DESC:“NOVEL PROCESSES FOR THE PREPARATION OF RUCAPARIB”
FIELD OF THE INVENTION:
The present invention relates to novel, improved and economic industrial processes for the preparation of Rucaparib with high yield. The present invention further relates to use of novel intermediates to synthesize Rucaparib with high purity.

BACKGROUND OF THE INVENTION:
Rucaparib is a fluoro-azepino aromatic-ring containing small molecule that is acting as an PARP (poly-ADP ribose polymerase-1) inhibitor, having antineoplastic activity.
Rucaparib chemically known as 8-fluoro-2-{4-[(methylamino)methyl] phenyl}-1,3,4,5-tetrahydro-6H-azepino [5,4,3- cd] indol-6-one and is structurally represented as Formula-I:

Rucaparib is indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.
Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that Rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased Rucaparib-induced cytotoxicity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.
Rucaparib has a steady-state volume of distribution of 113 L to 262 L following a single intravenous dose of 12 mg to 40 mg Rucaparib. In vitro, the protein binding of Rucaparib is 70% in human plasma at therapeutic concentrations. Rucaparib is preferentially distributed to red blood cells with a blood-to-plasma concentration with ratio of 1.83. The mean terminal T1/2 of Rucaparib is 17 to 19 hours, following a single oral dose of 600 mg Rucaparib. The median Tmax for Rucaparib is 1.9 hours at the approved recommended dosage.
Rucaparib was first disclosed in US6495541 and is marketed by Clovis oncology Corporation as oral tablets containing Rucaparib camsylate salt. It is approved by USFDA during 2016 as RUBRACA® as oral tablets of various strengths including 200 mg, 250 mg, and 300 mg. The recommended daily dose of RUBRACA® is 600 mg orally twice daily with or without food.
RUBRACA® film coated oral tablets are reported to contain Rucaparib camsylate salt. Rucaparib camsylate is a white to pale yellow powder; formulated into a tablet for oral use. Rucaparib shows pH independent low solubility of approximately 1 mg/mL across the physiological pH range. Rucaparib camsylate is structurally depicted as Formula-II:

RUBRACA® film coated tablets contains excipients like microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The cosmetic blue film coating for 200 mg tablets and cosmetic yellow film coating for 300 mg tablets is Opadry-II containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc. The coating is colorized as blue using brilliant blue aluminum lake and indigo carmine aluminum lake, or yellow using yellow iron oxide.
The preparation of Rucaparib (I) is disclosed in WO2000/042040. The said synthesis involves, starting with intermediate (III), closing to give indol-azepine (IV), followed by a bromination reaction to generate bromo-indole (V), which is used in a Suzuki coupling with boronic acid (VI) to give aldehyde (VII). Rucaparib (I) may be obtained in two steps from aldehyde (VII) by a reductive amination reaction (Scheme-1).

The main disadvantage of this process is poor yield and requires the use of toxic, environmentally harmful reagents such as pyridinium tribromide for the bromination process.
WO2004/087713 discloses processes for the preparation of various salt forms of Rucaparib such as mesylate, hydrochloride and tartrate. The process for producing mesylate salt includes dissolving 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino [5,4,3-cd] indol-6-one in methanol and followed by treatment with methanesulfonic acid to yield the same. However, none of these salts are preferable for incorporating them in the pharmaceutical composition. Moreover, the said patent does not disclose more in detail about superior process for preparation of Rucaparib base.
An alternate process for the preparation of Rucaparib (I) is disclosed in WO2006/033003 involves coupling of the Sonogashira reaction between triflate (X) and alkyne (XI), followed by reduction of the nitro group to amine and ring closure to give the indole structure. After a series of further steps designed to construct the azepine ring, including Raney nickel reduction, Rucaparib (I) is obtained (Scheme-2).

