FIELD OF THE INVENTION
The present invention relates to an improved process for the Preparation of pyrazole substituted
aminoheteroaryl compounds, more particularly 3-[(IR)-1-(2,6-dichloro-3-fluorophenyl)ethoxy ]-
5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine and its intermediates which is simple,
convenient, economical and industrially viable.
BACKGROUND OF THE INVENTION
The compound (R)-3-[ 1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy ]-5-(1-piperidin-4-yl-1 H -pyrazol-
4-yl)-pyridin-2-ylamine, also known as Crizotinib, is represented by the Formula (1):
Cl
FVYif:::::-N,N-cNH
Cl 0 ~ H2N :-.... N
Formula (I)
Crizotinib is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor
receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Enantiomerically pure
compound of formula I was first disclosed in US Patent No. 7,858,643. Additionally, the
racemate of compound of formula I was disclosed in U.S. patent application 2006/0128724, both
of these references discloses similar methods for the synthesis of Compound of Formula I.
Conventionally, the compounds of formula I are prepared by reacting Bis(pinacolato )diboron
with proteQted 5-bromo-3-[ 1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy ]-pyridin-2-ylamine in the
presence ofPd catalyst. The obtained product after deprotection is reacted with N-protected 4-(4-
bromo-pyrazol-1-yl)-piperidine in the presence of Pd Catalyst. The obtained product is filtered
through celite pad and purified by Column Chromatography. The final product of formula I was
obtained by deprotection of the purified compound by using HCl/dioxane.
US Patent No. 7,858,643 provides enantiomerically pure aminoheteroaryl compounds,
particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity. More
particularly, US 7,858,643 describes process for the preparation of 3-[(IR)-1-(2,6-dichloro-3-
fluorophenyl)ethoxy ]-5-( 1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine. The Scheme IS
summarized below in Scheme-l :
2
..
+
-W
Cl ~~-.: hN
0
N(Boc) 2
I
F
+
a
Boc ¢
rNn N~
Br
3
b
c
d
..
e
¢Co
F
Scheme-l
wherein, "Boc" means tert-butoxycarbonyl; and a) (Boc)z, DMF, Dimethylaminopyridine b)
Pd(dppf)Ch, KOAc, Dichloromethane; c) HCl, Dioxane, Dichloromethane; d) Pd(PPh3)zCh,
NazC03, DMEIHzO; e) 4M HCl/Dioxane, Dichloromethane
A similar process has been disclosed in the U.S. patent application 2006/0128724 for the
preparation of Crizotinib. J. Jean Cui et. a/. in J. Med. Chern. 2011, 54, 6342-6363, also
provides a similar process for the preparation of Crizotinib and its derivatives.
However, above mentioned synthetic process requires stringent operational conditions such as
filtration at several steps through celite pad. Also column chromatography is required at various
steps which. is not only tedious but also results in significant yield loss.
Another disadvantage of above process involves extensive use of palladium catalysts, hence
metal scavengers are required to remove palladium content from the desired product at various
steps which makes this process inefficient for commercial scale.
Yet another disadvantage of above process is the cost of Bis(pinacolato )diboron. This reagent is
used in excess in the reaction mixture resulting in considerable cost, especially during large-scale
syntheses.
US Patent No. 7,825,137 also discloses a process for the preparation of Crizotinib where Boc
protected 4-( 4-iodo-pyrazol-1-yl)-piperidine is first reacted with Bis(pinacolato )diboron in the
presence of Pd catalyst. The reaction mixture is filtered through a bed of celite and the obtained
filtrate is concentrated and purified by silica gel chromatography to give to form tert-butyl-4-[ 4-
( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate. To this
compound, 5-bromo-3-[ 1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy ]-pyridin-2-ylamine is added in
4
..
the presence of a Pd catalyst. The reaction mixture is stirred for 16h at 87°C. The reaction
mixture is filtered through celite pad and the concentrated filtrate is purified on silica gel column
to obtain ( 4-{ 6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy ]-pyri- din-3-yl }-pyrazol-
1-yl)-piperidine-1-carboxylic acid tert-butyl ester of 95% purity. To the solution of resulting
compound in dichloromethane 4N HCl/Dioxane is added and thereby getting the reaction
suspension is filtered in Buchner funnel lined with filter paper. The obtained solid is dissolved in
HPLC water and pH is adjusted to 10 with the addition ofNazCOJ. Compound is extracted using
dichloroform and is purified on a silica gel column by eluting with CHzCh/MeOHINEt3 system
to obtain Crizotinib. The scheme is summarized below in scheme 2:
Formula (iii)
Boc ¢
N~
I
Formula (i)
+
a
Boc ¢
N~
!~
Formula (ii)
5
Boc ¢
N~
d~
Formula (ii)
b
¢Co
F
Formula (iv)
..
