WO2015049645A2

WO2015049645A2 - An improved process for the preparation of dasatinib

Info

Publication number: WO2015049645A2
Application number: PCT/IB2014/064988
Authority: WO
Inventors: Venkatraman JAYARAMAN; Samir Patel; Samir Mistry; Bhupendra Parmar
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2013-10-04
Filing date: 2014-10-01
Publication date: 2015-04-09
Also published as: WO2015049645A3

Abstract

The present invention relates to a novel synthetic route to N-(2-chloro-6-methylphenyl)- 2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl] -2-methyl-4-pyrimidyl] amino]-5- thiazolformamide of the formula I and also relates to the process for the preparation of novel amorphous forms of dasatinib (formula I).

Description

TITLE: AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB

This application claims the benefit of priority of our Indian patent application numbers 3169/MUM/2013 filed on 04^th October 2013 and 3633/MUM/2013 filed on 19^th November 2013 which are incorporated herein by reference.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Dasatinib, with the trade name SPRYCEL™, is a oral tyrosine kinase inhibitor and developed by BMS Company. It is used to cure adult chronic myelogenous leukemia (CML), and acute lymphatic leukemia (ALL) with positive Philadelphia chromosome, etc. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl] -2-methyl-4-pyrimidyl] amino]-5-thiazolformamide and its chemical structure is as following:

The compound of formula (I) and its preparation have been previously described in U.S. Pat. No. 6,596,746, issued Jul. 22, 2003.

According to this method, ethyl 2-[(tert-butoxycarbonyl)amino]thiazole-5-carboxylate was original raw material, and dasatinib was synthesized through the following route:

WO2005077945A2 describes method for synthesizing dasatinib by Chen Bangchi, which was published on 13th June 2007 with the public number. According this method isocyanate or thiourea was used to form thiazole ring to synthesize dasatinib.

Alternatively

The International Patent application WO 2007/106879 A2, which was published on 20th September 2007 disclose method for synthesizing dasatinib. According this method another thiourea derivatives was used to form thiazole ring, in which amino groups were protected by triphenylmethyl, and then deprotection, and reation with 2-methyl-4,6- dichloropyrimidine and 1 -(2-hydroxyethyl)-piperazine to synthesize dasatinib.

J. Med. Chem. 2006, 49: 6819-6832 describes method for synthesizing Dasatinib was disclosed by Das et al. This paper discloses structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-pyperizinyl]- 2-methyl-4-pyrimidinyl] amino]-l,3-thiazole-5-carboxamide'. By this method 2- chlorothiazole was the original raw material and 4-methoxyphenmethyl was adopted to protect amino group to synthesize dasatinib:

According to EP0275312A1 substituted amino thiazoles can be obtained by reaction of substituted thiourea with a a-chloro carbonyl compound wherein the carbonyl compound may be protected as a dialkyl acetal.

The above methods present drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps. New and efficient processes for preparing 2-Amino-N-(2-chloro- 6-methylphenyl)-l, 3-thiazole-5-carboxamide are desired.

Reaction of N,N-dimethyl-N'-(aminothiocarbonyl)-formamidines with a-haloketones and esters to give 5-carbonyl-2-aminothiazoles has been reported. See Lin, Y. et al, J. Heterocycl. Chem. (1979), 16, at 1377; Hartmann, H. et al, J. Chem. Soc. Perkin Trans.

(2000) , 1, at 4316; Noack, A. et al; Tetrahedron (2002), 58, at 2137; Noack, A.; et al. Angew. Chem. (2001), 113, at 3097; and Kantlehner, W. et al., J. Prakt. Chem./Chem.- Ztg. (1996), 338, at 403. Reaction of β-ethoxy acrylates and thioureas to prepare 2- aminothiazole-5-carboxylates also has been reported. Zhao, R., et al., Tetrahedron Lett.

(2001) , 42, at 2101.

