PROCESS FOR THE PREPARATION OF DASATINIB AND ITS
INTERMEDIATES
Field of the Invention
The present invention relates to processes for t e preparation of dasatinib and
its intermediates.
Background of the Invention
Dasatinib monohydrate of Formula A, chemically, N -(2-chloro-6-methylphenyl)-2
[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
thiazolecarboxamide monohydrate, is a cyclic protein tyrosine kinase inhibitor. Dasatinib
monohydrate is marketed under t e brand name SPRYCEL® and is indicated for the
treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase
Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) with resistance
or intolerance to prior therapy including imatinib. SPRYCEL® is also indicated for the
treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia
(Ph+ ALL) with resistance or intolerance to prior therapy.
Formula A
The compound of Formula la,
wherein R1and R2 can be independently selected from the group consisting of hydrogen,
amino protecting group, and 6-chloro-2-methyl-pyrimidin-4-yl, 6-[4-(2-hydroxyethyl)-lpiperazinyl]-
2-methyl-4-pyrimidinyl, encompasses dasatinib of Formula B,
Formula B
and key intermediates of dasatinib of Formula lb, Formula lc, and Formula Id, or salts
thereof.
Formula l b
Formula l c Formula Id
U.S. Patent No. 6,596,746 provides a process for the preparation of -butyl {5-
[(2-chloro-6-methylphenyl)carbamoyl]-l, 3-thiazol-2-yl}carbamate (Formula lb), 2-
amino-N -(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (Formula lc), and N -(2-
chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-
carboxamide (Formula Id) which are the intermediates for t e preparation of dasatinib.
The process provided in the '746 Patent for t e preparation of -butyl {5-[(2-
chloro-6-methylphenyl) carbamoyl]-l, 3-thiazol-2-yl}carbamate (Formula lb), 2-amino-N-
(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (Formula lc), and N-(2-chloro-6-
methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-carboxamide
(Formula Id) involves four, five, and six synthetic steps, respectively, starting from ethyl
2-amino-l,3-thiazole-5-carboxylate as depicted in the chemical scheme below:
Third step
Dasatinib of Formula B
The first step of the process involves stirring a suspension of ethyl 2-amino- 1,3-
thiazole-5-carboxylate, 4-dimethylaminopyridine, and di- -butyl dicarbonate in dry
tetrahydrofuran for a time period of 24 hours. The solvent was evaporated in vacuo and
the residue obtained was suspended in ether, washed with ether, and dried in vacuo to
obtain ethyl 2-[(fert-butoxycarbonyl)amino] -1,3-thiazole-5 -carboxylate .
The second step involves treating a stirred solution of ethyl 2-[(tertbutoxycarbonyl)
amino]-l,3-thiazole-5-carboxylate in tetrahydrofuran-methanol with 6N
aqueous sodium hydroxide solution at room temperature for 24 hours. Most of the
tetrahydrofuran-methanol were removed by distillation under reduced pressure and the
aqueous solution was acidified with 6N hydrochloric acid to obtain a solid which was
filtered, washed with water and ether, then air dried, followed by drying in vacuo to obtain
2-[(fert-butoxycarbonyl)amino]-l,3-thiazole-5-carboxylic acid.
The third step involves adding a 2M solution of oxalyl chloride in dichloromethane
to a stirred solution of 2-[(tert-butoxycarbonyl)amino]-l,3-thiazole-5-carboxylic acid in
tetrahydrofuran and N,N -dimethylformamide, and then stirring the solution at room
temperature for 4 hours. The solvent was evaporated under reduced pressure and in vacuo
to obtain teri-butyl[5-(chlorocarbonyl)-l,3-thiazol-2-yl]carbamate.
The fourth step involves adding 2-chloro-6-methylaniline to a stirred solution of
-butyl [5-(chlorocarbonyl)-l,3-thiazol-2-yl]carbamate in dichloromethane at 0°C.
Diisopropylamine was added to the reaction mixture, warmed to room temperature, stirred
for 24 hours, diluted with dichloromethane, and washed with 2N hydrochloric acid. The
organic extract thus obtained was dried, filtered, and concentrated to obtain a residue. The
residue was diluted with ethyl acetate-ether, filtered, washed with ether, and dried in
vacuo to obtain fert-butyl{5-[(2-chloro-6-methylphenyl) carbamoyl]-l,3-thiazol-2-
yl}carbamate (Formula lb) in an overall yield of 48%.