Boc H QI Q ,N ,N
N\ h c N\ h
¢C 0 ¢C 0
NH2 NH2
I I
F F
Formula (v) Formula (I)
Scheme-2
wherein, "Boc" means tert-butoxycarbonyl; and a) Bis(pinacolato )diboron, Potassium Acetate,
DMSO, dichlorobis(triphenylphosphino)palladium (II), 80° C b) Pd(PPh3)zC12, DME/HzO,
NazC03; c) 4M HCl/Dioxane, CHzClz, NazC03
The inventors of present invention have found that, compound of Formula (ii) obtained by
following the process of Scheme-2 contain (pyrazol-1-yl)-piperidine dimer as an impurity as
represented.by Formula (A), hence reduces the yield ofthe desired compound. Boc,Q
%:)---\:%Y'l
~N'Boc
Wherein, "Boc" means tert-butoxycarbonyl
Formula (A)
Additionally the compound of Formula (ii) thus prepared also contain other impurities such as
unreacted starting material i.e. compound of Formula (i), other by-products such as compound of
Formula (B), as represented hereinbelow:
Boc ¢
N ON
Formula (B)
6
..
HPLC assay of the crude reaction mixture for the preparation of compound of Formula (ii) by
following the process of Scheme-2 is provided hereinbelow in Table-t:
Compound % in the Reaction Mixture
Compound of Formula (i) 26.61%
Compound of Formula (ii) 8.87%
Compound of Formula (A) 7.75%
Compound of Formula (B) 13.09%
From Table- I, it is evident that compound of Formula (ii) prepared by following the process of
Scheme-2 is only 8.87% that means reaction does not proceed to completion and contain starting
material in significant amount with other major byproduct or impurities.
Accordingly, to remove such byproducts or impurities these processes involve stringent
operational conditions such as filtration at several steps through celite pad or Buchner funnel.
Also column chromatography is required at various steps which needless to mention, are not
only tedious but also results in significant yield loss.
Another disadvantage of hereinabove mentioned prior art processes i.e. Scheme-l and as well in
Scheme-2 is the use of highly expensive Bis(pinacolato)diboron. This reagent is used in excess
in the reaction mixture resulting in considerable cost, especially during large-scale synthesis,
which renders such methods as particularly not having any significant economic, industrial or
commercial viability, application or advantage.
The prior art, as known to the inventor additionally includes the process disclosed in Org.
Process Res. Dev. 2011, 15, 1018-1026. This describes a process that obviates the use of
bis(pinacolato )diboron for the preparation of compound of Formula (ii) as used in conventional
methods.
This process involves the reaction of Hoc-protected 4-(4-iodo-pyrazol-1-yl)-piperidine with iPrMgCl
in THF at 20°C, which was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane yielding tert-butyl-4-[ 4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-IHpyrazol-
1-yl]piperidine-1-carboxylate in a modest 70-80% yield after workup, precipitation
from ethanol and water and subsequent recrystallization. The reaction scheme is summarized as
below in scheme 3:
7
..
Boc Boc
I
QI Q a
NQ N~
I B-0
Formula (i) Fonnula (ii)QF
Scheme 3
a) (i) i-PrMgCl in THF, 0°C, then warm to 20°C; (ii) 2-methoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane, THF, 20°-30°C, then EtOAc; (iii) EtOH/water cryt, 70-80%.
However, in this process particular care was required to ensure that sufficient water was added
during the crystallization process to maximize recovery of the compound. Also, inventors of the
present invention found that, by following the same procedure and conditions as mentioned in
Org. Process Res. Dev. 2011, 15, 1018-1026, solid compound of Formula (ii) was not obtained.
