FIELD OF THE INVENTION
The present invention relates to an efficient and industrially advantageous process
for the preparation of pure 1H-pyrazolo[3,4-d] pyrimidine derivative. In particular
the present invention provides a process for the preparation of pure 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine, a key intermediate of 5 ibrutinib,
wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-
5-(4-phenoxy phenyl)pyrazole, an important precursor.
BACKGROUND OF THE INVENTION
Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4-
10 phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl] prop-2-en-1-one
is an orally administered drug that targets Bruton's tyrosine kinase (BTK). Ibrutinib
may be used for treating both B cell-related hematological cancers/ B cell chronic
lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis,
Sjogrens syndrome, lupus and asthma and is represented by following chemical
15 formula:
Ibrutinib and its pharmaceutically acceptable salts were first disclosed in US patent
US7,514,444. This patent discloses a process for the preparation of Ibrutinib by
involving use of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, as
intermediate as shown below:
20
3
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, a key intermediate
of ibrutinib, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl)
pyrazole was first disclosed in a PCT patent publication WO2001/019829 A2 as
shown in below sche5 me.
Various other publications like US patents US7,514,444; US7,718,662;
US8,883,803 and PCT publications WO2012/158843A2; WO2013/010136A2
follow the same process for the preparation of 4-amino-3-(4-phenoxyphenyl)-1H10
pyrazolo[3,4-d]pyrimidine as described above.
The process comprises the conversion of 4-phenoxybenzoic acid to the
corresponding acid chloride, which is then taken up in mixture of toluene and
tetrahydrofuranand further reacted with malononitrile in the presence of
diisopropylethylethylamine in toluene. The reaction mixture is stirred overnightand
15 after completion of reaction, followed by work up 1,1-dicyano-2-hydroxy-2-(4-
phenoxyphenyl)ethene is isolated as a residue and which is further purified.
The resulting 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with
trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the
presence of diisopropylethylamine as a base. The resulting reaction mixture is
4
stirred for 2 days to give 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (Omethylated
product) as an oil, which is purified by flash chromatography.
The O-methylated product is treated with hydrazine hydrate to give 3-amino-4-
cyano-5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a
temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[5 3,4-
d]pyrimidine as pale brown-grey solid.
Since, the above process involves the isolation of intermediates and takes long time
during reaction completion. Therefore, it is lengthy, not efficient. Further
publication is silent about the purity of 4-amino-3-(4-phenoxyphenyl)-1H10
pyrazolo[3,4-d]pyrimidine. Acetonitrile solvent has been used in methylation
reaction, which is carcinogenic.
The cyclization reaction has been carried out at 180°C and it is observed that the
cyclization reaction at high temperature of 180°C, results in grey brown solid
colour of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, may be
15 due to presence of inorganic impurities.
The said process also requires the use of expensive (trimethylsilyl)diazomethane to
obtain O-methylated product, which is sensitive to air and water, and hence, the
methylation reaction has to be carried out in the absence of water, under anaerobic
conditions; silica and flash chromatography are also used for purifying O20
methylated product. Since the above process involves complicated operation
processes, which leads to high production cost and therefore is not an attractive
option at industrially scale.
PCT publication WO2014/173289A1 discloses a process for preparation of 3-
amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion
25 into 4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidine has not been
disclosed.
5
The process involves conversion of 4-phenoxybenzoic acid to the corresponding
acid chloride, followed by reaction with malononitrile in the presence of
diisopropylethylethylamine in tetrahydrofuran. The reaction mixture has been
stirred for 16 hours and thereafter 1,1-dicyano-2-hydroxy-2-(4-phenoxypheny5 l)
ethene is isolated from reaction mixture.A solution of 1,1-dicyano-2-hydroxy-2-(4-
phenoxyphenyl)ethene in trimethoxymethane has been heated for 16 hours to give
1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product), which
is then reacted with hydrazine hydrate to give 3-amino-4-cyano-5-(4-phenoxy
10 phenyl)pyrazole.
The above process is inefficient, since it involves isolation of intermediates and
takes long time to complete the reactions and purity of 3-amino-4-cyano-5-(4-
phenoxyphenyl)pyrazole has not been disclosed.
A similar approach has been described in PCT publication WO2014/082598A1 for
15 preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole and is presented as
below:
The process involves conversion of4-phenoxybenzoic acid to the corresponding
acyl chloride by using sulfurous dichloride, followed by reaction with
20 malononitrile in the presence of sodium hydride to obtain 1,1-dicyano-2-hydroxy-
2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane. The
6
hydroxy moiety is then methylated using dimethyl sulphate to give 1,1-dicyano-2-
methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is
recrystallized from a mixture of hexane and ethylactetate. The solution of resulting
O-methylated product in ethanol was treated with hydrazine hydrate at reflux
temperature to give 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, followed b5 y
its recrystallization in hexane and further, its conversion into 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine was not disclosed.