U.S. Pat. No. 6,596,746 Bl disclosed the preparation of dasatinib is described as

Where the process is final step is reacting compound-I with N-(2-hydroxyethyl) piperazine at 80° C. Several crystalline forms are described in the literature, these were designated forms 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 WO2005/077945A2. In addition US2006/0004067A1, which is continuation of WO2005/077945A2 also describes two ethanol solvates (E2-1; T1E2- 1) and two anhydrous forms (N-6; T1H1-7) The present invention describes the preparation of new amorphous forms of dasatinib.

Polymorphism, the occurrence of different crystal forms, is a property of some compounds and compound complexes. A single compound, like dasatinib, may give rise to a variety of crystalline forms having distinct crystal structures and physical characteristics like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point,

thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional solid state forms of dasatinib.

The disadvantages of abovementioned prior arts is that the amorphous form of dasatinib obtained by these processes is in form of lumps and difficult to filter at plant scale.

It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Konno T., Chem. Phar. Bull. 1990, 38, 2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. There is a constant need for processes which enable the preparation of dasatinib in an amorphous form without simultaneous formation of crystalline forms, or which will enable the conversion of the crystalline forms into the amorphous form.

However, desires still exist in this field: a new method suitable for industrial production and by the method easily available material is adopted to synthesize Dasatinib of high purity simply.

The process of the present invention has following advantages:

(i) It eliminates the requirement of purification of intermediates at various stages and provides a process which is economical, operational on and industrially applicable.

(ii) The process provides less number of steps as it eliminates the steps of protection and deprotection.

(iii) The process is simple and easy to handle and does not require special handling care or critical temperature conditions.

(iv) It eliminates the use of reagents which is greatly air and moisture sensitive. The present invention also provides a novel and industrially viable process for preparing dasatinib in pure amorphous form to avoid the drawback associated with the prior art.

SUMMARY OF INVENTION

The present invention is to provide an improved process for the preparation dasatinib of the Formula I.

In another aspect, the present invention provides a process for the preparation of dasatinib of the Formula I,

comprising

a) reacting compound of the fo

with tritylthiourea of formula III,

to give a compound of formula

b) the compound of formula IV is reacted with compound of formula V

in an base and solvent to give the compound of formula VI.

c) reacting compound of formula VI with N-(2-hydroxyethyl)piperazine (HEP) compound of formula VII to give Dasatinib compound of formula I.

which comprises the steps of ;

a) reacting compound of the formula II N-(2-chloro-6-methylphenyl)-3- ethoxyprop-2-enamide

with thiourea in presences of 1,4 dioxane and water and optionally in the presence of base to give a compound of formula IV 2-Amino-N-(2-chloro- 6-methylphenyl)-l,3-thiazole-5-carboxamide,

b) reacting the compound of formula IV 2-Amino-N-(2-chloro-6- methylphenyl)-l,3-thiazole-5-carboxamide with compound of formula V 4,6-Dichloro-2-methylpyrimidine

in a base and solvent to give the compound of formula VI N-(2-Chloro-6- methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl) amino]- 1, 3-thiazole- 5-carboxamide,

c) reacting compound of formula VI N-(2-Chloro-6-methylphenyl)-2-[(6-chloro- 2-methylpyrimidin-4-yl) amino]-l, 3-thiazole-5-carboxamide with compound of formula VII N-(2-hydroxyethyl)piperazine (HEP) in a base and solvent to give dasatinib compound of formula I.

In another aspect, the present invention provides a novel amorphous form of dasatinib.

In another aspect of the present invention encompasses amorphous dihydrate form of dasatinib.

In another aspect of the present invention encompasses an amorphous hemihydrate form of dasatinib.

In another aspect of the present invention encompasses an amorphous monohydrate form of dasatinib.

In another aspect of the present invention encompasses process for the preparation of amorphous dihydrate form of dasatinib.

In another aspect of the present invention encompasses process for the preparation of amorphous hemihydrate form of dasatinib.

In another aspect of the present invention encompasses process for the preparation of amorphous monohydrate form of dasatinib. Further aspect of the present invention provides a process for the preparation of dasatinib of formula (I) which is operationally simple, economical and commercially viable.