Inventors further revealed that, reaction does not proceed to completion and starting material i.e.
compound of Formula (i) was detected in HPLC assay even after 9h of reaction time period. The
HPLC assay of the crude is provided hereinbelow in Table-2:
Compound % in the Reaction Mixture
Compound of Formula (ii) 67.95%
Compound of Formula (i) 15.61%
In addition to above, major content of about 13.17% of an unknown impurity was found in the
HPLC assay of the reaction mixture.
Additionally, it was observed by the inventors that, inadequate purification of compound of
Formula (ii) at this stage lead to unacceptable impurities in the forthcoming reaction steps, which
involves the reaction with highly expensive compound of Formula (iii).
It was found that, if purity of compound of Formula (ii) is less than 90%, the reaction does not
proceed to completion for the preparation of compound of Formula (iv) and difficulties were
encountered in the isolation of compound of Formula (iv).
From the foregoing, it would be thus apparent that the reported methods for the preparation of
Crizotinib suffer from one or more of the following disadvantages or limitations viz.
8
..
a) Scavenger support for the removal of metal values especially palladium makes reported
processes cost extensive;
b) Formation of significant amounts of undesired compounds e.g. compounds of Formula
(A) and Formula (B);
c) Utilization of tedious chromatographic, extraction, and/or multiple crystallization
techniques for separation and removal of said undesired compounds;
d) Use of expensive reactants like bis(pinacolato)diboron makes the reported processes cost
extensive;
e) Palladium Catalyzed boronation involves high level of dimerization impurities, resulting
in wastage of expensive materials and reducing yield of the reaction;
t) Strict adherence to critical reaction conditions and parameters e.g. inadequate purification
after the coupling reaction leading to the formation unacceptable impurities in the
forthcoming reaction steps.
Considering the therapeutic and commercial importance of Crizotinib, a need, therefore, exists
for a method for synthesis of Crizotinib, which is simple, convenient, economical, industrially
viable.
OBJECT OF THE INVENTION
It is an object of the invention to overcome the drawbacks of the prior art. It is another object of
the invention to provide a method for synthesis of Crizotinib and its intermediates which is
simple, convenient, economical and industrially viable.
SUMMARY OF INVENTION
In first embodiment, the present invention provides an improved process for the preparation of a
compound of Formula (I) or its pharmaceutically acceptable salt,
Cl
Fyyif:::::-....N,NDH
Cl 0 ~ H2N ~ N
Formula (I)
9
..
comprising the steps of:
a) reaction of a compound of Formula (II),
('t;J.-P <(,J)V
Br
Formula (II)
wherein, P represents a protecting group
with the compound of Formula (III),
R2 R3
PjdR4 R1 0,....... B' o Rs
Formula (III)
wherein, R1, Rz, R3, ~or Rs may be independently selected from the group comprising of
hydrogen or straight or branched chain alkyl, alkylene, alkene or alkoxy group
in the presence of a base to obtain a compound ofFormula (IV),
r't-:J"p SJAJ
o-B,
R __J..._ /0
3 ~ {-.R
R4 s
Formula (IV)
wherein R1, R2, R3, ~or Rs have the meanings given under Formula (Ill) and P represents
a protecting group;
b) coupling the compound of Formula (IV) with compound of Formula (iii),
Cl ~
o~N
I NH2
F
Formula (iii)
10
to obtain a compound of Formula (V),
NCI ~ N
F~t:f:::-... ·N-cN-P Cl 0 1?' I
,...
H2N N
Formula (V)
wherein, P represents a protecting group; and
c) deprotecting the compound of Formula (V) with an Acid to obtain the compound of
Formula (I) of high purity.
In second embodiment, the present invention provides a process for the preparation of a
compound of Formula (IV),
Formula (IV)
wherein, R1, R2, R3, ~or R5 may be independently selected from the group comprising of
hydrogen or straight or branched chain alkyl, alkylene, alkene or alkoxy group and P
represents a protecting group
by reacting a compound of Formula (II),
('r·rP
~A/
Br
Formula (II)
wherein, P represents a protecting group in the presence of a base with a compound of
Formula (III),
11
Formula (III)
wherein, R1, R2, R3, Rt or Rs have the meanings given under Formula (IV).
In another embodiment, the compound of Formula (IV) may be converted to compound
of Formula (I).
In third embodiment the present invention provides a process for the purification of the
compound of Formula (V).
Formula (V)
wherein, P represents a protecting group comprising the steps of:
a) preparing an acid addition salt of the compound of Formula (V) to obtain a compound of
Formula (VI);
Formula (VI)
wherein, X includes organic or inorganic acids and P represents a protecting group; and
b) isolating the purified compound of Formula (V) by adjusting the pH in the range of 6-9.
