Zelandopam hydrochloride, MYD-37, YM-435, -Drug Synthesis Database

【结构式】

【药物名称】Zelandopam hydrochloride, MYD-37, YM-435

【化学名称】(-)-(S)-4-(3,4-Dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate
　　　　　　(-)-(S)-4-(3,4-Dihydroxyphenyl)-1,2,3,4-tetrahydro-7,8-isoquinolinediol hydrochloride hydrate

【CA登记号】138086-00-7 (anhydrous), 139233-53-7 (anhydrous free base), 119085-25-5 (anhydrous free base; non-specified stereoch.), 119086-1

【分子式】C₁₅H₁₈ClNO₅

【分子量】327.76741

【开发单位】Yamanouchi (Originator), Mochida (Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Dopamine D1 Agonists

合成路线1 合成路线2

合成路线1

Amino alcohol (III) was prepared from veratraldehyde (I) by addition of cyanotrimethylsilane, followed by borane reduction of the resultant cyanohydrin (II). Reductive condensation of amine (III) with 2,3-dimethoxybenzaldehyde (IV) gave the secondary amine (V). This was cyclized to the tetrahydroisoquinoline (VI) under acidic conditions. Resolution of the racemic (VI) by means of dibenzoyltartaric acid furnished the desired (S)-amine, which was further acylated with Ac2O to yield the chiral amide (VII). Demethylation of (VII) with boron tribromide afforded the tetrahydroxy compound (VIII). Finally, acetamide hydrolysis under acidic conditions yielded the title compound.

参考文献中间体

【1】 Anan, H.; Tanaka, A.; Tsuzuki, R.; Yokota, M.; Yatsu, T.; Honda, K.; Asano, M.; Fujita, S.; Furuya, T.; Fujikura, T.; Synthesis, resolution, and renal vasodilation activity of novel DA1 agonists: 4-(3,4-Dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives. Chem Pharm Bull 1991, 39, 11, 2910.

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)	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(II)	63099	2-(3,4-dimethoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile		C₁₃H₁₉NO₃Si	详情	详情
(III)	63100	2-amino-1-(3,4-dimethoxyphenyl)-1-ethanol		C₁₀H₁₅NO₃	详情	详情
(IV)	17615	2,3-Dimethoxybenzaldehyde	86-51-1	C₉H₁₀O₃	详情	详情
(V)	63101	2-[(2,3-dimethoxybenzyl)amino]-1-(3,4-dimethoxyphenyl)-1-ethanol		C₁₉H₂₅NO₅	详情	详情
(VI)	63102	4-(3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 4-(3,4-dimethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether		C₁₉H₂₃NO₄	详情	详情
(VII)	63103	1-[(4R)-4-(3,4-dimethoxyphenyl)-7,8-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]-1-ethanone		C₂₁H₂₅NO₅	详情	详情
(VIII)	63104	1-[(4R)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-3,4-dihydro-2(1H)-isoquinolinyl]-1-ethanone		C₁₇H₁₇NO₅	详情	详情

合成路线2

The reductocondensation of 2,3-dimethoxybenzaldehyde (I) with 2-(3,4-dimethoxyphenyl)-2-hydroxyethylamine (II) by means of NaBH4 in methanol gives N-(2,3-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)-2-hydroxyethylamine (III), which is cyclized by means of H2SO4 in TFA, followed by an azeotropic distillation with toluene to yield the tetrahydroisoquinoline (IV). Finally, this compound is demethylated by means of refluxing 48 % HBr to provide the target racemic tetrahydroisoquinoline.

参考文献中间体

【1】 Tanaka, A.; Fujikura, T.; Tsuzuki, R.; Yokota, M.; Yatsu, T. (Yamanouchi Pharmaceutical Co., Ltd.); Substd. tetrahydroisoquinoline cpds., their production,and pharmaceutical compsns. containing them. EP 0286293; EP 0399626; JP 1989199948; US 4876261; US 5079256 .

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)	17615	2,3-Dimethoxybenzaldehyde	86-51-1	C₉H₁₀O₃	详情	详情
(II)	63100	2-amino-1-(3,4-dimethoxyphenyl)-1-ethanol		C₁₀H₁₅NO₃	详情	详情
(III)	63101	2-[(2,3-dimethoxybenzyl)amino]-1-(3,4-dimethoxyphenyl)-1-ethanol		C₁₉H₂₅NO₅	详情	详情
(IV)	63102	4-(3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 4-(3,4-dimethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether		C₁₉H₂₃NO₄	详情	详情

Extended Information