In another aspect, the present invention provides a process for the preparation of amorphous form of dasatinib of formula (I) which is operationally simple and easy to handle at commercial scale.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure- 1 : shows the X-ray powder diffraction pattern of amorphous dihydrate form of dasatinib.

Figure-2: shows the X-ray powder diffraction pattern of amorphous monohydrate form of dasatinib.

Figure-3 : shows the X-ray powder diffraction pattern of amorphous hemihydrate form of dasatinib.

DETAILS DESCRIPTION OF THE INVENTION

The invention is related to processes for the preparation of dasatinib.

The overall synthetic route can be carried out as outlined in the following simplified scheme

In one of the preferred embodiments wherein N-(2-chloro-6-methylphenyl)-3- ethoxyprop-2-enamide compound of formula (II) is reacted with a thiourea a suitable solvent and optionally in the presence of base, but preferably, no base is used. Suitable solvent(s) include solvents such hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, ketones and alcohols. The reaction may be carried out at room temperature, or heat may be applied. As one skilled in the field may appreciate, this reaction provides an efficient method of producing compounds of formula (IV).

In the present invention the compound of formula (II) is treated with halogenating agent before reacting with thiourea. Suitable halogenating agents are N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS).

Suitable solvent is selected from the group such as water, N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), Toluene, Tetrahydrofuran (THF), 1,4-dioxane, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, cyclopentyl methyl ether (CPME), methyl t-butyl ether, dimethoxymethane, and ethylene glycol dimethyl ether; alcohol solvents such as methanol (MeOH), ethanol (EtOH), n-propanol, n- butanol, tert-butanol, n-pentanol and isopropanol (IP A); and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane. Mixtures of solvents may also include biphasic mixtures. Preferably the solvents used are 1, 4-dioxane and water.

Suitable bases herein include metal oxides, hydroxides or alkoxides, hydrides, or compounds such as ammonia, that accept protons in water or solvent. Thus, exemplary bases include, but are not limited to, alkali metal hydroxides and alkoxides (i.e., MOR, wherein M is an alkali metal such as potassium, lithium, or sodium, and R is hydrogen or alkyl, as defined above, more preferably where R is straight or branched chain CI -5 alkyl, thus including, without limitation, ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert- butoxide, lithium hydroxide, etc.); other hydroxides such as magnesium hydroxide (Mg(OH)₂) or calcium hydroxide (Ca(OH) ₂); alkali metal hydrides (i.e., MH, wherein M is as defined above, thus including, without limitation, sodium hydride and lithium hydride); alkylated disilazides, such as, for example, potassium hexamethyldisilazide and lithium hexamethyldisilazide; carbonates such as potassium carbonate (K2C03), sodium carbonate (Na₂C03), potassium bicarbonate (KHCO₃), and sodium bicarbonate (NaHCC ), alkyl ammonium hydroxides such as n-tetrabutyl ammonium hydroxide (TBAH); and so forth. Preferred bases herein include organic bases more particularly tertiary amines such as N-methylmorpholine, tri ethyl amine, and N,N- diisopropylethylamine (DIPEA).

In one of the preferred embodiments the 2-Amino-N-(2-chloro-6-methylphenyl)-l,3- thiazole-5-carboxamide compound of formula (IV) is reacted with 4,6-Dichloro-2- methylpyrimidine compound of formula (V) in the presences of base and organic solvent, after completion of reaction, the reaction mass was treated with acidic medium to give N- (2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-l,3-thiazole-5- carboxamide compound of formula (VI). The acidic medium is provided by the presence of a strong acid. Suitable strong acids are hydrochloric acid or hydrobromic acid, preferably hydrochloric acid.

Suitable bases comprise both organic and inorganic bases. The bases include, but are not limited to, TEA (triethylamine), NMM (N-methyl morpholine), pyridine, NaH, NaOBu-t, KOBu-t, Ν,Ν-diisopropylethylamine (DIPEA), NaOH, KOH and/or LiOH. Preferably the base used is NaOBu-t.