The fifth step involves treating teri-butyl{5-[(2-chloro-6-methylphenyl)
carbamoyl]-l,3-thiazol-2-yl}carbamate (Formula lb) obtained in the fourth step with
trifluoroacetic acid at room temperature to obtain 2-amino-N-(2-chloro-6-methylphenyl)-
l,3-thiazole-5-carboxamide (Formula lc).
The sixth step involves reacting 2-amino-N-(2-chloro-6-methylphenyl)-l,3-
thiazole-5-carboxamide (Formula lc) with 4,6-dichloro-2-methylpyrimidine in the
presence of sodium hydride in tetrahydrofuran to obtain N-(2-chloro-6-methylphenyl)-2-
[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-carboxamide (Formula Id).
The seventh step of the process involves reacting N-(2-chloro-6-methylphenyl)-2-
[(6-chloro-2-methylpyrimidin-4-yl)amino] -1,3-thiazole-5-carboxamide (Formula 1d)
obtained in the sixth step with l-(2-hydroxyethyl)piperazine to obtain dasatinib of
Formula B.
J. Med. Chem., 47(27), 6658-6661 (2004), provides a four step process for t e
preparation of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-
l,3-thiazole-5-carboxamide (Formula Id) from 2-chlorothiazole.
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-
methylphenylisocyanate in the presence of «-butyl lithium in tetrahydrofuran to obtain 2-
chloro-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide. The second step
involves reacting 2-chloro -N-(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide with
4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain
2-chloro-N-(2-chloro-6-methylphenyl )-N-(4-methoxybenzyl)- 1,3-thiazole-5-carboxamide .
The third step involves reacting 2-chloro -N-(2-chloro-6-methylphenyl)-N-(4-
methoxybenzyl)-l,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine
in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-
chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino ]-N-(4-
methoxybenzyl)-l,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-
chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino ]-N-(4-
methoxybenzyl)-l,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and
trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-
chloro-2-methylpyrimidin-4-yl)amino] -1,3-thiazole-5-carboxamide (Formula 1d).
PCT Publication No. WO 2005/077945 provides a process for the preparation of 2-
amino-N-(2-chloro-6-methylphenyl)- 1,3 -thiazole-5-carboxamide (Formula lc) which
involves adding 3-ethoxyacryloyl chloride to a cold stirring solution of 2-chloro-6-
methylaniline and pyridine in tetrahydrofuran at a temperature of 0°C to 5°C. The mixture
thus obtained was then warmed, stirred for 2 hours at 20°C, and hydrochloric acid was
added at 0°C to 10°C. The mixture was diluted with water and the resulting solution was
concentrated under vacuum to a thick slurry. The slurry was diluted with toluene and
stirred for 15 minutes at 20°C to 22°C then for 1 hour at 0°C to obtain (E)-N-(2-chloro-6-
methylphenyl)-3 -ethoxyacrylamide .
N-Bromosuccinamide was added to a mixture of (E)-N-(2-chloro-6-methylphenyl)-
3-ethoxyacrylamide in 1,4-dioxane and water at -10°C to 0°C to obtain a slurry which was
warmed and stirred at 20°C to 22°C for 3 hours. Thiourea was added and the mixture was
heated to 80°C. After 2 hours, the resulting solution was cooled to 20°C to 22°C and
concentrated ammonium hydroxide was added dropwise. The resulting slurry was
concentrated under vacuum to about half volume and cooled to 0°C to 5°C to obtain a
solid which was collected by vacuum filtration, washed with cold water, and dried to
obtain 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula lc).
Several processes are known in t e literature for the preparation of 2-amino-N-(2-
chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (Formula lc), for example, PCT
Publication Nos. WO 2007/019210, WO 2007/106879, WO 2008/076883, andWO
2010/144338.
Several processes are known in t e literature for the preparation of N-(2-chloro-6-
methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-carboxamide
(Formula Id), for example, U.S. Publication No. US 2006/0004067; PCT Publication Nos.
WO 2007/106879 and WO 2 / 95 25 ARKIVOC, 2010(6), 32-38 (2010); and J. Med.
Chem., 49(23), 6819-6832 (2006).