The above process also involves isolation of intermediates; their purification which
leads to longer time in reaction completion, and it does not disclose the purity of
10 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. Further the above process
involves use of sodium hydride, which is a hazardous reagent and can ignite in air
during scale up.
Several alternative methods have been reported in literature, wherein process for
the preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
15 has been disclosed and are discussed herein.
A Chinese patent application CN103121999A discloses a process of preparation of
4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, as below:
The process involves reaction of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
20 with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic
solvents to give 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.
The said Chinese application is also silent about the purity of target compound and
even starts with the advance intermediates, which are expensive and make the
process unattractive from industrial point of view.
25 A similar approach has been described in US patent US8,940,893; PCT publication
WO2013/113097A1 and WO2015/018333A1 for preparing 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine .
7
In US patent US8,940,893 and PCT publication WO2013/113097A1, 4-amino-3-
(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is purified by using Combiflash
chromatography on silica gel. In PCT publication WO2015/018333A1, 4-
amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is purified by
recrystallization in ethyl acetate5 .
The purity of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine has not
been reported in above publications too. Further two of the above processes involve
tedious step of chromatographic purification, which is not industrial viable.
Another Chinese patent application CN103965201A discloses a process for the
10 preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine,
wherein 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl
tin (4-phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidine and followed by its recrystalliztion in isopropanol, as shown below:
15 The said Chinese application is also silent about the purity of 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it
starts with advance intermediates, which are expensive. Therefore, said route of
synthesis is not industrially applicable.
Purity of an API as well as intermediates is of great importance in the field of
20 pharmaceutical chemistry. It is well documented in the art that direct product of a
chemical reaction is rarely a single compound with sufficient purity to comply with
pharmaceutical standards. The impurities that can be present in pharmaceutical
compounds are starting materials, by-products of the reaction, products of side
reactions, or degradation products.
25 According to ICH guidelines, process impurities should be maintained below set
limits by specifying the quality of raw materials, their stoichiometric ratios,
8
controlling process parameters, such as temperature, pressure, time and including
purification steps, such as crystallization, distillation and liquid-liquid extraction
etc., in the manufacturing process. Typically, these limits should less than about
0.15 % by weight of each identified impurity. Limits for unidentified and/or
uncharacterized impurities are obviously lower, typically less than 0.10 % b5 y
weight. The limits for genotoxicimpurties could be much lower depending upon the
daily dose of the drug and duration of the treatment. Therefore, in the manufacture
of a drug substance, the purity of the starting materials is also important, as
impurties may carry forward to the active pharmaceutical ingredient such as
10 ibrutinib.
In view of the above, most of the prior art processes involve isolation of
intermediates, additional purification steps and silent about the purity or the assay
of 4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidine.
Thus, there is an urgent need for the development of a synthetic process which
15 produces pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidineor its
acid addition salts.
The present invention fulfills the need in the art and provides an improved,
industrially advantageous process for the synthesis of pure 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine, a key intermediate in the
20 preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-
phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent
and none of the intermediates have been isolated.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved and industrially
25 advantageous process for the preparation of pure 4-amino-3-(4-phenoxyphenyl)-
1H-pyrazolo[3,4-d]pyrimidine, a key intermediate in the preparation of ibrutinib or
pharmaceutically acceptable salt thereof. by minimizing the use of mixture of
solvents during the preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole.
9
Yet another object of the present invention is to provide process for the preparation
of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole wherein none of the
intermediates have been isolated.
Yet another object of the present invention is to provide a process for the
purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyraz5 ole.
Yet another object of the present invention is to provide process for the conversion
of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole into pure 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine.
SUMMARY OF THE INVENTION
10 Accordingly, the present invention provides a convenient, industrially
advantageous, efficient process for preparation of pure 4-amino-3-(4-
phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine compound of formula I, a key
intermediate in the preparation of ibrutinib or pharmaceutically acceptable salt
thereof,
Formula I
15 comprises the steps of:
a) reacting 4-phenoxybenzoic acid with a suitable reagent at a suitable temperature
to give 4-phenoxybenzoyl chloride of formula II;
Formula II
b) reacting in-situ the resulting compound of formula II with malononitrile in the
presence of a base, in a suitable organic solvent at a suitable temperature for
20 sufficient time to give 2-hydroxy-ethene compound of formula III;
Formula III
c) reacting in-situ the resulting compound of formula III with a suitable
methylating agent in the presence of a base at a suitable temperature to give 2-
methoxy-ethene compound of formula IV;
10
Formula IV
d) reacting in-situ the resulting compound of formula IV with hydrazine hydrate at
a suitable temperature to give 3-amino-4-cyano-pyrazole compound of formula V;
Formula V
e) optionally, purifying 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound
of formula V;
f) reacting resulting compound of formula V with formamide at a suita5 ble
temperature to give pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidine compound of formula I.
