DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Niraparib Tosylate monohydrate of Formula (I) as given below.

Formula (I)
Background of the Invention
Niraparib, having the chemical designation 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide, is a small molecule poly (ADP-ribose) polymerase (PARP) inhibitor. Niraparib is used to treat ovarian cancer. Niraparib has the following structure:

Formula (Ia)
Niraparib Tosylate is commercially marketed under the name Zejula.
US 8071623 discloses a process for the preparation of Niraparib tosylate by reacting methyl 3-formyl-2-nitrobenzoate of Formula-(II) with (3S)-3-(4-Aminophenyl)-1-piperidinecarboxylic acid tert-butylester of Formula-(III) in ethanol to obtain (3S)-3-[4-[[[3-(methoxycarbonyl)-2-nitrophenyl]methylene]amino]phenyl]-1-piperidine carboxylic acid 1,1-dimethylethyl ester of Formula-(IV). Compound of Formula-(IV) is reacted with sodium azide (NaN3) in the presence of 2,6-Lutidine in DMF followed by hydrolysis with NaOH in THF to obtain 2-{4-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]phenyl}-2H-indazole-7-carboxylic acid of Formula-(V). Later, Compound of Formula-(V) is further reacted with di-tert-butyl carbonate in the presence of pyridine in dichloromethane followed by amidation with ammonium bicarbonate to obtain tert-butyl(3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidine-1-carboxylate of Formula-(VI), which is further reacted with p-toluene sulphonic acid monohydrate in THF to obtain Niraparib tosylate monohydrate (I).

Objective of the Invention
The main objective of the present invention is to provide a simple, cost-effective and improved process for the preparation of Niraparib Tosylate monohydrate of Formula-(I) with high purity and yield on a commercial scale.
Summary of the Invention
The present invention relates to a process for the preparation of Niraparib Tosylate monohydrate of Formula-(I)

Formula-(I)
comprising the steps of:
a) reacting a compound of Formula-(II)

Formula-(II)
with a compound of Formula-(III)

Formula-(III)
in a suitable solvent to afford compound of Formula-(IV)

Formula-(IV)
b) reacting the compound of Formula-(IV) with sodium azide in the presence of a base in a suitable solvent to afford compound of Formula-(VII)

Formula-(VII)

c) cyclization of compound of Formula-(VII) in a suitable solvent to afford compound of Formula-(VIII)

Formula-(VIII)

d) reacting the compound of Formula-(VIII) with formamide in the presence of a base in a suitable solvent to afford compound of Formula-(VI)

Formula-(VI)

e) reacting the compound of Formula-(VI) with methanesufonic acid in a suitable solvent followed by salt exchange with p-toluenesulfonic acid monohydrate in a suitable solvent to afford crude Niraparib Tosylate monohydrate of Formula-(I).

Formula-(I)

f) purification of Niraparib Tosylate monohydrate of Formula-(I) in an organic solvent and water or mixture thereof to afford pure Niraparib Tosylate monohydrate of Formula-(I).

Detailed Description of the Invention
The present invention relates to a simple and cost-effective process for the preparation of Niraparib Tosylate monohydrate of Formula-(I) comprising the steps of:
a) reacting a compound of Formula-(II) with a compound of Formula-(III) in a suitable solvent to afford compound of Formula-(IV);
b) reacting the compound of Formula-(IV) with sodium azide in the presence of a base in a suitable solvent to afford compound of Formula-(VII);
c) cyclization of compound of Formula-(VII) in a suitable solvent to afford compound of Formula-(VIII);
d) reacting the compound of Formula-(VIII) with formamide in the presence of a base in a suitable solvent to afford compound of Formula-(VI);
e) reacting the compound of Formula-(VI) with methanesufonic acid in a suitable solvent followed by salt exchange with p-toluenesulfonic acid monohydrate in a suitable solvent to afford crude Niraparib Tosylate monohydrate of Formula-(I).
f) purification of Niraparib Tosylate monohydrate of Formula-(I) in an organic solvent and water or mixture thereof to afford pure Niraparib Tosylate monohydrate of Formula-(I).

In step (a) of the present invention, a suitable solvent used is selected from alcohol such as methanol, isopropyl alcohol, ethanol, etc.; ether such as tetrahydrofuran, diethyl ether, methyl t-butyl ether, 1,4-dioxane, isopropyl ether, 1,2-dimethoxyethane, etc.; aromatic hydrocarbon such as toluene, xylene, benzene; dimethylformamide, dimethylsulfoxide, or mixture thereof.
In step (a) of the present invention, the temperature at which condensation step carried out at 20° to 150°C for 2 to 48 hours, preferably 75-85°C for 5 to 10 hours.

