Claims:WE CLAIM:

1. A process for preparation of (3-chloropyrazin-2-yl)methanamine and its acid addition salt of formula (I) comprising:

i) chlorination of compound of formula (IV) to form a compound of formula (III)

by adding a predefined chlorinating agentat a first predefined temperature in a predefined chlorinated solvent and carrying out the reaction at a second predefined temperature;
ii) hydrogenation of compound of formula (III) formed in step i),

in presence of BOC anhydride and in presence of a predefined metal catalyst in a predefined solvent at predefined pressure and temperature to form compound of formula (II) and;
iii) deprotection of compound of formula (II) to a compound of formula (I).
a) ;
using a predefined acid in a predefined solvent at a predefined temperature.

2. The process as claimed in claim 1, wherein the predefined chlorinating agent is selected from the group of sulfuryl chloride, thionyl chloride and chlorine gas.

3. The process as claimed in claim 1, wherein the predefined chlorinated solvent is selected from methylene dichloride, ethylene dichloride and chloroform; and dimethylformamide.

4. The process as claimed in claim 1, wherein the first predefined temperature is below 10°C and the second predefined temperature is in the range of 25-35°C.

5. The process as claimed in claim 1, wherein the predefined metal catalyst is selected from palladium, platinum, nickel, and rhodium.

6. The process as claimed in claim 1, wherein the predefined solvent used in step (ii) is an alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol.

7. The process as claimed in claim 1, wherein the predefined pressure used in step (ii) is in the range of 6-15 kg/Cm2, preferably 12 kg/Cm2.

8. The process as claimed in claim 1, wherein the predefined temperature used in step (ii) is in the range of 30-50°C, preferably 40-45°C.

9. The process as claimed in claim 1, wherein the predefined acid used in step (iii) is selected from sulfuric acid, hydrochloric acid, acetic acid, methane sulfuric acid and trifluoro acetic acid.

10. The process as claimed in claim 1, wherein the predefined solvent used in step (iii) is an alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol.

11. The process as claimed in claim 1, wherein the predefined temperature used in step (iii) is in the range of 40-70°C, preferably 50-55°C.

12. A process for preparation of compound of formula (VI) comprising, reacting compound of formula (I) with N-protected proline compound of formula (V), wherein R1 is (1-4C alkyl), (1-4C alkyl) substituted by phenyl or substituted phenyl,
in presence of a predefined coupling agent and hydroxyl benzotriazole (HoBt) in a predefined solvent and a predefined base.

13. The process as claimed in claim 12, wherein the predefined coupling agent is dicyclohexylcarbodiimide (DCC)

14. The process as claimed in claim 12, wherein the predefined solvent is selected from methylene dichloride, chloroform and ethylene dichloride, dimethyl formamide and ethyl acetate.

15. The process as claimed in claim 12, wherein the predefined base is selected from inorganic and organic bases.

16. The process as claimed in claim 15, wherein the inorganic base is selected from hydroxides and alkoxides and organic base is selected from Triethylamine and N,N-diisopropylethylamine.

Dated this 6th day of May 2020
FOR AARTI INDUSTRIES LIMITED

ANAND MAHURKAR
(IN/PA- 1862)
(Agent for Applicant)

, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparation of intermediates of Bruton’s tyrosine kinase inhibitor and more to an improved process for preparation of Acalabrutinib intermediates (3-chloropyrazin-2-yl)methanamine and acid salt thereof and 2-((3-chloropyrazin-2-yl)methylcarbamoyl) pyrrolidine-1-carboxylic acid ester.

