DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PREPARATION OF DASATINIB MONOHYDRATE

INTRODUCTION
The present invention provides a process for the preparation of monohydrate form of dasatinib.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name “dasatinib” has a chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyridiminyl]amino]-5-thiazolecarboxamide, and is structurally represented by Formula I.

Formula I
Dasatinib is sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblasticjeukemia (Ph+ ALL).
The PCT application WO2005077945 discloses several crystalline forms of Dasatinib which are designated as monohydrate, butanol solvate, ethanol solvate, crystalline neat form (?-6) and crystalline neat form (T1H1-7). WO ‘945 also discloses process for the preparation of these crystalline forms.
US patent no. 7973045 discloses anhydrous form and various other solvates of dasatinib. US ‘045 also disclose process for the preparation of amorphous dasatinib by evaporating the solvent from the suspension. The solvents used in the process were selected from dimethylformamide, 1, 2-dichlorobenzene, propylene glycol, ethylene glycol and glycerol. Example 60 of US ‘045 discloses preparation of amorphous Dasatinib by slurring in propylene glycol and heating.
US20140343073A1 discloses process for the preparation of amorphous form of dasatinib by milling.
The inventors of the present invention provide a process for the preparation of crystalline form of dasatinib monohydrate.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of crystalline form of Dasatinib monohydrate using methanol and water.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the PXRD pattern of Dasatinib N-6 form.
Figure 2 illustrates the PXRD pattern of Dasatinib monohydrate form.
DETAILED DESCRIPTION
In an aspect, the present invention provides a process for the preparation of crystalline form of Dasatinib monohydrate using methanol and water.
In an aspect, the present invention provides a process for the preparation of crystalline form of Dasatinib monohydrate comprising the steps of:
a) obtaining a mixture of dasatinib, methanol and water;
b) stirring and maintaining the mixture at 30 - 70 oC;
c) filtering and drying the material obtained in step b).
The dasatinib used in step a) may be prepared as per the procedure known in the art. In a preferred embodiment, N-6 form of dasatinib disclosed in WO2005077945 is used as the input material for the preparation of dasatinib monohydrate.
In step a), the ratio of methanol and water may vary from about 4:1 to 4:4 by volume.
Step b) comprises stirring and maintaining the reaction mixture at a temperature of about 30 to 70 oC, more preferably at about 50-60 oC. In an embodiment, the reaction mixture of step b) is maintained for a time period of about 1 hour to about 10 hours, more preferably for about 6-8 hours.
Step c) involves filtering and drying the material obtained in step b). The crystalline dasatinib is isolated in a manner known per se, which include, but not limited to filtration by gravity or by suction/vacuum, distillation, centrifugation, or slow evaporation or the like. In an embodiment, crystalline dasatinib may be isolated by filtration under vacuum and suction drying at a temperature of about 25°C to about 35°C. The obtained material may optionally be dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, Thin Film Dryer and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressure. In an embodiment, the drying may be carried out at a temperature of about 30-60 °C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
In an aspect, the present invention provides a process for the preparation of crystalline form of dasatinib monohydrate, comprising the steps of:
a) reacting the compound of formula II with the compound of formula III in presence of suitable solvent and optionally in the presence of base;
b) stirring and maintaining the reaction mixture at 30 - 70oC;
c) optionally, removing the solvent from the above reaction mixture;
d) adding methanol and water to the contents of step c) and maintaining the reaction mixture;
e) filtering and drying the material obtained in step b).
Suitable solvents that may be used in step a) include, but not limited to: alcohols, such as methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, or the like; ketones, such as acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; nitriles, such as acetonitrile, propionitrile, or the like; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; or any mixtures thereof.
Suitable bases that may be used include, but are not limited to: organic bases, such as triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, or the like.
In step c) the solvent from the reaction mixture is removed in a manner known per se, which include, but not limited to filtration by gravity or by suction/vacuum, distillation, centrifugation, or slow evaporation or the like at a temperature of about 25°C to about 65°C.
In step d), the ratio of methanol and water may vary from about 4:1 to 4:4 by volume.
Step d) comprises stirring and maintaining the reaction mixture at a temperature of about 30 to 70 oC, more preferably at about 50-60 oC. In an embodiment, the reaction mixture of step b) is maintained for a time period of about 1 hour to about 10 hours, more preferably for about 6-8 hours.
Step e) involves filtering and drying the material obtained in step b). The crystalline dasatinib is isolated in a manner known per se, which include, but not limited to filtration by gravity or by suction/vacuum, distillation, centrifugation, or slow evaporation or the like. In an embodiment, crystalline dasatinib may be isolated by filtration under vacuum and suction drying at a temperature of about 25°C to about 35°C. The obtained material may optionally be dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, Thin Film Dryer and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressure. In an embodiment, the drying may be carried out at a temperature of about 30-60 °C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
The particle size of the dasatinib monohydrate obtained in the present invention ranges from about 30-140 microns.
The following examples further illustrate the invention but should not be construed as in any way limiting its scope.