Suitable solvent is selected from the group such as water, N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), Toluene, Tetrahydrofuran (THF), 1,4-dioxane, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, cyclopentyl methyl ether (CPME), methyl t-butyl ether, dimethoxymethane, and ethylene glycol dimethyl ether; alcohol solvents such as methanol (MeOH), ethanol (EtOH), n-propanol, n- butanol, tert-butanol, n-pentanol and isopropanol (IP A); and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane. Mixtures of solvents may also include biphasic mixtures. Preferably the solvents used is THF.

Optionally the resulting compound of formula (VI) is obtained as the salt of the strong acid, from which the free base can be obtained by any known manner, for instance by treating the salt with a base.

In further embodiments wherein the N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2- methylpyrimidin-4-yl)amino]-l,3-thiazole-5-carboxamide compound of formula (VI) and N-(2-hydroxyethyl)piperazine (HEP) are mixed in a suitable solvent optionally in the presence of base to obtain dasatinib compound of formula (I).

The compound of formula (VI) is either dissolved partially or completely in the solvent system. The mixture of compound of formula (VI) and HEP in solvent system and base may be sonicated or subjected to stirring or heating. In particularly preferred embodiments the reaction mixture of compound of formula (VI) and HEP compound of formula (VII) is heated until clear solution is obtained.

Suitable solvent is selected form the group such as water, N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), Toluene, Tetrahydrofuran (THF), 1,4-dioxane, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, cyclopentyl methyl ether (CPME), methyl t-butyl ether, dimethoxymethane, and ethylene glycol , dimethyl ether; alcohol solvents such as methanol (MeOH), ethanol (EtOH), n-propanol, n- butanol, tert-butanol, n-pentanol and isopropanol (IP A); and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane. Mixtures of solvents may also include biphasic mixtures. Preferably the solvents used are n-propanol and ethylene glycol. Suitable bases comprise both organic and inorganic bases. The bases include, but are not limited to, TEA (triethylamine), NMM (N-methyl morpholine), pyridine, NaH, NaOBu-t, KOBu-t, Ν,Ν-diisopropylethylamine (DIPEA), NaOH, KOH and/or LiOH.

In the present invention suitable solvent system is mixture of n-propyl alcohol and ethylene glycol and suitable base is Ν,Ν-diisopropylethylamine (DIPEA). In preferred embodiments the mixture is heated to about 10-120°C for between about 1-24 hours, most preferably 5-10 hours. The preferable temperature for the reaction will depend on the solvents such as DMF, NMP and DMAc are used, the heating conditions may differ.

One of the preferred embodiments of the present invention provides novel amorphous dihydrate form of dasatinib; amorphous hemihydrate form of dasatinib; amorphous hemihydrate form of dasatinib.

The term "amorphous" refers to a solid without long-range crystalline order. The amorphous form of a compound of Formula I of the present invention preferably contains less than about 20% crystalline forms, more preferably less than 5% crystalline forms, and still more preferably less than 1% or is essentially free of crystalline forms. "Essentially free of crystalline forms" means that no crystalline polymorph forms can be detected within the limits of an X-ray Powder Diffractometer.

The amorphous dihydrate form of dasatinib prepared by the present invention may be characterized by an X-ray Powder Diffraction Pattern (XRPD) as depicted in Figure 1. The amorphous dihydrate form of dasatinib prepared by the present invention may be further characterized by moisture content. Amorphous dihydrate form of dasatinib of present invention preferably contains about 5.0% to 9.0% of moisture content, more preferably about 5.5% to 7.5%.

The amorphous monohydrate form of dasatinib prepared by the present invention may be characterized by an X-ray Powder Diffraction Pattern (XRPD) as depicted in Figure 2. The amorphous monohydrate form of dasatinib prepared by the present invention may be further characterized by moisture content. Amorphous monohydrate form of dasatinib of present invention preferably contains about 3.0% to 5.0% of moisture content, more preferably about 3.5% to 4.5%.