Another object of present invention provides a process for preparation of pure 4-
amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine compound of formula I
Formula I
10 comprises the steps of:
a) reacting 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula
V,
Formula V
with formamide at a suitable temperature not higher than140°C;
b) isolating pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
15 compound of formula I.
Another object of present invention is to provide a processes for the preparation of
3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V
Formula V
11
starting from 4-phenoxybenzoic acid using a single and same organic solvent
during all reaction steps.
Another object of present invention is to provide a processes for the preparation of
3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V
Formula V
comprises the 5 steps of:
a) reacting 4-phenoxybenzoic acid with a suitable reagent at a suitable temperature
to give 4-phenoxybenzoyl chloride compound of formula II;
Formula II
b)reacting in-situ the resulting compound of formula II with malononitrile in the
presence of a base, in a suitable organic solvent, at a suitable temperature for
10 sufficient time to give 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene
compound of formula III;
Formula III
c)reacting in-situ the resulting compound of formula III with a suitable methylating
agent in the presence of base at a suitable temperature to give 1,1-dicyano-2-
methoxy-2-(4-phenoxyphenyl)ethene compound of formula IV;
Formula IV
15 d) reacting in-situ the resulting compound of formula IV with hydrazine hydrate at
a suitable temperature to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of
formula V;
Formula V
e) optionally, purifying the resulting compound of formula V to give pure 3-
amino-4-cyano-5-(4-phenoxyphenyl) pyrazole of formula V.
12
Another object of present invention is to provide a process for the purification of 3-
amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of formula V
comprises the steps of:
a) suspending 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of formula V in a
suitable 5 ble solvent;
b) heating the reaction mixture at reflux temperature to obtain a solution;
c) optionally, adding a suitable second solvent to the solution;
d) cooling the reaction mixture;
e) isolating pure 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of formula V.
10 Use of pure 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole compound of
formula V, prepared by using process of present invention in the preparation of 4-
amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine compound of formula
I, a key intermediate of ibrutinib.
Use of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine compound of
15 formula I, prepared by using pure 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole
compound of formula V, prepared by using process of present invention, in the
preparation of ibrutinib.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and industrially advantageous process
20 for preparation of preparation of pure 4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[
3,4-d] pyrimidine compound of formula I, a key intermediate in the
preparation of ibrutinib or pharmaceutically acceptable salt thereof.
Pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine compound of
formula I refers to have purity greater than 95% by HPLC, preferably greater than
25 99% by HPLC and assay more than 97%, preferably greater than 98%.
As used herein, the term 'assay' represents a quantitative measurement of the major
component in the desired chemical substance/drug substance. It refers tocontent or
potency to provide an exact result which allows an accurate statement on the
content or potency of the analyte in a sample.
13
Pure 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V
refers to have purity greater than 93% by HPLC, preferably greater than 97% by
HPLC.
Generally the process involves the conversion of 4-phenoxybenzoic acid to the
corresponding acid chloride by reacting with a suitable reagent such as thiony5 l
chloride, oxalyl chloride or sulfuryl chloride. The reaction can be carried out at a
temperature of 20°C to 70 °C and it take about 1 to 5 hours for completion of
reaction. Specifically the reaction is carried out using thionyl chloride. After
completion of reaction, thionyl chloride may be distilled off and a suitable organic
10 solvent can be added. The suitable organic solvent can be selected from non-polar
aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and
the like, preferably toluene and preferably toluene. In a specific embodiment,
toluene is added to the resulting acid chloride and followed by distillation of
solvent to give 4-phenoxybenzoyl chloride compound of formula II, which is used
15 as such in the next step.
The resulting 4-phenoxybenzoyl chloride compound of formula II is then reacted
in-situ with malononitrile in a suitable solvent, in the presence of a base at a
suitable temperature for sufficient period of time to give 1,1-dicyano-2-hydroxy-2-
(4-phenoxyphenyl)ethene compound of formula III.
