-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】5-Chloro-N-(1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-yl]-2-methoxy-4-(methylamino)benzamide dimaleate

【CA登记号】206434-63-1, 206434-53-9 (free base), 206434-54-0 (free base, (S)-isomer), 206434-49-3 (free base, non-specified stereoch.)

【分子式】C₂₅H₃₅ClN₄O₁₀

【分子量】587.0315

【开发单位】Dainippon Pharmaceutical (Originator)

【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists, Dopamine D2 Antagonists

合成路线1 合成路线2

合成路线1

The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III), which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV). The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI), which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX). The reduction of (IX) with NaBH4 gives the racemic amide (X), which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2). The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII), which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV). Finally, this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).

参考文献中间体

【2】 Hirokawa, Y.; et al.; Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist. Chem Pharm Bull 2002, 50, 7, 941.
【1】 Harada, H.; et al.; Synthesis and resolution of (±)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide by preferential crystallization. Tetrahedron Asymmetry 1997, 8, 14, 2367.

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)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(II)	41077	3-methylbenzaldehyde	620-23-5	C₈H₈O	详情	详情
(III)	58175	2-[(3-methylbenzyl)amino]-1-ethanol		C₁₀H₁₅NO	详情	详情
(IV)	58176	2-chloro-N-(3-methylbenzyl)-1-ethanamine; N-(2-chloroethyl)-N-(3-methylbenzyl)amine		C₁₀H₁₄ClN	详情	详情
(V)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(VI)	54009	N~1~-methyl-N~2~-(3-methylbenzyl)-1,2-ethanediamine; N-methyl-N-{2-[(3-methylbenzyl)amino]ethyl}amine	n/a	C₁₁H₁₈N₂	详情	详情
(VII)	58177	ethyl 3-{[(1-formylvinyl)amino]carbonyl}-1H-indazole-1-carboxylate		C₁₄H₁₃N₃O₄	详情	详情
(VIII)	58178	ethyl 3-({[1-formyl-2-(methyl{2-[(3-methylbenzyl)amino]ethyl}amino)ethyl]amino}carbonyl)-1H-indazole-1-carboxylate		C₂₅H₃₁N₅O₄	详情	详情
(IX)	58179	6-({[1-(ethoxycarbonyl)-1H-indazol-3-yl]carbonyl}amino)-4-methyl-1-(3-methylbenzyl)-3,4,5,6-tetrahydro-2H-1,4-diazepin-1-ium		C₂₅H₃₀N₅O₃	详情	详情
(X)	58180	N-[1-methyl-4-(3-methylbenzyl)-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide		C₂₂H₂₇N₅O	详情	详情
(XI)	58181	N-[(6S)-1-methyl-4-(3-methylbenzyl)-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide		C₂₂H₂₇N₅O	详情	详情
(XII)	58182	N-[(6S)-1-methyl-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide		C₁₄H₁₉N₅O	详情	详情
(XIII)	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
(XIV)	58183	N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide		C₁₆H₂₃N₅O	详情	详情
(XV)	17802	(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine		C₈H₁₉N₃	详情	详情

合成路线2

The methylation of 2-hydroxy-4-(4-methylphenylsulfonamido)benzoic acid (XVI) with dimethyl sulfate and KOH in refluxing acetone gives the N,O-dimethylated benzoic acid (XVII), which is chlorinated by means of NCS in hot DMF to yield the chlorobenzoic acid derivative (XVIII). The hydrolysis of (XVIII) with H2SO4 affords 5-chloro-3-methoxy-4-(methylamino)benzoic acid (XIX), which is finally condensed with the aminodiazepine (XV) by means of EDC in dichloromethane to obtain the target chiral benzamide derivative.

参考文献中间体

【1】 Hirokawa, Y.; et al.; Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist. Chem Pharm Bull 2002, 50, 7, 941.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	17802	(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine	C₈H₁₉N₃	详情	详情
(XVI)	58184	2-hydroxy-4-{[(4-methylphenyl)sulfonyl]amino}benzoic acid	C₁₄H₁₃NO₅S	详情	详情
(XVII)	58185	2-methoxy-4-{methyl[(4-methylphenyl)sulfonyl]amino}benzoic acid	C₁₆H₁₇NO₅S	详情	详情
(XVIII)	58186	5-chloro-2-methoxy-4-{methyl[(4-methylphenyl)sulfonyl]amino}benzoic acid	C₁₆H₁₆ClNO₅S	详情	详情
(XIX)	31708	2-Methoxy-4-methylamino-5-chlorobenzoic acid; 5-Chloro-2-methoxy-4-(methylamino)benzoic acid	C₉H₁₀ClNO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)