The amorphous hemihydrate form of dasatinib prepared by the present invention may be characterized by an X-ray Powder Diffraction Pattern (XRPD) as depicted in Figure 3. The amorphous hemihydrate form of dasatinib prepared by the present invention may be further characterized by moisture content. Amorphous hemihydrate form of dasatinib of present invention preferably contains about 0.5% to 3.0% of moisture content, more preferably about 1.5% to 2.5%.

The amorphous dihydrate dasatinib prepared by the present invention is stable and does not convert to any other polymorphic form on storage at 25°C and 52% relative humidity (RH) for 24 days as depicted by X-ray Powder Diffraction Pattern

The amorphous monohydrate dasatinib prepared by the present invention is stable and does not convert to any other polymorphic form on storage at 25 °C and 52% relative humidity (RH) for 24 days as depicted by X-ray Powder Diffraction Pattern

The amorphous hemihydrate dasatinib prepared by the present invention is stable and does not convert to any other polymorphic form on storage at 25 °C and 52% relative humidity (RH) for 24 days as depicted by X-ray Powder Diffraction Pattern.

Further embodiment of the present invention provides a process for the preparation of an amorphous dihydrate dasatinib wherein the process comprises:

a) obtaining a solution of dasatinib;

b) removing the solvent from the solution obtained in step a);

c) treating dasatinib with water; and

d) isolating amorphous dihydrate dasatinib from the reaction mixture.

A solution of dasatinib can be obtained by treating dasatinib with one or more solvents. The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.

The solvent may be selected from the group consisting of water, alkanol, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.

Suitable alkanol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2- dichloroethane. A solvent may preferably be a mixture of water with alkanol, for example, a mixture of water with methanol, ethanol, or 2-propanol.

Treating dasatinib with one or more solvents may include adding, dissolving, slurrying, stirring, or a combination thereof. Dasatinib may be treated with a solvent at a temperature of about 60°C to about 100°C, preferably at about 70°C to about 80°C. The solvent may be removed in step b) by using various drying techniques, for example, spray drying, vacuum drying, freeze drying, or agitated thin film drying. Isolation of the amorphous dihydrate dasatinib in step c) comprises a common isolation technique such as evaporation, evaporation under vacuum, cooling, extraction, one or more washings, crystallization, precipitation, filtration, filtration under a vacuum, decantation and centrifugation, or a combination thereof.

XRPD of the samples were determined by using a Panalytical X'Pert Pro X-Ray Powder Diffractometer in the range 3-40 degree 2 theta and under a tube voltage and current of 45 Kv and 40 niA, respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.

Preparation of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2- methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (Dasatinib), the synthetic route can be carried out as outlined in the following simplified scheme:

Reaction Scheme:

Formula la

Formula I

In further embodiments the resulting compound of formula (I) is obtained as the salt of the strong acid i.e salts of dasatinib compound of formula (la), the acidic medium was provided by the presence of a strong acid to obtain salts of dasatinib. Suitable strong acids are hydrochloric acid or hydrobromic acid, preferably hydrochloric acid. Dasatinib hydrochloride compound of formula (la) from which the free base can be obtained by any known manner, for instance by treating the salt with a base.

Suitable bases comprise both organic and inorganic bases. The bases include, but are not limited to, TEA (triethylamine), NMM (N-methyl morpholine), pyridine, NaH, NaOBu-t, KOBu-t, ethyldiisopropylamine, NaOH, KOH and/or LiOH, potassium bicarbonate (KHC0₃), sodium bicarbonate (NaHC0₃). In one of the preferred embodiments to a solution of N-(2-chloro- 6-methylphenyl) -2- [(6-chloro-2- methylpyrimidin-4-yl)amino] -l,3-thiazole-5-carboxamide and N-(2- hydroxyethyl) piperazine in a mixture of n-propyl alcohol and ethylene glycol, was added Ν,Ν-diisopropylethylamine and heated till reaction complies. The reaction mixture was cooled; separated solid was filtered and washed with methanol. The wet material was treated with methanolic HCl. The solid was stirred, filtered, washed with methanol and dried under vacuum for 6-8h to give dasatinib hydrochloride. Purification of the target compound can be carried by recrystallization.