This synthesis method suffers from a number of drawbacks, including the use of strongly corrosive reagents such as triflic anhydride for the preparation of intermediate (X), poor yield, and two reduction steps requiring reactions performed at a high hydrogen pressure of 150 psi.
WO2011/098971 discloses process for the preparation of Rucaparib maleate and camsylate salt wherein at reflux, Rucaparib is slurried in tetrahydrofuran and water in a jacketed reaction vessel with overhead stirring, and remained as a free base slurry. S-camphor sulfonic acid solution followed by water is added to yield Rucaparib S-camsylate salt. Further, the said patent also discloses various process for preparation of S-camsylate polymorph Form A, S-camsylate polymorph Form B, S-camsylate polymorph Form C and R-camsylate polymorph Form A. However, the said patent does not disclose more in detail about improved process for preparation of Rucaparib base.
WO2019/020508 claims a process that involves coupling reaction between a compound of formula (XVII) with a compound of formula (XVIII) to obtain a compound of formula (XIX). Here, R1, R2 are C1-C6 alkyl and X is halogen.

Further, reaction of a compound of formula (XIX) with N-phthalimido-ethylamino-acetaldehyde to obtain compound of formula (XX). In addition, compound of formula (XX) is converted to obtain a compound of formula (XXI). Lastly, hydrolysis of a compound of formula (XXI) to obtain Rucaparib (I). (Scheme-3)
The main disadvantage of above-mentioned process is that it requires the use of toxic, environmentally harmful reagents such as monodentate or bidentate phosphine.
Thus, there was an unmet need to design the new improved process which is able to overcome the disadvantages of the above cited prior-art processes.
Surprisingly, the inventors of the present invention have found novel processes, as described in this invention, those can produce high yields and high-purity Rucaparib with high yield and avoiding the use of environmentally harmful organic solvents in the key step of the processes. These processes are also advantageous from the industrial standpoint as those provide high regioselectivity without the use of complex intermediates or potentially toxic, environmentally harmful solvents.

OBJECTIVE OF THE INVENTION:
The principal objective of the present invention is to provide novel processes for the preparation of Rucaparib to ameliorate one of the disadvantages of the prior-art processes.
Another objective of the present invention is to provide efficient, improved and industrially advantageous processes for the preparation of Rucaparib which are conveniently applicable to industrial scale.
Yet another objective of the present invention is to provide processes for preparation of Rucaparib having high purity and yield as well.
Yet one more objective of the present invention is to produce Rucaparib with high yield and avoiding the use of environmentally harmful organic solvents.
Yet additional objective of the present invention is to synthesize Rucaparib using high regioselectivity processes without the use of complex intermediates or potentially toxic, environmentally harmful solvents.
Another key objective of the present invention is to provide pure Rucaparib having HPLC purity not less than 99.5%.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides novel processes for the preparation of Rucaparib of formula-I,

which provides to be efficient and industrially viable.
One of the processes of the present invention comprises following steps:
a) Suzuki coupling of the compound of formula-2 with a compound of formula-4 in the presence of catalyst tetrakis(triphenylphosphine)palladium to obtain compound of formula-5;
b) the compound of formula-5a (R1 is =N- in formula-5) is converted to obtain formula-6 using acrylic acid and acetic anhydride by addition reaction;
c) dissolving the compound of formula-6 in dichloroethane followed by addition of thionyl chloride and chloroacetyl chloride in the presence of catalyst aluminium chloride to obtain a cyclized compound of formula-7;
d) reducing the compound of formula-7 by dissolving the same in dichloromethane followed by addition of sodium borohydride to yield a compound of formula-8;
e) expansion of ring of the compound of formula-8 by dissolving in mixture of water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to get a compound of formula-I (Rucaparib).
In above process, a compound of formula-2 is prepared by chlorinating 6-fluoro-1,3-dihydro-2H-indol-2-one (formula-1) in toluene followed by addition of phosphorus oxychloride and dimethylacetamide.
Moreover, a compound of formula-4 is prepared by imine formation of 4-formylphenyl boronic acid (formula-3) in methanol.
Accordingly, above-mentioned process of the present invention is summarized in below scheme-4.

wherein, X is halogen (compound-2a) or -OTf (compound-2b) or -OSO2CF3 (compound-2c) and R1 is =N-CH3 (compound-5a) or -C=N (compound-5b).