20 Generally, the reaction can be performed at a temperature of 20°C to 55°C for few
minutes to 5 hours. The suitable organic solvent can be selected from non-polar
aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and
the like, and is the same organic solvent which is used during first step to remove
traces of chlorinating reagent used during acid chloride formation. The base can
25 be selected from diisopropylethylamine,triethylamine, 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) and tertiary amines;sodium bicarbonate,
sodium carbonate, sodium hydride and the like,
After completion of the reaction, the reaction mass can be cooled to a temperature
of 15 °C to 40°C and treated with a suitable acid such as sulfuric acid. The reaction
30 mixture can be then stirred at a temperature of 15°C to 40°C for few minutes to
14
about 2 hours, preferably for 30 minutes. Thereafter, the layers can be separated
and organic layer can be washed with 10 % sodium chloride solution. The resulting
organic layer can be sed directly in next reaction.
The resulting compound of formula III then can be reacted in-situ with a suitable
methylating agent in the presence of a base at a suitable temperature to give 5 ive Omethylated
product, 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene compound
of formula IV.
The suitable methylating agent can be selected from dimethyl sulphate, methyl
iodide, dimethyl carbonate, tetramethylammonium chloride, methyl triflate
10 preferable dimethyl sulphate is used.
Generally, the base can be selected from inorganic base such as sodium hydroxide,
sodium carbonate, sodium bicarbonate, calcium hydroxide, and calcium carbonate.
The reaction may take place at a temperature of 20°C to 90 °C for 20 minutes to 5
hours. After completion of the reaction, the resulting reaction mass may be cooled
15 to 15°C to 60°C and water is added to the reaction mass. The reaction mass can be
stirred to form layers and the layers are separated. The aqueous layer is extracted
with a suitable solvent. The suitable organic solvent can be selected from non-polar
aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and
the like, and is the same organic solvent which is used during earlier steps. Both
20 the organic layers can be combined, washed with sodium chloride solution and the
resulting organic layer can be used directly in next reaction.
The resulting 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene compound of
formula IV in-situ is reacted with hydrazine hydrate at a suitable temperature for
sufficient time to complete the reaction. Generally, hydrazine hydrate can be added
25 slowly, since the reaction may be exothermic during addition of hydrazine hydrate
and temperature may rise up to 50°C. Thereafter the reaction mixture can stirred at
ambient temperature over a period of 20 minutes to 5 hours.
After completion of the reaction, the resulting solid can be collected by any means
known the art such as filtration, centrifugation, distillation, and the like and
30 preferably filtration.
15
The resulting 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V can optionally be purified by combining any suitable means such as
processing by extraction, treatment with activated carbon, acid-base treatment,
slurry wash and recrystalliztion and solvent/ antisolvent like addition of second
solvent to facilitate the crystallization. The said purification methods can optionall5 y
be combined and repeated to achieve the desired purity.
Particularly, the purification process involves the preparation of a solution of 3-
amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V in a suitable
solvent. Solution can be prepared by heating up to reflux temperature in a suitable
10 solvent. Thereafter, to the resulting solution optionally, a suitable second solvent
can be added as antisolvent to facilitate the complete crystallization. Thereafter, the
reaction mixture can be cooled and resulting solid can be collected to obtain pure
3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V.
Alternatively the reaction solution can be cooled to a temperature of less than 15°C
15 to facilitate crystallization. In an alternate way, 3-amino-4-cyano-5-(4-phenoxy
phenyl)pyrazole compound of formula V, can be slurry washed using a suitable
solvent. The suitable solvent used for the purification of 3-amino-4-cyano-5-(4-
phenoxy phenyl)pyrazole compound of formula V can be selected from alcoholic
solvent such as methanol, ethanol, n-propanol, isopropanol, butanol, n-butanol; a
20 chlorinated solvent such as chloroform, dichloromethane and the like. The suitable
second solvent used to facilitate the crystallization can be selected from but not
limited to water, ethers such asdipropyl ether, diisopropyl ether, diethyl ether,
isopropyl ether methyl tert-butyl ether, 1,2-dimethoxy ether,1,2-diethoxy ether and
the like. The purification using addition of second solvent to solution of 3-amino-
25 4-cyano-5-(4-phenoxy phenyl)pyrazole compound of formula V is advantageous
since it removes inorganic impurities along with some unknown colored impurities
and resulting compound has increased purity of 3-amino-4-cyano-5-(4-
phenoxyphenyl) pyrazole compound of formula V.
16
The resulting 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V prepared by using process of present invention is pure and have purity
of grater than 93% by HPLC, preferably more than more than 97% by HPLC.
The preparation of 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V from 4-phenoxybenzoic acid in four steps, without isolating an5 y
intermediate and using a same single organic solvent during all reactions forms an
inventive part of the invention.