BACKGROUND OF THE INVENTION
(3-chloropyrazin-2-yl)methanamineor salts thereof and 2-((3-chloropyrazin-2-yl)methylcarbamoyl) pyrrolidine-1-carboxylic acid ester are important intermediates of Acalabrutinib.
Acalabrutinib is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential anti-neoplastic activity. It is a novel experimental anti-cancer drug and a 2ndgeneration Bruton’s tyrosine kinase (BTK) inhibitor developed by Acerta Pharma. Acalabrutinib is used for treatment of non-hodgkin lymphoma known as mantle cell lymphoma. Specifically it is for people who have previously been treated with another therapy.
Acalabrutinib and its intermediates are disclosed in product patent US9290504. The process involves catalytic reduction of solution of 3-chloropyrazine-2-carbonitrile in aceticacid using Raney Nickel. The patent further states that remaining brown solid was dissolved in ethyl acetate at 50°C, but practically the remaining material is sticky greenish colour and was not dissolved/miscible at 50°C with ethyl acetate.
The isolation of the pure amine is very tricky due to use of acetic acid as a solventin this process and nickel acetate used for salt formation. N-[(3-Chloropyrazine-2-yl)methyl] acetamide is generated as a major impurity during the reaction. As 1-(3-Chloropyrazine-2-yl)methanamine is very polar molecule, the material goes in filtrate during isolation of product which increases the load of effluent and impact on environment.
Product patent US9290504 further describes preparation of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate. To the solution of (3-chloropyrazin-2-yl)methanamine hydrochloride,(2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid in dichloromethane and triethylamine was added. The mixture was stirred at 0°C and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was added. The mixture was stirred for 1 hour at0°C and then overnight at room temperature. The mixture was washed with HCl solution, 5% NaHCO3 solution, water and brine. The organic layer was dried over Sodium sulfate and concentrated in vacuum. The product was purified using silica gel chromatographyto give of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate. The process uses costly coupling reagents like HATU. HATU is 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, which in the reaction decomposes into side products which all are soluble in water. This makes the separation of these products very difficult from the effluent. It needs special techniques for effluent treatments and hence the process is not feasible on industrial scale.
US20070129547 discloses a process for preparing amine by the conversion of the corresponding 2-hydroxymethyl or 2-chloromethyl-3-chloropyrazine through the intermediacy of the corresponding phthalamido, diformylamide, or hexamethyltetramine adducts followed by hydrazinolysis or acid hydrolysis as shown below.

However, this process is expensive and it is tedious to isolate the amine compound.
Thus there is a need for an improved process for the synthesis of (3-chloropyrazin-2-yl)methanamine and acid salt thereof, that provides easy and effective isolation of pure 1-(3-Chloropyrazine-2-yl)methanamine using easily and commercially available reagents.

OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for synthesis of Acalabrutinib intermediates, that does not require any special techniques for effluent treatment and is cost effective.

Another object of the present invention is to provide an improved process for synthesis of Acalabrutinib intermediates, that is cost effective as it uses commercially feasible reagents.

Another object of the present invention is to provide an improved process for synthesis of Acalabrutinib intermediates, that is environment friendly and gives product at higher yield and better purity.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for synthesis of Acalabrutinib intermediates.
In one aspect, the present invention provides a process for the preparation of (3-chloropyrazin-2-yl)methanamine and its acid addition salt of formula (I).
In another aspect, the present invention provides a process for the preparation of (3-chloropyrazin-2-yl)methanamine and its acid addition salt of formula (I) with an additional step that comprises converting compound of formula (I), formed by the process of the present invention into 2-((3-chloropyrazin-2-yl)methylcarbamoyl) pyrrolidine-1-carboxylic acid ester of formula (VI).
In a preferred embodiment, a process for preparation of compound of formula (I) is disclosed.

The process comprises:
i) chlorination ofcompound of formula (IV) by adding a predefined chlorinating agentat a first predefined temperature in a predefined chlorinated solvent and carrying out the reaction at a second predefined temperature to form a compound of formula (III);

ii) hydrogenation of compound of formula (III) formed in step i), in presence of BOC anhydride and in presence of a predefined metal catalyst in a predefined solvent at predefined pressure and temperature to form compound of formula (II);

iii) deprotection of compound of formula (II) using a predefined acid in a predefined solvent at a predefined temperature to form a compound of formula (I).

