DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF 5-BROMO-4-(4- CHLOROTHIOPHEN-2-YL) THIAZOL-2-AMINE, SUBSTANTIALLY FREE OF DIBROMO IMPURITY AND NOVEL POLYMORPHIC FORMS OF AVATROMBOPAG FREE BASE & IT’S INTERMEDIATE”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA - 500 081

The following specification particularly describes the invention and the manner in which it is performed.
AN IMPROVED PROCESS FOR THE PREPARATION OF 5-BROMO-4-(4- CHLOROTHIOPHEN-2-YL) THIAZOL-2-AMINE, SUBSTANTIALLY FREE OF DIBROMO IMPURITY AND NOVEL POLYMORPHIC FORMS OF AVATROMBOPAG FREE BASE & IT’S INTERMEDIATE

FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine and novel crystalline forms of avatrombopag free base & it’s intermediate with higher purity and yield.

BACKGROUND OF THE INVENTION:
5-Bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine, having structural formula as represented by formula (II):

Formula (II)

which is one of the key intermediates useful in the preparation of avatrombopag maleate, having structural formula as represented by formula (I).

Formula (I)

Avatrombopag maleate developed by Astellas Pharma Inc., owns the patents and licensed them to Dova Pharmaceuticals, Inc. (and its subsidiary AkaRx, Inc.). Avatrombopag maleate is chemically known as 4-piperidinecarboxylic acid, 1-[3-chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino] carbonyl]-2-pyridinyl]-, (2Z)-2-butenedioate (1:1) and it is marketed in USA and Europe under the trade name DOPTELET® in the form of tablets having strength 20mg. DOPTELET® is a thrombopoietin receptor agonist indicated for the treatment of Thrombocytopenia in adult patients with chronic liver disease and chronic immune thrombocytopenia.

U.S. Patent no. 7,638,536 discloses the avatrombopag, or a pharmaceutically acceptable salt thereof. This patent disclosed the preparation of avatrombopag or salts thereof, which comprises bromination of 4-chloro-2-acetylthiophene of formula (1) with bromine in diethyl ether under ice cooling conditions, the mixture was stirred at room temperature for 2 hours to afford 2-bromo-1-(4-chlorothiophen-2-yl)ethan-1-one of formula (2), which is further treated with thiourea at room temperature, and the mixture was stirred at 80°C overnight to provide 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (3). Reacting compound of formula (3) with N-bromosuccinimide in the presence of N,N-dimethylformamide under ice cooling, and the reaction mixture was stirred at the same temperature for 50 minutes followed by reacting with cyclohexylpiperazine and triethylamine, the mixture was stirred at 70°C for 3 days to provide 2-amino-4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazole of formula (4). Then, the compound of formula (4) is converted into avatrombopag or salts thereof. The process is as shown in scheme-1 below:

wherein the molar ratio of N-bromosuccinimide used in stage-3 to compound of formula 3 is 1: >1;
PCT publication no. 2021021000 discloses a method for producing avatrombopag or salt thereof, which comprises bromination of 4-chloro-2-acetylthiophene of formula (1) with dropwise addition of bromine for 20 minutes at 0 °? in the presence of diethyl ether, the reaction mixture was stirred at the same temperature for 2 hours to provide 2-bromo-1-(4-chlorothiophen-2-yl)ethan-1-one of formula (2), which is further reacting with thiourea in the presence of ethanol and boiled for 1 hour to provide 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (3). Reacting compound of formula (3) with dropwise addition of N-bromosuccinimide for 1 hour at 10°?-15°? in the presence of dioxane. At this stage, a characteristic impurity of 5-bromo-4-(5-bromo-4-chlorothiophen-2-yl)thiazol-2-amine is also formed and this impurity carry forward in simultaneous reactions in preparation of Avatrombopag leads less purity of the compound. The process is as shown in scheme-2 below:

wherein the molar ratio of N-bromosuccinimide used in stage-3 to compound of formula 3 is 1: >1;

