyrimidin-7(8H)-one, represented
by the Formula (I).
N
N
N NH N O
N
HN O
formula (I)
Palbociclib is a potent and selective inhibitor of CDK4 and CDK6.
Patent no. US 6,936,612 (IN218291) discloses palbociclib and a process
15 for the preparation of its hydrochloride salt.
Method of preparing the isoethionate salt forms of Palbociclib is disclosed
in WO 2005005426 (IN247860). Further WO 2014128588
(IN4540/CHENP/2015) teaches that palbociclib free base obtained according to
salt break procedures, as described in example 4 of WO 2005005426, was highly
20 static prone and formed small primary particles, which agglomerated into large,
hard agglomerates that were difficult to disperse by sieving and were unsuitable
for further development (see page 2, lines 4 to 7). Therefore, WO 2014128588
(IN4540/CHENP/2015) provides palbociclib having larger primary particles and
3
reduced specific surface area, and also mentioned that these larger particles
demonstrate improved physicochemical and manufacturability properties.
Palbociclib is a class II of the Biopharmaceutical Classification System
(BCS). Hence it is believed that decrease in specific surface area results in slower
5 dissolution because of less solid-solvent interaction and hence it is important to
have the palbociclib of having less particle size/larger surface area. For drug
substances of commercial importance such as palbociclib it is important to
develop a preparation process, which is commercially viable, simple, economical,
and at the same time obtaining the drug substance with higher purity and yield.
10 SUMMARY OF THE INVENTION
The present invention relates an improved process of preparation of
Palbociclib of Formula-(I).
N
N
N NH N O
N
HN O
formula (I)
An aspect of the present invention provides an improved process of
15 preparation of Palbociclib intermediate of Formula (II)
N
O N N
CH3
NH N
N
N
H2C
O
alkyl PG
formula (II)
which comprises reacting a compound of Formula (III)
N
O N N
CH3
NH N
N
N
Hal
PG
formula (III)
4
with a compound of Formula (IV) in a closed system.
alkyl
O
formula (IV)
Another aspect of the present invention provides an improved process of
preparation of crystalline palbociclib of Formula-(I) having surface area greater
than 6.0 m2/g as determined b 5 y BET-nitrogen adsorption analysis.
Another aspect of the present invention provides an improved process of
preparation of crystalline palbociclib of Formula-(I) having surface area less than
2.0 m2/g as determined by BET-nitrogen adsorption analysis.
Another aspect of the present invention provides an improved process of
10 preparation of crystalline palbociclib of Formula-(I) having surface area between
2.0-6.0 m2/g as determined by BET-nitrogen adsorption analysis.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention relates to an improved process of
preparation of Palbociclib intermediate of Formula (II).
N
O N N
CH3
NH N
N
N
H2C
O
alkyl PG
formula (II)
15
which comprises reacting a compound of Formula (III)
N
O N N
CH3
NH N
N
N
Hal
PG
formula (III)
with a compound of Formula (IV) in a closed system
5
alkyl
O
formula (IV)
wherein the reaction is performed in presence of a transition metal catalyst, a base
and optionally phosphine compounds, in a suitable solvent, further, during
isolation reaction mixture is treated with metal scavenger to obtain a compound of
5 Formula (II).
The inventors of the present invention surprisingly found that performing
the above coupling reaction (Heck coupling) in a closed system or container such
as in an autoclave reduces the reaction time thereby increased yield is obtained as
compared to the known processes.
10 The closed system or container is a pressure vessel, preferably in an
autoclave.
In certain embodiments, the reaction is performed in autoclave under inert
atmosphere, preferably nitrogen atmosphere.
In certain embodiments, by performing the Heck reaction in closed system
15 the reaction time is decreased to less than half of the time required in the known
processes.
In an embodiment, the reaction time is less than 10 hrs, whereas in the
known process reaction time is more than 20 hrs. Preferably the reaction time for
the reaction in closed system is about 6 hours.
20 The alkyl mentioned in the present invention is any alkyl group, preferably
C1-C6 alkyl group.