Yet, in another embodiment, the purified compound of Formula (V) may be converted to
compound of Formula (1).
In fourth embodiment the present invention provides an intermediate of Formula (VI),
Formula (VI)
wherein, X represents organic or inorganic acids and P represents a protecting group.
12
DETAILED DESCRIPTION OF THE INVENTION
The present invention is detailed as hereinunder.
The compound of Formula (II) as used herein may be obtained by treating 4-bromopyrazole with
N-protected methanesulfonyloxy-piperidine in the conventional manner known in the art or by
methods as described in US 7,858,643; which is incorporated herein for reference purpose only.
The examples of suitable protecting agents for the protection of methanesulfonyloxy-piperidine
include, but are not limited to, those that lead to the formation of carbamates or amides or cyclic
imide derivatives or N-Alkyl or N-Aryl amines or imine derivatives or enamine derivatives. In
certain exemplary embodiments, the protecting agent may be selected from the group comprising
of acetic anhydride, di-tert-butyl dicarbonate (i.e., Boc anhydride) or 9-fluorenylmethoxy
carbonyl reagent (i.e., Fmoc reagent).
R1, R2, R3, ~ or Rs in the compound of Formula Ill, may be independently selected from the
group comprising of hydrogen or straight or branched chain alkyl, alkylene, alkene or alkoxy
group. Preferably, R1, R2, R3, ~or Rs may be independently selected from the group comprising
of methyl, ethyl or propyl etc.
In first embodiment of the present invention, Step a) provides a process for the reaction
(generally referred herein as boronation) of compound of Formula (II) with compound of
Formula (III) to obtain a compound of Formula (IV). The reaction may be performed in the
presence of a suitable base. Suitable base may be selected from the group comprising of metal
hydrides such as sodium hydride or the like or metal hydroxides such as sodium hydroxide,
potassium hydroxide, lithium hydroxide, barium hydroxide or the like or metal carbonates such
as sodium carbonate, calcium carbonate, cesium carbonate or the like or metal alkoxides such as
sodium methoxide, sodium ethoxide, potassium t-butoxide or the like or sodium hydrogen
carbonate such as sodium hydrogen carbonate or the like or organic amines such as
triethylamine, diisopropylethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene, 2,6-lutidine or the
like or pyridine or alkyl lithiums such as n-butyllithium, sec- butyllithium, tert- butyllithium or
the like. Preferably, the reaction may be performed in the presence ofn- butyllithium.
The reaction may be carried out in the presence of a suitable solvent. Suitable solvent may be
selected from the group comprising of alcohols, halogenated hydrocarbons, non-polar solvents,
13
polar aprotic solvents, polar protic solvents, water, ketones, esters, ethers or mixtures thereof.
Suitable solvent may be selected from the group comprising of alcohols such as methanol,
ethanol, t-butanol, n-butanol, isopropanol or the like mixtures thereof or halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixture
thereof or non-polar solvents such as benzene, toluene, dioxane, ethers, halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixtures
thereof or. polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide, acetonitrile, dimethyl sulfoxide or the like or mixtures thereof or polar
protic solvents such as methanol, ethanol, t-butanol, n-butanol, isopropanol, formic acid, acetic
acid, nitromethane or the like or mixture thereof or water or ketones such as acetone, diisobutyl
ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone,
acetylacetone or the like or mixture thereof or esters such as methyl acetate, ethyl acetate or the
like or mixture thereof or ethers such as Dimethyl ether, Diethyl ether, Tetrahydrofuran, Dioxane
or the like or mixture thereof. Preferably, the reaction may be carried out in tetrahydrofuran.
The reaction may be performed at a temperature range of about -100 to 50°C. Preferably, the
reaction may be carried out at a temperature range of -70°C to about -80°C.
It was found that in the reaction of compound of Formula (II) with compound of Formula (III)
for the preparation of compound of Formula (IV), a very significant reduction of undesired
impurities could be achieved by carrying the reaction in the presence of a suitable base. It was
observed that selection of base in this reaction is very critical. It was found that by the selection
of an appropriate base the compound of Formula (IV) can be obtained with high purity and free
of undesired impurities. Typically, it was found that, compound of Formula (IV) obtained by
following the process of present invention has a purity ~ 98% and was essentially free of starting
material or reagents or any corresponding dimer of(pyrazol-1-yl)-piperidine, such as represented
by Formula (A) hereinbefore.
