WO2017098391A1

WO2017098391A1 - Process for the preparation of dasatinib

Info

Publication number: WO2017098391A1
Application number: PCT/IB2016/057337
Authority: WO
Inventors: Sriram RAMPALLI; Pradeep POTHANA; Suresh GARBAPU; Akshaykant CHATURVEDI
Original assignee: Shilpa Medicare Limited
Priority date: 2015-12-11
Filing date: 2016-12-03
Publication date: 2017-06-15

Abstract

The present invention relates to a process for preparation of stable Dasatinib base (I). The present invention further, relates to a process for preparation of amorphous Dasatinib base (I). Said stable Dasatinib base (I) may be useful in preparing pharmaceutical dosage form for the treatment of cancer.

Description

PROCESS FOR THE PREPARATION OF DASATINIB

FIELD OF INVENTION

The present invention relates to a process for preparation of Dasatinib (I).

BACKGROUND OF THE INVENTION

Dasatinib is chemically described as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide and is represented by Formula I).

The monohydrate form of Dasatinib is a kinase inhibitor and has been approved by USFDA as SPRYCEL™ for the treatment of chronic phase Philadelphia chromosome- positive (Ph+) Chronic Myeloid Leukemia (CML), in newly diagnosed adult patients or patients having resistance or intolerance to prior therapy like Imatinib. SPRYCEL™ is also indicated for the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Das et al in US patent No. 6596746 Blprovided the first disclosure of the compound Dasatinib along with the process for preparation thereof. Further to this Lajeunesse et al. in US 7491725 B2 provided the crystalline monohydrate, crystalline butanol solvate, crystalline ethanol solvate and neat forms of Dasatinib.

Chidambaram et al in WO2007035874 Al disclosed various pharmaceutically acceptable salt forms of Dasatinib. The pharmaceutically acceptable salts disclosed in WO2007035874 Al are for example, fumaric acid, hydrobromic acid, maleic acid, methanesulfonic acid, phosphoric acid, salicylic acid, sulfuric acid, tartaric acid, or p- toluenesulfonic acid. Amongst other disclosures, Vraspir et al in WO2010062715 A2disclosedisosorbide dimethyl ether solvate, Ν,Ν'-dimethylethylene urea solvate and N,N'-dimethyl-N,N'- propylene urea solvate of Dasatinib. Parthasaradhi et al in WO 2010067374A2disclosedcrystalline solvates of Dasatinib with DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.Also, Sudershan et al in WO2012014149 Al disclosed N-Methylformarnide solvate of Dasatinib.

Several crystalline forms of Dasatinib are described in the literature; these are designated as Hl-7, BU-2, E2-1, N-6, T1H1-7, and T1E2-1. Crystalline dasatinib monohydrate (Hl-7) and butanol solvate (BU-2)) along with the processes for their preparation are described in WO 2005077945. Additionally US 2006/0004067, also describe two ethanol solvates (E2-1 ; T1E2-1) and two anhydrous forms (N-6; T1H1 -7).

WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.US patent No. 7973045 further discloses the anhydrous form of Dasatinib and process for preparation thereof. The anhydrous form disclosed therein has typical characteristic XRD peaks at about 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value. The process involves by drying Dasatinib at 200°C under nitrogen atmosphere for 2hours, which is not feasible in bulk prospective. Further, this patent not disclosed the process related impurities formed during the development of Dasatinib.

Further US8067423B2 discloses crystalline forms of isopropyl alcohol solvate of Dasatinib, along with many other solid state forms of Dasatinib.

WO 2010062715 discloses isosorbide dimethyl ether solvate, N, '- dimethylethylene urea solvate and N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib.

WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.

WO 2010139979 discloses MDC solvate of Dasatinib, process of its preparation and use in the manufacture of pure Dasatinib. WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.

