DESC:Field of the Invention:
The present invention relates to an improved and industrially viable process for the preparation of Acalabrutinib starting material.

The present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale.

Background of the Invention:
Acalabrutinib is an inhibitor of Bruton tyrosine kinase, chemically known as 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide and structurally represent as below.

Formula (1)
Acalabrutinib is sold under the brand name CALQUENCE® and it is indicated for the treatment of mantle cell lymphoma.

Preparation of Acalabrutinib key starting material is disclosed in WO2013010868 (US9290504) (Scheme-1). According to process, (3-Chloropyrazin-2-yl)methanamine hydrochloride is condensed with Cbz protected L-proline (, Z-Pro-OH) in the presence of HATU and triethylamine to afford (S)-Benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate () which is then intra molecularly cyclized in the presence of phosphorous oxychloride at elevated temperatures to afford (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate . Thereafter, (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate is brominated using NBS in DMF to afford (S)-Benzyl 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate which is later subjected to amination using ammonia gas under pressure (~4.5 bar) at 110°C to afford (S)-Benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate .

Scheme-1

The process disclosed in WO2013010868 (US9290504) suffers from the following limitations that reduce its industrial applicability. For example:-
1. Process needs preparative HPLC and chromatographic purification techniques to purify the product. On higher scale production, preparative HPLC and chromatographic purification techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale.
2. Process requires cryogenic reaction conditions, which will be additional burden on commercial production.

The inventors of the present invention have developed an improved process for the preparation of Acalabrutinib starting material. The present process is cost effective and feasible in large scale production also.

Object of the Invention:
The main objective of the present invention is to provide a process for the preparation of Acalabrutinib key starting material.

Another object of the present invention is to provide a process, which is simple, economical and suitable for industrial scale up.

Summary of the Invention:
One Aspect of the present invention is to provide a process for the preparation of key starting material of Acalabrutinib as depicted in below scheme- 2.

Scheme-2
Another aspect of the present invention is compounds having the following structural general formulae.

Detailed description of the Invention:
One embodiment of the present invention is to provide a process for the preparation of Acalabrutinib intermediate of formula-6 comprising the steps of:
a) reacting the L-Proline of compound of formula (13) with methyl chloroformate in the presence of base in an organic or aqueous organic solvent to obtain compound of formula (12),
b) reacting compound of formula (12) in the presence of chlorinating agent to obtain acid chloride of formula (11),
c) condensing the acid chloride of formula (11) with compound of formula (14) in the presence of a base in an organic solvent to afford compound of formula (10),
d) cyclizing compound of formula (10) in the presence of dehydrating agent to obtain compound of formula (9),
e) brominating compound of formula (9) with suitable brominating agent in an organic solvent to obtain compound of formula (8),
f) reacting compound of formula (8) with 4-Methoxybezylamine

in the presence of a base to obtain to obtain compound of formula (7),
g) selective de-protection of compound of formula (7) in the presence of base in an organic solvent to obtain compound of formula (6) as hydrate,
h) optionally purifying compound of formula (6) from suitable solvent medium.

In step (a) of the present invention, wherein the base is selected from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tertiary butylamine or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide or calcium hydroxide or any other equivalent base.

In step (a) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, ethylacetate, toluene, THF, DMF, xylene or any other suitable organic solvent or organic solvent mixture.

In step (b) of the present invention, wherein the chlorinating agent is selected from thionyl chloride, Oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride or any other suitable chlorinating agents.
In step (b) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.

In step (c) of the present invention, wherein, the base is selected from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tri butylamine or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base.
In step (c) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.
In step (d) of the present invention, wherein the dehydrating agent may be selected from thionyl chloride, Oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride or any other suitable dehydrating agent.
In step (d) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.
In step (e) of the present invention, wherein, the brominating agent is selected bromine, N-Bromosuccinimide, dibromohydantoin or any other suitable brominating agent.
In step (e) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.
In step (f) of the present invention, wherein, the base is selected from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tri butylamine or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base.
In step (f) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.
In step (g) of the present invention, wherein, the base is selected from sodium hydroxide, sodium acetate, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium acetate, potassium bicarbonate, potassium carbonate, lithium hydroxide, cesium carbonate, or any other equivalent base.
In step (g) of the present invention, wherein, the organic solvent is selected from 1,4-dioxane, acetonitrile, toluene, DMF, xylene, n-butanol, tertiary butanol or any other suitable organic solvent or organic solvent mixture.
In step (g) of the present invention, wherein, the temperature at which reaction performed between 50 to 150°C, preferably at ~120°C.
In step (h) of the present invention, wherein, for purification of key starting material (6) of Acalabrutinib, the purification solvent is selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, 1-pentanol, 1,4-dioxane, acetonitrile, DMF, n-butanol, water or any other suitable solvent or its mixture

Another embodiment of the present invention is compounds having the following structural general formulae.