In accordance with this embodiment, the predefined chlorinating agent in step i) is selected from the group of sulfuryl chloride, thionyl chloride and chlorine gas. The first predefined temperature at which the chlorinating agent is added is below 10°C. The chlorinated solvent is selected from the group of methylene dichloride, ethylene dichloride and chloroform. Use of chlorinated solvent provides selectivity of chlorination at 3-position. The chlorinated solvent is used along with dimethyl formamide. After complete addition of chlorinating agent, the temperature is raised gradually to the second predefined temperature at which the reaction is carried out i.e. 25-35°C. The predefined metal catalyst in step (ii) is selected from palladium, platinum, nickel, and rhodium.The predefined solvent in step (ii) is alcoholic in nature and selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol. The predefined pressure in step (ii) is in the range of 6-15 kg/Cm2, preferably 12 kg/Cm2.The predefinedtemperature in step (ii) of the reaction ranges from30-50°C, preferably from 40-45°C. The predefined acid in step (iii) is selected from the range of sulfuric acid, hydrochloric acid, acetic acid, methane sulfuric acid and trifluoro aceticacid. The predefinedsolvent in step (iii) is alcoholic in nature and selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol. The predefined temperature in step (iii) of the reaction ranges from 40-70°C, preferably from 50-55°C.
In another embodiment of the present invention, the process of the present invention comprises converting compound of formula (I), formed by the process of the present invention into compound of formula (VI) is disclosed, wherein the compound of formula (I) is reacted with N-protected proline compound of formula (V) in presence of a predefined coupling agent and hydroxyl benzotriazole (HoBt) in a predefined solvent and a predefined base.

In this embodiment, the predefined coupling agent is dicyclohexylcarbodiimide (DCC). The solvent is selected from selected from methylene dichloride, chloroform and ethylene dichloride, dimethyl formamide and ethyl acetate. The base used is selected from inorganic bases such as hydroxides, alkoxides and organic bases such as Triethylamine and N,N-diisopropylethylamine.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates toan improved process for the preparation of (3-chloropyrazin-2-yl)methanamine and its acid addition salt of formula (I), which is an important intermediate of anti-cancer drug Acalabrutinib.
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
In an embodiment of the present invention, an improved process for the preparation of compound of formula (I), is disclosed.

The process comprising:
i) chlorination ofcompound of formula (IV) by adding a predefined chlorinating agentat a first predefined temperature in a predefined chlorinated solvent and carrying out the reaction at a second predefined temperature to form a compound of formula (III);

ii) hydrogenation of compound of formula (III) formed in step i), in presence of BOC anhydride and in presence of a predefined metal catalyst in a predefined solvent at predefined pressure and temperature to form compound of formula (II);

iii) deprotection of compound of formula (II) using a predefined acid in a predefined solvent at a predefined temperature to form a compound of formula (I).

In accordance with this embodiment, a process of chlorination of a compound of formula (IV) to a compound of formula (III) in step (i) is disclosed, wherein the process comprising chlorination is carried out by adding a predefined chlorinating agentat a first predefined temperature in a predefined chlorinated solvent and carrying out the reaction at a second predefined temperature.
In this embodiment, the predefined chlorinating agent is selected from the group of sulfuryl chloride, thionyl chloride andchlorine gas.The first predefined temperature at which the chlorinating agent is added is below 10°C. The chlorinated solvent is selected from the group of methylene dichloride, ethylene dichloride and chloroform. Use of chlorinated solvent provides selectivity of chlorination at 3-position.The chlorinated solvent is used along with dimethyl formamide. After complete addition of chlorinating agent, the temperature is raised gradually to the second predefined temperature at which the reaction is carried out i.e. 25-35°C. The compound of formula (IV) is pyrazine-2-carbonitrile. The compound of formula (III) is 3-chloropyrazine-2-carbonitrile.
In accordance with this embodiment, hydrogenation of compound of formula (III) to a compound of formula (II) in step (ii) is disclosed, wherein the process comprising hydrogenation is carried out by reacting the compound of formula (III) with BOC anhydride in presence of a predefined metal catalyst on carbon in a predefined solvent at predefined pressure and temperature.
In this embodiment, the predefined metal catalyst is selected from palladium, platinum, nickel, and rhodium.The solvent is alcoholic in nature and selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol. The pressure is in the range of 6-15 kg/Cm2, preferably 12 kg/Cm2.The temperature of the reaction ranges from30-50°C, preferably from 40-45°C.The compound of formula (III) is 3-chloropyrazine-2-carbonitrile. The compound of formula (II) is tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate. The preparation of the compound of formula (IV)occurs in situ which avoids dimer impurity formation which is otherwise formed easily during hydrogenation. The compound of formula (II) can be isolated easily with higher purity with higher yield. The compound of formula (II) is characterized by LCMS and 1H NMR.
In accordance with this embodiment, a process of deprotection of a compound of formula (II) to yield a compound of formula (I) in step (iii) is disclosed, wherein the process comprising deprotection is carried out using a predefined acid in a predefined solvent at a predefined temperature.
In this embodiment, the predefined acid is selected from the range of sulfuric acid, hydrochloric acid, acetic acid, methane sulfuric acid and trifluoro acetic acid. The solvent is alcoholic in nature and selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol. The temperature of the reaction ranges from 40-70°C, preferably from 50-55°C. The compound of formula (II) is tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate. The compound of formula (I) is(3-chloropyrazin-2-yl)methanamine and its acid addition salt.
In another embodiment of the present invention, the process of the present invention comprises converting compound of formula (I), formed by the process of the present invention into compound of formula (VI) is disclosed, wherein the compound of formula (I) is reacted with N-protected proline compound of formula (V) in presence of a predefined coupling agent and hydroxyl benzotriazole (HoBt) in a predefined solvent and a predefined base.

