Process for the preparation of Olaparib, and crystalline form thereof

A process for the preparation of olaparib, a compound of formula I,

• the process comprising:
• (a) reacting 2-fluoro-5-formylbenzoic acid, a compound of formula V, with cyclopropyl(piperazin-1-yl) methanone, a compound of formula VI, in the presence of a coupling agent,
• to obtain 3-{[4-(cyclopropylcarbonyl) piperazin-1-yl]carbonyl}-4-fluoro benzaldehyde, a compound of formula III,
• (b) reacting the compound of formula III with dimethyl 3-oxo-1,3-dihydro-2-benzofuran-1-yl) phosphonate, a compound of formula IV,
• to obtain (3E/Z)-3-({3-[4-(cyclopropanecarbonyl) piperazine-1-carbonyl]-4-fluorophenyl}methylidene)-2-benzofuran-1 (3H)-one, a compound of formula II,
• and
• (c) reacting the compound of formula II with hydrazine hydrate to obtain olaparib, the compound of formula I;
• wherein the compound of formula III obtained in step (a) is not isolated, and wherein the coupling agent is selected from the group consisting of EDCI (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), HOBt (hydroxybenzotriazole hydrate), HOSu (N-hydroxysuccinimide), HOAt (1-hydroxy-7-azabenzotriazole), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4 (3H)-one), HOOBt (hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine), HDMC (N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate), HCTU (2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate), HOTT (S-(1-oxido-2-pyridyl)-N,N,N′,N′-tetramethylthiuronium hexafluorophosphate), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), TATU (O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate), TSTU (N,N,N,N-tetramethyl-O—(N-succinimidyl) uronium tetrafluoroborate), TDBTU (O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′ N′-tetramethyluronium tetrafluoroborate), TPTU (O-(2-oxo-1 (2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), TOTU (O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate), TOTT (N,N,N′,N′-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium tetrafluoroborate), IIDQ (isobutyl 1,2-dihydro-2-isobutoxy-1-quinolinecarboxylate), EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate), PyOxim ([ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), Oxyma (ethyl(hydroxyimino) cyanoacetate), FDPP (pentafluorophenyl diphenylphosphinate), and T3P (propylphosphonic anhydride), or a mixture thereof.