【结 构 式】 |
【分子编号】17615 【品名】2,3-Dimethoxybenzaldehyde 【CA登记号】86-51-1 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号:(X)Elgodipine can be obtained in three main steps: The alkylation of N-methyl-2-aminoethanol (I) with 4-fluorobenzyl chloride (II) gives 2-[N-(4-fluorobenzyl)-N-methylamino]ethanol (III), which is esterified with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (IV) yielding the corresponding acetoacetic ester (V). The condensation of (V) with 2,3-methylenedioxybenzaldehyde (VI) affords 2-[N-(4-fluorobenzyl)-N-methylamino]ethyl 2-(2,3-methylenedioxybenzylidene]acetoacetate (VII), which is finally cyclized with isopropyl 3-aminocrotonate (VIII). The intermediate aldehyde (VI) is obtained starting from 2,3-dimethoxybenzaldehyde (X), which by demethylation with HCl or HBr yields 2,3-dihydroxybenzaldehyde (XI). Finally, this compound is converted into (VI) in the usual way. The intermediate crotonate (VIII) is obtained by reaction of isopropyl acetoacetate (IX) with ammonia.
【1】 Galiano, A.; Elgodipine Hydrochloride. Drugs Fut 1995, 20, 3, 231. |
【2】 Fernandez Torija, C.; Galiano Ramos, J.A. (IIDQB (Madrid)); 1,4-Dihydropyridines, process for their preparation and their use as medicaments. AU 8820330; BE 1001055; CH 675999; EP 0302980; GB 2208861; JP 1989294675; US 4952592 . |
【3】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633. |
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) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
(II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
(III) | 13333 | 2-[(4-Fluorobenzyl)(methyl)amino]-1-ethanol | C10H14FNO | 详情 | 详情 | |
(IV) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one;2,2,6-trimethyl-1,3-dioxin-4-one;2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
(V) | 13328 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl 3-oxobutanoate | C14H18FNO3 | 详情 | 详情 | |
(VI) | 13329 | 2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde | 7797-83-3 | C8H6O3 | 详情 | 详情 |
(VII) | 13330 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl (Z)-2-acetyl-3-(1,3-benzodioxol-4-yl)-2-propenoate | C22H22FNO5 | 详情 | 详情 | |
(VIII) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
(IX) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
(X) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
(XI) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)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.
【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3
该中间体在本合成路线中的序号:(I)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.
【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 |
合成路线4
该中间体在本合成路线中的序号:(VI)The condensation of 2,3-dimethoxybenzaldehyde (VI) with pyruvic acid (VII) by means of KOH in ethanol/water gives 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII), which is reductocondensed with methylamine (IV) by means of H2 over Pd/C in ethanol/ acetic acid to yield 4-(2,3-dimethoxyphenyl)-2-methylamino)butyric acid (IX). Reaction of acid (IX) with benzyl chloroformate (X) and NaOH in water affords the carbamate (XI), which is treated with refluxing SOCl2 to provide 4-[2-(2,3-dimethoxyphenyl)ethyl]-3-methyloxazolidine-2,5-dione (XII). Reaction of oxazolidinone (XII) with AlCl3 in dichloromethane provides 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII), which is reduced with H2 over Pd/C in ethanol containing some methanolic HCl in an autoclave at 80 C to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V). Finally, this compound is demethylated by treatment with AlCl3 in hot toluene. Alternatively, 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII) can first be demethylated with 48% HBr to give 5,6-dihydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIV), which is then reduced by means of H2 over Pd/C in an autoclave at 80 C.
【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046. |
【2】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 . |
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) | 49435 | 6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol | C11H15NO2 | 详情 | 详情 | |
(IV) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
(V) | 37381 | N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C13H19NO2 | 详情 | 详情 | |
(VI) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
(VII) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
(VIII) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 详情 | 详情 | |
(IX) | 37377 | 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid | C13H19NO4 | 详情 | 详情 | |
(X) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
(XI) | 37378 | 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid | C21H25NO6 | 详情 | 详情 | |
(XII) | 37379 | 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione | C14H17NO5 | 详情 | 详情 | |
(XIII) | 37380 | 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C13H17NO3 | 详情 | 详情 | |
(XIV) | 37387 | 5,6-dihydroxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C11H13NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(I)Condensation of 2,3-dimethoxybenzaldehyde (I) with pyruvic acid (II) in the presence of KOH produced oxobutenoic acid (III), which was hydrogenated in the presence of methylamine to give amino acid (IV). Reaction of (IV) with benzyl chloroformate afforded carbamate (V), which was subsequently cyclized to the N-carboxyanhydride (VI) upon treatment with SOCl2. Friedel-Crafts intramolecular acylation using AlCl3 yielded amino tetralone (VII). Reduction of the keto group of (VII) to give amino tetralin (VIII) was effected by catalytic hydrogenation over Pd/C. Finally, dealkylation of the methyl ether groups of (VIII) with AlCl3 in hot toluene afforded the title dihydroxy compound.
【1】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
(I) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
(II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
(III) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 详情 | 详情 | |
(IV) | 37377 | 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid | C13H19NO4 | 详情 | 详情 | |
(V) | 37378 | 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid | C21H25NO6 | 详情 | 详情 | |
(VI) | 37379 | 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione | C14H17NO5 | 详情 | 详情 | |
(VII) | 37380 | 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C13H17NO3 | 详情 | 详情 | |
(VIII) | 37381 | N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C13H19NO2 | 详情 | 详情 |