Ioxipride, NCQ-298, -Drug Synthesis Database

【结构式】

【药物名称】Ioxipride, NCQ-298

【化学名称】(-)-(S)-N-(1-Ethyl-2-pyrrolidinylmethyl)-2-hydroxy-3-iodo-5,6-dimethoxybenzamide

【CA登记号】124929-10-8 ([123I]-labeled), 124929-13-1 ([125I]-labeled)

【分子式】C₁₆H₂₃IN₂O₄

【分子量】434.27711

【开发单位】AstraZeneca (Originator)

【药理作用】PHARMACOLOGICAL TOOLS, Dopamine D2 Antagonists

合成路线1 合成路线2

合成路线1

The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-iodo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.

参考文献中间体

【1】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036.
【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664.
【3】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333.
【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63.

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)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(II)	10925	Iodoethane;ethyl iod	75-03-6	C₂H₅I	详情	详情
(III)	42895	ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate		C₉H₁₇NO₂	详情	详情
(IV)	42896	(2S)-1-ethyl-2-pyrrolidinecarboxamide	55446-83-8	C₇H₁₄N₂O	详情	详情
(V)	21345	(2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine		C₇H₁₆N₂	详情	详情
(VI)	42906	3-iodo-2,5,6-trimethoxybenzoyl chloride		C₁₀H₁₀ClIO₄	详情	详情
(VII)	42907	N-[[(2S)-1-ethylpyrrolidinyl]methyl]-3-iodo-2,5,6-trimethoxybenzamide		C₁₇H₂₅IN₂O₄	详情	详情

合成路线2

The lithiation of N-(1-ethylpyrroidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (I) with n-BuLi gives the dilithium salt (II), which by treatment with butyl borate, H2O2 and ammonium chloride yields N-(1-ethylpyrrolidin-2(S)-ylmethyl)-6-hydroxy-2,3-dimethoxybenzamide (III). Finally, this compound is iodinated with 123INa and chloramine T.

参考文献中间体

【1】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	42899	N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,3-dimethoxybenzamide	C₁₆H₂₄N₂O₃	详情	详情
(II)	42900	lithium [2-[([[(2S)-1-ethylpyrrolidinyl]methyl]imino)(oxido)methyl]-3,4-dimethoxyphenyl]lithium	C₁₆H₂₂Li₂N₂O₃	详情	详情
(III)	42908	N-[[(2S)-1-ethylpyrrolidinyl]methyl]-6-hydroxy-2,3-dimethoxybenzamide	C₁₆H₂₄N₂O₄	详情	详情

Extended Information