Another process of the present invention comprises following steps:
a) suzuki coupling of the compound of formula-2 with compound of formula-4 in the presence of catalyst tetrakis(triphenylphosphine)palladium to obtain compound of formula-5;
b) the compound of formula-5b (R1 is -C=N in formula-5) is converted to obtain formula-9 using acrylic acid and acetic anhydride by addition reaction;
c) dissolving the compound of formula-9 in dichloroethane followed by addition of thionyl chloride and chloroacetyl chloride in the presence of catalyst aluminium chloride to obtain a cyclized compound of formula-10;
d) expansion of ring of the compound of formula-10 by dissolving the same in water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to yield a compound of formula-11;
e) reducing the compound of formula-11 by dissolving the same in dichloromethane followed by addition of Raney Nickel to get a compound of formula-12.
f) dissolving the compound of formula-12 in paraformaldehyde followed by addition of sodium borohydride to obtain a compound of formula-I (Rucaparib) by N-methylation.
OR
f) dissolving the compound of formula-12 in n-butanol followed by addition of methyl iodide to obtain a compound of formula-I (Rucaparib).
OR

g) dissolving the compound of formula-12 in triethyl amine followed by addition of methyl iodide to obtain a compound of formula-I (Rucaparib).
In above process, a compound of formula-2 is prepared by chlorinating 6-fluoro-1,3-dihydro-2H-indol-2-one (formula-1) in toluene followed by addition of phosphorus oxychloride and dimethylacetamide.
Accordingly, above-mentioned process of the present invention is summarized in below scheme-5.

wherein, X and R1 is as described as earlier.

DETAILED DESCRIPTION OF THE INVENTION:
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by the person skilled in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
According to the principal embodiment of the present invention, it provides an industrially feasible and economically viable process for preparation of formula-I.

One of the embodiments of the present invention comprises following steps:
a) Suzuki coupling of the compound of formula-2 with a compound of formula-4 in the presence of catalyst tetrakis(triphenylphosphine)palladium to obtain compound of formula-5;

wherein, X is halogen (compound-2a) or -OTf (compound-2b) or -OSO2CF3 (compound-2c) and R1 is =N-CH3 (compound-5a)

b) the compound of formula-5a (R1 is =N- in formula-5) is converted to obtain formula-6 using acrylic acid and acetic anhydride by addition reaction;

c) dissolving the compound of formula-6 in dichloroethane followed by addition of thionyl chloride and chloroacetyl chloride in the presence of catalyst aluminium chloride to obtain a cyclized compound of formula-7;

d) reducing the compound of formula-7 by dissolving the same in dichloromethane followed by addition of sodium borohydride to yield a compound of formula-8;

e) expansion of ring of the compound of formula-8 by dissolving in mixture of water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to get a compound of formula-I (Rucaparib).

In above process, a compound of formula-2 is prepared by chlorinating 6-fluoro-1,3-dihydro-2H-indol-2-one (formula-1) in toluene followed by addition of phosphorus oxychloride and dimethylacetamide.
Moreover, a compound of formula-4 is prepared by imine formation of 4-formylphenyl boronic acid (formula-3) in methanol.