China publication no. 107383000 discloses a process for the preparation of avatrombopag, which comprises dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole in solvent such as methyl tert-butyl ether, N-methylpyrrolidone or N,N-dimethylformamide, and cooled in an ice-water bath. N-bromosuccinimide was added dropwise, and the reaction mixture was stirred at the same temperature for 30 minutes to provide 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine. Then, the obtained compound 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine was converting into avatrombopag. The process is as shown in scheme-3 below:

wherein the molar ratio of N-bromosuccinimide used in the above reaction to 2-amino-4-(4-chlorothiophen-2-yl)thiazole is 1:>1;

The above prior-art methods have one or more disadvantages, for example, those as mentioned as follows:
i. During the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), formation of dibromo impurity was observed. This will lead to the formation of bromo-Avatrombopag impurity in API as the dibromo impurity will have similar reactivity as the compound of formula (II).
ii. 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) or avatrombopag requires additional purification to purge the impurity which leads to the lower yield which is not suitable for pharmaceutical preparations.
iii. The reaction conditions known in prior methods were not optimal like temperature and mole ratio of the brominating agent etc., leads impure compounds with less yields and required complicated isolation procedures.

Therefore, there is a need in the art for an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) which is economical, easy to scale up and commercially viable.

The present inventors surprisingly found an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) with substantially free of dibromo impurity & avatrombopag free base of formula (Ia) with substantially free of bromo-Avatrombopag impurity and this step plays an important role in the reduction of impurities in final avatrombopag maleate of formula (I).

Thus, the main objective of the present invention is to provide an improved process for the preparation of key raw material i.e., 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) & avatrombopag free base of formula (Ia) which avoids the shortcomings of prior methods. Therefore, the present invented process is suitable for large scale operations and thereby commercially viable.

There still remains a need for development of new polymorphic forms of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl) carbamoyl)pyridin-2-yl)piperidine-4-carboxylate of formula (VI) & avatrombopag free base of formula (Ia) and improved process for preparation thereof. The present inventors have developed novel crystalline forms compound of formula (VI) & avatrombopag free base of formula (Ia) and its process for preparation.

OBJECTIVES OF THE INVENTION:
It is an object of the present invention to overcome the shortcomings of the prior art.

In one object of the present invention is to provide an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), substantially free of the dibromo impurity.

In another object of the present invention is to provide an improved process for the preparation of avatrombopag free base of formula (Ia) or salts thereof, substantially free of bromo-Avatrombopag impurity.

In another object of the present invention is to provide an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) and avatrombopag free base of formula (Ia) or salts thereof, which involves the specific reaction conditions like temperature and mole ratios of the reactants.

In another object of the present invention to provide novel crystalline forms of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl) pyridin-2-yl)piperidine-4-carboxylate of formula (VI) & avatrombopag free base of formula (Ia), a process for its preparation, use of it in the preparation of avatrombopag maleate of formula (I).

SUMMARY OF THE INVENTION:
The main aspect of the present invention, there is provided an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), substantially free of dibromo impurity.

In another aspect of the present invention, there is provided an improved process for the preparation of avatrombopag free base of formula (Ia) or salts thereof, substantially free of bromo-Avatrombopag impurity.

In another aspect of the present invention, there is provided an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) and use of the compound of formula (II) in the preparation of avatrombopag free base of formula (Ia) or salts thereof.

In another aspect of the present invention, there is provided a novel crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate of formula (VI), characterized by its XRPD pattern having one or more peaks at about 7.1, 11.1, 13.2, 14.3, 14.5, 15.0, 16.7, 17.5, and 21.3° 2?± 0.2°.

In another aspect of the present invention, there is provided a process for the preparation of crystalline form G of compound of formula (VI) and use of the compound of formula (VI) in the preparation of avatrombopag free base of formula (Ia) or salts thereof.

In another aspect of the present invention, there is provided a novel crystalline form K of avatrombopag free base of formula (Ia), characterized by its XRPD pattern having one or more peaks at about 5.9, 8.5, 8.9, 11.8, 12.8, 14.2, 14.7, 16.7, 21.6, and 21.9° 2?± 0.2°.