The term Hal in compound of Formula (III) represent halogen, preferably
Br or I.
The term PG represents an amine protecting group selected from (CO)OR
25 or (CO)R where R is C1-5 linear or branched alkyl or R is aryl or alkyl6
(unsubstituted or substituted) aryl, Cbz, BoC, benzoyl, acetyl, phenylsulfonyl, tolylsulfonyl, methylsulfonyl or any other amine protecting group. Preferably PG is BoC.
In an embodiments of the invention, the transition metal catalyst is a palladium compound selected from the group consisting of 5 tetrakis(triphenylphosphine)palladium [(Ph3P)4Pd],tris (dibenzylideneacetone)dipalladium[Pd2(dba)3], bis(dibenzylideneacetone) palladium (0) [(dba)2Pd], palladium acetate [Pd(OAc)2], palladium chloride (PdCl2), bis(benzonitrile) dichloropalladium [(C6H5CN)2PdCl2] and (Bis-(diphenylphosphinoferrocene) palladium dichloride dichloromethane complex 10 (Pd(dppf)2Cl2), and the phospine compound is selected from 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 1,3 bis(diphenylphosphino) propane, triphenylphosphine (Ph3P), triorthotolylphosphine [(o-CH3Ph)3P], Bis[(2-diphenylphosphino)phenyl] ether and tri-t-butylphosphine. Preferably, the transition metal catalyst is palladium acetate and phosphine compounds are 15 triorthotolylphosphine and Bis[(2-diphenylphosphino)phenyl] ether. Performing the above coupling reaction (Heck coupling) in presence of phosphine compounds such as triorthotolylphosphine and Bis[(2-diphenylphosphino)phenyl] ether helps to remove heavy metal content as compared to the known processes.
In another embodiment of the invention, the base is selected from the 20 group consisting of diisopropyl ethylamine, lithium carbonate, dicyclohexyl methylamine and triethylamine. Preferably, the base is triethylamine.
In another embodiment of the invention, the suitable solvent or mixture thereof, is a solvent and/or that does not essentially obstruct the reaction.
In another embodiment of the invention, the suitable solvent is selected 25 from alcohol such as n-butanol.
In another embodiment of the invention, during isolation the suitable metal scavenger is Cysteine, N-acetylcysteine, thiourea and Silica-based commercially
7
available metal scavengers such as siliamets@thiol, SiliaMetS® Triamine, SiliaMetS® Cysteine.
In certain embodiments of the invention, the compound of Formula (III) can be prepared by methods known to those in the art.
The present invention also relates to a process for the removal of heavy 5 metals from palbociclib by treatment with cysteine or N-acetyl-cysteine in organic solvents with water.
Another aspect of the present invention relates to process of preparation of crystalline palbociclib of Formula-I having surface area greater than 6.0 m2/g as determined by BET-nitrogen adsorption analysis, comprising; 10
1) providing acid addition salt of palbociclib in alcohol solvent such as methanol; and
2) treating the step (1) solution with aqueous NaOH (sodium hydroxide).
It was surprisingly found that by following the improved or modified salt break procedure according to present invention, the crystalline palbociclib free 15 base having surface area greater than 6.0 m2/g is consistently obtained; crystalline palbociclib obtained is viable for pharmaceutical processing and further shows better dissolution rate, which in turn impacts the bioavailability.
In another embodiment, the crystalline form obtained by following improved or modified salt break procedure according to present invention, is 20 Form-A having surface area greater than 6.0 m2/g as determined by BET-nitrogen adsorption analysis as disclosed in WO2014128588.
In certain embodiments, the suitable acid addition salts which may be used are selected from acid addition salts of palbociclib with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, from acid 25 addition salts of palbociclib with organic acids such as isethionic acid, methanesulfonic acid, ethane-1,2-disulfonic acid, naphthalene-1 ,5-disulfonic acid, p-toluenesulfonic, thiocyanic acid, cyclamic acid and trifluoroacetic acid or
8
mixtures thereof. Acid addition salts of palbociclib may be employed as mono-salts having approximately 1:1 stoichiometry such as palbociclib monohydrochloride or as di-salts having approximately 1:2 stoichiometry such as palbociclib dihydrochloride.