The resulting 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V can be then converted to pure 4-amino-3-(4-phenoxyphenyl)-1H10
pyrazolo[3,4-d] pyrimidine compound of formula I using any method reported in
literature. Preferably 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V can be reacted with a suitable reagent such as formamide at a suitable
temperature to give pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]
pyrimidine compound of formula I.
15 Generally the reaction may take place at a temperature of not higher than 140°C for
few hours till the completion of reaction. Preferably the reaction can be carried out
at a temperature between 120°C to 140°C for 20 hours to 30 hours. After
completion of the reaction, the resulting reaction mass may be cooled to 25°C to
60°C and treated with a suitable solvent such as water and resulting reaction
20 mixture is stirred for 10 to 30 minutes. The resulting solid can be collected by
suitable means known the art. Generally the resulting compound can be washed
with water or suitable organic solvent. The suitable organic solvent can be selected
from hydrocarbon solvent selected from toluene, hexane, cyclohexane, heptane;
alcohol solvent such as methanol, ethanol, propanol, isopropanol; ketone solvent
25 such acetone, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone and a
like, preferably organic solvent selected from methanol, isopropanol, acetone and
toluene. The pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
compound of formula I have purity of greater than 95% by weight as determined
using HPLC, preferably greater than 99% by HPLC and assay more than 97%,
30 preferably greater than 98%.
17
According to one another aspect, the present invention provides a process for the
conversion of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V into pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine
compound of formula I. The process parameters for said conversion may be same
as mentioned above5 .
According to one another aspect, the present invention provides a process for the
preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V by using same organic solvent; wherein none of the intermediates have
been isolated.
10 The process parameters for said conversion may be same as mentioned above.
According to one aspect, the present invention provides a process for the
purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V.
The purification process involves suspension of 3-amino-4-cyano-5-(4-
15 phenoxyphenyl)pyrazole compound of formula V in a suitable solvent. Then, the
resulting reaction mixture is then heated at reflux temperature to obtain a solution;
optionally, suitable second solvent is added to the resulting solution to facilitate the
crystallization, the reaction mixture is cooled and the product is filtered to obtain
pure 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V.
20 The suitable solvent used for the purification of 3-amino-4-cyano-5-(4-
phenoxyphenyl)pyrazole compound of formula V is selected from alcoholic
solvents such as methanol, ethanol, isopropanol, n-propanol, butanol, n-butanol; a
chlorinated solvent such as chloroform, dichloromethane and the like. The suitable
second solvent are those solvent which facilitate crystallization; preferably selected
25 from water, ethers such as diethyl ether, dipropyl ether, diisopropyl ether, isopropyl
ether methyl tert-butyl ether, 1,2-dimethoxy ether,1,2-diethoxy ether and the like.
The above purification is advantageous because with recrystallization in alcoholic
solvent or with alcoholic solvent followed by addition of second solvent results in
enhanced purity such as removal of inorganic impurities/unknown colored
30 impurities and traces of heavy metal if present. The resulting 3-amino-4-cyano-5-
18
(4-phenoxyphenyl)pyrazole compound of formula V, qualify heavy metal test i.e.
less than 20ppm and residue on ignition test i.e. not more than 0.05%.
According to one another aspect, the present invention provides conversion of 3-
amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V, prepared by
using process of present invention into 4-amino-3-(4-phenoxyphenyl)-5 1Hpyrazolo[
3,4-d] pyrimidine compound of formula I.
According to one another aspect, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d] pyrimidine compound of formula I, prepared by using process of present
invention can be converted to ibrutinib.
10 Generally the process involves introduction of piperidinyl moiety at IH [on NHof
pyrazole moiety] of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]
pyrimidine compound of formula I under known reaction conditions such as
Mitsunobu reaction conditions to prepare tert-butyloxycarbonyl protected (1S)-1-
[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine of
15 formula VI.
Formula VI
The resulting compound of formula VI can be purified by any means such as
crystallization, by using chromatographic techniques such as column
chromatography or flash chromatography to remove triphenylphosphine oxide.
Thereafter, tert-butyloxycarbonyl protected (1S)-1-[(3R)-3-piperidyl]-3-(p20
phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine of formula VI is deprotected
using a suitable reagent to prepare (1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-
1,2,5,7-tetraza-1H-inden-4-ylamine of formula VII.
19
Formula VII
Boc-deprotectioncan be accomplished with strong acids such as trifluoroacetic acid
neat or in a suitable solvent or with HCl in a suitable solvent. The suitable solvent
can be selected from dichloromethane, chloroform, diethyl ether, 1,4-dioxane,
toluene, alcohols , preferably trifluoroacetic acid is used in dichloromethane.
