Darifenacin hydrobromide, UK-88525(free base), UK-88525-04, Emselex, Enablex

氢溴酸达非那新 达非那新 Chemical Name: 2-[1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]pyrrolidin-3(S)-yl]-2,2-diphenylacetamide hydrobromide
CAS No. 133099-07-7, 133099-04-4 (free base)
项目整合开发状态: Registered-2004
项目研究机构: Novartis (Proprietary), Pfizer (Originator)
合成路线:Darifenacin can be obtained by three related ways:1) The decarboxylation of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) by heating at 154 C in cyclohexanol/2-cyclohexenone gives 3(R)-hydroxypyrrolidine (II),which is N-tosylated with p-toluenesulfonyl chloride and pyridine yielding (III).The reaction of (III) with methyl p-toluenesulfonate,triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords 1-tosyl-3(S)-(tosyloxy)pyrrolidine (IV),which is condensed with 2,2-diphenylacetonitrile (V) by means of NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(S)-yl]acetonitrile (VI).Elimination of the tosyl group of (VI) with HBr and phenol in refluxing water yields 2,2-diphenyl-2-[2(S)-pyrrolidinyl]acetonitrile (VII),which by treatment with 95% H2SO4 at 100 C is converted into the corresponding acetamide (VIII).The condensation of (VIII) with 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) by means of potassium carbonate in industrial methylated spirits affords the ketonic amide (X),which is finally reduced with H2 over Pd/C in acetic acid.The intermediate 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) has been obtained by Friedel-Crafts condensation of 2,3-dihydrobenzofuran (XI) with chloroacetyl chloride by means of AlCl3 in dichloromethane.3) The condensation of 5-(2-bromoethyl)benzofuran (XV),with the previously obtained acetamide (VIII) by means of K2CO3 in refluxing acetonitrile affords the condensation product (XVI),which is hydrogenated with H2 over Pd/C in hot acetic acid.