Advantages of the present invention:
a) The process of the present invention does not require chromatographic purification techniques like column chromatography in the any stage of the process.
b) The process of the present invention does not require cryogenic reaction condition thereby reducing cost burden.
c) The process of the present invention successfully adopts simple work-up, isolation procedures and thereby improve the overall yield.
d) The process of the present invention one pot synthesis of novel key starting material (1) of Acalabrutinib.
The Present invention is further illustrated in detail with reference to following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the invention in any way.

Experimental procedure:
Example 1: Preparation of (2S)-1-Methoxycarbonyl pyrrolidine-2-carboxylic acid (12):
Into the reaction flask, L-Proline (250g), dichloromethane (1250 ml), potassium carbonate (375.11 g) and DM water (1125 ml) were added and cooled to 0-5°C under stirring. To this, methyl chloroformate (256.5 g) was added. After addition, the reaction mixture was stirred at 25-30°C for ~12 h. After completion of reaction, the pH adjusted to ~ 2.0 and separated the organic layer and concentrated under vacuum to afford colourless thick oil.
Weight: 371 g, Yeild : 98%
1H-NMR (DMSO)?: 1.80-1.86 (m, 3H), 2.15-2.21 (m, 1H), 3.33-3.36 (m, 2H), 3.58 (s, 3H), 4.11-4.17 (m, 1H), 12.59 (br, 1H)
Example 2: Preparation of Methyl (2S)-2-Chlorocarbonyl pyrrolidine-1-carboxylate (11):
In the reaction flask, the above thick oily compond (12) (369 gm) was dissolved in toluene (1875 ml) and DMF (15.86 g) under stirring and cooled to 0-5°C. To the cooled soluton, thionyl chloride (310 g) was added drop wise and the reaction mixture was stirred at 25-30°C for ~4h. After completion of reaction, the solvent was distilled off completely under vaccum to afford light brown colour oil which is further utilized in the next stage without further purification.
Weight: 421 g; Yeild : 100%
Example 3: Preparation of Methyl (2S)-2-[(3-chloropyrazin-2-yl)methylcabamoyl] pyrrolidine-1-carboxylate (10):
In the the reaction flask, (3-chloropyrazin-2-yl)methanamine hydrochloride (14) (100 g , 0.55 mol) followed by dichloromethane (250 ml) were added and cooled to 0-5°C. Thereafter, aqueous potassium carbonate solution (400 ml) was added. To this, a solution of Methyl (2S)-2-Chlorocarbonyl pyrrolidine-1-carboxylate (11) (63.86g) in dichloromethane (100 ml) was added. After addition, the reaction mixture was stirred at 5-10°C for ~2 h. After completion of reaction, the organic layer was separated and concentrated under vacuum to afford brown syrup.
Weight: 168 g; Yeild: 100%
1H-NMR (DMSO)?: 1.81-1.89 (m, 3H), 2.08-2.16 (m, 1H), 3.30-3.36 (m, 1H), 3.41-3.42(m, 1H), 3.51 (s, 3H), 4.22 (m, 1H), 4.44-4.55 (m, 2H), 8.42-8.43 (d, J=2.4, 1H), 8.45 (br, 1H), 8.61-8.62 (d, J=2.0, 1H)
Example 4: Preparation of Methyl (2S)-2-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl) pyrrolidine-1-carboxylate (8):
In to the reaction flask, Methyl (2S)-2-[(3-chloropyrazin-2-yl)methylcabamoyl] pyrrolidine-1-carboxylate (10) (168 g) and DMF (500 ml) were added and cooled to 0-5°C under stirring. To this, phosphorous oxychloride (110.7 g) was added and the reaction mixture stirred for ~3h. After completion of reaction, N-Bromosuccinimide (103.82 g) was added and maitained for ~3h. After completion of the reaction, reaction mixture was diluted with dichloromethane (700 ml) and quenched into chilled aq ammonia. The organic layer is separated and concentrated under vacuum. The resulting product was further purified from cyclohexane to afford pure compound of formula (8).
Weight: 150 g, Yield: 75%
1H-NMR (DMSO)?: 1.93-1.99 (m, 1H), 2.09-2.31 (m, 3H), 3.48-3.55 (m, 2H), 3.52 (s, 3H), 5.37-5.40 (m, 1H), 7.45-7.47 (d, J=4.8, 1H), 8.51-8.52 (d, J=4.8, 1H).
Example 5: Preparation of 1-Bromo-N-[(4-methoxyphenyl)methyl]-3-[(2S)-pyrrolidin-2-yl]-imidazo[1, 5-a]pyrazin-8-amine monohydrate (6):
In to the reaction flask, Methyl (2S)-2-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl) pyrrolidine-1-carboxylate (100 g), sodium carbonate (44.21g,), 4-Methoxybezylamine (45.77 g) and Acetonitrile (300 ml) were added, heated and maintained for 16-18h at 75-80°C. After completion of reaction, the reaction mixture was cooled and quenched with water. The product was extracted with toluene and separeted. The organic layer was concentrated under vacuum to afford Methyl (2S)-2-[1-bromo-8-[(4-methoxyphenyl)methylamino]-imidazo[1,5-a]pyrazin-3-yl]pyrrolidine-1-carboxylate as syrupy mass (7).
Thereafter, compound (7) was dissolved in n-butanol (400 ml) and added sodium hydroxide (33.41 g). The resulting suspension was refluxed for 3h. After completion of reaction, the reaction mixture was cooled and diluted with water. The product was extracted with toluene and separated the orgnaic layer. The organic layer was concentrated under vacuum. The resulting product was further purified from aqueous methanol to afford 1-Bromo-N-[(4-methoxyphenyl)methyl]-3-[(2S)-pyrrolidin-2-yl]-imidazo[1,5-a]pyrazin-8-amine hydrate (6).
Weight: 101 g; Yield: 87%
1H-NMR (DMSO)?: 1.66-1.76 (m, 1H), 1.78-1.87 (m, 1H), 1.99-2.07 (m, 1H), 2.09-2.18 (m, 1H), 2.78-2.88 (m, 3H), 3.72 (s, 3H), 4.44-4.47 (t, J=7.6, 1H), 4.61-4.63 (d, J=6.0, 2H), 6.79-6.82 (t, J=5.6, 1H), 6.87-6.89 (d, J=8.8, 2H), 7.02-7.03 (d, J=5.2, 1H), 7.27-7.30 (d, J=8.8, 2H), 7.70-7.71 (d, J=4.8, 1H).
,CLAIMS:We claim:
1. A process for the preparation of Acalabrutinib intermediate of formula-6 comprising the steps of:
a) reacting the L-Proline of compound of formula (13) with methyl chloroformate in the presence of base in an organic or aqueous organic solvent to obtain compound of formula (12),
b) reacting compound of formula (12) in the presence of chlorinating agent to obtain acid chloride of formula (11),
c) condensing the acid chloride of formula (11) with compound of formula (14) in the presence of a base in an organic solvent to afford compound of formula (10),
d) cyclizing compound of formula (10) in the presence of dehydrating agent to obtain compound of formula (9),
e) brominating compound of formula (9) with suitable brominating agent in an organic solvent to obtain compound of formula (8),
f) reacting compound of formula (8) with 4-Methoxybezylamine