WO 2014086326 discloses a process for the preparation crystalline Form N-6 of dasatinib, consisting preparation and isolation of Dasatinib in the form of a solvate or in unsolvated form; dissolution of Dasatinib obtained in a crystallization solvent selected from lower alcohols;addition of a co-solvent selected from acetonitrile and propionitrile, or a mixture thereof, and isolation of crystalline dasatinib in the polymorph form N-6. The present inventors now developed a process for the crystalline Dasatinib Form-SDN without using any co-solvent system selected from acetonitrile and propionitrile, or a mixture thereof

WO 2015090259 discloses a processof preparing the crystalline Form N-6 of dasatinib, consisting drying a dasatinib solvate from the group of the ethanol solvate, methanol solvate, and acetonitrile solvate of dasatinib, or their mixtures.

Dasatinib being an important drug in the treatment of cancer, there still appears to be a need for new forms of Dasatinib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore novel forms of Dasatinib, which may further improve the characteristics of drug Dasatinib.

Inventors of the present application here in this application reportedcrystalline Form- SDN of Dasatinib. Crystalline Form-SDN of Dasatinib are sufficiently stable and pharmaceutically acceptable. This stable form offers various advantages in terms of storage, shelf life and favorable impurity profile.

Further, inventors of the present application here in this application reported amorphous Dasatinib. Amorphous Dasatinib is sufficiently stable and pharmaceutically acceptable. This stable form offers various advantages in terms of storage, shelf life and favorable impurity profile.

Present invention also provides a process for preparation of crystalline Form-SDN of Dasatinib, which is industrially amenable and commercially viable. Crystalline Form-SDN of Dasatinib can be a valuable input for the preparation of various pharmaceutically acceptable pure salt forms of Dasatinib without any requirement for repeated purification processes, thus giving both economic and operational advantage.

SUMMARY OF THE INVENTION

Particular aspects of the present invention relates to a process for preparing crystalline Dasatinib (I),

comprising the steps of:

a) reacting 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (II) with 4,6- Dichloro-2-methyl pyrimidine (III) in presence of solvent and a base to yield N-(2- chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazole carboxamide of Formula (IV);

b) reacting N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5- thiazolecarboxamide (IV) with l-(3-Hydroxy)ethylpiperazine (V) in presence of amyl alcohol without using any base to yield Dasatinib amyl alcohol solvate; and

c) treating Dasatinib amyl alcohol solvate with methanol to get crystalline base as Form -SDN.

In another aspect of the present invention relates to a process for preparing amorphous Dasatinib (I),

comprising the steps of:

a) reacting 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (II) with 4,6- Dichloro-2-methyl pyrimidine (III) in presence of solvent and a base to yield N-(2- chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5- thiazolecarboxamide of Formula (IV);

c) treating Dasatinib amyl alcohol solvate with dimethyl formamide and water combination to get amorphous Dasatinib.

Another aspect of the present invention relates to Crystalline Dasatinib designated as Form- SDN, characterized by

a) X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ± 0.2° 2Θ;

b) DSC isotherm comprising an endothermic peaks ranging between 280-290°C; and c) Crystalline Dasatimb Form-SDN containing the process related impurities A, B, C, D, E, F, and G collectively below 0.3%.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form-SDN of Dasatinib.

Fig. 2 is an example of Differential Scanning Calorimetry ("DSC") curve of crystalline Form-SDN of Dasatinib.

Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of Amorphous Dasatinib (I) base.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a rocess for preparing crystalline Dasatinib (I),

comprising reacting 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (II) with 4,6-Dichloro-2-methyl pyrimidine (III) in presence of solvent selected from tetrahydrofuran,l,4-Dioxane, Methyl tertiary butyl ether, dimethyl formamide, dichloromethane, toluene, 2-methyl tetrahydrofuran, dimethoxy ethane;and a base selected from inorganic / organic base such as sodium hydroxide, potassium hydroxide, sodium tertiary butoxide, Sodamide,potassium tertiary butoxide, sodium bicarbonate, potassium bicarbonate, diisopropyl ethyl amine, pyridine, methyl amine, trimethylamine or triethyl amine; stirred the reaction mass for 2 hours to 3 hours at a temperature ranging from 25- 30°C. Cool the reaction mass temperature to -5 to 5°C and then adjust the pH of the reaction mass to 1-1.5 with 2N Aqueous HC1. To the obtained reaction mass DM Water was added at 0-5°C and stirred the reaction mass for 2 hours to 3 hours at 0-5°C. Suck dried the material and washed with wet cake with acetone. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5-thiazolecarboxamide of Formula (IV).

