Field of the invention:
The present invention provides an improved process for the preparation of crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate compound represented by the following structural formula-1 a.
Background of the invention:
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piPerazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide is generally known as Dasatinib and is represented by the following structural formula-!.
Dasatinib is a cyclic protein tyrosine kinase inhibitor indicated for newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib; and, adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy. It is also being evaluated for use in numerous other cancers, including advanced prostate cancer.
Dasatinib is approved in USFDA as SPRYCEL® and is chemically mentioned in the label as N-(2-chloro-6-methylphenyl)-2- [[6- [4-(2-hydroxyethyl)- l-piperazinyl] -2-meihyl-4-pyrimidinyl] amino]-5-thiazo!ecarboxamide, monohydrate.

It is a white to off-white powder, insoluble in water and slightly soluble in alcoholic solvents like ethanol and methanol.
US 6596746 Bl (herein after US'746) provided the first disclosure of N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide, which also describes the process for preparing Dasatinib.
According to the basic patent US'746, dasatinib is prepared by reaction of the key intermediate of formula-2 with l-(2-hydroxyethy!)piperazine in the presence of a base and a suitable solvent. A similar preparation method was later used in a number of other process patents, only varying the corresponding base or solvent. Through the selection of a suitable solvent or procedure a great number of solvates or polymorphs can be prepared. Polymorphs have been one of the most frequently studied physical characteristics of active pharmaceutical substances (API) recently. Thus, different polymorphs of one API may have entirely different physical-chemical properties such as solubility, melting point, mechanical resistance of crystals but they may also influence the chemical and physical stability. Then, these properties may have an impact on further processes such as handling of the particular API, grinding or formulation method. These various physical-chemical characteristics of polymorphs influence the resulting bioavailability of the solid dosage form. Therefore, looking for new polymorphs and solvates is becoming an important tool for obtaining a polymorph form with the desired physical-chemical characteristics.
US 7491725 B2 (herein after US'725) describes the crystalline monohydrate, crystalline butanol solvate, crystalline ethanol solvate and anhydrous forms of Dasatinib (i.e.. N-6 and T1H1-7). US '725 B2 also provides processes for the preparation of these mentioned forms of Dasatinib. Its continuation patent'US8242270B2 also describes two ethanol solvates, i.e., hemi-ethanol and diethanol solvates.
PCT International Publication No WO2010067374A2 describes the preparation of other solvates/mixed solvates such as dimethyl formamide, isopropyl acetate, toluene, dimethyl sulfoxide and processes for the preparation.

API solvates or salts are used in drug formulations in many cases. In the case of solvates the limits for individual solvents, their contents or maximum daily doses have to be strictly observed. Then, these limits can dramatically restrict their effective use. Thus, the clearly most convenient option is the use of sufficiently stable polymorphs of API that do not contain any solvents bound in the crystalline structure.
The pending application of the present inventor's describes 1,2-propanediol solvate or
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-|-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazo.]e carboxamide compound of formula-lb.
The present inventors surprisingly found the stable and pure monohydrate form of the
compound of formula-la via 1,2-propanediol solvate of N-(2-chloro-6-methylphenyl)-2-[[6-
[4-(2-hydroxyethyl)-l-piperaZinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide, which is showing advantageous properties.
Brief description of the invention:
The first aspect of the present invention is to provide an improved process for the preparation of crystalline N-(2-chloro-6-methylpheny!)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide monohydrate compound of formula-1 a.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of N-(2-chloro-6-methyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyt] amino]-5-thiazole carboxamide monohydrate compound of formula-la.
Figure 2: Illustrates the DSC pattern of N-(2-chloro-6-methyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-pipera2inyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide monohydrate compound of formula-1 a.
Figure 3: Illustrates the Infrared spectrum of N-(2-chloro-6-methyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide monohydrate compound of formula-la.

Detailed description of the invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, methylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobuty(ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2-propanediol (propylene glycol), 2-methoxyethanol, I, 2-ethoxyethanol, diethylene glycol, I, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium.carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl

amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-luiidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS). sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The first aspect of the present invention provides an improved process for the preparation of stable crystalline N-(2-ch]oro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide monohydrate of compound of formula-1 a,
comprising of:
a) Reacting the 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methyl
phenyl)thiazole-5-carboxamide compound of formuIa-2 with 2-(piperazin-l-
yl)ethanol compound of formula-3 in 1,2-propanediol in presence of a suitable base at
a suitable temperature to get i ,2-propanediol solvate of N-(2-chloro-6-methylphenyl)-
2-[[6-[4-C2-hydroxyethy])-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of compound of formula-1 b,
b) optionally purifying the compound obtained in step-a) with 1,2-propanediol,
c) dissolving the compound obtained in step-a) or step-b) in a suitable solvent at a suitable temperature,
d) optionally treating the reaction mixture with carbon,
e) cooling the reaction mixture obtained in step-c) or step-d),
f) filtering the precipitated solid,
g) dissolving the compound obtained in step-f) in a suitable solvent at a suitable temperature,