The processes described in the prior art for the preparation of fert-butyl{5-[(2-
chloro-6-methylphenyl)carbamoyl]-l, 3-thiazol-2-yl}carbamate (Formula lb), 2-amino-N-
(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (Formula lc), and N-(2-chloro-6-
memylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-carboxamide
(Formula Id) suffer from one or more disadvantages such as a low yield, high number of
chemical reaction steps, difficulties in isolation of the products, and usage of hazardous
reagents such as oxalyl chloride, thionyl chloride, «-butyl lithium, and Nbromosuccinamide.
Therefore, processes described in the prior art for the preparation of
-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl] -1,3-thiazol-2-yl}carbamate (Formula
lb), 2-amino-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (Formula lc), and
N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5-
carboxamide (Formula Id) are believed to be unsuitable and/or undesirable for
commercial scale production.
Summary of the Invention
The present inventors have found an improved process for the preparation of the
compound of Formula l a by directly reacting the compound of Formula 2a with an
activated derivative of 2-chloro-6-methylaniline produced in situ by treating 2-chloro-6-
methylaniline with ethylmagnesium bromide. The present invention does not involve the
use of a hazardous reagent such as oxalyl chloride, thionyl chloride, «-butyl lithium, or N -
bromosuccinamide .
Thus, the present invention provides an efficient, industrially preferable, and
economic process for t e preparation of compound of Formula l a in good yield with
excellent chemical purity and a reduced number of process steps. The present invention
avoids the excess usage of environmentally hazardous reagents and organic solvents,
thereby promoting green chemistry and ensuring a cleaner surrounding by putting a
reduced load on the environment.
Detailed Description of the Invention
The term "amino protecting group", as used herein, refers to a chemical group that
prevents an otherwise reactive amino group from participating in undesirable chemical
reactions and which may be subsequently removed easily during t e process steps when
protection of the reactive amino group is no longer required. Examples of amino
protecting groups include, but are not limited to, acyl groups such as acetyl,
trifluoroacetyl, benzoyl, and the like; alkoxycarbonyl groups such fert-butyloxycarbonyl
(BOC); aryl-lower alkoxycarbonyl such as benzyloxycarbonyl; trityl; and 9-
fluorenylmethoxycarbonyl.
The term "combining" includes adding, dissolving, slurrying, stirring, or a
combination thereof.
The term "solvent", as used herein, refers to any solvent or solvent mixtures,
including, for example, water, aromatic hydrocarbons, esters, halogenated
hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples
of aromatic hydrocarbons include toluene and xylene. Examples of esters include
ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of
halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-
dichloroethane. Examples of ketones include acetone and methyl ethyl ketone.
Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar
aprotic solvents include N N-dimethylformamide, N N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, and N -methylpyrrolidone.
A first aspect of the present invention provides a process for the preparation of
compound of Formula l a or a salt thereof
Formula l a
which comprises, reacting a compound of Formula 2a or a salt thereof with a
compound of Formula 3,
Formula 2a Formula 3
wherein R1and R2 can be independently selected from t e group consisting of
hydrogen, amino protecting group, 6-chloro-2-methyl-pyrimidin-4-yl, and 6-[4-(2-
hydroxyethyl)-l-piperazinyl] -2-methyl-4-pyrimidinyl; and R can be independently
selected from the group consisting of Ci-C6 alkyl, C -C12 aryl, C7-C12 arylalkyl, and
C7-C 12 alkylaryl.
Reacting a compound of Formula 2a or a salt thereof with a compound of
Formula 3 comprises combining a compound of Formula 2a or a salt thereof with a
compound of Formula 3.
Reacting a compound of Formula 2a or a salt thereof with a compound of
Formula 3 may be performed in one or more solvents at a temperature of about 15°C
to about 40°C for a time period sufficient to complete the reaction.
The compound of Formula 3 of the present invention may be prepared in situ
by combining 2-chloro-6-methylaniline with ethylmagnesium bromide in one or more
solvents at a temperature of -10°C to 10°C for a time period sufficient to complete the
reaction.
After the completion of the reaction, the compound of Formula l a can be isolated
by a common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a
combination thereof.
The isolated compound of Formula l a may be purified by crystallization from
solvents, chromatographic methods, or a combination thereof.
A second aspect of the present invention provides a process for the preparation
of compound of Formula lb or a salt thereof
Formula l b
which comprises reacting a compound of Formula 2b or a salt thereof with a
compound of Formula 3,
Formula 2b Formula 3
wherein R can be independently selected from the group consisting of Ci-C6 alkyl,
C6-C12 aryl, C7-C12 arylalkyl, and C7-C12 alkylaryl.
