Process for the preparation of Olaparib, and crystalline form thereof

1 . 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.

2 . The process of claim 1 , wherein the coupling agent is EDCI (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride).

3 . The process of claim 1 , wherein the reaction of the compound of formula V with the compound of formula VI in step (a) occurs in the presence of a base.

4 . The process of claim 3 , wherein the base is selected from the group consisting of diisopropylethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine, collidine, imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N′,N′-tetramethyl-1,8-naphthalenediamine, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine, and HOBt (hydroxybenzotriazole hydrate), or a mixture thereof.

5 . The process of claim 1 , wherein the reaction of the compound of formula V with the compound of formula VI in step (a) occurs in the presence of a solvent.

6 . The process of claim 5 , wherein the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, and sulfoxides, or a mixture thereof.

7 . The process of claim 1 , wherein the reaction of the compound of formula III with the compound of formula IV in step (b) occurs in the presence of a base.

8 . The process of claim 7 , wherein the base is selected from the group consisting of diisopropylethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine, collidine, imidazole, DMAP, DABCO, DBU, DBN, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine, and lithium hexamethyldisilazide, or a mixture thereof.

9 . The process of claim 8 , wherein the base is triethylamine or DMAP.

10 . The process of claim 1 , wherein the reaction of the compound of formula III with the compound of formula IV in step (b) occurs in the presence of a solvent.

11 . The process of claim 10 , wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, hydrocarbons, esters, nitriles, amides, and sulfoxides, or a mixture thereof.

12 . A process for the preparation of crystalline form G1 of olaparib, the process comprising:

a) reacting a solution of a compound of formula II,

in an amide solvent with hydrazine hydrate at a temperature ranging from about 15° C. to about 35° C. to obtain a reaction mixture;

b) heating the reaction mixture as obtained in step (a) for about 3 hours to about 7 hours at a temperature ranging from about 60° C. to about 80° C. under stirring to obtain olaparib through a compound of formula IIIa:

c) adding a haloalkane solvent to a reaction mass as obtained in step (b) to obtain a clear solution, followed by stirring for about 1 hour to 3 hours at a temperature ranging from about 15° C. to about 35° C.;

d) cooling the reaction mass obtained in step (c) to a temperature ranging from about 10° C. to about 0° C. with stirring to obtain crystalline form G1 of olaparib; and

e) isolating crystalline Form G1 of olaparib obtained in step (d), wherein the crystalline form G1 of olaparib has an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 15.5, 21.5, 27.4, 30.6 and 38.4±0.2 degrees 2 theta.

13 . The process of claim 12 , wherein the amide solvent of step (a) is selected from dimethylacetamide or dimethylformamide.

14 . The process of claim 12 , wherein the crystalline form G1 of olaparib is substantially free of the dimer impurity represented by the following chemical structure.

15 . The process of claim 12 , wherein the process further comprising converting the crystalline form G1 of olaparib to crystalline form H of olaparib by a process comprising the steps of:

(a) providing a solution of crystalline form G1 of olaparib in dimethylsulfoxide; and

(b) obtaining crystalline form H of olaparib from the solution of step (a) by combining the solution of step (a) with water; wherein form H has an X-ray powder diffraction pattern containing specific peaks at 6.5, 6.9, 8.4 and 12.8±0.1 degrees 2 theta.

16 . A process for the preparation of form H of Olaparib, the process comprising:

(1) reacting a solution of a compound of formula II;

in dimethylsulfoxide with hydrazine hydrate at a temperature ranging from about 20° C. to about 30° C. to obtain a solution;

(2) heating the solution obtained in step (1) for about 5 hours to about 9 hours at a temperature ranging from about 60° C. to about 70° C. under stirring to obtain a reaction mass;

(3) cooling the reaction mass obtained in step (2) to a temperature ranging from about 20° C. to about 30° C., and filtering it to obtain a filtrate;

(4) adding the filtrate obtained in step (3) to water, and stirring the resulting reaction mass; and

(5) isolating crystalline Form H of olaparib obtained in step (4).

17 . The process of claim 12 , further comprising converting the crystalline form G1 of olaparib to crystalline form A of Olaparib by a process comprising:

(a) providing a solution of crystalline form G1 of olaparib in a water-miscible solvent and water;

(b) stirring a reaction mass obtained from the solution of step (a) at a temperature from about 0° C. to about 10° C.;

(c) filtering the reaction mass obtained from the solution of step (b); and

(d) obtaining crystalline form A of olaparib from step (c) by combining the filtered reaction mass of step (c) with water.