Preferably, purification is carried out by recrystallization in suitable solvents. Preferably the recrystallization is carried out at temperatures from -20°C to 100°C, especially temperatures from 0°C and 60°C.

The solvent may be selected from the group consisting of water, alkanol, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, 2-propanol, and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. A solvent may preferably be a mixture of water with alkanol, for example, a mixture of water with methanol, ethanol, or 2-propanol.

In further embodiments, a process for the preparation of amorphous form of dasatinib comprising

a. treating Hydrochloride salt of dasatinib with aqueous solution of base

b. removing the solvent from the solution obtained in step a);

c. treating dasatinib with aqueous solution of base; and d. isolating amorphous dasatinib from the reaction mixture.

Base is ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), sodium hydride, lithium hydride, potassium carbonate (K2C03), sodium carbonate (Na2C03), potassium bicarbonate (KHC03), sodium bicarbonate (NaHC03).

Suitable solvent is selected form the group such as water, N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), Toluene, Tetrahydrofuran (THF), 1,4-dioxane, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, cyclopentyl methyl ether (CPME), methyl t-butyl ether, dimethoxymethane, and ethylene glycol , dimethyl ether; alcohol solvents such as methanol (MeOH), ethanol (EtOH), n-propanol, n- butanol, tert-butanol, n-pentanol and isopropanol (IP A); and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane. Mixtures of solvents may also include biphasic mixtures.

All steps of the synthesis are carried out under reflux of the respective solvent used in each step at 10 to 100°C, preferably at 50 to 65°C. The reaction can be carried out at atmospheric pressure

In the following section, embodiments are described by way of examples to illustrate the process of invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

Examples:

Preparation of 2-Amino-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide

(IV) : To a stirred solution of N-(2-chloro-6-methylphenyl)-3-ethoxyprop-2-enamide (100.0 gm) in dioxane:water(400 ml: 400 ml), was added N-bromosuccinimide(81.67 gm) under cooling and allowed to stir at 0-10°C. l-trityl thiourea(31.75 gm) was added to the above reaction mixture and heated the reaction mixture at 20-30°C. The reaction mixture was heated for l-2h at 60-80°C. Cooled the reaction mixture to 20-30°C and ammonium hydroxide (84.0 ml) was added. Distilled off the reaction mixture to a half volume and cooled it. Separated solid was filtered off and washed with water (200 ml) and dried to obtain 2-Amino-N-(2-chloro-6-methylphenyl)-l, 3-thiazole-5-carboxamide (85 gm).

Preparation of 2-Amino-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5-carboxamide (IV) :

To a stirred solution of N-(2-chloro-6-methylphenyl)-3-ethoxyprop-2-enamide (100.0 gm) in dioxane:water(400 ml: 400 ml), was added N-bromosuccinimide(81.67 gm) under cooling and allowed to stir at 0-10°C.Thiourea(31.75 gm) was added to the above reaction mixture and heated the reaction mixture at 20-30°C. The reaction mixture was heated for l-2h at 60-80°C. Cooled the reaction mixture to 20-30°C and ammonium hydroxide (84.0 ml) was added. Distilled off the reaction mixture to a half volume and cooled it. Separated solid was filtered off and washed with water (200 ml) and dried to obtain 2-Amino-N-(2-chloro-6-methylphenyl)-l, 3-thiazole-5-carboxamide (85 gm).

