S-33084, -Drug Synthesis Database

【结构式】

【药物名称】S-33084

【化学名称】N-[4-[(3aR,9bS)-8-Cyano-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-c]pyrrol-2-yl]butyl]biphenyl-4-carboxamide hydrochloride

【CA登记号】220647-52-9 (stereoisomer)

【分子式】C₂₉H₃₀ClN₃O₂

【分子量】488.03435

【开发单位】Servier (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D3 Antagonists

合成路线1 合成路线2

合成路线1

Reduction of the ester function of trans pyrrolidine (I) with LiAlH4 gave alcohol (II). Subsequent cleavage of the methyl ether of (II) using EtSNa in hot DMF furnished diol (III), which was submitted to ring closure under Mitsunobu conditions, yielding chromene (IV). The 8-cyano group was introduced by displacement of the bromine of (IV) by means of Zn(CN)2 and Pd(PPh3)4 in DMF. The resulting nitrile (V) was N-debenzylated by hydrogenolysis over Pd/C to provide intermediate (VI).

参考文献中间体

【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.

中间体序号	中间体编号	品名	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)	33763	(3aR,9bS)-2-benzyl-8-bromo-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole	C₁₈H₁₈BrNO	详情	详情
(V)	33764	(3aR,9bS)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile	C₁₉H₁₈N₂O	详情	详情
(VI)	33765	(3aR,9bS)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile	C₁₂H₁₂N₂O	详情	详情

合成路线2

Coupling of 4-aminobutanol (VII) with 4-phenylbenzoyl chloride (VIII) produced hydroxy amide (IX). Further Swern oxidation of the alcohol group of (IX) using oxalyl chloride and DMSO afforded aldehyde (X). Finally, reductive condensation of aldehyde (X) with pyrrolidine (VI) in the presence of NaBH(OAc)3 afforded the title compound.

参考文献中间体

【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
(VI)	33765	(3aR,9bS)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile		C₁₂H₁₂N₂O	详情	详情
(VII)	33766	4-amino-1-butanol	13325-10-5	C₄H₁₁NO	详情	详情
(VIII)	28439	[1,1'-biphenyl]-4-carbonyl chloride	14002-51-8	C₁₃H₉ClO	详情	详情
(IX)	33767	N-(4-hydroxybutyl)[1,1'-biphenyl]-4-carboxamide		C₁₇H₁₉NO₂	详情	详情
(X)	33768	N-(4-oxobutyl)[1,1'-biphenyl]-4-carboxamide		C₁₇H₁₇NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)