2-[(3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidinyl]-4-bromophenol -Drug Synthesis Database

【结构式】

【分子编号】33762

【品名】2-[(3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidinyl]-4-bromophenol

【CA登记号】

【分子式】C₁₈H₂₀BrNO₂

【分子量】362.26634

【元素组成】C 59.68% H 5.56% Br 22.06% N 3.87% O 8.83%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(III)

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

合成目标

【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

Extended Information