In this embodiment, the predefined coupling agent is dicyclohexylcarbodiimide (DCC). The solvent is selected from selected from methylene dichloride, chloroform and ethylene dichloride, dimethyl formamide and ethyl acetate. The base used is selected from inorganic bases such as hydroxides, alkoxides and organic bases such as Triethylamine and N,N-diisopropylethylamine. The compound of formula (I) is(3-chloropyrazin-2-yl)methanamine and its acid addition salt. The compound of formula (V) is N-protected proline, wherein R1 is (1-4C alkyl), (1-4C alkyl) substituted by phenyl or substituted phenyl. The compound of formula (VI) is2-((3-chloropyrazin-2-yl)methylcarbamoyl) pyrrolidine-1-carboxylic acid ester.
In a preferred embodiment, the process for preparation of compound of formula (I) comprises:
a) chlorination of pyrazine-2-carbonitrile of formula (IV) by adding sulfuryl chloride in chloroform to form 3-chloropyrazine-2-carbonitrile of formula (III);
b) hydrogenation of 3-chloropyrazine-2-carbonitrile of formula (III) in presence of BOC anhydride and in presence of raney nickel in methanol to form tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate of formula (II);
c) deprotection of tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate of formula (II) using hydrochloric acid in isopropyl alcohol.
In this preferred embodiment, (3-chloropyrazin-2-yl)methanamine hydrochloride of formula (I) formed by the process of the present invention is converted to benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate of formula (VI).

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 3-chloropyrazine-2-carbonitrile
Chloroform (1050 ml) and DMF (108 ml) was charged to pyrazine-2-carbonitrile (150 gm) under inert atmosphere. Sufuryl chloride (465 ml) was slowly added by maintaining the temperature of the mixture less than 10°C. After completion of sulfuryl chloride addition, the reaction mixture was maintained at 25-35°C for 5-6 hours. The reaction mixture was slowly quenched to previously chilled water (1.5 L) at 5-10°C. The mixture was stirred for 30 minutes below 15°C.After quenching, the temperature of mass was raised gradually to 25-35°C and stirred for 30 minutes.
The layers were separated and aqueous layer was extracted with chloroform (450 ml). The aqueous layer was separated and again extracted with chloroform (300 ml x 3). The combined organic layer was charged to previously cooled water (1.5 L) at 10°C. The pH of mixture was adjusted to 7-8 using sodium bicarbonate at 10°C. The temperature of the reaction mass was raised to 25-35°C gradually and stirred for 30 minutes. The aqueous layer was extracted with chloroform (450 ml) and all the organic layers were combined and distilled out completely at 55-60°C under vacuum to get oily mass. The oil was degassed and 3-chloropyrazine-2-carbonitrile was isolated as solid.
Yield = 112.5 gm, 56.82%
HPLC Purity = 96.0%