EXAMPLES
Example 1: Preparation of dasatinib monohydrate
5.0 g of dasatinib form N-6 and 80 mL of methanol and 20 mL of demineralized water were charged into a round bottom flask at 25 to 30 oC. The contents were stirred at 60 ± 5 oC and further 240 mL of methanol and 60 mL of demineralized water were added to the flask. The contents were maintained for 50-70 minutes and were cooled to 20-30 oC. The material was filtered on suction pump for 10-15 minutes to afford the title compound.
Example 2: Preparation of dasatinib monohydrate
3.0 g of dasatinib form N-6 and 24 mL of methanol and 6 mL of demineralized water were charged into an easy max reactor at 25 to 30 oC. The contents were heated to 50 ± 5 oC and maintained for 30 minutes. 0.15 g of dasatinib monohydrate seed material (Obtained in example 1) was added to above flask and maintained for 7-8 hours at 50-55 oC. The contents were cooled to 20-30 oC and filtered on Buckner funnel. The obtained material was dried in vacuum tray dryer at 50 oC for 5-6 hours to afford the title compound.

Example 3: Preparation of dasatinib monohydrate
3.0 g of dasatinib form N-6 and 15 mL of methanol and 15 mL of demineralized water were charged into an easy max reactor at 25 to 30 oC. The contents were heated to 50 ± 5 oC and maintained for 20 hours. The contents were cooled to 20-30 oC and filtered on Buckner funnel. The obtained material was dried in vacuum tray dryer at 50 oC for 5-6 hours to afford the title compound.
Example 4: Preparation of dasatinib monohydrate
3.0 g of dasatinib form N-6 and 15 mL of methanol and 15 mL of demineralized water were charged into an easy max reactor at 25 to 30 oC. The contents were maintained for 12-13 hours at 28 oC and filtered to afford the title compound.
Example 5: Preparation of dasatinib monohydrate
3.0 g of dasatinib form N-6 and 24 mL of methanol and 6 mL of demineralized water were charged into an easy max reactor at 25 to 30 oC. The contents were maintained for 5-6 hours at 50-55 oC and filtered to afford the title compound.
Example 6: Preparation of dasatinib monohydrate
100.0 g of dasatinib form N-6 and 800 mL of methanol and 200 mL of demineralized water were charged into a round bottom flask at 25 to 30 oC. The contents were heated to 50-55 oC and stirred at same temperature for 2-3 hours. The contents were cooled to 20-30 oC and filtered on suction pump for 10-15 minutes. The filtered compound was dried in vacuum tray dryer at 28 oC for 1 hour and then at 50 oC for 5 hours to afford the title compound.
Example 7: Preparation of dasatinib monohydrate
1000 g of 2-((6-chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide, 1000 g of 2-(piperazin-1-yl)ethan-1-ol and 6000 mL of N-methylpyrrolidone were taken in a reactor under nitrogen atmosphere and heated to 60-70oC. After the completion of the reaction, 7000 mL of demineralized water was added to the above reaction mixture and cooled to 20-30oC. The reaction mixture was filtered and the filtered material was taken into a fresh reactor. 2700 mL of methanol and 2000 mL of demineralized water were added to the above fresh reactor and the contents were heated to 60-70oC. Charcoal slurry was prepared by dissolving in 2000 mL of methanol and added to the above reactor. The contents of the above reactor were filtered and to the filtrate 2000 mL of methanol was added and heated to 60-70oC. Demineralized water (1300 mL) was added slowly and cooled to 0-10oC. The isolated solid was filtered and the purification operation with methanol and water was repeated again and filtered at 20-30oC.
Yield: 1.28 kg.
,CLAIMS:1. A process for the preparation of crystalline dasatinib monohydrate using methanol and water.
2. The process of claim 1, wherein the ratio of methanol and water may varies from 4:1 to 4:4 by volume