in the presence of a base to obtain to obtain compound of formula (7),
g) selective de-protection of compound of formula (7) in the presence of base in an organic solvent to obtain compound of formula (6) as hydrate,
h) optionally purifying compound of formula (6) from suitable solvent medium.

2. The process as claimed in claim 1, wherein,
In step (a), the base is selected from organic base or inorganic base, the organic base is selected from triethylamine, diisopropylethylamine, tertiary butylamine or any other equivalent organic base, the inorganic base is selected from alkali and alkaline metal carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide or calcium hydroxide.
In step (a), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, ethylacetate, toluene, THF, DMF, xylene or any other suitable organic solvent or organic solvent mixture.
In step (b) the chlorinating agent is selected from thionyl chloride, Oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride.
In step (b), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene.
In step (c), the base is selected from organic base or inorganic base, the organic base is selected from triethylamine, diisopropylethylamine, tri butylamine, the inorganic base is selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate.
In step (c), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene.
In step (d), the dehydrating agent is selected from thionyl chloride, Oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride.
In step (d), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene.
In step (e) the brominating agent is selected bromine, N-Bromosuccinimide, dibromohydantoin.
In step (e), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene,
In step (f), the base is selected from organic base or inorganic base, the organic base is selected from triethylamine, diisopropylethylamine, tri butylamine the inorganic base is selected from alkali and, alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate.
In step (f), the organic solvent is selected from 1,4-dioxane, dichloromethane, chloroform, acetonitrile, toluene, DMF, xylene or any other suitable organic solvent or organic solvent mixture.,
In step (g) the base is selected from sodium hydroxide, sodium acetate, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium acetate, potassium bicarbonate, potassium carbonate, lithium hydroxide, cesium carbonate
In step (g) the organic solvent is selected from 1,4-dioxane, acetonitrile, toluene, DMF, xylene, n-butanol, tertiary butanol.
In step (h), for purification of key starting material (6) of Acalabrutinib, the purification solvent is selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, 1-pentanol, 1,4-dioxane, acetonitrile, DMF, n-butanol, water.

3. Compounds having the following structural general formulae.