Another embodiment of the present invention comprises following steps:
a) suzuki coupling of the compound of formula-2 with compound of formula-4 in the presence of catalyst tetrakis(triphenylphosphine)palladium to obtain compound of formula-5;

wherein, X is halogen (compound-2a) or -OTf (compound-2b) or -OSO2CF3 (compound-2c) and R1 is -C=N (compound-5b).

b) the compound of formula-5b (R1 is -C=N in formula-5) is converted to obtain formula-9 using acrylic acid and acetic anhydride by addition reaction;

c) dissolving the compound of formula-9 in dichloroethane followed by addition of thionyl chloride and chloroacetyl chloride in the presence of catalyst aluminium chloride to obtain a cyclized compound of formula-10;

d) expansion of ring of the compound of formula-10 by dissolving the same in water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to yield a compound of formula-11;

e) reducing the compound of formula-11 by dissolving the same in dichloromethane followed by addition of Raney Nickel to get a compound of formula-12.

f) dissolving the compound of formula-12 in paraformaldehyde followed by addition of sodium borohydride to obtain a compound of formula-I (Rucaparib) by N-methylation.

OR
f) dissolving the compound of formula-12 in n-butanol followed by addition of methyl iodide to obtain a compound of formula-I (Rucaparib).

OR
g) dissolving the compound of formula-12 in triethylamine followed by addition of methyl iodide to obtain a compound of formula-I (Rucaparib).

In above process, a compound of formula-2 is similarly prepared by chlorinating 6-fluoro-1,3-dihydro-2H-indol-2-one (formula-1) in toluene followed by addition of phosphorus oxychloride and dimethylacetamide.
Another embodiment of the present invention relates to novel routes using less environmentally harmful organic solvents and reagents to prepare Rucaparib (I).
Yet another embodiment of the present invention relates to use of novel and simple intermediates for the synthesis of Rucaparib (I).
The present invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Therefore, the following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.

EXAMPLES:
Example-1: Preparation of 2-chloro-6-fluoro-3H-indole (Formula 2a)
Toluene (500ml), 6-fluoro-1,3-dihydro-2H-indol-2-one (50g, 0.330moles) (formula 1) dimethyl acetamide (50ml) were charged at 25-30°C in assembly equipped with water condenser and heating bath. Slowly added phosphorus oxychloride (123.2g, 0.803moles), the reaction mass was heated at 110°C for 3-4 hours. Reaction monitored by TLC. Distilled out reaction mass under vacuum and degas. Cooled to RT and 10 % sodium carbonate solution was added slowly to get neutral pH at 25-30°C, ethyl acetate (500ml) was charged to the reaction mass and stirred for 30 to 40 min. layers ware separated out and distilled out organic layer under vacuum to get 45g of 2-chloro-6-fluoro-3H-indole (formula-2a).

Example-2: Preparation of [4-(methylimino) methylphenyl]boronic acid (Formula 4a)
Methanol (450ml), (4-formylphenyl) boronic acid (50g, 0.333moles) (formula 3) and methyl amine hydrochloride (33.72g, 0.499moles) were charged in assembly at 25-30°C. Slowly added N, N-Diisopropyl ethyl amine (77.56g, 0.599moles) and stirred the reaction mass at 25-30°C for 12 hours. Reaction monitored on TLC, filtered the reaction mass under vacuum and washed with methanol (50ml). Wet cake was dried in vacuum tray drier at 40-45°C to get 38.5g 2-chloro-6-fluoro-3H-indole (formula 4a)

Example-3: Preparation of 1-[4-(6-fluoro-3H-indol-2-yl) phenyl]-N-methylmethan imine (formula-5a):
N, N-dimethyl acetamide (300ml), 2-chloro-6-fluoro-3H-indole (50g, 0.294moles) (formula-2a) and [4-(methylimino) methylphenyl] boronic acid (57.66g, 0.353moles) (formula 4a) were charged in assembly equipped with water condenser and heating bath at 25-30°C, charged potassium carbonate (101.7g, 0.737moles) at 25-30°C and purged the nitrogen in to reaction mass for 30 min. Tetrakis (triphenylphosphine) palladium (0) as catalyst (2.5g, 0.05%w/w) was added at 25-30°C, reaction mass was heated at reflux for 5-6 hours. Reaction monitored on TLC, the reaction mass was cooled to RT and filtered the reaction mass through celite bed and washed with N, N-dimethyl acetamide (50ml), water (2100ml) was added slowly in to the filter ml at 10-15°C, stirred reaction mass for 2 hours at 25-30°C, solid was filtered and washed the wet cake with water (100ml). Wet cake was died in air tray drier at 60-65°C for 10-12 hours to get 52-55g 1-[4-(6-fluoro-3H-indol-2-yl) phenyl]-N-methylmethanimine (formula 5a).