Reacting a compound of Formula 2b or a salt thereof with a compound of
Formula 3 comprises combining a compound of Formula 2b or a salt thereof with a
compound of Formula 3.
Reacting a compound of Formula 2b or a salt thereof with a compound of
Formula 3 may be performed in one or more solvents at a temperature of about 15°C
to about 40°C for a time period sufficient to complete the reaction.
The compound of Formula 3 of the present invention may be prepared in situ
by combining 2-chloro-6-methylaniline with ethylmagnesium bromide in one or more
solvents at a temperature of -10°C to 10°C for a time period sufficient to complete the
reaction.
After the completion of the reaction, the compound of Formula lb can be isolated
by a common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a
combination thereof.
The isolated compound of Formula lb may be purified by crystallization from
solvents, chromatographic methods, or a combination thereof.
The compound of Formula lb is a suitable intermediate for the preparation of
dasatinib or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
A third aspect of t e present invention provides a process for the preparation of
compound of Formula l c or a salt thereof
which comprises reacting a compound of Formula 2c or a salt thereof with a
compound of Formula 3,
Formula 2c Formula 3
wherein R can be independently selected from the group consisting of Ci-C6 alkyl,
C6-C12 aryl, C7-C12 arylalkyl, and C7-C12 alkylaryl.
Reacting a compound of Formula 2c or a salt thereof with a compound of
Formula 3 comprises combining a compound of Formula 2c or a salt thereof with a
compound of Formula 3.
Reacting a compound of Formula 2c or a salt thereof with a compound of
Formula 3 may be performed in one or more solvents at a temperature of about 15°C
to about 40°C for a time period sufficient to complete the reaction.
The compound of Formula 3 of the present invention may be prepared in situ
by combining 2-chloro-6-methylaniline with ethylmagnesium bromide in one or more
solvents at a temperature of -10°C to 10°C for a time period sufficient to complete the
reaction.
After the completion of the reaction, t e compound of Formula l c can be isolated
by a common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a
combination thereof.
The isolated compound of Formula l c may be purified by crystallization from
solvents, chromatographic methods, or a combination thereof.
The compound of Formula l c is a suitable intermediate for the preparation of
dasatinib or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
A fourth aspect of t e present invention provides a process for the preparation
of compound of Formula Id or a salt thereof
Formula Id
which comprises reacting a compound of Formula 2d or a salt thereof with a
compound of Formula 3,
Formula 2d Formula 3
wherein R can be independently selected from the group consisting of Ci-C6 alkyl,
C -C12 aryl, C7-C 12 arylalkyl, and C7-C 12 alkylaryl.
Reacting a compound of Formula 2d or a salt thereof with a compound of
Formula 3 comprises combining a compound of Formula 2d or a salt thereof with a
compound of Formula 3.
Reacting a compound of Formula 2d or a salt thereof with a compound of
Formula 3 may be performed in one or more solvents at a temperature of about 15°C
to about 40°C for a time period sufficient to complete the reaction.
The compound of Formula 3 of the present invention may be prepared in situ
by combining 2-chloro-6-methylaniline with ethylmagnesium bromide in one or more
solvents at a temperature of -10°C to 10°C for a time period sufficient to complete the
reaction.
After the completion of the reaction, the compound of Formula Id can be isolated
by a common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a
combination thereof.
The isolated compound of Formula Id may be purified by crystallization from
solvents, chromatographic methods, or a combination thereof.
The compound of Formula Id is a suitable intermediate for the preparation of
dasatinib or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
A fifth aspect of the present invention provides a process for the purification of
-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl] -1,3-thiazol-2-yl }carbamate of
Formula lb or a salt thereof
Formula l b
comprising the steps of:
a) providing a mixture of teri-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-
l,3-thiazol-2-yl}carbamate of Formula lb or a salt thereof and aqueous
methanol; and
b) isolating -butyl{5-[(2-chloro-6-methylphenyl)carbamoyl] -1,3-thiazol-2-
yl}carbamate of Formula lb or a salt thereof.
Step a) includes combining feri-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-
l,3-thiazol-2-yl}carbamate of Formula lb or a salt thereof with aqueous methanol.