Another aspect of the present invention relates to process of preparation of 5 crystalline palbociclib of Formula-I having surface area less than 2.0 m2/g as determined by BET-nitrogen adsorption analysis, comprising;
1) providing solution of palbociclib in mixture of methanol and dichloromethane,
2) precipitating palbociclib by addition of antisolvent like methyl-tert-butyl-ether,
3) isolating palboliclib having surface area less than 2.0 m2/g. 10
Another aspect of the present invention relates to process of preparation of crystalline palbociclib of Formula-I having surface area between 2.0-6.0 m2/g as determined by BET-nitrogen adsorption analysis, comprising;
1) providing solution of palbociclib in mixture of methanol and dichloromethane,
2) isolating palboliclib having surface area between 2.0-6.0 m2/g. 15
Another aspect of the present invention relates to process of preparation of crystalline palbociclib of Formula-I comprising treating Palbociclib acid addition salt with base in presence of methanol and water at adequate temperature; wherein the adequate temperature is 40-70 ºC. The said process gives Palbociclib with higher surface area. 20
In an aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the Formula (I) obtained according to present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.
In an embodiment, the process for the preparation according to present 25 invention is represented schematically in scheme-I as shown below
9
N
N
HN
N
N
N
N
O
O
BOC
N
N
Cl
N
Br
O
NH2
N
N
N
BOC
+
O
N
N
HN
N
N
N
N
Br
O
BOC
N
N
HN
N
N
N
N
H
O O
N
N
HN
N
N
N
N
H
O O
2.HCl
Formula (III)
Formula (II)
Formula (IV)
Formula (I)
Scheme (I)
The following examples are given for the purpose of illustrating the present
invention and should not be considered as limitation on the scope of the invention.
Examples
5 Example-1: tert-butyl 4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-
7,8-dihydropyrido [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-
carboxylate [Formula (II)]
To a solution of tert-butyl 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-
10 carboxylate (100 g) in n-butanol, n-butyl vinyl ether (102 g), and bis[(2-
diphenylphosphino)phenyl] ether (4.1 g), triethyl amine (52 g) were added at
room temperature in an inert autoclave system with nitrogen gas, followed by
addition of palladium acetate (1.2 g, 3 mol%). The resulting reaction mixture was
heated to 90-100 °C and maintained the system for 3 hours in the autoclave (under
15 closed condition). After completion of the reaction, tri-o-tolyl phosphine (10.4, 20
10
mol%) was added to reaction mixture and heated, then reaction mass was filtered and concentrated to remove the solvent. The resulting crude product was purified by using SiliameS@thiol, dichloromethane and ethyl acetate to afforded tert-butyl4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl)piperazine-1-carboxylate 5 (83 g, 80% yield, HPLC purity NLT 99.0%)
Example-2: Palbociclib [Formula (I)]
To a solution of tert-butyl4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate (100 g) in methanol, conc. (30-35%) HCl was added slowly. The 10 resulting mixture was heated to 53±3°C and stirred till completion of reaction, then cooled to 30±5°C, stirred, filtered, washed with methanol to obtain palbociclib dihydrochloride salt. To palbociclib dihydrochloride salt in methanol and water was added aqueous sodium hydroxide solution (19.8g NaOH in 150 mL water), the reaction mixture is stirred. The solid obtained was filtered and washed 15 with aqueous methanol to afford palbociclib [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazine-1-yl) pyridine-2-yl]amino}pyrido[2,3-d]pyrimidin-7-(8H)-one-1] (74-87.8% yield, HPLC purity NLT 99.9% ; BET surface area 7.8 m2/g).