Example-4: Preparation of 6-fluoro-3H-indol-2-yl-trifluoro-methanesulfonate (formula-2c)
Dichloromethane (250ml), 6-fluoro-1, 3-dihydro-2H-indol-2-one (50g, 0.330moles) (formula-1) and 4-dimethyl amino pyridine (10g, 0.081moles) were charged in assembly equipped with cooling bath. Reaction was cooled to 0-10°C, triflic anhydride (139.9g, 0.496moles) was added slowly at 0-10°C, stirred reaction mass for 2-3 hours at 0-10°C, reaction monitored by TLC. Water (150ml) and 10% sodium bicarbonate solution were added to get neutral pH at 0-10°C, stirred for 30 to 40 min. at 0-10°C, layer was separated and distilled out organic layer under vacuum to get 38g 6-fluoro-3H-indol-2-yl trifluoro methanesulfonate (formula-2c).

Example-5: Preparation of 1-[4-(6-fluoro-3H-indol-2-yl)phenyl]-N-methylmethan imine (formula-5a):
N, N-dimethyl acetamide (300ml), 6-fluoro-3H-indol-2-yl trifluoromethanesulfonate (50g, 0.176moles) (formula-2c) and [4-(methylimino) methylphenyl] boronic acid (57.66g, 0.353moles) (formula-4a) were charged in assembly equipped with water condenser and heating bath at 25-30°C, charged potassium carbonate (101.7g, 0.737moles) at 25-30°C and purged the nitrogen in to reaction mass for 30 min, Tetrakis (triphenylphosphine) palladium (0) as catalyst (2.5g, 0.05%w/w) was added at 25-30°C, reaction mass was heated at reflux for 5-6 hours. Reaction monitored on TLC, the reaction mass was cooled to RT and filtered the reaction mass through celite bed and washed with N, N-dimethyl acetamide (50ml), water (2100ml) was added slowly in to the filter ml at 10-15°C, stirred reaction mass for 2 hours at 25-30°C, solid was filtered and wet cake was washed with water (100ml). wet cake was dried in air tray drier at 60-65°C for 10-12 hours to get 52-55g 1-[4-(6-fluoro-3H-indol-2-yl) phenyl]-N-methylmethanimine (formula-5a).

Example-6: Preparation of 3-(6-fluoro-2-{4-(methylimino) methylphenyl}-3H-indol-3-yl)propanoic acid (formula-6)
Acetic acid (200ml), acetic anhydride (85ml) and 1-[4-(6-fluoro-3H-indol-2-yl) phenyl]-N-methylmethanimine (50g, 0.198moles) (formula-5a) were charged at 25-30°C in assembly equipped with water condenser and heating bath, slowly added acrylic acid (67g, 0.93moles) at 25-30°C, heated the reaction mass at 85-90° C for 4-5 hours, reaction monitored on TLC, distilled out reaction mass under vacuum at 85-90°C, 10% sodium hydroxide solution (400ml) was added and stirred for 1-2 hours at 10-15°C, filtered insoluble particles and filter ml acidify with con. hydrochloric acid, stirred for 1 to 2 hours at 10-15°C and filtered solid under vacuum, wet cake was dried in air tray drier at 60-65°C for 12-15 hours to get 40-45g 3-(6-fluoro-2-{4-(methylimino) methylphenyl}-3H-indol-3-yl) propanoic acid (formula-6).