In another aspect of the present invention, there is provided a process for the preparation of crystalline form K of avatrombopag free base of formula (Ia) and use of the compound of formula (Ia) in the preparation of avatrombopag maleate of formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1: Illustrates the X-Ray Powder Diffraction (XRPD) pattern of crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl)carbamoyl) pyridine-2-yl)piperidine-4-carboxylate of formula (VI).
Figure-2: Illustrates the X-Ray Powder Diffraction (XRPD) pattern of crystalline form K of avatrombopag free base of formula (Ia).

DETAILED DESCRIPTION:
The following description with accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.

Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.

It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.

It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

The term “solvent/ suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from the group consisting of methanol, ethanol, iso-propanol (IPA), n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate (IPAc); ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile (ACN), propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethyl acetamide (DMAc) and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

The term “brominating agent” used in the present invention is selected from but not limited to bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinimide (NBS), carbon tetrabromide or phosphorous tribromide, dibromoisocyanuric acid (DBI), bromine chloride, aluminum tribromide, 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH), 2,4,4,6-Tetrabromo-2,5-cyclohexadien one (TBCHD) and the like.

The term “base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo [2.2.2]octane (DABCO) or mixtures thereof.

The term “suitable halogenating agent” is selected from but not limited to bromine, phenyltrimethylammonium tribromide, N-bromosuccinimide, tribromophosphine, hydroperbromic acid, borontribromide, 1,3-Dibromo-5,5-dimethylhydantoin, phosphorous oxy chloride, phosphorus trichloride, phosphorus pentachloride, phosphorous tribromide, phosphorus pentabromide, phosphorus triiodide, oxalyl chloride, thionyl chloride, thionyl bromide, HBr, TMSCl, TMSBr and, Hydrogen halide, mesyl halide, tosyl halide, nosyl halide and triflyl chloride halide and the like.

In one embodiment, the present invention provides an improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II);

Formula (II)
wherein the process comprising the following steps:
a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent, at a suitable temperature;

Formula (III)
b) adding brominating agent to step-a) solution at a suitable temperature; and
c) isolating the 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II).

The starting compound of formula (III) is commercially available and it can be prepared according to the methods known in the art.

In other embodiment, step a) involves dissolution of 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, preferably amide solvent such as N,N-dimethylformamide and N,N-dimethyl acetamide. The solution can be carried out at a suitable temperature of about 20°C to about 40°C; preferably at about 25°C to about 35°C.

In other embodiment, the bromination of step b) by drop wise addition of brominating agent selected from but not limited to bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinimide (NBS), carbon tetrabromide or phosphorous tribromide, dibromoisocyanuric acid (DBI), bromine chloride, aluminum tribromide, 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) and 2,4,4,6-Tetrabromo-2,5-cyclohexadien one (TBCHD) to reaction mass of step-a) over a period of 30 min to 2 hours at about 0 to about -10°C. Preferably at about 0°C to about -5°C and maintained for 2 to 4 hours.

In an embodiment, the molar ratio of brominating agent used in step b) to compound of formula (III) is 1:1 or less. Preferably, the brominating agent is 0.45 to 0.99 mole per 1 mole of compound of formula (III).

Isolation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II) can be carried out by any conventional techniques known in the art, for example filtration and followed by drying.

However, the inventors of the present invention surprisingly found that, while using lower equiv. (=1.0 eq.) of brominating agent in the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), when compared to compound of formula (III), at lower temperature eliminates the formation of dibromo impurity. The reaction conditions are mild, operation friendly and industrially applicable, and could directly achieve compound of formula (II) with <0.15% of dibromo impurity without any further purification steps or column chromatography.

Hence, the inventors of the present invention avoided laborious purification techniques like column chromatography and provided an improved process, which is simple, cost effective and industrially feasible.

