达泊西汀(dapoxetine)路线推荐.doc

【药物名称】 Dapoxetine, LY-210448 【化学名】 (S)-(+)-N,N-Dimethyl-3-(1-naphthyloxy)-1-phenylpropylamine; (+)-(S)-N,N-Dimethyl-alpha[2-(1-naphthyloxy)ethyl]benzylamine 【CAS登记号】 119356-77-3, 129938-20-1 (HCl) 【结构式】 【分子式】 C21-H23-N-O 【分子量】 305.4187 【原研厂家】 Lilly (Originator), Dynogen Pharmaceuticals (Not Determined), Alza (Licensee), PPD GenuPro (Licensee) 【作用类别】 Prevention of Premature Ejaculation, RENAL-UROLOGIC DRUGS, Treatment of Male Sexual Dysfunction, 5-HT Reuptake Inhibitors 【研发状态】 Phase III 【合成情况】 　 〖来源〗 J Label Compd Radiopharm 〖合成路线〗 〖标题〗 A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer 〖合成方法〗 In the original synthesis of the title compound, Knoevenagel condensation of benzaldehyde (I) with malonic acid (II) in the presence of ammonium acetate produced the beta-aminoacid (III). Reductive alkylation of the amino group of (III) with formaldehyde produced the dimethyl amine (IV). Then, Fischer esterification of (IV) with ethanolic HCl furnished the intermediate amino ester (V). Amino ester (V) was alternatively obtained by Michael addition of dimethylamine to ethyl cinnamate (VI). Reduction of the ester function of (V) provided amino alcohol (VII). The sodium alkoxide of (VII) was then coupled with 1-fluoronaphthalene (VIII) to produce the racemic amino ether, which was finally resolved into enantiomers by means of tartaric acid. 〖作者〗 Wheeler, W.J.; OBannon, D.D. 〖参考〗 Wheeler, W.J.; OBannon, D.D.; A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer. J Label Compd Radiopharm 1992, 31, 4, 305 〖出处〗 J Label Compd Radiopharm1992,31,(4):305 〖来源〗 J Label Compd Radiopharm 〖合成路线〗 〖标题〗 A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer 〖合成方法〗 An alternative synthesis starting from the chiral precursor N-Boc-(R)-phenylglycine (IX) was reported. Borane reduction of (IX) provided the N-Boc aminoalcohol (X), which was activated as