Example-7: Preparation of 7-fluoro-2-{4-(methylimino)methylphenyl}-3,4-dihydro benzo[cd]indol-5(2aH)-one (formula-7)
Dichloro methane (300ml) and 3-(6-fluoro-2-{4-(methylimino)methylphenyl}-3H-indol-3-yl)propanoic acid (50g, 0.154moles) (formula-6) were charged in assembly equipped with cooling bath at 25-30°C, reaction was cooled to 0-10°C, slowly added thionyl chloride (27.5g, 0.231moles) at 0-10°C, stirred the reaction for 1hour at 0-10°C. slowly added chloroacetyl chloride (20.89g, 0.184moles) at 0-10°C and then aluminium chloride (8.89g, 0.046moles) as catalyst and raise the temperature to 25-30°C, stirred at for 2 hours at 25-30°C, reaction monitored on TLC, water (500ml) was added and stirred for 30-40 min. layers were separated and organic layer was washed with water (250ml), distilled out organic layer under vacuum at 50-55°C to get 32-33g 7-fluoro-2-{4-(methylimino) methylphenyl}-3, 4-dihydrobenzo [cd] indol-5(2aH)-one (formula-7).

Example-8: Preparation of (E)-7-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydrobenzo[cd]indol-5(2aH)-one (formula-8)
Tetrahydrofuran (250ml), methanol (500ml) and 7-fluoro-2-{4-(methylimino) methyl phenyl}-3, 4-dihydrobenzo(indol-5(2aH)-one (formula-7) were charged at 25-30°C in assembly equipped with cooling bath, reaction was cooled to 0-10°C and sodium borohydride (18.5g, 0.489moles) was added at 0-10° C, stirred for 5-6 hours, reaction monitored on TLC, methanol (85ml) and water (200ml) ware charged at 0-10°C in to reaction mass, stirred for 2 hours at 0-10°C, filter the solid and washed with mixture of methanol and water (20:80 ) volume and unload wet cake, wet cake was dried in air tray drier at 60-65°C for 12 hours to get 7-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydrobenzo[cd]indol-5(2aH)-one 40-42g (formula-8).

Example-9: Preparation of Rucaparib (formula-I)
Water (150ml), methanol (250ml), tetrahydrofuran (150ml) and 7-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydrobenzo (indol-5(2aH)-one (50g, 0.162moles (formula-8) were charged at 25-30°C in assembly equipped with water condenser and heating bath, slowly added hydroxyl amine hydrochloride (16.88g, 0.243moles) and sodium acetate trihydrate (33g, 0.243moles) at 50-55° C, stirred reaction 2-3 hours at 50-55°C, monitored reaction on TLC, addition of 5% sodium bicarbonate to get neutral pH, stirred reaction for 1 hours at 25-30°C, solid was filtered and washed with water, wet cake was dried in vacuum tray drier at 50-55°C for 12 hours to get 45-46g Rucaparib (formula-I).

Example-10: Preparation of 4-(6-fluoro-3H-indol-2-yl) benzonitrile (formula-5b)
N,N-dimethyl acetamide (300ml), 2-chloro-6-fluoro-3H-indole (50g, 0.294moles) (formula-2a) and 4-cyano phenyl boronic acid (51.82g, 0.352moles) (formula-4b) were charged under nitrogen in assembly equipped with water condenser and heating bath at 25-30°C, charged potassium carbonate (101.7g, 0.737moles) at 25-30°C and purged the nitrogen in to reaction mass for 30 min, Tetrakis (triphenylphosphine) palladium (0) was added as catalyst (2.5g, 0.05%w/w). Reaction mass was heated at reflux for 5-6 hours. Reaction monitored on TLC, reaction mass was cooled to RT and filtered the reaction mass through celite bed and washed with N, N-dimethyl acetamide (50ml), water (2100ml) was added in to the filter ml at 10-15°C, stirred reaction mass for 2 hours at 25-30°C, solid was filter and washed the wet cake with water (100ml). Wet cake was died in air tray drier at 60-65°C for 10-12 hours to get 52-55g 4-(6-fluoro-3H-indol-2-yl) benzonitrile (formula-5b).