Example 2
Preparation of tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate
Toluene (200 ml) was charged to chloropyrazine-2-carbonitrile (100 g) prepared in example 1 at 25-30°C. The mixture was stirred for 30 minutes at 25-30°C.
Separately prepared solution of Sodium hypochlorite (100 ml in 100 ml water) was charged in 30-60 minutes. The mixture was stirred and the mass was settled for 30 minutes. The layers were separated and organic layer was extracted with water (100 ml). The separated organic layer was dried over sodium sulfate and distilled out at 50-55°C. Methanol (500 ml) was charged to the oily mass obtained.
Raney nickel (50 gm) and BOC anhydride (188 gm) was added to the reaction mixture at 25-30°C. Autoclave was flushed with hydrogen and nitrogen gas. 12 kg/cm3 pressure was applied and the mixture was heated to 40-45°C. The mass was maintained at 40-45°C for 8-10 hours. The mass was filtered and washed with methanol (100 ml). From filtrate methanol was distilled out under vacuum at 40-45°C and toluene (300 ml) was charged to the mass. The mixture was heated to 55-60°C. The mass was stirred for 30 minutes after adding charcoal (10 gm) and hyflo (50 gm) at 55-60°C. The mixture was filtered through hyflo bed and washed with toluene (100 ml). The filtrate was distilled under vacuum till slurry was obtained. IPA (150 ml) was charged at 40-50°C and heated to 70-80°C till clear solution is obtained and maintained for 30 minutes. The mass was cooled to 25-30°C and further chilled to 0-5°C and maintained for 1 hour. The mass was filtered and washed with chilled IPA (50 ml). The tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate obtained was dried under vacuum at 40-50°C for 4-6 hours.
Yield = 100 gm, 57.4%
HPLC Purity = 99.5%
LCMS:Mass value(243) in LCMS instead of molecular ion peak shows (M-56) 187.9; Breakage of tert-butyl and CO2 group.
1H NMR (DMSO-d6):
8.59-8.57 (1H, d, Ar), 8.43-8.42 (1H, d, Ar), 7.32-7.29 (1H, t, -NH), 4.39-4.37 (2H, d, -CH2), 1.39 (9H, s, -C(CH3)3).

Example 3
Preparation of (3-chloropyrazin-2-yl)methanamine hydrochloride
Isopropyl alcohol hydrochloric acid (138 gm) was charged to tert-butyl N-[(3-chloropyrazin-2-yl)methyl]carbamate (100 g) prepared in example 2 at 25-30°C. The mixture was heated gradually at 50-55°C for 1 hour. The reaction mass was cooled to 25-35°C and further chilled to 0-5°C. The mass was stirred for 1 hour at 0-5°C. The suspension was filtered and washed with chilled isopropanol (100 ml). The compound was suck dried and further dried at 100-105°C.
Yield = 94%
HPLC Purity = 99.5%
LCMS: M+1 = 181
Example 4
Preparation of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
(3-chloropyrazin-2-yl)methanamine hydrochloride (152.5 gm) and (2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid (100 gm) was charged to MDC (800 ml) at 25-30°Cand stirred for 10 minutes. HoBt (19 gm) was charged to the mixture and stirred for 10 minutes. Triethylamine (112 gm) was charged and the mass was stirred for 10 minutes. Dicyclohexylcarbodimide (115 gm) and methylene dichloride (200 ml) was charged to the reaction mass and maintained for 24 hours. N-Heptane (100 ml) was charged and the mass was chilled to 0-5°C. The mass was filtered and HCl solution (500 ml) was charged to the filtrate. The mass was stirred for 30 minutes and settled for 30 minutes. The organic layer was extracted with sodium bicarbonate (500 ml) solution.The mass was stirred for 30 minutes and settled for 30 minutes. The layers were separated and the organic layer was dried over sodium sulfate (10 gm).The layer was distilled out under vacuum at 55-60°C. The benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl] pyrrolidine-1-carboxylateobtained was further purified.

Example 5
Purification of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate
Toluene (500 ml) was charged to the crude benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylateand the mixture was heated to 55-60°C for 30 .Methyl tert-butyl ether (400 ml) was charged to the mixture at 55-60°C. The mass was stirred for 30 min. Activated charcoal (10 g) was charged and the mass was maintained for 30 minutes.The mass was filtered and washed with Methyl tert-butyl ether (100 ml x 2). The wet cake was dried under vacuum at 50-55°C for 6-7 hours.Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (298.0 gm)was isolated.
Yield = 94%
HPLC Purity = 99.5%
In the context of the present invention, the process of the present invention isan eco-friendly and a cost effective process. Further dimer impurity formation is avoided during hydrogenation. The process of the present invention is an easy processand givesproduct at higher yield and better purity.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.