h) adding water to the reaction mixture obtained in step-g) at a suitable temperature,
i) cooling the reaction mixture,
j) isolating the stable crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-
hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate of compound of formula-la. Wherein,
in step-a) a suitable base is selected from organic or inorganic base; a suitable temperature refers to 0°C to reflux temperature, preferably 30°C to 130°C, most preferably 100°Cto 120°C;
in step-c) and step-g)" the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, hydrocarbon solvents, ester solvents, ether solvents, polar solvents, water or mixtures thereof;
in step-c), step-g) and step-h) a suitable temperature refers to about 25°C to reflux temperature,
in step-j) isolating refers to the solvent removed by filtration or distillation of solvent or decanted the solvent from the reaction mixture.
The preferred embodiment of the above aspect of the present invention provides an improved process for the preparation of stable crystalline N-(2-chloro-6-methylphenyl)-2-
[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate of compound of formula-la, comprising of:
a) Reacting the 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methyl
phenyl)thiazole-5-carboxamide compound of formula-2 with 2-(piperazin-l-
yl)ethanol compound of formula-3 in 1,2-propanediol in presence of diisopropyl
ethylamine at 110-I20°C to get 1,2-propanediol solvate of N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide of compound of formula-lb,
b) dissolving the compoundof formula-lb obtained in step-a) in methanol at 60-70°C,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture,

e) filtering the precipitated solid,
0 dissolving the compound obtained in step-e) in the mixture of water and methanol at 60-70°C,
g) adding water to the reaction mixture obtained in step-f) at 60-70°C,
h) cooling the reaction mixture,
i) filtering the obtained solid to get stable crystalline N-(2-chloro-6-methylphenyl)-2-
[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate of compound of formula-la.
. Process for the preparation of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide the compound of formula-2 is well disclosed in the prior art.
The present invention controls all the impurities to below ICH limits in which few of them are controlled to not detected level.
N-(2-chloro-6-methyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piPera2inyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide, its hydrates or solvates produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed on a Q2000 V24.I I Build 124 calorimeter with closed aluminium pans, heating the samples from 40°C to 350°C in a rate of IO°C/min.
1R spectra were recorded on a Perkin-Elmer FTIR spectrometer. The present invention represented in the scheme-1,
The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
Example-l: Preparation of crystalline N-(2-chloro-6-methylpheny|)-2-|[6-|4-<2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidiny!]amino]-5-thiazole carboxamide monohydrate compound of formula-la

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methy] phenyl) thiazole-5-carboxamide compound of formula-2 (100 gm), 2-(piperazin-l-yl)ethanol compound of formula-3 (165 gm) & 1,2-propanediol (2250 ml) is expelled with nitrogen for 30 minutes. N,N-diisopropylethylamine (49 ml) was added to the reaction mixture at 25-30°C and heated the reaction mixture to 115-I20°C. Stirred the reaction mixture for 13 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 6 hours at the same temperature. Filtered the precipitated solid and washed with 1,2-propanediol. Methanol (4000 ml) was added to the obtained wet compound and heated the reaction mixture to 65-70°C. Stirred the reaction mixture for 60 minutes at the same temperature. Carbon (2 gm) was added to the reaction mixture at 65-70°C and stirred it for 30 minutes at the same temperature. Filtered the reaction mixture through hyflo bed and washed with methanol. Cooled the obtained filtrate to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with methanol. Water (300 ml) and methanol (2000 ml) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C and stirred it for 1 hour at the same temperature. Water (800 ml) was slowly added to the reaction mixture at 65-70°C and cooled the reaction mixture slowly to 0-5°C. The reaction mixture was stirred for 2 hours at 0-5°C. Filtered the precipitated solid, washed with the mixture of water and methanol and dried to get the title compound.
Yield: 60 gm; Water content: 3.55% w/w. PXRD pattern of the obtained compound is depicted in figure-1. Purity by HPLC: 99.89%

