氢溴酸达非那新的合成研究

Study on the Synthesis of Darifenacin Hydrobromide

以(S)-(-)-3-羟基吡咯烷盐酸盐为原料,经氨基和羟基同时保护、取代、脱N-保护基、氰基水解,与L-(+)-酒石酸成盐等4步反应,制得3-(S)-(-)-(1-氨甲酰基-1,1-二苯基甲基)四氢吡咯酒石酸盐,经皂化后与5-(2-溴乙基)-2,3-二氢苯并呋喃缩合、成盐制得氢溴酸达非那新,总收率为23.4%。产物经1H NMR和质谱进行了确认。对文献工艺条件进行了优化,适合于工业化生产,同时对文献报道目标化合物的旋光度数据进行了修正。

Darifenacin hydrobromide was prepared from （S）-（-）-3-hydroxylpyrrolidine hydroehloride as raw material by NH and OH protection, replacement with 1,1-diphenylacetonitrile, deproteetion, hydrolysis and salt formation to give the key intermediate 3-（S）-（-）-（1-carbomoyl-1,1-diphenylmethyl）pyrrolidine L- （＋）-tartrate. followed by saponification and condensation with 5-（2-bromoethyl）-2,3-dihydrobenzofuran. Then darifenacin hydrobromide was obtained by salt formation with 40 % HBr with an overall yield of about 23.4%. The product was confirmed by ~H NMR and MS. Technical parameters were optimized, So that the process was more suitable for industrialization. The optical rotatory degree of darifenacin hydrobromide was tested, which was [a]D^20= ＋ 49.4° （c = 1, CH2Cl2）.