In another embodiment, the present invention provides an improved process for the preparation of avatrombopag free base of formula (Ia) or salts thereof;

Formula (Ia)
wherein the process comprising the following steps:
a) dissolving compound of formula (III) in a suitable solvent at a suitable temperature;

Formula (III)
b) adding brominating agent to the step-b) solution at a suitable temperature to provide a compound of formula (II);

Formula (II)
c) reacting compound of formula (II) with 1-cyclohexylpiperazine with a base in the presence of a suitable solvent at a suitable temperature to provide a compound of formula (IV);

Formula (IV)
d) condensing the compound of formula (IV) with a compound of formula (V) and a suitable halogenating agent in the presence of a suitable solvent,

Formula (V)
followed by treating with a base at a suitable temperature to provide a compound of formula (VI);

Formula (VI)
and
e) hydrolyzing the compound of formula (VI) with a suitable base in the presence of a suitable solvent to provide avatrombopag free base of formula (Ia) or salts thereof.

The starting compound of formula (III) is commercially available and it can be prepared according to the methods known in the art.

In other embodiment, step a) involves dissolution of 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, preferably amide solvent such as N,N-dimethylformamide and N,N-dimethyl acetamide. The solution can be carried out at a suitable temperature of about 20°C to about 40°C; preferably at about 25-35°C.

In other embodiment, the bromination of step b) by drop wise addition of brominating agent selected from but not limited to bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinimide (NBS), carbon tetrabromide or phosphorous tribromide, dibromoisocyanuric acid (DBI), bromine chloride, aluminum tribromide, 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) and 2,4,4,6-Tetrabromo-2,5-cyclohexadien one (TBCHD) to reaction mass of step-b) solution over a period of 30 min to 2 hours at about 0 to about -10°C. Preferably at about 0°C to about -5°C and maintained for 2 to 4 hours.

In an embodiment, the molar ratio of brominating agent used in step b) to compound of formula (III) is 1:1 or less. Preferably, the brominating agent is 0.45 to 0.99 mole per 1 mole of compound of formula (III).

In other embodiment, step c) involves the reaction of a compound of formula (II) with 1-cyclohexylpiperazine with a base selected from inorganic bases or organic bases, preferably inorganic bases such as potassium carbonate, in the presence of a suitable solvent selected from water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons, and halogenated hydrocarbons, preferably nitriles such as acetonitrile, to provide a compound of formula (IV). The solution can be carried out at a suitable temperature of about 20°C to about 150°C, preferably at about 25°C to about 90°C.

In other embodiment, step d) involves condensation of a compound of formula (IV) with a compound of formula (V) and a suitable halogenating agent selected from but not limited to thionyl chloride in the presence of a suitable solvent selected from water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons, and halogenated hydrocarbons, preferably halogenated hydrocarbons such as dichloromethane, followed by treating with a base selected from inorganic bases or organic bases, preferably organic bases such as pyridine, to provide a compound of formula (VI). The solution can be carried out at a suitable temperature of about 20°C to about 60°C, preferably at about 25°C to about 50°C.

In other embodiment, step e) involves hydrolyzing the compound of formula (VI) with a suitable base in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula (Ia), wherein base and solvent are as defined above.

In another embodiment, use of specific reaction conditions like temperature and mole ratios of the reactants facilitate to significantly eliminate the following impurities are observed during the synthesis of the compound of formula (I) as per the present invention. Along with these impurities, intermediates obtained according to the present invention, the starting materials are well controlled as per ICH guide lines in the compound of formula (I).

Dibromo impurity
Bromo-thiazole impurity

Bromo-Ester impurity
Bromo-Avatrombopag impurity

Bromo-Avatrombopag maleate impurity

In another embodiment, the present invention provides a novel crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate of formula (VI), characterized by its XRPD pattern having one or more peaks at about 7.1, 11.1, 13.2, 14.3, 14.5, 15.0, 16.7, 17.5 and 21.3° 2?± 0.2°.

The crystalline form G of the compound of formula (VI) is further characterized by an XRPD pattern as depicted in Figure 1.

