达泊西汀(dapoxetine)路线.doc

【药物名称】Dapoxetine, LY-210448【化学名】(S)-(+)-N,N-Dimethyl-3-(1-naphthyloxy)-1-phenylpropylamine; (+)-(S)-N,N-Dimethyl-alpha2-(1-naphthyloxy)ethylbenzylamine【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 the mesylate (XI) by reaction with methanesulfonyl chloride in pyridine, yielding (XI). Displacement of the mesylate group of (XI) with NaCN furnished the Boc-aminonitrile (XII). Hydrolysis of the nitrile group of (XII) with concomitant N-Boc group cleavage under acidic conditions gave aminoacid (XIII). This was reduced to amino alcohol (XIV) using borane in THF. Eschweiler-Clarke methylation of aminoalcohol (XIV) yielded the dimethyl amine (XV). This was finally condensed with 1-fluoronaphthalene (VIII) to produce the title naphthyl ether. The 14C-labeled compound was similarly prepared employing 14C-sodium cyanide.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Nucl Med Biol合成路线标题Synthesis of 11Cdapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey合成方法The synthesis of the 11C-labeled compound was also reported. Selective tosylation of the primary hydroxyl of (R)-1-phenyl-1,3-propanediol (XVI) provided (XVII). From this, naphthyl ether (XIX) was prepared by Williamsons synthesis with the sodium alkoxide of 1-naphthol (XVIII). The remaining hydroxyl group of (XIX) was then converted to mesylate (XX) upon treatment with methanesulfonyl chloride and DMAP. Subsequent displacement with methylamine in a sealed vessel afforded the secondary amine (XXI). This was finally alkylated with 11CH3I to yield the target 11C-labeled compound.作者Livni, E.; et al.参考Livni, E.; et al.; Synthesis of 11Cdapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey. Nucl Med Biol 1994, 21, 4, 669出处Nucl Med Biol1994,21,(4):669来源AU 8814335; EP 0288188; JP 1988258837; US 5135947合成路线标题1-Phenyl-3-naphthalenyloxypropanamines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Robertson, D.W.; Thompson, D.C.; Wong,