In step (a) of the present invention, diluted & isolated with hydrocarbon or ether solvent to afford compound of Formula-(IV). The hydrocarbon solvent selected n-heptane, n-hexane or mixture thereof; Ether solvent selected from as tetrahydrofuran, diethyl ether, methyl t-butyl ether, 1,4-dioxane, isopropyl ether, 1,2-dimethoxyethane or mixture thereof.

In step (b) of the present invention, a base used is selected from organic base like diisopropylethylamine, triethylamine, pyridine, picoline, diisopropylamine, etc.
In step (b) of the present invention, a suitable solvent used is selected from organic solvent like DMF, DMSO, Ethyl acetate, toluene, or mixture thereof.

In step (b) of the present invention, the temperature at which reaction is carried out at 20° to 130°C for 8 to 48 hours, preferably 50-80°C for 10 to 24 hours.

In step (b) of the present invention, after aqueous workup, the resulting product (VII) is directly used in the next step without further isolation.

In step (c) of the present invention, a suitable solvent used is selected from organic solvent like DMF, DMSO, Ethyl acetate, toluene, or mixture thereof.

In step (c) of the present invention, the temperature at which cyclization reaction is carried out at 40° to 150°C for 8 to 48 hours, preferably 80-130°C for 10 to 24 hours.

In step (c) of the present invention, after aqueous workup, the resulting product (VIII) is directly used in the next step without further isolation.

In step (d) of the present invention, a base used is selected from sodium methoxide, ammonium bicarbonate or methanolic ammonia or ammonium hydroxide.

In step (d) of the present invention, a suitable solvent used is selected from organic solvent like methanol, ethanol, isopropylalcohol, DMF, DMSO, Ethyl acetate, toluene, or mixture thereof.

In step (d) of the present invention, the temperature at which reaction is carried out at -15° to 80°C for 30 min to 5 hours, preferably 0-30°C for 30 min to 2 hours.
In step (d) of the present invention, after workup, compound of Formula-(IV) is isolated from organic solvent selected from toluene, xylene, methyl t-butyl ether, ethylacetate, n-hexane, n-heptane or mixture thereof.

In step (e) of the present invention, a suitable solvent used is selected from dichloromethane, acetonitrile, toluene, methyl t-Butylether, THF, water or mixture thereof.

In step (e) of the present invention, the temperature at which reaction is carried out at 5° to 40°C for 30 minutes to 5 hours, preferably 15-40°C for 30 minutes to 2 hours.

In step (e) of the present invention, after aqueous work-up the resulting aqueous layer containing Niraparib methanesulfonic acid salt is reacted with p-toluenesulfonic acid monohydrate in a suitable solvent selected from dichloromethane, acetonitrile, methanol, ethanol, isopropyl alcohol, THF or mixture thereof.

In step (e) of the present invention, the temperature at which salt exchange is carried out between 10-60°C for 30 minutes to 12h preferably between 20-40°C for 30 min to 8h.

In step (f) of the present invention, a suitable solvent used is selected from methanol, isopropyl alcohol, ethanol, DMSO, acetonitrile, water or mixture thereof.
In step (f) of the present invention, the temperature at which reaction is carried out at 20° to -90°C for 30 minutes to 8 hours, preferably 20-40°C for 2 to 8 hours.

Advantages of the present invention:

a) Process for the present invention is a cheap and viable on commercial scale.
b) Process of the present invention avoids acid impurity formation in the final drug substance.
c) Process of the present invention is very effective in elimination of Niraparib nitrosamine impurity.
d) Process of the present invention is very effective in controlling the chiral isomeric impurity of Niraparib tosylate monohydrate.
e) Process of the present invention produces Niraparib tosylate monohydrate having >99.8% HPLC purity.
f) Process of the present invention produces Niraparib tosylate monohydrate having all known impurities well below ICH limits.

The following examples provide for illustration purpose only and are not intended to limit the scope of invention.

EXAMPLES:
EXAMPLE-1: PREPARATION OF (3S)-3-[4-[[[3-(METHOXYCARBONYL)-2-NITROPHENYL]METHYLENE]AMINO]PHENYL]-1-PIPERIDINE CARBOXYLIC ACID 1,1-DIMETHYLETHYL ESTER OF FORMULA-(IV).
To a mixture of compound of Formula-(III) (200g) in IPA (1.0L) was added compound of Formula-(II) (156.6g) and heated the reaction mass to 75-80°C for 6-8h. Progress of the reaction was monitored by HPLC analysis. After completion of reaction, cooled the reaction mass to 40-50°C and added IPA (1.0L). Further cooled the reaction mass to 25-30°C and maintained for 2h, filtered, washed wet material with 1:1 pre-mixture of IPA and n-heptane (200+200 mL), dried the wet material in vacuum oven at 55-60°C to afford (3S)-3-[4-[[[3-(methoxycarbonyl)-2-nitrophenyl]methylene]amino]phenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester of Formula-IV as white crystalline solid (297g, 87.7% yield)
HPLC purity: >99.0%

EXAMPLE-2: PREPARATION OF (3S)-3-[4-[7-(AMINOCARBONYL)-2H-INDAZOL-2-YL]PHENYL]-1-PIPERIDINE CARBOXYLIC ACID 1,1-DIMETHYLETHYL ESTER OF FORMULA-(VI).
To a solution of compound of Formula-(IV) (250g) in DMSO (1.0L) and ethyl acetate (1.0L) was added sodium azide (42g) followed by Triethylamine (98g) at 25-30°C. Thereafter, heated the reaction mass to 60-65°C and maintained for about 16-18h. Progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was cooled to 25-30°C and diluted the reaction mass with ethyl acetate (1.0L). Washed the organic layer with water (1.25L) followed by aq. NaCl (500mL x 3) and layers separated. The organic layer was concentrated under vacuum until 1.8L of ethyl acetate is collected. To the partially distilled mass containing (3S)-3-[4-[[[2-Azido-3-(methoxycarbonyl)phenyl]methylene]amino] phenyl]-1-piperidinecarboxylic acid 1,1-dimethylethylester of Formula-(VII), added DMSO (2.0L), heated to 110±2.5°C and maintained for about 16-18h. Progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was cooled to 20-25°C and treated with MTBE (3.0L) and aq. NaCl (3.0L) under stirring. Separated the organic layer, aqueous layer further extracted with MTBE (750mL) and layers separated. Combined organic layer washed with dil.HCl (1.5L) followed by water (500mL), aq.ammonia (450mL) and aq.NaCl (1.0L). Separated the organic layer, distilled under rotavpour to afford 2-[4-[(3S)-1-[(1,1-dimethylethoxy)carbonyl]-3-piperidinyl]phenyl]-2H-indazole-7-carboxylic acid methyl ester of Formula-(VIII). The crude compound was dissolved in DMSO (1.25L) and added formamide (750ml) at 25-35°C. To the reaction mass was then added sodium methoxide (231g) at 10-15°C and maintained the reaction mass for 1h at 10-15°C. Progress of the reaction mass monitored by HPLC. After completion of reaction, added reaction mass to water (6.25L) at <35°C and stirred for 2h at 25-30°C. Filtered the reaction mass under vacuum and wet material treated with ethyl acetate (3.75L) and aq.sodium chloride solution (1.0L) under stirring for 15-20min. Separated the organic layer, washed with aq.ammonia solution (450ml) followed by aq.sodium chloride (1.0L x 3). Separated the organic layer, distilled under vacuum, co-distilled with Toluene (250ml x 2). To the concentrated mass, added MTBE (2.5L) and Toluene (125ml), heated to reflux temperature for 2-3h. Then, cooled the reaction mass to 25-30°C, stirred for 2h at 25-30°C and filtered. The wet product treated with toluene (625ml) and heated to 90-95°C for 30-45min. Cooled the reaction mass to 25-30°C, added MTBE (25ml), stirred for 90-12min, filtered, washed with toluene (100ml) followed by 1:1 Toluene: MTBE (100mL) and MTBE (100mL), dried under vacuum at 55-60°C for 7-8h to afford (3S)-3-[4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl]-1-piperidine carboxylic acid 1,1-dimethylethyl ester of Formula-(VI) as pale brown solid (132g; 58.7% yield over three steps).
HPLC purity: >99.5%

EXAMPLE-3: PREPARATION OF 2-{4-[(3S)-PIPERIDIN-3-YL]PHENYL}-2HINDAZOLE-7-CARBOXAMIDE 4-METHYLBENZENESULFONATE HYDRATE (1:1:1) (NIRAPARIB TOSYLATE MONOHYDRATE) OF FORMULA-(I):
Compound of Formula-(VI) in MDC (640mL) was reacted with methanesulfonic acid (73.14g) in MDC (160ml) at 10-15°C. Thereafter, raised the reaction mass to 25-30°C and maintained for about 3h. Progress of the reaction is monitored by HPLC. After completion of reaction, cooled the reaction mass to 5-15°C and added water (400ml), stirred for 20min and separated the MDC layer. Aqueous layer further washed with MDC (400ml x 5), separated the aqueous layer. To the aqueous layer, added MDC (160ml) & ACN (80ml) followed by aqueous p-TSA.H2O (54.28g dissolved in 160ml water) dropwise at 25-30°C. Stirred the slurry mass for 1h at 25-30°C, filtered, washed the wet material with DM water (80ml), suck dried for 30min. To the wet material was added aqueous MeOH (160mL methanol mixed with 240ml water), heated to 75-80°C and maintained at 75-80°C till clear solution. Then, cooled the reaction mass to 25-30°C and stirred for 1h. Further cooled the reaction mass to 10-15°C and maintained for 30min, filtered, washed wet material with water (160ml), suck dried for 60min.To the wet material was added DMSO (280ml) at 25-30°C, stirred for 10min and filtered. The filtrate was transferred to clean RBF, cooled to 15-20°C and added particle free water (640ml) at 15-30°C. Stirred the slurry mass for 1h and filtered, washed wet material with water (160ml), dried in vacuum oven at 30-35°C to afford 2-{4-[(3S)-piperidin-3-yl]phenyl}-2Hindazole-7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) (Niraparib Tosylate Monohydrate) of Formula-(I) as white solid (81.88g; 84.3% yield). HPLC purity: >99.8%
,CLAIMS:We Claim:
1. A process for the preparation of Niraparib Tosylate monohydrate of Formula-(I)

Formula-(I)
comprising the steps of:
a) reacting a compound of Formula-(II)

Formula-(II)
with a compound of Formula-(III)

Formula-(III)
in a suitable solvent to afford compound of Formula-(IV)

Formula-(IV)

b) reacting the compound of Formula-(IV) with sodium azide in the presence of a base in a suitable solvent to afford compound of Formula-(VII)

Formula-(VII)

c) cyclization of compound of Formula-(VII) in a suitable solvent to afford compound of Formula-(VIII)

Formula-(VIII)

d) reacting the compound of Formula-(VIII) with formamide in the presence of a base in a suitable solvent to afford compound of Formula-(VI)

Formula-(VI)

e) reacting the compound of Formula-(VI) with methanesufonic acid in a suitable solvent followed by salt exchange with p-toluenesulfonic acid monohydrate in a suitable solvent to afford crude Niraparib Tosylate monohydrate of Formula-(I).

Formula-(I)
f) purification of Niraparib Tosylate monohydrate of Formula-(I) in an organic solvent and water or mixture thereof to afford pure Niraparib Tosylate monohydrate of Formula-(I).

2. The process as claimed in claim 1, wherein, in step-a) the suitable solvent used is selected from alcohol solvents, ether solvents and aromatic hydrocarbon solvents or mixture thereof.

3. The process as claimed in claim 1, wherein, in step-b) the base used is selected from organic base such as diisopropylethylamine, triethylamine, pyridine, picoline, diisopropylamine and the like.

4. The process as claimed in claim 1, wherein, in step-b) the suitable solvent is selected from DMF, DMSO, ethyl acetate, toluene or mixture thereof.

5. The process as claimed in claim 1, wherein, in step-c) the suitable solvent is selected from DMF, DMSO, ethyl acetate, toluene or mixture thereof.

6. The process as claimed in claim 1, wherein, in step-d) the base used is selected from sodium methoxide, ammonium bicarbonate or methanolic ammonia or ammonium hydroxide.

7. The process as claimed in claim 1, wherein, in step-d) the suitable solvent used is selected from methanol, ethanol, isopropyl alcohol, DMF, DMSO, Ethyl acetate, toluene, or mixture thereof.
8. The process as claimed in claim 1, wherein, in step-e) the suitable solvent used is selected from dichloromethane, acetonitrile, toluene, methyl t-butylether, THF, water or mixture thereof.

9. The process as claimed in claim 1, wherein, in step-f) the suitable solvent used is selected from methanol, isopropyl alcohol, ethanol, DMSO, acetonitrile, water or mixture thereof.