【结 构 式】 |
【药物名称】S-33138 【化学名称】N-[4-[2-[(3aS,9bR)-8-Cyano-1,2,3,3a,4,9b-hexahydro[1]benzopyrano[3,4-c]pyrrol-2-yl]ethyl]phenyl]acetamide 【CA登记号】245514-32-3 【 分 子 式 】C22H23N3O2 【 分 子 量 】361.44751 |
【开发单位】Servier (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D3 Antagonists |
合成路线1
The reduction of the ester function of (I) with LiAlH4 in THF gives (II). O-demethylation of (II) with EtSNa in DMF yields alcohol (III), which is then cyclized by Mitsunobu reaction with DEAD·Ph3P in THF to yield (IV). Displacement of the Br of (IV) by means of Zn(CN)2 and Pd(PPh3)4 in DMF affords cyano derivative (V), which is then converted into (VI) after debenzylation by treatment with HCl/EtOH and H2 over Pd/C. Finally (VI) is coupled with aldehyde (VII) by reductive amination in 1,2-dichloroethane in presence of NaBH(OAc)3.Alternatively the final product can be obtained by reaction of (VI) with chloro derivative (X) in CH3CN in presence of K2CO3 and KI. (X) can be obtained by acylation of acetanilide (VIII) with chloride (A) in 1,2-dichloroethane in presence of AlCl3 followed by treatment with TFA and Et3SiH.
【1】 Audinot, V.; Dubuffet, T.; Newman-Tancredi, A.; Cussac, D.; Millan, M.J.; Lavielle, G.; Loutz, A.; Novel benzopyrano[3,4-c]pyrrole derivatives as potent and selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1999, 9, 14, 2059. |
【2】 Lejeune, F.; Hautefaye, P.; Millan, M.; Dubuffet, T.; Lavielle, G. (ADIR et Cie.); Chromene derivs., process for their preparation and pharmaceutical compsns. containing them. EP 0887350; JP 1999071376; US 6090837 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 33760 | methyl (3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)-3-pyrrolidinecarboxylate | C20H22BrNO3 | 详情 | 详情 | |
(II) | 33761 | [(3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)pyrrolidinyl]methanol | C19H22BrNO2 | 详情 | 详情 | |
(III) | 33762 | 2-[(3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidinyl]-4-bromophenol | C18H20BrNO2 | 详情 | 详情 | |
(IV) | 41665 | (3aS,9bR)-2-benzyl-8-bromo-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole | C18H18BrNO | 详情 | 详情 | |
(V) | 41666 | (3aS,9bR)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile | C19H18N2O | 详情 | 详情 | |
(VI) | 41667 | (3aS,9bR)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile | C12H12N2O | 详情 | 详情 | |
(VII) | 41662 | N-[4-(2-oxoethyl)phenyl]acetamide | C10H11NO2 | 详情 | 详情 | |
(VIII) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
(IX) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
(X) | 41663 | N-[4-(2-chloroacetyl)phenyl]acetamide | C10H10ClNO2 | 详情 | 详情 | |
(XI) | 41664 | N-[4-(2-chloroethyl)phenyl]acetamide | C10H12ClNO | 详情 | 详情 |