In first embodiment of the present invention, Step b) provides a process for the coupling of
compound of Formula (IV) with compound of Formula (iii) to obtain a compound of Formula
(V). The reaction may be carried out in the presence of a suitable catalyst. Suitable catalyst may
be selected from the group comprising of 1,1 '-Bis( diphenylphosphino )ferrocene-palladium(II)
14
dichloride dichloromethane, Palladium-tetrakis(triphenylphosphine ), Palladium(II) chloride,
Tris( dibenzylideneacetone )dipalladium(O), Palladium(O) his( dibenzylideneacetone) or the like.
The reaction may be performed in the presence of a suitable base. Suitable base may be selected
from the group comprising of metal hydrides such as sodium hydride or the like or metal
hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium
hydroxide or the like or metal carbonates such as sodium carbonate, calcium carbonate, cesium
carbonate or the like or metal alkoxides such as sodium methoxide, sodium ethoxide, potassium
t-butoxide or the like or sodium hydrogen carbonate such as sodium hydrogen carbonate or the
like or organic amines such as triethylamine, diisopropylethylamine, 1 ,8-
Diazabicyclo[5.4.0]undec-7-ene, 2,6-lutidine or the like or pyridine or alkyllithiums such as nbutyllithium,
sec- butyllithium, tert- butyllithium or the like. Pr~ferably, the reaction may be
performed in sodium carbonate, calcium carbonate, cesium carbonate or the like.
The reaction may be carried out in the presence of a suitable phase transfer catalyst. Suitable
phase transfer catalyst may be selected from the group comprising of tetramethylammonium
chloride, tetramethylammonium bromide, benzyltriethylammonium chloride,
methyltrioctylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium hydrogen sulfate, tetrabutylphosphonium chloride, tetraphenyl
phosphonium bromide, tetraphenylphosphonium chloride, triphenylmethyl phosphonium
bromide, triphenylmethylphosphonium chloride or 4-dialkylaminopyridinium salts such as
tetraphenylarsonium chloride, bis[tris(dimethylamino)phosphine]iminium chloride and
tetratris[tris( dimethylamino )phosphinimino ]phosphonium chloride. Preferably, reaction may be
performed in the presence oftetrabutylammonium bromide.
The reaction may be carried out in the presence of a suitable solvent. Suitable solvent may be
selected from the group comprising of alcohols, halogenated hydrocarbons, non-polar solvents,
polar aprotic solvents, polar protic solvents, water, ketones, esters, ethers or mixtures thereof.
Suitable solvent may be selected from the group comprising of alcohols such as methanol,
ethanol, t-butanol, n-butanol, isopropanol or the like mixtures thereof or halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixture
thereof or non-polar solvents such as benzene, toluene, dioxane, ethers, halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixtures
thereof or polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone,
15
dimethylformamide, acetonitrile, dimethyl sulfoxide or the like or mixtures thereof or polar
protic solvents such as methanol, ethanol, t-butanol, n-butanol, isopropanol, formic acid, acetic
acid, nitromethane or the like or mixtures thereof or water or ketones such as acetone, diisobutyl
ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone,
acetylacetorie or the like or mixture thereof or esters such as methyl acetate, ethyl acetate or the
like or mixture thereof or ethers such as Dimethyl ether, Diethyl ether, Tetrahydrofuran, Dioxane
or the like or mixture thereof. Preferably, the reaction may be performed in water or toluene or
the like or in the mixture thereof.
As mentioned hereinabove, compound of Formula (V) can be converted to compound of
Formula (I) by any of the known literature methods, specifically by the process of step c) of the
first embodiment of the present invention.
In first embodiment of the present invention, Step c) provides a process for the deprotection of
compound of Formula (V) to obtain a compound of Formula (1). The reaction may be carried out
in the presence of a suitable acid. Suitable acid may be selected from the group comprising of
inorganic a~ids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and the like;
or organic acids such as formic acid, acetic acid, citric acid, trifluoroacetic acid, ptoluenesulfonic
acid and the like. Preferably, the reaction may be performed in organic acids
such as hydrochloric acid.