In another embodiment, the present invention provides a process for the preparation of crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate of formula (VI), comprising:
a) dissolving ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate in a halogenated solvent, alcohol solvent, ether solvent, or mixture thereof;
b) isolating crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate of formula (VI).

Wherein in step-a), the halogenated solvent is selected from dichloromethane, chloroform, chlorobenzene, bromobenzene, preferably dichloromethane; the alcohol solvent is selected from methanol, ethanol, iso-propanol (IPA), n-butanol, iso-butanol, preferably ethanol; and ether solvent is selected from methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane, preferably methyl tert-butyl ether.

Wherein in step-b), the isolation of the crystalline form G of formula (VI) is by solvent removal by known techniques, which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid, followed by filtration of the mixture, crystallization, or by adding an anti-solvent.

In another embodiment, the present invention provides the use of crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate of formula (VI) in the preparation of avatrombopag free base of formula (Ia) or its pharmaceutically salts.

In another embodiment, the present invention, there is provided a novel crystalline form K of avatrombopag free base of formula (Ia), characterized by its XRPD pattern having one or more peaks at about 5.9, 8.5, 8.9, 11.8, 12.8, 14.2, 14.7, 16.7, 21.6, and 21.9° 2?± 0.2°.

The crystalline form K of avatrombopag free base of formula (Ia) is further characterized by an XRPD pattern as depicted in Figure 2.

In another embodiment, the present invention provides a process for the preparation of crystalline form K of avatrombopag free base of formula (Ia) comprising:
a) treating crystalline form G of compound of formula (VI) with a base in a suitable solvent to provide avatrombopag free base of formula (Ia);
b) dissolving the step-a) solution in a hydrocarbon solvent; and
c) isolating crystalline form K of avatrombopag free base of formula (Ia).

Wherein the base is sodium hydroxide; the solvent is ethanol; and the hydrocarbon solvent is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane, preferably toluene.

The isolation of the crystalline form K of avatrombopag free base of formula (Ia) is by solvent removal by known techniques, which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid, followed by filtration of the mixture, crystallization, or by adding an anti-solvent.

In another embodiment, the present invention provides the use of crystalline form K of avatrombopag free base of formula (Ia) in the preparation of avatrombopag maleate of formula (I).

Avatrombopag free base of formula (Ia) or its pharmaceutically acceptable salts produced by the processes of the present invention can be further micronized or milled to get desired particle sizes to achieve desired solubility profiles based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include but are not limited to a single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills, and roller mills. Milling or micronization may be performed before drying or after drying of the product.

Avatrombopag maleate of formula (I) obtained according to the present invention has particle size of less than about 100 µm or less than about 80 µm or less than about 60 µm or less than about 40 µm or less than about 20 µm or any other suitable particle sizes.

In another embodiment, the present invention relates to an improved process for the preparation of avatrombopag maleate, which is schematically represented by the following scheme:

In another embodiment, the present invention provides the use of avatrombopag maleate of formula (I) and their polymorphs of the present invention for the preparation of various pharmaceutical formulations.

In another embodiment, the present invention provides pharmaceutical composition comprising avatrombopag maleate of formula (I) and their polymorphs or mixture thereof obtained according to the present invention and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Avatrombopag maleate of formula (I) and their polymorphs produced by various processes of the present invention and one or more pharmaceutically acceptable carriers for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.
ANALYSIS OF DIBROMO IMPURITY LEVELS:
To summarize, we have used HPLC as an analytical method for validating and estimating dibromo impurity content in 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II).