Above obtainedN-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5-thiazolecarboxamide (IV) was charged in to a reaction flask containing amyl alcohol without using any base at 25-30°C. Raised the temperature to 135-140°C and then charged 1 -(3 -Hydroxy)ethylpiperazine (V) amyl alcohol solution. Stirred the reaction mass for 4 hours to 5 hours at 135-140°C and then cooled the reaction mass temperature gradually to 25-30°C. Again, stirred the reaction mass for 2 hours at 25-30°C. Filtered the reaction mass and washed with Amyl alcohol and suck dried the material at 25-30°C. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield Dasatinib amyl alcohol solvate.

After performing several experiments, the present inventors found that the condensation is carried without using any base to form Dasatinib amyl alcohol solvate at specific temperature 135-140°C.

Dasatinib has a tendency to form a solvate, use of mixture of solvents in this step, leads to the formation of mixture of Dasatinib solvates. The present inventors found the use of single solvent system directly yields in the formation of pure Dasatinib amyl alcohol solvate, which is free of other solvents.

Dasatinib amyl alcohol solvate obtained above was charged in to a reaction flask containing Methanol at 25-30°C. Raised the temperature of the reaction mass to reflux temperature and stirred the reaction mass for 30 minutes at reflux (65-70°C). Filtered the reaction mass at 60-65 °C and collected the filtrate. The collected filtrate was partially distilled off under atmospheric pressure at 65-70°C. Cooled the reaction mass temperature slowly to 0-5°C and stirred for 1 hour to 2 hours at 0-5°C. Filtered the reaction mass and washed with Methanol and suck dried the material at 25-30°C for 15 to 20 minutes. Again, charged the wet material in to a reaction flask containing Methanol at 25-30°C. Raised the reaction mass temperature to reflux (65-70°C) and stirred the reaction mass for 15 minutes to 20 minutes at reflux (65-70°C). Cooled the reaction mass slowly to 25-30°C and stirred for 2 hours to 3 hours at 25-30°C.Filtered the reaction mass and washed with Methanol. Suck dried the material for 15-20 min at 25-30°C and Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield pure crystalline Dasatinib.

Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ± 0.2° 2Θ as disclosed in Figure 1.

Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by DSC isotherm comprising an endothermic peaks ranging between 280- 290°C.

In an another embodiment Crystalline Dasatinib obtained by the above process containing the process related impurities A, B, C, D, E, F and G collectively below 0.3%.

of amorphous Dasatinib comprises treating Dasatinib amyl alcohol solvate obtained above was charged in to a reaction flask containing dimethyl formamide at 25-30°C. Stirred the reaction mass for 15 minutes to 30 minutes at 25-30°C and then cooled the reaction mass slowly to 0-5°C. Charged cold water in to the reaction flask at 0-5°C and then stir the reaction mass for 60 minutes to 80 minutes at 0-5°C. Filtered the reaction mass and washed the material with DM water. Suck dried the material at 25-30°C for 15-20 min. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield amorphous Dasatinib. The PXRD obtained as per this process is disclosed in Fig.3.

In an another embodiment amorphous Dasatinib obtained by the above process containing the process related impurities A, B, C, D, E, F and G collectively below 0.3%.

As set forth herein, embodiments of the present invention relate to the novel crystalline Form-SDN of Dasatinib (I) and processes for its preparation.

Process of isolating crystalline Form-SDN of Dasatinib may comprise processes but not limited to conventional processes including scrapping, if required filtering from slurry and optional further drying, which may be carried out at room temperature for the suitable durations to retain the characteristics of crystalline Form-SDN of Dasatinib.

The process of the present invention is advantageous in being commercially viable and industrially feasible as the crystalline Form-SDN of Dasatinib is directly obtained from the reaction without any additional purification steps.