The indenylamine compound of formula VII is then acylated using acryloy5 l
chloride in the presence of a base in a suitable solvent to obtain ibrutinib. The base
can be selected from triethylamine, tri-n-butylamine, diisopropylethylamine,Nmethylmorpholine,
DBU and the like. The suitable solvent can be selected from
dichloromethane, chloroform, dichloroethane, ether such as tetrahydrofuran, 2-
10 methyl tetrahydrofuran, 2-dimethoxy ether, 2- diethoxy ether, isopropyl ether and
methyl tert butyl ether; toluene, xylene, acetonitrile and the like. The acylation
reaction can be accomplished at a temperature of 0oC- 50oC and it takes 30 minutes
to sevral hours to complete the reaction and preferably reaction is carried out at
ambient temperature. The resulting ibrutinib can be purified by any means such as
15 crystallization, by using chromatographic techniques such as column
chromatography or flash chromatography.
The completion of reaction, at any stage can be monitored by any one of the
chromatographic techniques such as thin layer chromatography (TLC), high
pressure liquid chromatography (HPLC), ultra-high pressure liquid
20 chromatography (UPLC), IR, NMR and the like.
Major advantages realized in the present invention is that the process of present
invention is less time consuming, since isolation of intermediates have been
avoided, cost effective and industrial friendly.
The process described in present invention will be demonstrated in more details
25 with reference to the following examples, which are provided by way of illustration
20
only and should not be construed as limit to the scope of the reaction in any
manner.
Examples:
Example 1: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
4-Phenoxybenzoic acid (200g) was slowly added to thionyl chloride (400ml) at 5 a
temperature of 25-30oC and resulting reaction mixture was heated under stirring to
a temperature of 60-65oC for 5 hours. Thionyl chloride was distilled off under
vacuum at temperature below 60oC. Toluene (2x400ml) was added to the resulting
oily residue and thereafter distilled out completely under vacuum below 60ºC to
10 remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous
oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in
toluene (2000ml). Malononitile (80g) and diisopropylethylamine (320ml) were
sucessively added to the reuslting solution at a temperature of 25-30oC slowly,
maintaining reaction temperature 50-55°C. The reaction mass was further stirred
15 for 30 minutes. After completion of the reaction, the reaction mass was cooled to
25-30°C and a solution of sulfuric acid (1.25 M) was added. The reaction mixture
was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were
separated. The organic layer was washed with a solution of sodium chloride (10%)
and the resulting organic layer was used directly in next reaction.
20 Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the
resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of
reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours.
After completion of reaction, the reaction mass was cooled to a temperature of 25-
30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The
25 layers were separated and the aqueous layer was extracted with toluene (1000ml).
All the organic layers were combined and washed with sodium chloride solution
(10%). Activated carbon (20g) was added and reaction mixture was stirred for 30
minutes. The solution was filtered through hyflo bed and to the resulting organic
layer hydrazine hydrate (120ml) was added at a temperature of 25-30°C. During the
30 addition exothermicity was observed, and temperature of the reaction mass was
21
rose up to 40-50°C. Thereafter, the reaction mass was stirred at a temperature of
25-30°C for 1-2 hours. The resulting precipitated solid was filtered, slurry washed
with dichloromethane (400ml) and finally, dried to obtain title compound of
formula V (140g) purity 93.28% measured by HPLC.
Example 2: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyraz5 ole
4-Phenoxybenzoic acid (100g) was slowly added to thionyl chloride (200ml) at a
temperature of 25-30oC and resulting reaction mixture was heated under stirring to
a temperature of 50-55oC for 5 hours. Thionyl chloride was distilled off under
vacuum at temperature below 50oC. Toluene (250ml) was added to the resulting
10 oily residue and thereafter distilled out completely under vacuum below 50ºC to
remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a
viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved
in toluene (500ml). Malononitile (35.58ml) and diisopropylethylamine (160ml)
were sucessively added to the reuslting solution at a temperature of 25-30oC
15 slowly, maintaining reaction temperature around 50-55°C. The reaction mass was
further stirred for 10 minutes. After completion of the reaction, the reaction mass
was cooled to 25-30°C and a solution of sulfuric acid (70 ml in 1000 ml water) was
added. The reaction mixture was then stirred at a temperature of 25-30°C for 30
minutes, and the layers were separated. The organic layer was washed with a
20 solution of sodium chloride (10%) and the resulting organic layer was used directly
in next reaction.
Dimethyl sulfate (95.11ml) and sodium bicarbonate (96.16g) were added to the
resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of
reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours.