Table 1: Impact of temperature on dibromo impurity content
Experiment No. Input (g) Temp (°C) Yield (%) In-process Profile by HPLC (% area) Reaction profile by HPLC (% area)
Dibromo impurity Dibromo impurity
AOG/C122/ 1A/41 30.0 10 to 15 85.48 0.21 0.23
AOG/C161/ 1A/28 300.0 0 to -5 92.00 ND ND

Table 2: Impact of NBS equivalent on dibromo impurity content
Experiment No. Input (g) Brominating agent, ex: NBS (equivalent) Reaction profile by HPLC (% area)
Dibromo impurity

AOG/C135/1A/30 30.0 1.05 1.12
AOG/C161/1A/28 300.0 0.98 ND
AOG/C122/1A/004 20.0 0.95 ND

EXAMPLES
The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.

Example-1: Preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine (II)
To a clean and dry RBF (Round-bottom flask), 4-(4-chlorothiophen-2yl)thiazol-2-amine (III) (75.0 g; 1.0 eq) and N,N-Dimethylformamide (225.0 mL; 3.0 v) were added at 25 to 35oC, stirred for 20 to 40 minutes at the same temperature. The reaction mass was cooled to -5 to -10oC, N-bromosuccinimide solution (60.37 g; 0.98 eq) was added slowly over a period of 1 to 2 hours at 0 to -10oC and maintained for 2 to 4 hours at 0 to -5oC. After completion of reaction, aqueous sodium sulfite solution was added at below 20oC and maintained for 20 to 40 minutes. Then slowly warmed to 25 to 35oC and maintained for 2 to 3 hours at the same temperature. The solid obtained was filtered, washed with water and dried to obtained the title compound. Yield: 92.5g; Dibromo impurity: Not detectable.

Example-2: Preparation of 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine (IV)
A mixture of acetonitrile (1000mL; 10 vol.), potassium carbonate (32.73g; 0.70eq.) and 1-cyclohexylpiperazine (85.40g; 1.50eq.) were taken into RBF and stirred for 5 to 15 minutes at 25 to 35oC. The compound (100g; 1eq.) obtained in Example-1 was added and stirred for 5 to 15 minutes at the same temperature. The reaction mass temperature was heated to 75 to 80°C and maintained for 5 to 7 hours at the same temperature. After completion of the reaction, the reaction mass temperature was cooled to 55 to 65°C, distilled solvent under vacuum until the inside mass volume reaches ~4.5 to 5.5. The reaction mass temperature was cooled to 25 to 35°C, then water (1000mL; 10 vol.) was added and stirred for 1.5 to 2.5 hours. The solid obtained was filtered, and washed with water (300mL; 3 vol.). The wet material was taken into RBF and Toluene (2000mL; 20 vol.) was added at 25 to 35oC, heated to reflux temperature. Water was removed azeotropiclly and cooled to 75 to 85°C. Activated carbon (10g) was added and stirred for 45 to 60 mins at the same temperature. Filtered the mass on hyflo bed and washed the bed with pre-heated toluene. Distilled solvent under vacuum until the inside mass volume reaches ~4.5 to 5.5 at 65°C. The reaction mass was cooled to 20 to 30°C and stirred for 1.5 to 2.5 hours. The solid obtained was filtered, washed with toluene, and dried to obtained the title compound. Yield: 100.2g;

Example-3: Preparation of 5-chloro-6-(4-(ethoxycarbonyl) piperidin-1-yl)nicotinic acid (V)
A mixture of N,N-dimethylacetamide (150mL; 3vol.), 5,6-dichloronicotinic acid (50g; 1eq.), ethyl piperidin-4-carboxylate (53.22g; 1.3eq.), triethylamine (65.87g; 2.5eq.) were added into RBF, stirred for 20 to 40 minutes at 25 to 35°C. The reaction mass was heated to reflux temperature and maintained for 14 to 16 hours at the same temperature. After completion of the reaction, the reaction mass temperature was cooled to 25 to 35°C, then water (1000mL; 20 vol.) was added and stirred for 20 to 40 minutes. Activated carbon (7.50g) was added and stirred for 50 to 70 mins at the same temperature. Filtered the mass on hyflo bed. aq. acetic acid solution (39.1g; 2.5eq) was added and stirred for 1 to 3 hours. The solid obtained was filtered and washed with water. The material was taken into RBF and Acetone (250mL; 5vol.) and activated carbon (5g) were added and stirred for 50 to 70 mins at 25 to 35°C. The mass was filtered and distilled solvent under vacuum until the inside mass volume reaches ~1.5 to 2.5 at 45°C. Water (250mL; 5vol.) was added and stirred for 1 to 3 hours at 25 to 35°C. The solid obtained was filtered and acetone (250mL; 5vol.) was added, stirred for 25 to 35 mins at 25 to 35°C. Distilled the solvent under vacuum until the inside mass volume reaches ~1.5 to 2.5 at 45°C. Water (250mL; 5vol.) was added and stirred for 1 to 3 hours at 25 to 35°C. The solid obtained was filtered, washed with water, and dried to obtained the title compound. Yield: 63.5g.