We claim:
1. Process for the preparation of crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxy ethyl)-1 -piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide monohydrate compound of formula-la; comprising of:
a) Dissolving 1,2-propanediol solvate of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-
hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide compound of formula-lb in methanol at a suitable temperature,
b) optionally treating the reaction mixture with carbon,
c) cooling the reaction mixture obtained in step-a) or step-b),
d) filtering the precipitated solid,
e) dissolving the compound obtained in stcp-d) in the mixture of water and methanol at a suitable temperature,
0 combining water with the reaction mixture obtained in step-e),
g) cooling the reaction mixture,
h) filtering the precipitated solid to get stable crystalline N-(2-chloro-6-methylphenyl)-2-
[[6-[4-(2-hydroxyethyi)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate of compound of formula-la.
2. The process according to claim 1, the suitable temperature in step-a) and step-e) is 25°C to reflux temperature of the corresponding solvent, preferably 50-70°C.
3. The process according to claim I, the mixture of water and methanol is used in the ratio of3:20.
4. Process for the preparation of crystalline N-(2-chioro-6-methylphenyl)-2-[[6-[4-(2-hydroxy ethyl)-!-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide monohydrate compound of formula-1 a; comprising of:
a) Dissolving 1,2-propanediol solvate of N-(2-chloro-6-methylpheny!)-2-[[6-[4-(2-hydroxyethy])-]-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide compound of formula-tb in methanol at 50-70°C,

b) optionally treating the reaction mixture with carbon,
c) cooling the reaction mixture obtained in step-b),
d) filtering the precipitated solid,
e) dissolving the compound obtained in step-d) in a mixture of water and methanol at about 60-70°C,
f) adding water to the reaction mixture obtained in step-e),
g) cooling the reaction mixture,
h) filtering the obtained solid to get stable crystalline N-(2-chloro-6-methylphenyl)-2-
[[6-[4-(2-hydroxyethyl)-]-pipera2inyl]-2-methyl-4-pyrimidinyl]amino]-5-thia2ole carboxamide monohydrate of compound of formula-1 a.
5. Process for the preparation of crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxy ethyl)-l.piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide monohydrate compound of formula-1 a; comprising of:
a) Reacting the 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methyl
pheny])thiazole-5-carboxamide compound of formula-2 with 2-(piperazin-1-
yl)ethanol compound of formula-3 in 1,2-propanediol in presence of a suitable base at
a suitable temperature to get 1,2-propanediol solvate of N-(2-chloro-6-methylphenyl)-
2-[[6-[4-(2-hydroxyethyl)-|-piperaziny[]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of compound of formula-lb,
b) optionally purifying the compound obtained in step-a) with 1,2-propanediol,
c) dissolving the compound obtained in step-a) or step-b) in a suitable solvent at a suitable temperature,
d) optionally treating the reaction mixture with carbon,
e) cooling the reaction mixture obtained in step-c) or step-d),
f) filtering the precipitated solid,
g) dissolving the compound obtained in step-f) in a suitable solvent at a suitable temperature,
h) adding water to the reaction mixture obtained in step-g) at a suitable temperature, i) cooling the reaction mixture,

j) isolating the stable crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-
hydroxyethyl)-l-piperazinyl]-2-methyl^pyrimidinyl]amino]-5-thiaZolecarboxamide monohydrate of compound of formula-la.
6. The process according to claim 4, wherein in step-a) a suitable base is selected from organic or inorganic base; a suitable temperature refers to 0°C to reflux temperature, preferably 30°C to 130°C, most preferably 100°C to I20°C;
in step-c) and step-g) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, hydrocarbon solvents, ester solvents, ether solvents, polar solvents, water or mixtures thereof;
in step-c), step-g) and step-h) a suitable temperature refers to about 25°C to reflux temperature,
in step-j) isolating refers to the solvent removed by filtration or distillation of solvent or decanted the solvent from the reaction mixture.
7. A process for the preparation of stable crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-
(2-hydroxyethyl)-l-Piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate of compound of formula-1 a, comprising of:
a) Reacting the 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methyl
phenyl)thiazole-5-carboxamide compound of formula-2 with 2-(piperazin-1-
yl)ethanol compound of formula-3 in 1,2-propanediol in presence of diisopropyl
ethylamine at 110-120°C to get 1,2-propanediol solvate of N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide of compound of formula-1 b,
b) dissolving the compound obtained in step-a) in methanol at 60-70°C,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture,
e) filtering the precipitated solid,
f) dissolving the compound obtained in step-e) in the mixture of water and methanol at 60-70°C,

g) adding water to the reaction mixture obtained in step-f) at 60-70°C,
h) cooling the reaction mixture,
i) filtering the obtained solid to get stable crystalline N-(2-chloro-6-methylphenyl)-2-
[[6-[4-(2-hydroxyethyl)-l-pipera2inyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate of compound of formula-la.
8. The crystalline monohydrate form of N-(2-chloro-6-methyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-PiPerazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide obtained according to any of the preceding claims having purity >95%, preferably >99% by HPLC.
9. The pharmaceutical composition comprising monohydrate forms of N-(2-chloro-6-methyl Phenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piPera2inyl]-2-methyl-4-Pyrimidinylj amino]-5-thiazole carboxamide obtained according to any preceding claims, and a pharmaceutical^ acceptable carrier.