The reaction may be carried out in the presence of a suitable solvent. Suitable solvent may be
selected from the group comprising of alcohols, halogenated hydrocarbons, non-polar solvents,
polar aprotic solvents, polar protic solvents, water, ketones, esters, ethers or mixtures thereof.
Suitable solvent may be selected from the group comprising of alcohols such as methanol,
ethanol, t-butanol, n-butanol, isopropanol or the like mixtures thereof or halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixture
thereof or non-polar solvents such as benzene, toluene, dioxane, ethers, halogenated
hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane or the like or mixtures
thereof or polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide, acetonitrile, dimethyl sulfoxide or the like or mixtures thereof or polar
protic solvents such as methanol, ethanol, t-butanol, n-butanol, isopropanol, formic acid, acetic
acid, nitromethane or the like or mixtures thereof or water or ketones such as acetone, diisobutyl
ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone,
16
acetylacetone or the like or mixture thereof or esters such as methyl acetate, ethyl acetate or the
like or mixture thereof or ethers such as Dimethyl ether, Diethyl ether, Tetrahydrofuran, Dioxane
or the like or mixture thereof. Preferably, the reaction may be performed in tetrahydrofuran or
dioxane.
The reaction may be carried out at a temperature range from -20°C to room temperature.
Preferably, reaction may be carried at 0°C.
In second embodiment of the present invention, the reaction may be carried out under same
parameters as defined hereinabove for Step a) of the first embodiment.
In third embodiment of the present invention provides a process for the purification of compound
of Formula (V).
In third embodiment of the present invention, step a) provides a process for the preparation of
compound of Formula (VI) from the compound of Formula (V). The compound of Formula (VI)
may be prepared by treating compound of Formula (V) with an organic or inorganic acid. An
organic or inorganic acid may be selected from the group comprising of halogen acids such as
hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, carboxylic acids, sulfonic acids,
fumaric acid methansulfonic acid, toluenesulphonic acid etc. Preferably, the reaction may be
performed in an organic acid such as toluenesulphonic acid. A preferred compound of Formula
(VI) is a compound of Formula (VII),
Formula (VII)
wherein, P represents a protecting group.
The reaction may be carried out in the presence of a suitable solvent. Suitable solvent may be
selected from the group comprising of alcohols, halogenated hydrocarbons, non-polar solvents,
polar aprotic solvents, polar protic solvents, water, ketones, esters, ethers or mixtures thereof.
Suitable solvent may be selected from the group comprising of alcohols such as methanol,
17
ethanol, t-butanol, n-butanol, isopropanol or the like mixtures thereof or halogenated
hydrocarbol}s such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixture
thereof or non-polar solvents such as benzene, toluene, dioxane, ethers, halogenated
hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane or the like or mixtures
thereof or polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide, acetonitrile, dimethyl sulfoxide or the like or mixtures thereof or polar
protic solvents such as methanol, ethanol, t-butanol, n-butanol, isopropanol, formic acid, acetic
acid, nitromethane or the like or mixtures thereof or water or ketones such as acetone, diisobutyl
ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone,
acetylacetone or the like or mixture thereof or esters such as methyl acetate, ethyl acetate or the
like or mixture thereof or water or ethers such as Dimethyl ether, Diethyl ether, Tetrahydrofuran,
Dioxane or the like or mixture thereof. Preferably, the reaction may be performed in acetone or
the like.
In third embodiment of the present invention, Step b) provides a process for the isolation of
purified compound of Formula (V). The purified compound of Formula (V) may be obtained
from compound of Formula (VI) by adjusting the pH in the range of 6.0-9.0. The pH of the
solution may be adjusted by using a suitable base. Suitable base may be selected from the group
comprising of metal hydrides such as sodium hydride or the like or metal hydroxides such as
sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like or
metal carbonates such as sodium carbonate, calcium carbonate, cesium carbonate or the like or
metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or the like or
sodium hydrogen carbonate such as sodium hydrogencarbonate or the like or organic amines
such as triethylamine, diisopropylethylamine, 1 ,8-Diazabicyclo[ 5 .4.0]undec-7 -ene, 2,6-lutidine
or the like or pyridine or alkyl lithiums such as n-butyllithium, sec- butyllithium, tertbutyllithium
or the like. Preferably, the pH of the solution may be adjusted by using alkali metal
hydrogencarbonate such as sodium hydrogen carbonate.
