【结 构 式】 |
【分子编号】37376 【品名】(E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid 【CA登记号】 |
【 分 子 式 】C12H12O5 【 分 子 量 】236.22428 【元素组成】C 61.01% H 5.12% O 33.86% |
合成路线1
该中间体在本合成路线中的序号:(VIII)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2
该中间体在本合成路线中的序号:(VIII)Condensation of 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII) with methyl carbamate (XV) by means of TsOH in refluxing toluene gives the substituted furanone (XVI), which is hydrogenated with H2 over Pd/C in hot ethanol to yield 4-(2,3-dimethoxyphenyl)-2-(methoxycarbonylamino)butyric acid (XVII). Cyclization of acid (XVII) by means of PPA at 60 C affords tetralone (XVIII), which is reduced with H2 over Pd/C in an autoclave at 80 C to provide N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic acid methyl ester (XIX). Finally, the carbamoyl group of (XIX) is reduced with LiAlH4 in hot THF to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V).
【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 |
---|---|---|---|---|---|---|
(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 | |
(VIII) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 详情 | 详情 | |
(XV) | 40724 | methyl carbamate; carbamic acid methyl ester | 598-55-0 | C2H5NO2 | 详情 | 详情 |
(XVI) | 49436 | methyl 5-(2,3-dimethoxyphenyl)-2-oxo-2,5-dihydro-3-furanylcarbamate | C14H15NO6 | 详情 | 详情 | |
(XVII) | 49437 | 4-(2,3-dimethoxyphenyl)-2-[(methoxycarbonyl)amino]butyric acid | C14H19NO6 | 详情 | 详情 | |
(XVIII) | 49438 | methyl 5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C14H17NO5 | 详情 | 详情 | |
(XIX) | 49439 | methyl 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C14H19NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(III)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 |
合成路线4
该中间体在本合成路线中的序号:(III)Condensation of oxobutenoic acid (III) with methyl carbamate produced dihydrofuranone (X). Catalytic hydrogenation of this compound gave (ethoxycarbonylamino)butyric acid derivative (XI). Intramolecular cyclization of (XI) to the tetralone (XII) was carried out in hot polyphosphoric acid. After hydrogenolysis of the keto group of (XII), the resulting carbamate (XIII) was reduced with LiAlH4 to the methylamino derivative (VIII), which was finally demethylated.
【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 |
---|---|---|---|---|---|---|
40724 | methyl carbamate; carbamic acid methyl ester | 598-55-0 | C2H5NO2 | 详情 | 详情 | |
(III) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 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 | |
(X) | 37382 | ethyl 5-(2,3-dimethoxyphenyl)-2-oxo-2,5-dihydro-3-furanylcarbamate | C15H17NO6 | 详情 | 详情 | |
(XI) | 37383 | 4-(2,3-dimethoxyphenyl)-2-[(ethoxycarbonyl)amino]butyric acid | C15H21NO6 | 详情 | 详情 | |
(XII) | 37384 | ethyl 5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C15H19NO5 | 详情 | 详情 | |
(XIII) | 37385 | ethyl 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C15H21NO4 | 详情 | 详情 |