Example-11: Preparation of 3-[2-(4-cyanophenyl)-6-fluoro-3H-indol-3-yl]propanoic acid (formula-9):
Acetic acid (200ml), acetic anhydride (85ml), 4-(6-fluoro-3H-indol-2-yl) benzonitrile (50g, 0.211moles) (formula-5b) were charged at 25-30°C in assembly equipped with water condenser and heating bath, slowly added acrylic acid (67g, 0.93moles) at 25-30°C, heated the reaction mass at 85-90° C for 4-5 hours, reaction monitored on TLC, distilled out reaction mass under vacuum at 85-90°C, 10% sodium hydroxide solution (400ml) was added and stirred for 1-2 hours at 10-15°C, filter insoluble particles and filter ml acidified with con. hydrochloric acid, stirred for 1 to 2 hours at 10-15°C and filtered solid under vacuum, wet cake was dried in air tray drier at 60-65°C for 12-15 hours to get 40-45g 3-[2-(4-cyanophenyl)-6-fluoro-3H-indol-3-yl] propanoic acid (formula-9).

Example-12: Preparation of 4-(7-fluoro-5-oxo-2a,3,4,5-tetrahydrobenzo[cd]indol-2-yl) benzonitrile (formula-10)
Dichloro ethane (300ml) and 3-[2-(4-cyanophenyl)-6-fluoro-3H-indol-3-yl] propanoic acid (50g, 0.164moles) (formula-9) were charged in assembly equipped with cooling bath at 25-30°C, reaction was cooled to 0-10°C, thionyl chloride (27.5g, 0.231moles) was added at 0-10°C, stirred the reaction for 1hour at 0-10°C, chloroacetyl chloride (20.89g, 0.184moles) was added at 0-10°C and aluminium chloride (8.89g, 0.046moles) was added as catalyst and raised the temperature to 25-30°C, stirred for 2 hours at 25-30°C, reaction monitored on TLC, water (500ml) was added and stirred for 30-40 min, separated the layer and organic layer washed with water (250ml), layer was separated out and distilled out organic layer under vacuum at 50-55°C to get 32-33g 4-(7-fluoro-5-oxo-2a, 3, 4, 5-tetrahydrobenzo [cd] indol-2-l) benzonitrile (formula-10).

Example-13: Preparation of 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-2aH-azepino[5,4,3-cd] indol-2-yl) benzonitrile (formula-11)
Water (150ml), methanol (250ml), 4-(7-fluoro-5-oxo-2a, 3, 4, 5-tetrahydrobenzo [cd] indol-2-l) benzonitrile (50g, 0.172moles) (formula-10) and tetrahydrofuran (150ml) were charged in assembly equipped with water condensor and heating bath, hydroxyl amine hydrochloride (16.88g, 0.243moles) and sodium acetate trihydrate (33g, 0.243moles) at 50-55° C were added and stirred reaction 2-3 hours, monitored reaction on TLC, 5% sodium bicarbonate was added to get neutral pH, stirred reaction for 1 hours at 25-30°C, filtered solid and wash with water, wet cake was dried in vacuum tray drier at 50-55°C for 12 hours to get 40 - 42g 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-2aH-azepino[5,4,3-cd]indol-2-yl)benzonitrile (formula-11).