The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appear in the impurity profile of the Dasatinib may be substantially removed by the process of the present invention resulting in the formation of pure Form-SDN of Dasatinib in high yield. In view of maintaining the equilibrium to the impurity profile compliance, the process may require in- process quality checks to avoid unnecessary prolongation/repetitions of the same process steps. Substantially pure Form-SDN of Dasatinib obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% w/w.

The crystalline Form-SDN of Dasatinib obtained by the process of the present invention can be further used for the preparation of substantially pure pharmaceutically acceptable salts of Dasatinib. Other non-limiting examples of salts of Dasatinib that can be prepared from crystalline Form-SDN of Dasatinib include Dasatinib hydrochloride. Conversion of crystalline Form-SDN of Dasatinib to other salt forms of Dasatinib can be achieved by the person skilled in the art according to any process available in the prior art.In one of the preferred embodiment, preparation of the pharmaceutically acceptable salt of Dasatinib involved the treatment of the reaction mass obtained as end product, with an organic solvent characterized by boiling point of less than 70 °C. Organic solvent characterized by boiling point of less than 70 °C may be selected from ether solvents like Diisopropyl ether (DIPE), Tetrahydrofuran (THF) and MTBE or a mixture thereof. Use of crystalline Form-SDN as starting material is advantageous for preparation of pharmaceutically acceptable salts of Dasatinib as the required salt forms are obtained in the substantially pure form without any requirement for repeated purification processes, thus giving both economic and operational advantage.

Crystalline Form-SDN of Dasatinib is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics. Crystalline Form-SDN of Dasatinib retains its stoichiometry even on drying for more than 24hrs at 60-65 °C. This stable form thus, offers various advantages in terms of storage, shelf life and favorable impurity profile.

In an another embodiment, Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ± 0.2° 2Θ as disclosed in Figure 1.

Crystalline Form-SDN of Dasatinib is further characterized by X-ray powder diffraction pattern comprising peaks at 12.3, 16.4, 18.5, 24.8, 27.8 ± 0.20 2Θ⁰.

In a further embodiment of the present application, the crystalline Form-SDN of Dasatinib produced by the process of the present invention is characterized by- a) X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ± 0.2° 2Θ

b) DSC isotherm comprising an endothermic peaks ranging between280-290°C.

c) Crystalline Dasatinib obtained by the above process containing the process related impurities A, B, C, D, E, F and G collectively below 0.3%.

In another embodiment of the present application, substantially pure crystalline Form- SDN of Dasatinib exhibits an X-ray powder diffraction pattern as shown in Fig-l andDSC isothermal pattern as shown in Fig-2.The characteristic 20°peaks and their d- spacing values, for the new crystalline Form-SDN are tabulated in the Table- 1.

Table- 1 : Characteristic XRPD Peaks of Crystalline Form-SDN

Minor variations in the observed 26° angles values may be expected based on the analyst, the specific XRPD diffractometer employed and the sample preparation technique. Further possible variations may also be expected for the relative peak intensities, which may be largely affected by the non-uniformity of the particle size of the sample. The 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.

In view of possibility of marginal error in the assigning 2 theta angles and d-spacing, the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown fnrm nypr thf

in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of Dasatinib over FIG. 1 and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same or different w.r.t. the X-ray powder diffraction pattern of the crystalline form SDN of this invention.

The crystalline Form-SDN described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline Form-SDN of Dasatinib were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for crystalline Form-SDN of Dasatinibobtained in the Examples are set forth in the Figs. 1-2.

In a further embodiment according to the specification, the invention also relates to a composition containing crystalline Form-SDN in which at least 95% by total weight of Dasatinib in the composition is in the form of the crystalline Form- SDN. In yet another embodiment of the invention, the composition may be substantially free of any other known forms of Dasatinib.