Example-4: Preparation of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate (VI)
The compound (49g; 1.2eq.) obtained in Example-3 and DCM (500mL; 10vol.) were taken into RBF. SOCl2 (21.75; 1.4eq.) was added at 25 to 35°C, stirred for 15 to 25 minutes under nitrogen atmosphere. The mass was heated to reflux temperature and maintained for 3 to 5 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to 25 to 35°C. Distilled the solvent under vacuum until inside mass volume reaches ~4.5 to 5.5 at 45°C. DCM (250mL; 5vol.) was added and stirred for 20 to 40 minutes at 25 to 35°C. Distilled solvent under vacuum until the inside mass volume reaches ~4.5 to 5.5 at 45°C. DCM (250mL; 5vol.) and pyridine (103.30g; 10eq.) were added at 25 to 35°C and stirred for 25 to 35 minutes at the same temperature. The compound (50g; 1eq.) obtained in Example-2 was added lot wise and stirred for 2 to 4 hours at 25 to 35°C. After completion of reaction, water (250mL; 5vol.) was added, stirred for 15 to 25 mins, at 25 to 35°C and the layers were separated. Washed the organic layer with aq. hydrochloric acid solution followed by sodium bicarbonate solution and sodium chloride solution. Distilled the solvent (organic layer) under vacuum until the inside mass volume reaches ~2.5 to 3.5 at 45°C, followed by ethanol (500mL; 10vol.) was added, stirred for 25 to 35 mins at the same temperature. The reaction mass temperature was cooled to 20 to 30°C and stirred for 2 to 4 hours at the same temperature. The solid obtained was filtered, washed with ethanol, and dried to obtained the title compound. Yield: 67g;

Example-4: Preparation of Avatrombopag free base (Ia)
To a stirred solution, the compound (100g; 1eq.) obtained in Example-4 and ethanol (400mL; 4vol.) were added at 20 to 30°C and stirred for 5 to 15 mins at the same temperature. NaOH solution (17.70g; 3 eq.) was added and heated to 25 to 35°C and stirred for 2 to 4 hours at the same temperature. Activated carbon (20g) was added and stirred for 30 to 50 mins at the same temperature. Filtered the mass on a hyflo bed and washed with a water and ethanol mixture. Toluene (2 x 400mL; 4vol.) was added and stirred for 20 to 40 mins at the same temperature. Maleic acid solution (34.25g; 2eq.) was added at 25 to 35°C and stirred for 2 to 4 hours at the same temperature. The solid obtained was filtered, washed with water, followed by acetone, and dried to obtained the title compound. Yield: 85g;

Example-5: Preparation of Avatrombopag maleate (I)
To a stirred solution of dimethylsulfoxide (450mL; 4.5vol.), acetone (450mL; 4.5vol.) and maleic acid (22.26g; 1.3eq.) were added and stirred for 20 to 40 mins at 25 to 35°C. Avatrombopag (100g; 1eq.) was added and stirred for 1 to 3 hours at the same temperature. The solid obtained was filtered on a hyflo bed and washed with a dimethylsulfoxide and acetone mixture. Water (500mL; 5vol.) was added, stirred for 15 to 45 mins and acetone (500mL; 5vol.) was added, stirred for 15 to 45 mins, at 25 to 35°C. The reaction mass temperature was cooled to 5 to 10°C and stirred for 2 to 4 hours at the same temperature. The solid obtained was filtered and washed with acetone and water, followed by acetone, and dried to obtained the title compound. Yield: 100g;

Dated this: 17th day of September, 2024.

Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081 ,CLAIMS:We claim:
1. An improved process for the preparation of 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II);

Formula (II)
which comprises:
a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent at a suitable temperature;

Formula (III)
b) adding brominating agent to step-b) solution at a suitable temperature; and
c) isolating 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), which is a substantially free of dibromo impurity;

Dibromo Impurity
wherein the molar ratio of brominating agent used in step b) to compound of formula (III) is 1: =1.

2. The process as claimed in claim 1, wherein in step a) the solvent is selected from water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons, and halogenated hydrocarbons.

3. The process as claimed in claim 1, wherein in step b) the brominating agent is selected from bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinimide (NBS), carbon tetrabromide or phosphorous tribromide, dibromoisocyanuric acid (DBI), bromine chloride, aluminum tribromide, 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH), and 2,4,4,6-Tetrabromo-2,5-cyclohexadien one (TBCHD); and the suitable temperature is about 0°C to about -10°C.

4. An improved process for the preparation of avatrombopag free base of formula (Ia) or salts thereof;

Formula (Ia)
comprising:
a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent at a suitable temperature;

Formula (III)
b) adding brominating agent to the step-b) solution at a suitable temperature to provide a compound of formula (II);

Formula (II)
c) reacting compound of formula (II) with 1-cyclohexylpiperazine with a base in presence of a suitable solvent at a suitable temperature to provide a compound of formula (IV);

Formula (IV)
d) condensing the compound of formula (IV) with a compound of formula (V) and a suitable halogenating agent in presence of a suitable solvent,

Formula (V)
and followed by treating with a base at a suitable temperature to provide a compound of formula (VI);

Formula (VI)
and
e) hydrolyzing the compound of formula (VI) with a base in the presence of a suitable solvent to provide avatrombopag free base of formula (Ia) or salts thereof, which is substantially free of bromo-Avatrombopag impurity;

bromo-Avatrombopag impurity

wherein the molar ratio of brominating agent used in step b) to compound of formula (III) is 1: =1.

5. A novel crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate of formula (VI) characterized by its XRPD pattern having one or more peaks at about 7.1, 11.1, 13.2, 14.3, 14.5, 15.0, 16.7, 17.5 and 21.3° 2?± 0.2°.

6. A process for the preparation of crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate of formula (VI), comprising:
a) dissolving ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate in a halogenated solvent, alcohol solvent, ether solvent or mixture thereof;
b) isolating crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate of formula (VI).

7. The process as claimed in claim 6, wherein the halogenated solvent is selected from dichloromethane, chloroform, chlorobenzene, and bromobenzene; the alcohol solvent is selected from methanol, ethanol, iso-propanol (IPA), n-butanol, and iso-butanol; and ether solvent is selected from methyl tert-butyl ether, diisopropyl ether, diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane.

8. A novel crystalline form K of avatrombopag free base of formula (Ia), characterized by its XRPD pattern having one or more peaks at about 5.9, 8.5, 8.9, 11.8, 12.8, 14.2, 14.7, 16.7, 21.6, and 21.9° 2?± 0.2°.

9. A process for the preparation of crystalline form K of avatrombopag free base of formula (Ia) comprising:
a) treating crystalline form G of compound of formula (VI) with a base in a suitable solvent to provide avatrombopag free base of formula (Ia);
b) dissolving the step-a) solution in a hydrocarbon solvent; and
c) isolating crystalline form K of avatrombopag free base of formula (Ia).

10. The process as claimed in claim 9, wherein the base is sodium hydroxide; the solvent is ethanol; and hydrocarbon solvent is selected from heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, and cyclohexane.

Dated this: 17th day of September, 2024.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081