25 After completion of reaction, the reaction mass was cooled to a temperature of 55-
60°C, demineralized water (1000ml) was added. The reaction mass was cooled to a
temperature of 25-30°C and stirred for 10-15 minutes. The layers were separated
and the aqueous layer was extracted with toluene (500ml). All the organic layers
were combined and washed with sodium chloride solution (10%). To the resulting
30 organic layer hydrazine hydrate (50ml) was added at a temperature of 25-30°C.
22
During the addition exothermicity was observed, and temperature of the reaction
mass was rose up to 40-45°C. Thereafter, the reaction mass was stirred at a
temperature of 25-30°C for 1-2 hours. The resulting precipitated solid was filtered,
suck dried to obtain 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of
formula V (123g) purity 86.96% measured by HPLC5 .
Example 3: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in
isopropanol (350ml) and temperature of the reaction mixture was raised and
allowed to reflux to dissolve the solid completely to provide a clear solution. Then,
10 solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml)
was added and after stirring for hours the solid was filtered and dried to afford 3-
amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (26g) and
having purity of 97.54 % by HPLC .
Example 4: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
15 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in
isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux
to dissolve the solid completely upto clear solution. Water (1050ml) was added to
the solution and the reaction mixture was gradually cooled to crystallize the
product. The resulting solid was filtered, washed with two volumes of isopropanol,
20 dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-
phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity
of 97.23% .
Example 5: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[
3,4-d] pyrimidine compound of formula I
25 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in
formamide (100 ml) and heated at a temperature of 130°C, after completion of
reaction, the reaction mixture was cooled to a temperature of 30-35°C and
demineralized water (500ml) was added and the reaction mixture was stirred at a
temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone
30 (200ml) was added stirred the reaction mixture for 30-45 minutes. The resulting
23
solid was filtered, washed, dried to afford pure 4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[
3,4-d]pyrimidine compound of formula I (12g) having purity 99.6%
measured by HPLC.
Example 6: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[
3,4-d] pyrimidine compound of formula 5 la I
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (100g) was suspended in
formamide (500ml) and heated at a temperature of 135-140°C, after completion of
reaction, the reaction mixture was cooled to a temperature of 30-35°C and
demineralized water (1000ml) was added and the reaction mixture was stirred at a
10 temperature of 20-25°C for 1 hour. The resulting solid was filtered, washed with
water (500ml) then successively slurry washed with toluene (2 x 500ml) and dried
to afford pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine
compound of formula I (70g) having purity 99.8% measured by HPLC; assay >
98%; residue on ignition 0.05%; heavy metals < 20ppm.
15 Example 7: Preparation of (1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-
1,2,5,7-tetraza-1H-inden-4-ylamine
Diisopropyldiazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tertbutyloxycarbonyl-
3-(S)-hydroxypiperidine (1.0g,) and triphenylphosphine (2.59g)
in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p20
phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (1.0g) was added and warmed
till dissolution, and stirred overnight at room temperature. The reaction mixture
was filtered and the solvent was distilled under vacuum to get an oily residue,
which was further purified by flash chromatography (30-50 % ethyl acetate/
hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-
25 [(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine as a
light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and
trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water
was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0
ml). The layers were separated and the aqueous layer was basified with potassium
30 carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer
24
dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title
compound as light yellow oil.
Example 8: Preparation of l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo
[3,4-d]pyrimidin-l-yl)piperidin-l-yI)prop-2-en-l-one (Ibrutinib)
To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mix5 ture
of triethylamine (0.1g) and (1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-
tetraza-1H-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The
reaction mixture was stirred at 25-30°C for 18 hous and filtered. The solvent was
removed under vacuum to obtain crude ibrutinib, which was further purified by
10 column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.

WE CLAIM:
1. A process for preparation of pure 4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[
3,4-d]pyrimidine of formula I;
Formula I
comprises the steps of:
a) reacting 4-phenoxybenzoic acid with a suitable reagent at a suita5 ble
temperature to yield 4-phenoxybenzoyl chloride of formula II;
Formula II
b) reacting in-situ the resulting compound of formula II with malononitrile in the
presence of a base, in a suitable organic solvent at a suitable temperature for
sufficient time to yield 2-hydroxy-ethene compound of formula III;
Formula III
10 c) reacting in-situ the resulting compound of formula III with a suitable
methylating agent in the presence of a base at a suitable temperature to yield 2-
methoxy-ethene compound of formula IV;
Formula IV
d) reacting in-situ the resulting ethene compound of formula IV with hydrazine
hydrate at a suitable temperature to yield 3-amino-4-cyano-5-(4-phenoxy
15 phenyl)pyrazole of formula V;
Formula V
e) optionally, purifying amino pyrazole compound of formula V;
f) reacting the resulting compound of formula V, with formamide at a suitable
temperature to yield pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidine compound of formula I.
