Stable hydrate of a muscarinic receptor antagonist

#This invention relates to a stable solid hydrate of the muscarinic receptor antagonist (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide, otherwise known as darifenacin (VII): 1

#In addition, the invention relates to pharmaceutical compositions containing the hydrate of the invention and to uses of said hydrate in medicine. Such pharmaceutical compositions are particularly relevant to the treatment of conditions for which an antagonist of muscarinic receptors is required, such as irritable bowel syndrome, diverticular disease, oesophageal achalasia, chronic obstructive airways disease, over active bladder including symptoms of incontinence, urge and frequency, urinary incontinence, neurogenic urinary urgency or pollakiuria, treatment of bladder functional disorder, urinary leakage, painful or difficult urination caused by neurogenic bladder, spastic or hypertonic bladder, dysfunctional bladder syndrome, gastrointestinal disorders including gastrointestinal hyperactivity, and relaxing effect on intestinal smooth muscle cells.

#European patent 0388054 describes a family of 3-substituted pyrrolidine derivatives including darifenacin and pharmaceutically acceptable salts thereof as muscarinic receptor antagonists. The pharmaceutically acceptable salts include acid addition salts, specifically the hydrochloride, hydrobromide, hydrofluoride, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts.

#4

#A mixture of (S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinyl)acetonitrile (I) [see European Patent Publication No. 0388054] (83.8 Kg, 201.2 moles), 48% aqueous hydrobromic acid (419 L, 5 L/Kg of compound I) and phenol (16.8 Kg, 0.2 Kg/Kg of compound I) is heated at reflux for 3 hours. The mixture is cooled and extracted with dichloromethane (1×560 Kg, 1×523 Kg). The extracts are combined and washed with aqueous sodium chloride solution (15 Kg in 150 Kg of water). The organic layer is concentrated and essentially replaced with ethyl acetate to a total volume of about 440 L. Hexane (276 Kg) is added at 40° C. and product is collected at 0-5° C. by filtration. The (S)-2,2-diphenyl -2-(3-pyrrolidinyl)acetonitrile hydrobromide is washed with chilled ethyl acetate and dried under vacuum at 60° C. Yield 52.8 Kg (76%).

#ν=3441, 2940, 2745, 2455, 2246, 1972, 1886, 1806, 1596, 1585, 1561, 1494, 1450, 1392, 1289, 1255, 1217, 1159, 1104, 1070, 1034, 1002, 967, 917, 899, 833, 766, 750, 702, 664, 645, 546, 496, 472 cm−1.