It was found that purification of compound of Formula (V) achieves a significant reduction of
palladium content in the isolated compound without using any tedious purification techniques or
by using highly expensive metal scavenger as used in the reported methods.
It was found that palladium contents were reduced from -1500 ppm to -105 ppm by using the
process of present invention and compound of Formula (V) was obtained with purity ~99%.
18
The purified compound of Formula (V) can be optionally converted to compound of Formula (I)
by any of the known literature methods. It was found that palladium content in the compound of
Formula (I) obtained by the process of the present invention was well within the prescribed
regulatory guidance. More specifically, palladium content in the compound of Formula (I) was in
the range of- 0.3 ppm to - 0.4 ppm with purity ~99% in a reproducible yield.
In fourth embodiment of the present invention, an intermediate of Formula (VI) is provided.
Detailed experimental parameters suitable for the preparation of Crizotinib according to present
invention are provided by the following examples, which are intended to be illustrative and not
limiting of all possible embodiments of the invention.
Example-!
Preparation of Tert-butyl 4-[ 4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-
yl]piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-(4-bromo-IH-pyrazol-1-yl)piperidine-1-carboxylate ( 25.0g,
0.076 mole) in THF ( 500 ml) at -70°C was added BuLi 1.6 Min Hexane solution ( 56.75 ml,
0.091 mole) dropwise followed by addition of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborola.ne (18.52 ml , 0.091 mole) at same temperature. Reaction mixture was stirred at -
70°C for lh then warmed to room temperature and continued stirring for 2h at room temperature.
Reaction mixture was quenched with ammonium chloride solution (25 ml) water (500 ml), and
ethyl acetate (750 ml) was added to reaction mixture, followed by extraction with ethylacetate
(100 ml x 2). The combined organic layer was washed with brine, concentrated under vacuum to
get crude product which was crystallized from n-Heptane to give pure title compound.
Yield: 51% (14.7g)
HPLC Purity: 96.7 %
MS (m/z): 378 (M + 1)
1HNMR (400 MHz, CDCh) o: 7.81 (s, IH), 7.75 (s, IH), 4.27 (m, 3H), 2.9 (m, 2H), 2.14 (m,
2H), 1.91 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12 H).
Example-2·
Preparation of Tert-butyl 4-( 4-{ 6-amino-5-[ ( 1 R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy ]pyridin-
3-yl }-1 H-pyrazol-1-yl)piperidine-1-carboxylate
19
5-bromo-3-[ 1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy ]-pyridin-2-ylamine ( 17 .Og, 0.044 moles),
tert-butyl 4-[ 4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-lcarboxylate
(20.25g, 0.054 moles) and tetrabutylammonium bromide (0.0741g, 0.00223 moles)
were dissolved in toluene ( 136 ml), and the resulting solution was added to a solution of cesium
carbonate (46.6g, 0.143 moles) in water (102 ml) at room temperature. The resulting mixture was
degassed with nitrogen. PdCb (dppf)2. CH2Cb (0.456 g, 0.00558 moles) was added to the
mixture and reaction mixture was degassed again by purging nitrogen. The reaction mixture was
heated to 90°C for 3h. After the completion of reaction solution was cooled to room temperature,
filtered through celite bed and water ( -170 ml) was added to filtrate. Organic layer was separated
and aqueous layer was extracted with ethyl acetate ( -85ml x 3). Combined organic layers were
washed with water (170 ml), concentrated under vacuum to give gummy mass. Crude product
was dissolved in toluene ( -85 ml) at 50-60°C. Heptane ( -170 ml) was added dropwise to this
mixture at 50-60°C. Mixture was stirred at room temperature for 12h. The obtained solid was
filtered and washed with heptane, dried under vacuum to give title compound.
Yield: 20 g (81 %)
HPLC Purity: 97 %
Example-3
Purification of Ten-butyl 4·(4·{6-amino·S·[( 1 R)·1·(2,6·dichloro·3·fluorophenyl)ethoxy]pyridin·
3-yl}-1 H-pyrazol-1-yl)piperidine-1-carboxylate
To a stirred solution of material obtained in Example -2 (17.0 g, 0.0308 moles) in acetone (140
ml) was added p-toluenesulphonic acid ( 5.8g, 0.0308 moles ) at room temperature. Reaction
mixture wa.S stirred at room temperature for 12h. Precipitated salt was filtered and washed with
acetone (-20 ml x 2). Obtained product was taken in water (170 ml), pH was adjusted to 7.0-8.0,
and the product was extracted with ethyl acetate (100 ml x 2). Combined organic layers were
washed with water and concentrated under vacuum to get title compound.