Preparation of N-(2-Chloro-6-methylphenyl)-2- [(6-chloro-2-methylpyrimidin-4-yl) amino]-l, 3-thiazole-5-carboxamide (VI):

To a cooled solution of 2-amino-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5- carboxamide(100 gm) and 4,6-Dichloro-2-methylpyrimidine(66.96 gm) in THF(500 ml), was added sodium tert-butoxide(125.62 gm). The reaction mixture was allowed to cooled at 0-10°C. Concentrated HC1 (80 ml) was added. The reaction mixture was heated to 25±5°C for l-2h and was cooled to 0-10°C. The precipitated solid was filtered, washed with water (200 ml) and dried to obtain N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2- methylpyrimidin-4-yl) amino]- 1, 3-thiazole-5-carboxamide (90gm). Preparation of N-(2-chloro-6-methylphenyl)-2- [ [6- [4-(2-hydroxy ethyl)- 1- piperazinyl] -2-methyl-4-py rimidinyl] amino] -5-thiazolecarboxamide (I) :

To a solution of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4- yl)amino]-l,3-thiazole-5-carboxamide(100 gm) and N-(2-hydroxyethyl)piperazine (163.87 gm) in a mixture of n-propanol (500 ml)and ethylene glycol(500 ml), was added N,N-diisopropylethylamine (163.87 gm) and the reaction mixture was heated 100-120°C in suspension form for 4-5h. The reaction mixture was cooled to 20-30°C, separated solid was filtered and washed with n-propyl alcohol (200 ml) and dried to obtain N-(2-chloro- 6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide(95gm).

Preparation of N-(2-chloro-6-methylphenyl)-2- [ [6- [4-(2-hydroxy ethyl)- 1- piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide hydrochloride (Dasatinib HC1):

To a solution of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4- yl)amino]-l,3-thiazole-5-carboxamide(100 gm) and N-(2-hydroxyethyl)piperazine (163.87 gm) in a mixture of n-propanol (500 ml)and ethylene glycol(500 ml), was added N,N-diisopropylethylamine (163.87 gm) and the reaction mixture was heated 100-120°C in suspension form for 4-5h. The reaction mixture was cooled to 20-30°C, separated solid was filtered and washed with n-propyl alcohol (200 ml) and dried to obtain N-(2-chloro- 6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide.To the wet cake of N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]- 5-thiazolecarboxamide, methanol (1000 ml)and Concentrated hydrochloric acid (30.0 ml) was added ,heated at 65±5°C.The reaction mixture was cooled at room temperature. The obtained solid was filtered, washed with methanol (200 ml) and dried to obtain N-(2- chloro-6-methylphenyl)-2-[[6-[4-(2 -hydroxy ethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl] amino]-5-thiazolecarboxamide hydrochloride (95gm). Preparation of amorphous form of dasatinib:

Hydrochloride salt of Dasatinib (100 gm) was treated with aqueous solution of sodium hydroxide (1000 ml) at 20-30°C. The reaction mixture was filtered, cooled at 10-20°C and Concentrated HC1 (65.0 ml) was added. The solid was filtered, washed with water (200 ml) and dried. Sodium bicarbonate solution (1000 ml) was charged at 25±5°C to the dried material. The reaction mixture was stirred for 3h at 25±5°C.The obtained solid was washed with water (400 ml) and filtered off the solid. The solid was dried to obtain amorphous dasatinib (75gm).

Preparation of amorphous dihydrate form of dasatinib:

Hydrochloride salt of Dasatinib (100 gm) was treated with aqueous solution of sodium hydroxide (1000 ml) at 20-30°C. The reaction mixture was filtered, cooled at 10-20 °C and Concentrated HC1 (65.0 ml) was added. The solid was filtered, washed with water (200 ml) and dried. Sodium bicarbonate solution (1000 ml) was charged at 25±5°C to the dried material. The reaction mixture was stirred for 3h at 25±5°C.The obtained solid was washed with water (400 ml) and filtered off the solid. The solid was dried to obtain amorphous dihydrate dasatinib. [Water content 6.0-7.0%]

Preparation of amorphous hemihydrate form of dasatinib:

Dasatinib dihydrate Form was dried under vacuum for about 1 to 60 hours to obtain amorphous hemihydrate Dasatinib. [Water content 1.5-2.5%]

Preparation of amorphous monohydrate form of dasatinib:

Dasatinib hemihydrate was stirred with 5% solution of potassium carbonate in water. Solid was filtered off and dried under vacuum for 10-12h to obtain amorphous monohydrate Dasatinib. [Water content 3.0-4.0%]

Dasatinib monohydrate Form was dried under vacuum for about 1 to 60 hours to obtain amorphous hemihydrate dasatinib. [Water content 1.5-2.5%].