The crystalline Form-SDN obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvant, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising crystalline Form-SDN of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of crystalline Form- SDN of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE

Example-01: Process for preparation of N-(2-chIoro-6-methyI phenyl)-2-[6-chloro-2- methyl-4-pyrimidinyl) amino]-5-thiazolecarboxamide (IV)

4, 6-Dichloro-2-methylpyrimidine (III) (DCMP, 73.05 g) was charged in to a reaction flask THF (1300.0 mL) at 25-30°C and stirred the reaction mass for 10-15 min at 25-30°C. 2- Amino 5-thiazolecarboxamide(II) (100.0 g) was charged in to the reaction mass at 25-30°C and stirred the reaction mass at 25-30°C for 10 -15 minutes. Cooled the reaction mass to 10- 20°C and sodium tertiary butoxidesolution (435.1 g; 33% in THF) was added slowly over 20- 30 min under Nitrogenatmosphere. Stirred the contents for 5 to 10 minutes at 10-20°C. Raisedthe reaction mass temperature to 20-25°C and again stirred the contents for 2 hours to 2 hours 30 minutes at 20-25°C. Cooled the reaction mass to -5 to 5°C and adjusted the pH of reaction mass to 1 -1.5 with 2N Aq. HQ (-600.0 mL). Stirred for 5 tolO min and then charged DM Water (-600.0 mL) at 0-5°C. Again, stirred the reaction mass for 2 hours to 2 hours 30 minutes at 0-5°C.Filtered the reaction mass and washed with DM Water (400.0 mL). Suck dried the material and washed the wet cake with Acetone (200.0 mL).Dried the material under vacuum at 60-65°C for 12 hours to 15 hoursto yield the title compound.

Yield: 118.9 gm

HPLC Purity: 96.82 %

Example-02: Process for preparation of Dasatinib Amyl alcohol

N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazole carboxamide (IV) was charged in to a reaction flask containing amyl alcohol (2000 mL) and stirred the reaction mass for 10-15 min at 25-30°C. Raised the reaction mass temperature to 135-140°C and then chargedHydroxyethylpiperazine solution (82.5g of Hydroxyethylpiperazine in 500 ml of amyl alcohol) over 5-10 minutes at 130-140°C. Stirred the reaction mass for 4 hours to 5 hours at 135-140°C and then cooled the reaction mass temperature gradually to 25-30°C. Again, stirred the reaction mass for 2 hours to 3 hours at 25-30°C.Filtered the reaction mass and washed with amyl alcohol (200.0 mL). Suck dry for 15-20 min at 25-30°C and dried the material under vacuum at 60-65°C for 12 hours to 15 hours

Yield: 119.7

HPLC Purity: 99.59 %

Example-03: Process for preparation of crystalline Dasatinib Form-SDN.

Dasatinib amyl alcohol solvate (75 g) obtained from example-2 was charged in to a reaction flask containing Methanol(3000 mL) at 25-30°C. Raised the temperature of the reaction mass to reflux temperature and stirred the reaction mass for 30 minutes at reflux (65-70°C). Filtered the reaction mass at 60-65°C and collect the filtrate. The collected filtrate was partially distilled off under atmospheric pressure at 65-70°C. Cooled the reaction mass slowly to 0-5°C and stirred for 1 hour to 2 hours at 0-5°C. Filtered the reaction mass and washed with Methanol (150 mL). Suck dried the material at 25-30°C for 15 to 20 minutes. Again, charged the wet material in to a reaction flask containing Methanol (1875 mL) at 25-30°C. Raised the reaction mass temperature to reflux (65-70°C) and stirred the reaction mass for 15 minutes to 20 minutes at reflux (65-70°C). Cooled the reaction mass slowly to 25-30°C and stirred for 2 hours to 3 hours at 25-30°C. Filtered the reaction mass and washed with Methanol. Suck dried the material for 15-20 min at 25-30°C and dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield pure crystalline Dasatinib.

Yield: 50.8 gm

HPLC Purity: 99.81 %

PXRD resembles with Fig.l

DSC resembles with Fig.2

Impurity profile (By HPLC):

Example-04: Process for preparation of amorphous Dasatinib.

Dasatinib amyl alcohol solvate (1.0 gm) obtained from example-2 was charged in to a reaction flask containing dimethyl formamide (10 mL) at 25-30°C. Stirredthe reaction mass for 15 minutes to 30 minutes at 25-30°C and then cooled the reaction mass slowly to 0-5°C. Charged cold water (80 mL) in to the reaction flask at 0-5°C and then stir the reaction mass for 60 minutes to 80 minutes at 0-5°C. Filtered the reaction mass and washed the material with DM water (2 x 5 mL). Suck dried the material at 25-30°C for 15-20 min. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield amorphous Dasatinib. The PXRD obtained as per this process is disclosed in Fig.3.