Yield: 14.6g
HPLC purity: 99.15 %
1HNMR (400 MHz, CDCh) o; 7.75 (d, J;;;:; 1.6 Hz, IH), 7.56 (s, lH), 7.48 (s, lH), 7.30 (dd, J;;;;;
9.2 Hz), 7.0 (m, lH), 6.86 (d, J = 1.6 Hz, lH), 6.07 ( q, J= 6.8 Hz, IH), 4.79 (brs, IH), 4.25 (m,
3H), 2.89 (m, 2H), 2.14 (m, 2H), 1.92 (m, 2H), 1.88 (d, J= 6.8 Hz, 3H), 1.47 (s, 15H).
Example-4
20
Preparation of Crizotinib:
To a stirred solution of Tert-butyl 4-(4-{6-amino-5-[(lR)-1-(2,6-dichloro-3-
fluorophenyl)ethoxy]pyridin-3-yl }-1H-pyrazol-1-yl)piperidine-1-carboxylate (material obtained
in Example 3) (l.Og, 0.00181 moles) in dichloromethane (~13 ml) at 0°C was added 4.0 M
dioxane HCl (6.7 ml, 0.0272 moles). Reaction mixture was stirred at room temperature for 4h.
After the completion of reaction monitored by TLC, solid was filtered and washed with
dichloromethane (1 0 ml). The obtained solid was dissolved in water (20 ml); aqueous layer was
extracted with dichloromethane (10x2). The pH of aqueous layer was adjusted to 9-10 with
Na2C03 and compound was extracted with dichloromethane (10 x 3), combined organic layers
were washed with water (20 ml), evaporated under vacuum to get solid product. The solid was
stirred with ether (10 ml), filtered off, washed well with ether, dried under vacuum to get
Crizotinib.
Yield: 0.45g (55 %)
HPLC Purity: 99.35 %
1HNMR (400 MHz, CDCh) o: 7.76 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.30 (dd, J =
9.2 Hz), 7.0 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.09 ( q, J= 6.8 Hz, 1H), 4.75 (brs, 1H), 4.19 (m,
1H), 3.25 (m, 2H), 2.76 (m, 2H), 2.16 (m, 2H), 1.92 (m, 2H), 1.85 (d, J= 6.8 Hz, 3H), 1.67 (brs,
1H)

WE CLAIM:
1. A process for the preparation of a compound of Formula (1),
F~C l 0~N(:~'> --cNH
H2N N
Formula (I)
Comprising the steps of:
a) reacting a compound of Formula (II),
D
. P
<;)
Br
Formula (II)
wherein, P represents a protecting group
with a compound of Formula (III),
R2 R3
Pj2R4 R1 B 0 ......... 'o Rs
Formula (III)
wherein, R1, Rz, R3, ~or Rs may be independently selected from the group comprising of
hydrogen or straight or branched chain alkyl, alkylene, alkene or alkoxy group
in the presence of a base to obtain a compound of Formula (IV),
rt:-J .. P
~A/
o-B,
R~ ~0
3 ~ --y.,_R
R4 s
Formula (IV)
22
wherein R1. Rz, R3, ~or Rs have the meanings given under Formula (III) and P represents
a protecting group;
b) coupling of the compound of Formula (IV) with a compound of Formula (iii),
Cl ~ oA.rN
NH2
F
Formula (iii)
to obtain a compound of Formula (V),
(I(CI ~ N
F~t.r;:,.....· N-cN-P
Cl 0 ~I
,....
H2N N
Formula (V)
wherein, P represents a protecting group; and
c) deprotecting the compound of Formula (V) to obtain the compound of Formula (I).
2. A process for the preparation of a compound of Formula (IV),
('r·rP f:JA_/
o-B,
R --L ,0
3 ~ -,._R
R4 s
Formula (IV)
wherein, R1, R2, R3 or ~ may be independently selected from the group comprising of
hydrogen or straight or branched chain alkyl, alkylene, alkene or alkoxy group and P
represents a protecting group
by reacting a compound of Formula (II),
23
("'t;J.-P