The ratio of methanol and water in aqueous methanol may be about 1:1.
The volume of aqueous methanol may be about 2 times to about 15 times,
preferably, 3 times to 10 times, more preferably, 3 times to 6 times more than the weight
of fert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-l,3-thiazol-2-yl}carbamate of
Formula lb.
Step b) involves isolating tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-l,3-
thiazol-2-yl}carbamate of Formula lb or a salt thereof by common isolation techniques
such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a
combination thereof.
A sixth aspect of the present invention provides a process for the preparation of
dasatinib of Formula B
Formula B
or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising the steps
of:
a) reacting a compound of Formula 2a or a salt thereof with a compound of
Formula 3
Formula 2a Formula 3
to provide a compound of Formula la, or a salt thereof,
Formula l a
wherein R1can be selected from hydrogen; R2 can be selected from the
group consisting of hydrogen, amino protecting group, 6-chloro-2-
methyl-pyrimidin-4-yl, and 6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-
methyl-4-pyrimidinyl; and R can be independently selected from the
group consisting of C1-C6 alkyl, C -C12 aryl, C7-C12 arylalkyl, and C7-C12
alkylaryl; and
b) converting the compound of Formula l a to dasatinib or a
pharmaceutically acceptable salt, solvate, or hydrate thereof when R2 is
not 6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl.
Step a) of reacting a compound of Formula 2a or a salt thereof with a
compound of Formula 3 comprises combining a compound of Formula 2a or a salt
thereof with a compound of Formula 3.
Reacting a compound of Formula 2a or a salt thereof with a compound of
Formula 3 may be performed in one or more solvents at a temperature of about 15°C
to about 40°C for a time period sufficient to complete the reaction.
The compound of Formula 3 of the present invention may be prepared in situ
by treating 2-chloro-6-methylaniline with ethyl magnesium bromide in one or more
solvents at a temperature of -10°C to 10°C for a time period sufficient to complete the
reaction.
After completion of the reaction, the compound of Formula l a can be isolated by a
common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a
combination thereof.
The isolated compound of Formula l a may be purified by crystallization from
solvents, chromatographic methods, or a combination thereof.
In step b), t e compound of Formula la may be converted to dasatinib or a
pharmaceutically acceptable salt, solvate, or hydrate thereof by suitable processes
known in the art, for example, as in U.S. Patent Nos. 6,596,746 and 7,491,725; PCT
Publication No. WO 2007/106879; and ARKIVOC 2010(6), 32-38 (2010).
Methods:
Residue on Ignition: Analysis was performed as per the procedure provided as
Test 281 "Residue on Ignition", in United States Pharmacopeia 29.
HPLC purity was determined using an Agilent Technologies®, Kromasil C8 (250 x
4.6 mm), 5 mih column with a flow rate 1.2 mL/min; Column oven temperature 50°C;
Sample oven temperature disable; Detector UV at 285 nm; Injection volume 10 m ; Run
time 55 minutes.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of t e present invention.
EXAMPLES
Example 1 : Preparation of rf-butyl {5-[(2-chloro-6-methylphenyl)carbamoyl]-1.3-
thiazol-2-yl carbamate
Magnesium turnings (3.87 g) were charged into a round bottom flask.
Tetrahydrofuran (15 mL) was added to the flask. A solution of ethyl bromide (16 g in 60
mL tetrahydrofuran) was prepared and 10 mL of this solution was slowly charged to the
round bottom flask. Iodine (30 mg) was added to the reaction mixture and stirred at 25°C
to 32°C for 5 minutes. The reaction mixture was warmed to 27°C and the remaining
amount of ethyl bromide was added slowly over 30 minutes. The reaction mixture was
heated to gentle reflux for 30 minutes and was then cooled to 0°C. 2-Chloro-6-
methylaniline (22.86 g) was added drop-wise at 0°C and the temperature of the reaction
mixture was slowly raised to 20°C to 25°C. Ethyl 2-[(teri-butoxycarbonyl)amino]-l,3-
thiazole-5-carboxylate (10 g) dissolved in tetrahydrofuran (60 mL) was slowly added to
the reaction mixture over 30 minutes. The reaction mixture was stirred for 3 hours. The
reaction mixture was poured slowly into 25% ammonium chloride solution (200 mL) with
stirring. Ethyl acetate (200 mL) was added and stirred for 30 minutes, filtered, suck dried,
and dried under vacuum at 40°C to 45°C to obtain the title compound.