Claims

We Claim,

1. A process for the preparation of dasatinib of the Formula I,

which comprises the steps of ;

a) reacting N-(2-chloro-6-methylphenyl)-3-ethoxyprop-2-enamide; compound of the formula II

with thiourea in presences of 1,4 dioxane and water and optionally in the presence of base to give 2-Amino-N-(2-chloro-6-methylphenyl)-l,3- thiazole-5-carboxamide a compound of formula IV,

b) reacting the 2-Amino-N-(2-chloro-6-methylphenyl)-l,3-thiazole-5- carboxamide compound of formula IV with 4,6-dichloro-2- methylpyrimidine compound of formula V

in a base and solvent to give N-(2-Chloro-6-methylphenyl)-2-[(6-chloro- 2-methylpyrimidin-4-yl) amino]-l, 3-thiazole-5-carboxamide compound of the formula VI,

c) reacting compound N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2- methylpyrimidin-4-yl) amino]-l, 3-thiazole-5-carboxamide with N-(2- hydroxyethyl)piperazine (HEP) of formula VII in a base and solvent to give dasatinib compound of formula I.

2. A process according to claim 1, wherein in base is ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), sodium hydride, lithium hydride, potassium carbonate (K₂CC>3), sodium carbonate (Na₂CC>3), potassium bicarbonate (KHCO₃), sodium bicarbonate (NaHCC ), n-tetrabutyl ammonium hydroxide (TBAH), TEA (triethylamine), NMM (N-methyl morpholine), pyridine, Ν,Ν-diisopropylethylamine (DIPEA).

3. A process according to claim 1 , wherein the solvent are selected form group such as water, DMF, DMA, DMSO, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, THF, 1,4-dioxane, methyl t-butyl ether, dimethoxymethane, and ethylene glycol dimethyl ether; alcohol solvents such as MeOH, EtOH, and isopropanol; and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane.

4. An amorphous form of dasatinib having water content of about 1.5% to 7.5%.

5. A process for the preparation of amorphous form of dasatinib

comprising the steps of ;

a. treating hydrochloride salt of dasatinib with aqueous solution of base;

b. removing the solvent from the solution obtained in step a);

c. treating dasatinib with aqueous solution of base; and

d. isolating amorphous dasatinib from the reaction mixture.

6. A process for the preparation of amorphous dihydrate form of dasatinib comprising the steps of ;

a. providing a solution of dasatinib in suitable solvent;

b. removing the solvent from the solution obtained in step a);

c. treating dasatinib with water; and

d. isolating amorphous dihydrate dasatinib from the reaction mixture.

7. A process for the preparation of amorphous hemihydrate form of dasatinib comprising drying amorphous dihydrate form of dasatinib to obtain amorphous hemihydrate form of dasatinib.

8. A process for the preparation of amorphous monohydrate form of dasatinib comprising contacting amorphous hemihydrate form of dasatinib with solution of base in water.

9. A process according to claim 5 and 8, wherein in base is selected from ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), sodium hydride, lithium hydride, potassium carbonate (K₂CO₃), sodium carbonate (Na₂CC>3), potassium bicarbonate (KHCO₃), sodium bicarbonate (NaHCC^).

10. A process according to claim 5 and 6, wherein the suitable solvent is selected from the group such as water, Ν,Ν-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), Toluene, Tetrahydrofuran (THF), 1,4-dioxane, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, cyclopentyl methyl ether (CPME), methyl t-butyl ether, dimethoxymethane, and ethylene glycol , dimethyl ether; alcohol solvents such as methanol (MeOH), ethanol (EtOH), n-propanol, n- butanol, tert-butanol, n-pentanol and isopropanol (IPA); and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1 ,2-dichloroethane.