Yield: 0.68 gm

HPLC Purity: 99.54 %

PXRD resembles with Fig.3

While the foregoing provides a detailed description of the preferred embodiments of the invention, it is to be understood that the descriptions are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting scope sense.

Claims

We Claim:

1. A process for preparing crystalline Dasatinib (I),

comprising the steps of:

a) reacting 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide(II) with 4,6- Dichloro-2-methy] pyrimidine (III) in presence of solvent and a base to yield N-(2- chl oro-6-methylphenyl)-2- [6-chloro-2-methyl-4-pyrimidinyl ) amino] -5- thiazolecarboxamide of Formula (IV);

(III)

b) reacting N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5- thiazolecarboxamide (IV) with l-(3-Hydroxy)ethylpiperazine (V) in presence of amyl alcohol without base to yield Dasatinib amyl alcohol solvate; and

c) treating Dasatinib amyl alcohol solvate with methanol to get crystalline base as Form

-SDN.

2. A process for preparing crystalline Dasatinib according to claim 1, wherein the solvent used in step a) is selected from tetrahydrofuran,l ,4-Dioxane, Methyl tertiary butyl ether, dimethyl formamide, dichloromethane, toluene, 2-methyl tetrahydrofuran, dimethoxy ethane.

3. A process for preparing crystalline Dasatinib according to claim 1, wherein the base used in step a) is selected from inorganic / organic base such as sodium hydroxide, potassium hydroxide, sodium tertiary butoxide, Sodamide, potassium tertiary butoxide, sodium bicarbonate, potassium bicarbonate, diisopropyl ethyl amine, pyridine, methyl amine, trimethylamine or tri ethyl amine.

4. A process for preparing crystalline Dasatinib according to claim 1, wherein crystalline Dasatinib designated as Form-SDN, characterized by X-ray powder diffraction peaksat6.9, 13.2, 13.7, 16.7, 24.3 ± 0.2° 2Θ.

5. A process for preparin amorphous Dasatinib (I),

comprising the steps of:

a) reacting 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (II) with 4,6- Dichloro-2-methyl pyrimidine (III) in presence of solvent and a base to yield N-(2- chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino] -5- thiazolecarboxamide of Formula (IV);

(III)

b) reacting N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl) amino]-5- thiazolecarboxamide (IV) with l-(3-Hydroxy)ethylpiperazine (V) in presence of amyl alcohol without using base to yield Dasatinib amyl alcohol solvate; and

c) treating Dasatinib amyl alcohol solvate with dimethyl formamide and Watersolvent to get amorphous Dasatinib.

6. A process for preparing amorphousDasatinib according to claim 5, wherein the solvent used in step a) is selected from tetrahydrofuran,l,4-Dioxane, Methyl tertiary butyl ether, dimethyl formamide, dichloromethane, toluene, 2-methyl tetrahydrofuran, dimethoxy ethane.

7. A process for preparing amorphous Dasatinib according to claim 5, wherein the base used in step a) is selected from inorganic / organic base such as sodium hydroxide, potassium hydroxide, sodium tertiary butoxide,sodamide,potassium tertiary butoxide, sodium bicarbonate, potassium bicarbonate, diisopropyl ethyl amine, pyridine, methyl amine, trimethylamine or triethyl amine.

8. Crystalline Dasatinib designated as Form-SDN,characterized by

b) DSC isotherm comprising an endothermic peaks ranging between 280-290°C; and c) Crystalline Dasatinib Form-SDN containing the process related impurities A, B, C, D,

E, F and G collectively below 0.3%.

9) Crystalline Dasatinib according to claim 8, further characterized by X-ray powder diffraction pattern, substantially according to Fig-1 and DSC isothermal pattern substantially according to Fig-2.

10) Crystalline Dasatinib according to claim 8, pharmaceutical composition comprising Crystalline Form-SDN, together with at least one or more pharmaceutically acceptable excipients.