Example-14: Preparation of 2-[4-(aminomethyl)phenyl]-8-fluoro-2a,3,4,5-tetrahydro -6H-azepino[5,4,3-cd] indol-6-one (formula-12):
Methanol (300ml) and 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-2aH-azepino[5,4,3-cd]indol-2-yl)benzonitrile (30g, 0.098moles) (formula-11) were charged in assembly equipped with hydrogenator, raney nickel (3.0g, 10%w/w) was added at 25-30°C and applied hydrogen gas pressure 3 to 4 kg, heated the reaction for 55-60°C for 3-4 hours, monitored reaction on TLC, reaction was cooled to 25-30°C and filtered through celite bed and washed with methanol (50ml) and distilled out filter ml under vacuum at 50°C to get 20-22g 2-[4-(aminomethyl)phenyl]-8-fluoro-2a,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one (formula-12)

Example-15: Preparation of Rucaparib (Formula-I):
Formula-12, synthesized as per example-14, was dissolved in paraformaldehyde followed by sodium borohydride at 25-30°C and maintained for 5-6 h to get Rucaparib (Formula-I).

Example-16: Preparation of Rucaparib (Formula-I):
Formula-12, synthesized as per example-14, was dissolved in n-Butanol followed by addition of methyl iodide at 45-50°C and maintained for 5-6 h to get Rucaparib (Formula-I).

Example-17: Preparation of Rucaparib (Formula-I):
Tetrahydrofuran (300ml) and 2-[4-(aminomethyl)phenyl]-8-fluoro-2a,3,4,5-tetrahydro-6H-azepino[5,4,3]indol-6-one (30g, 0.096moles) (formula-12) were charged at 25-30°C in assembly equipped with water condenser and heating bath, triethyl amine (14.57g, 0.144moles) was added at 25-30°C and stirred the reaction mass for 30 min, methyl iodide (17.7g, 0.124moles), was slowly added and heated reaction at 40-45°C for 3-4 hours, monitored reaction on TLC, reaction was cooled to 25-30°C and water (150ml) was added slowly, stirred for 1-2 hours and filtered solid under vacuum, wet cake was dried in vacuum tray drier at 50-55°C to get Rucaparib (Formula-I).
,CLAIMS:
1. A novel process for the preparation of Rucaparib (Formula I) which comprises:

a) Suzuki coupling of formula-2 with formula-4a in the presence of catalyst to obtain compound of formula-5a
wherein, X is halogen (formula-2a) or -OTf (formula -2b) or -OSO2CF3 (formula 2c) in formula 2.

b) formula-5a is converted to obtain formula-6 in the presence of acetic anhydride and acrylic acid

c) dissolving formula-6 in dichloroethane followed by addition of thionyl chloride and aluminium chloride to obtain a cyclized formula-7;

d) reducing formula-7 to yield formula 8 in the presence of sodium borohydride

e) expansion of ring of formula-8 by dissolving in mixture of water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to get formula-I (Rucaparib).

2. A novel process for the preparation of Rucaparib (Formula I) which comprises:

a) suzuki coupling of formula-2 with compound of formula-4b in the presence of catalyst to obtain formula-5b;

wherein, X is halogen (formula-2a) or -OTf (formula -2b) or -OSO2CF3 (formula 2c) in formula 2

b) formula-5b is converted to obtain formula-9 in the presence of acetic anhydride and acrylic acid

c) dissolving formula-9 in dichloroethane followed by addition of thionyl chloride and aluminium chloride to obtain a cyclized formula-10;

d) expansion of ring of formula-10 by dissolving in water, methanol and tetrahydrofuran followed by addition of hydroxyl amine hydrochloride and sodium acetate trihydrate to yield a formula-11;

e) reducing formula-11 by dissolving the same in dichloromethane and addition of Raney Nickel to get a compound of formula-12.

f) dissolving formula-12 in combination of solvents and reagents to obtain a compound of formula-I (Rucaparib) by N-methylation.

Wherin conversion of formula 12 to formula I in step f comprises combination of solvents and reagents atleast as:
(i) paraformaldehyde with sodium borohydride or
(ii) n-Butanol with methyl iodide or
(iii) triethyl amine with methyl iodide

3. The Compounds of following formula:

wherein, X is halogen (compound-2a) or -OTf (compound-2b) or -OSO2CF3
(compound-2c) and

4. The Compounds of following formula: