DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 201941010672 filed on March 19, 2019.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of rucaparib and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Rucaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme. The chemical name is 8-fluoro-2-{4-[(methylamino)methyl] phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt is represented by the following structural formula.

Rucaparib is marketed under the brand name RUBRACA by Clovis Oncology.
Rucaparib is first reported in US 6495541. This patent describes process for the preparation of rucaparib comprising reacting 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one with 4-formyl Phenyl boronic acid in presence of a base and solvent gives 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde, which on reaction with methyl amine in presence sodium cyano borohydride gives rucaparib.
Rucaparib Camsylate salt is known in US 9045487.

OBJECT AND SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide an improved process for the preparation of rucaparib and its pharmaceutically acceptable salts.
In one aspect, present invention provides an in-situ process for preparing rucaparib and its pharmaceutically acceptable salts comprising the steps of:
a) reacting 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II with methylamine in a suitable solvent or mixtures thereof;
b) reducing the obtained product in presence of catalyst; and
a) isolating rucaparib or its pharmaceutically acceptable salts
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of rucaparib and its pharmaceutically acceptable salts.
One embodiment of the present invention provides a process for the preparation of rucaparib by in-situ reductive amination of 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II.
The schematic representation of the present invention is as depicted in Scheme-I.

One embodiment of the present invention provides an in-situ process for the preparation of rucaparib and its pharmaceutically acceptable salts comprising the steps of:
a) reacting 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II with methylamine in a suitable solvent or mixtures thereof;
b) reducing the obtained product in presence of catalyst; and
b) isolating rucaparib or its pharmaceutically acceptable salts.
In one embodiment, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II is reacted with methyl amine in a suitable solvent or mixtures thereof. The suitable solvent or mixtures thereof includes, but not limited to methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, dimethyl formamide; preferably the mixture of ethanol and tetrahydrofuran. The methyl amine used above is an alcoholic methyl amine solution. The alcoholic methyl amine solution is prepared by dissolving methyl amine in an alcoholic solvent selected from but not limited to methanol, ethanol, propanol, isopropanol, butanol.
Without isolating the resulting product, it is further reduced in presence of a catalyst selected from Pd/C, Raney-Ni, Pt/C to isolate rucaparib.
In one embodiment, the resulting rucaparib may further converted into its pharmaceutically acceptable salts as per the processes known in US 9045487.
In the prior art process, the reductive amination of 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II is carried out with methyl amine in presence of zinc chloride and sodium cyanoborohydride. The reaction pH is adjusted to 3 with concentrated HCl. The layers were separated, and the organic layers were dried and concentrated. Further subjected to chromatography and then crystallized to get rucaparib.
The pH adjusting as mentioned in prior art with HCl results into hydrochloride salt of rucaparib, where an additional step desaltification could be performed to get Rucaparib free base. Further, the use of sodium cyanoborohydride in reduction increases the formation of impurities in the final product rucaparib.
The present invention provides an improved process where the step of quenching reaction mixture is voided and directly yielding Rucaparib free base. Additionally, the use of Pd/C catalyst in the in-situ reductive amination process reduces the formation of impurities and the resulting rucaparib would be high in purity and yield.
In one embodiment, the resulting rucaparib may further converted into its pharmaceutically acceptable salts as per the processes known in US 9045487.
The following example should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Example-1:
1.0 mole of 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of Formula-II was charged into a mixture of ethanol and tetrahydrofuran (300 mL, 1:2). Further the slurry was charged with 5.0 moles of methylamine in methanol solution and 5% Pd/C. The reaction mixture was stirred at ambient temperature for an hour and then continued stirring under 5-6 Kg/m-2 hydrogen pressure. After completion of the reaction, the reaction mixture was filtered and separated the catalyst, and the filtrate was concentrated under reduced pressure. To the resulting solid was added water and filtered. The obtained solid was further crystallized from methanol and tetrahydrofuran.
,CLAIMS:1. An in-situ process for preparing rucaparib and its pharmaceutically acceptable salts comprising the steps of:
a) reacting 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde of formula II with methylamine in a suitable solvent or mixtures thereof;
b) reducing the obtained product in presence of catalyst; and
c) isolating rucaparib or its pharmaceutically acceptable salts.

2. The process as claimed in claim 1, wherein the methylamine is an alcoholic methyl amine.

3. The process as claimed in claim 1, wherein the suitable solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran and dimethyl formamide.

4. The process as claimed in claim 1, wherein the suitable solvent is mixture of ethanol and tetrahydrofuran.

5. The process as claimed in claim 1, wherein the catalyst is selected from Pd/C, Raney-Ni and Pt/C.

6. The process as claimed in claim 5, wherein the catalyst is Pd/C.