Yield: 10.22 g
Example 2 : Preparation of rf-Butyl {5- (2-chloro-6-methylphenyl)carbamovH-1.3-
thiazol-2-yl carbamate
Magnesium turnings (3 .87 g) were charged into a round bottom flask.
Tetrahydrofuran ( 15 mL) was added to the flask. Iodine (30 mg) was added. A solution
of ethyl bromide ( 16 g in 60 mL tetrahydrofuran) was prepared and 10 mL of this solution
was slowly charged to the round bottom flask. The reaction mixture was stirred at 20°C to
25°C for 5 minutes and the remaining amount of ethyl bromide was added slowly over 30
minutes. The reaction mixture was heated to gentle reflux for 30 minutes and was cooled
to -5°C to - 10°C. 2-Chloro-6-methylaniline (22.86 g) was added drop-wise at -5°C to
-10°C and t e temperature of the reaction mixture was slowly raised to 15°C to 20°C.
Ethyl 2-[(tert-butoxycarbonyl)amino]-l,3-thiazole-5-carboxylate (10 g) dissolved in
tetrahydrofuran (60 mL) was slowly added to the reaction mixture over 30 minutes. The
reaction mixture was stirred for 3 hours. The reaction mixture was poured slowly into
25% ammonium chloride solution (100 mL) with stirring. Ethyl acetate (100 mL) was
added and stirred for 30 minutes, filtered, suck dried, and dried under vacuum at 40°C to
45°C to obtain the title compound.
Yield: 13 .00 g
Residue on Ignition: 3.40% w/w
Example 3: Purification of rf-Butyl {5- (2-chloro-6-methylphenyl)carbamovH-1.3-
thiazol-2-yl }carbamate
-Butyl{5-[(2-chloro-6-methylphenyl)carbamoyl] -1,3-thiazol-2-yl}carbamate
(10 g) obtained from Example 2 was charged into a round bottom flask and aqueous
methanol (1:1, 50 mL) was added to it. The reaction mixture was stirred, filtered, and
dried under vacuum at 40°C to 45°C for 8 hours to obtain the title compound.
Yield: 9 .1 g
HPLC purity: 99.03%
Example 4 : Preparation of 2-Amino -N-(2-chloro-6-methylphenyl)-1.3-lhiazole-5-
carboxamide
Magnesium turnings (12.16 g) were charged into a round bottom flask.
Tetrahydrofuran (50 mL) was added to t e flask. A solution of ethyl bromide (50.2 g in
200 mL tetrahydrofuran) was prepared and 20 mL of this solution was slowly charged to
the round bottom flask. Iodine (30 mg) was added. The reaction mixture was stirred at
20°C to 22°C for 10 minutes and the remaining amount of ethyl bromide was added
slowly over 30 minutes. The reaction mixture was heated to gentle reflux for 30 minutes
and cooled to 0°C to -10°C. 2-Chloro-6-methylaniline (72.4 g) was added drop-wise at
0°C and the temperature of the reaction mixture was slowly raised to 20°C. Ethyl 2-
amino-l,3-thiazole-5-carboxylate (20 g) dissolved in tetrahydrofuran (200 mL) was slowly
added to the reaction mixture over 60 minutes. The reaction mixture was stirred for 3
hours. The progress of the reaction was monitored by thin layer chromatography. The
reaction mixture was further stirred for 16 hours and then poured slowly into 25%
ammonium chloride solution (200 mL) with stirring. The oily layer was separated, diluted
with ethyl acetate (200 mL), and washed with 2 N hydrochloric acid (200 mL). The layers
were separated and the pH of the aqueous layer was adjusted to between 8 and 9 with
saturated sodium bicarbonate solution (300 ml) and extracted with ethyl acetate (2 x 100
mL). The oily layer was collected, concentrated, and further purified by column
chromatography to obtain the title compound.
Yield: 17.0 g

Claims:
1. A process for the preparation of a compound of Formula la or a salt thereof
Formula l a
which comprises reacting a compound of Formula 2a or a salt thereof with a
compound of Formula 3,
Formula 2a Formula 3
wherein R1and R2 are independently selected from the group consisting of hydrogen,
amino protecting group, 6-chloro-2-methyl-pyrimidin-4-yl, and 6-[4-(2-hydroxyethyl)-
1-piperazinyl]-2-methyl -4-pyrimidinyl; and R is independently selected from t e
group consisting of C1-C6 alkyl, C6-C12 aryl, C7-C12 arylalkyl, and C7-C12 alkylaryl.