Example-3: Palbociclib [Formula (I)]
To a solution of tert-butyl4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-20 7,8-dihydropyrido [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate (100 g) in methanol, conc. (30-35%) HCl was added slowly. The resulting mixture was heated to 53±3°C and stirred till completion of reaction, then cooled to 5±5°C, stirred, filtered, washed with methanol to obtain palbociclib dihydrochloride salt. To the solution of palbociclib dihydrochloride salt in 25 methanol, water, N-acetyl cysteine and activated charcoal was added, stirred at 30±5°C and filtered. Obtained filtrate was heated up to 57±3°C followed by addition of aqueous sodium hydroxide solution (19.8 g NaOH in 150 mL water), the reaction mixture is stirred, filtered and washed with water and methanol to
11
afford palbociclib [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazine-1-yl) pyridine-2-yl]amino}pyrido[2,3-d] pyrimidin-7-(8H)-one-1] (67-91% yield; BET surface area 4.1 m2/g).
Example-4: Palbociclib [Formula (I)]
To a mixture of dichloromethane and methanol, palbociclib (100 g) was added. 5 The resulting mixture was heated to reflux and stirred, then cooled to 3±5°C, stirred. The solid obtained was filtered washed with dichloromethane:methanol to obtain palbociclib (80-90% yield ; BET surface area 2.0- 6.0 m2/g).
Example-5: Palbociclib [Formula (I)]
To a mixture of dichloromethane and methanol, palbociclib (100 g) was added. 10 The resulting mixture was heated/reflux and stirred followed by methyl-tert-butyl-ether was added and stirred, cooled to 25±5°C, stirred, cooled to 3±5°C. The solid obtained was filtered, and washed with methyl-tert-butyl-ether to obtain palbociclib (70-80% yield ; BET surface area < 2.0 m2/g).
Reference example 1: tert-Butyl 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-15 7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1- carboxylate [Formula (III)]
To a solution of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (163 g) and 6-Bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 g) in toluene (700 mL), 612% LiHMDS (Lithium bis(trimethylsilyl)amide ) solution (16.7 %) in THF (tetrahydro furan) was slowly added at 16-21°C then warmed to 27-30 °C and stirred. After completion of reaction, toluene (800 mL) and water (50 ml) was added and stirred. Reaction mass was filtered and obtained wet solid was stirred in water, filtered and dried to afford tert-Butyl 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- carboxylate (4) (130 g, 76% yield). ,CLAIMS:We claim;
1. A process of preparing palbociclib,
N
N
N NH N O
N
HN O
formula (I)
comprising;
5 a) reacting compound of Formula (III),
N
O N N NH N
N
N
Br
O
O
formula (III)
with a compound of Formula (IV)
O
formula (IV)
in a closed system under pressure to obtain compound of Formula (II);
N
O N N NH N
N
O N
O
O
formula (II)
10
b) converting the compound of Formula (II) to Palbociclib.
2. The process as claimed in claim 1, wherein closed system is a pressure vessel.
3. The process as claimed in claim 1, wherein the reaction is carried out at a
temeperature in the range of 80-100 °C in the presence of in presence of a
15 transition metal catalyst and a base.
13
4. The process as claimed in claim 1 further comprises optionally contacting solution of Palbociclib with metal scavenger.
5. The process as claimed in claim 4, wherein metal scavenger is cysteine, N-acetylcysteine, thiourea and silica-based metal scavengers selected from siliamets@thiol, SiliaMetS® Triamine, SiliaMetS® Cysteine. 5
6. A process of preparation of crystalline Palbociclib having surface area less than 2.0 m2/g as determined by BET-nitrogen adsorption analysis, comprising;
1) providing solution of palbociclib in mixture of methanol and dichloromethane,
2) precipitating palbociclib by addition of antisolvent like methyl-tert-10 butyl-ether,
3) isolating palboliclib having surface area less than 2.0 m2/g.
7. A process of preparation of crystalline Palbociclib having surface area between 2.0-6.0 m2/g as determined by BET-nitrogen adsorption analysis, comprising;
1) providing solution of palbociclib in mixture of methanol and 15 dichloromethane,
2) isolating palboliclib having surface area between 2.0-6.0 m2/g.
8. A process of preparation of crystalline Palbociclib comprises treating Palbociclib acid addition salt with base in presence of methanol and water at adequate temperature. 20
9. The process as claimed in claim 8, wherein the adequate temperature is 40-70 ºC.