26
2. The process as claimed in claim 1, wherein in step a) the suitable reagent is
selected from thionyl chloride, oxalyl chloride or sulfuryl chloride; the suitable
temperature is 20°C to 70°C.
3.The process as claimed in claim 1, wherein in step b) the base is selected from
diisopropylethylamine,triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)5 ,
tertiary amines;sodium bicarbonate, sodium carbonate, sodium hydride; the
suitable organic solvent is selected from non-polar aprotic solvents such as
toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and the like.
4.The process as claimed in claim 1, wherein in step c) the suitable methylating
10 agent is selected from dimethyl sulphate, methyl iodide, dimethyl carbonate,
tetramethylammonium chloride, methyl triflate; the base is selected from
inorganic base such as sodium hydroxide, sodium carbonate, sodium
bicarbonate, calcium hydroxide, and calcium carbonate; the suitable organic
solvent is selected from non-polar aprotic solvents such as toluene, xylene,
15 hexane, tetrahydrofuran, 1,4-dioxane and the like.
5. A process for the preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
compound of formula V
Formula V
comprises the steps of:
a) reacting 4-phenoxybenzoic acid with a suitable reagent at a suitable
20 temperature to yield 4-phenoxybenzoyl chloride compound of formula II;
Formula II
b) reacting in-situ the resulting compound of formula II with malononitrile in the
presence of a base, in a suitable organic solvent, at a suitable temperature to yield
2-hydroxy-ethene compound of formula III;
Formula III
27
c) reacting in-situ the resulting compound of formula III with a suitable
methylating agent in the presence of base to yield 2-methoxy-ethene compound
of formula IV;
Formula IV
d) reacting in-situ the resulting compound of formula IV with hydrazine hydrate
to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of formula 5 V;
Formula V
e) optionally, purifying the resulting compound of formula V to yield pure 3-
amino-4-cyano-5-(4-phenoxyphenyl) pyrazole of formula V.
6. The process as claimed in claim 5, wherein intermediates of formulae II, III and
IV are not isolated.
10 7. A process for preparation of ibrutinib of following formula,
comprises the steps of:
a) reacting 4-phenoxybenzoic acid with a suitable reagent at a suitable
temperature to yield 4-phenoxybenzoyl chloride of formula II;
Formula II
b) reacting in-situ the resulting compound of formula II with malononitrile in the
15 presence of a base, in a suitable organic solvent at a suitable temperature for
sufficient time to yield 2-hydroxy-ethene compound of formula III;
Formula III
28
c) reacting in-situ the resulting compound of formula III with a suitable
methylating agent in the presence of a base to yield 2-methoxy-ethene compound
of formula IV;
Formula IV
d) reacting in-situ the resulting compound of formula IV with hydrazine hydrate
at a suitable temperature to yield 3-amino-4-cyano-pyrazole compound 5 und of
formula V;
Formula V
e) optionally, purifying 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of
formula V;
f) reacting the resulting compound of formula V, with formamide at a suitable
10 temperature to yield pure 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidine of formula I, and
Formula I
g) converting pyrimidine compound of formula I to ibrutinib.
8. The process as claimed in claim 7, wherein in step g) the conversion of
pyrimidine compound of formula I to ibrutinib comprises the step of;
15 a) reacting pyrimidine compound of formula I with 1-boc-3-(S)-
hydroxypiperidine under Mitsunobu reaction conditions to prepare compound of
formula VI;
Formula VI
29
b) deprotecting compound of formula VI using a suitable reagent to prepare
amino compound of formula VII;
Formula VII
c)acylated the resulting amino compound of formula VII using acryloyl chloride
in the presence of a base in a suitable solvent to prepare ibrutinib.
9. The process as claimed in claim 8, wherein in step b) the suitable reagent 5 nt is
selected from strong acid such as trifluoroacetic acid or hydrochloric acid.
10. The process as claimed in claim 8, wherein in step c) the suitable base is
selected from triethylamine, tri-n-butylamine, diisopropylethylamine, Nmethylmorpholine,
DBU and the like; the suitable solvent is selected from
10 dichloromethane, chloroform, dichloroethane, ether such as tetrahydrofuran, 2-
methyl tetrahydrofuran, 2-dimethoxy ether, 2- diethoxy ether, isopropyl ether
and methyl tert butyl ether; toluene, xylene, acetonitrile and the like.