2 . The process according to claim 1, wherein reacting a compound of Formula 2a
or a salt thereof with a compound of Formula 3 is performed in one or more solvents at
a temperature of 15°C to 40°C.
3 . The process according to claim 1, wherein the compound of Formula 3 is
prepared in situ by combining 2-chloro-6-methylaniline with ethyl magnesium
bromide in one or more solvents at a temperature of -10°C to 10°C.
4 . The process according to claim 2 or claim 3, wherein the solvent is selected from
water, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar
aprotic solvents, or mixtures thereof.
5. The process according to claim 4, wherein the ester is selected from ethyl
acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
6 . The process according to claim 4, wherein the aromatic hydrocarbon is selected
from toluene and xylene.
7 . The process according to claim 4, wherein t e halogenated hydrocarbon is
selected from dichloromethane, chloroform, and 1,2-dichloroethane.
8. The process according to claim 4, wherein the ketone is selected from acetone
and methyl ethyl ketone.
9 . The process according to claim 4, wherein t e ether is selected from diethyl
ether and tetrahydrofuran.
10. The process according to claim 4, wherein the polar aprotic solvent is selected
from N,N-dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.
11. A process for the preparation of compound of Formula lb or a salt thereof
Formula l b
which comprises reacting a compound of Formula 2b or a salt thereof with a
compound of Formula 3,
Formula 2b Formula 3
wherein R is selected from the group consisting of Ci-C6 alkyl, C6-C12 aryl, C7-C12
arylalkyl, and C7-C12 alkylaryl.
12. The process according to claim 11, wherein reacting a compound of Formula
2b or a salt thereof with a compound of Formula 3 is performed in one or more
solvents at a temperature of 15°C to 40°C.
13. The process according to claim 11, wherein the compound of Formula 3 is
prepared in situ by combining 2-chloro-6-methylaniline with ethylmagnesium bromide
in one or more solvents at a temperature of -10°C to 10°C.
14. The process according to claim 12 or claim 13, wherein t e solvent is selected
from water, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers,
polar aprotic solvents, or mixtures thereof.
15. The process according to claim 14, wherein the ester is selected from ethyl
acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
16. The process according to claim 14, wherein the aromatic hydrocarbon is
selected from toluene and xylene.
17. The process according to claim 14, wherein the halogenated hydrocarbon is
selected from dichloromethane, chloroform, and 1,2-dichloroethane.
18. The process according to claim 14, wherein the ketone is selected from acetone
and methyl ethyl ketone.
19. The process according to claim 14, wherein the ether is selected from diethyl
ether and tetrahydrofuran.
20. The process according to claim 14, wherein the polar aprotic solvent is selected
from N,N -dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.
21. A process for the preparation of compound of Formula l c or a salt thereof
Formula l c
which comprises reacting a compound of Formula 2c or a salt thereof with a
compound of Formula 3,
Formula 2c Formula 3
wherein R is selected from the group consisting of C1-C6 alkyl, C6-C12 aryl, C7-C12
arylalkyl, and C7-C12 alkylaryl.
22. The process according to claim 2 1, wherein reacting a compound of Formula
2c or a salt thereof with a compound of Formula 3 is performed in one or more
solvents at a temperature of 15°C to 40°C.
23. The process according to claim 2 1, wherein t e compound of Formula 3 is
prepared in situ by combining 2-chloro-6-methylaniline with ethylmagnesium bromide
in one or more solvents at a temperature of -10°C to 10°C.
24. The process according to claim 22 or claim 23, wherein t e solvent is selected
from water, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers,
polar aprotic solvents, or mixtures thereof.
25. The process according to claim 24, wherein the ester is selected from ethyl
acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate.
26. The process according to claim 24, wherein the aromatic hydrocarbon is
selected from toluene and xylene.
27. The process according to claim 24, wherein the halogenated hydrocarbon is
selected from dichloromethane, chloroform, and 1,2-dichloroethane.
28. The process according to claim 24, wherein the ketone is selected from acetone
and methyl ethyl ketone.
29. The process according to claim 24, wherein the ether is selected from diethyl
ether and tetrahydrofuran.
30. The process according to claim 24, wherein the polar aprotic solvent is selected
from N,N-dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.
31. A process for the preparation of compound of Formula Id or a salt thereof
Formula Id
which comprises reacting a compound of Formula 2d or a salt thereof with a
compound of Formula 3,
Formula 2d Formula 3
wherein R is selected from the group consisting of Ci-C6 alkyl, C6-C12 aryl, C7-C12
arylalkyl, and C7-C12 alkylaryl.
32. The process according to claim 31, wherein reacting a compound of Formula
2d or a salt thereof with a compound of Formula 3 is performed in one or more
solvents at a temperature of 15°C to 40°C.
33. The process according to claim 32, wherein t e compound of Formula 3 is
prepared in situ by combining 2-chloro-6-methylaniline with ethylmagnesium bromide
in one or more solvents at a temperature of -10°C to 10°C.
34. The process according to claim 32 or claim 33, wherein the solvent is selected
from water, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers,
polar aprotic solvents, or mixtures thereof.
35. The process according to claim 34, wherein the ester is selected from ethyl
acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
36. The process according to claim 34, wherein the aromatic hydrocarbon is
selected from toluene and xylene.
37. The process according to claim 34, wherein the halogenated hydrocarbon is
selected from dichloromethane, chloroform, and 1,2-dichloroethane.
38. The process according to claim 34, wherein the ketone is selected from acetone
and methyl ethyl ketone.
39. The process according to claim 34, wherein the ether is selected from diethyl
ether and tetrahydrofuran.
40. The process according to claim 34, wherein the polar aprotic solvent is selected
from N,N-dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.
41. A process forthe purification of fert-butyl{5-[(2-chloro-6-
methylphenyl)carbamoyl]-l,3-thiazol-2-yl}carbamate of Formula lb or a salt thereof
comprising the steps of:
a) providing a mixture of teri-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-
l,3-thiazol-2-yl}carbamate of Formula lb or a salt thereof and aqueous
methanol; and
b) isolating -butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-
yl}carbamate of Formula lb or a salt thereof.
42. The process according to claim 41, wherein the ratio of methanol and water in
aqueous methanol is 1:1.
43. The process according to claim 41, wherein the volume of aqueous methanol is 2
times to 15 times more than t e weight of fert-butyl{5-[(2-chloro-6-methylphenyl)
carbamoyl]-l,3-thiazol-2-yl}carbamate of Formula lb.
44. A process for the preparation of dasatinib of Formula B
Formula B
or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising the
steps of:
a) reacting a compound of Formula 2a or a salt thereof with a compound of
Formula 3
Formula 2a Formula 3
to provide a compound of Formula la, or a salt thereof,
Formula l a
wherein R1is selected from hydrogen; R2 is selected from the group
consisting of hydrogen, amino protecting group, 6-chloro-2-methylpyrimidin-
4-yl, and 6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-
pyrimidinyl; and R is independently selected from the group consisting
of C1-C6 alkyl, C6-C12 aryl, C7-C12 arylalkyl, and C7-C12 alkylaryl; and
b) converting the compound of Formula l a to dasatinib or a
pharmaceutically acceptable salt, solvate, or hydrate thereof when R1 is
not 6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl.
45. The process according to claim 44, wherein reacting a compound of Formula
2a or a salt thereof with a compound of Formula 3 is performed in one or more
solvents at a temperature of 15°C to 40°C.
46. The process according to claim 44, wherein the compound of Formula 3 is
prepared in situ by treating 2-chloro-6-methylaniline with ethylmagnesium bromide in
one or more solvents at a temperature of -10°C to 10°C.
47. The process according to claim 45 or claim 46, wherein the solvent includes
water, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar
aprotic solvents, or mixtures thereof.
48. The process according to claim 47, wherein the ester is selected from ethyl
acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
49. The process according to claim 47, wherein the aromatic hydrocarbon is
selected from toluene and xylene.
50. The process according to claim 47, wherein the halogenated hydrocarbon is
selected from dichloromethane, chloroform, and 1,2-dichloroethane.
51. The process according to claim 47, wherein the ketone is selected from acetone
and methyl ethyl ketone.
52. The process according to claim 47, wherein the ether is selected from diethyl
ether and tetrahydrofuran.
53. The process according to claim 47, wherein the polar aprotic solvent is selected
from N,N -dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.