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【结 构 式】 
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【药物名称】CHF-1024 【化学名称】(±)-6-(Methylamino)-5,6,7,8-tetrahydronaphthalene-1,2-diol hydrochloride 【CA登记号】90060-20-1, 39478-89-2 (free base) 【 分 子 式 】C11H16ClNO2 【 分 子 量 】229.70867 |
【开发单位】Chiesi (Originator), Ist. di Ricerche Farmacol. Mario Negri (Codevelopment) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, alpha2-Adrenoceptor Agonists, Dopamine D2 Agonists |
合成路线1
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2
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 |
合成路线3
Aminotetralin (VIII) was obtained by reductive amination of the 2-tetralone (XIV) in the presence of NaBH3CN.
| 【1】 Chiesi, P.; Villani, V. (Chiesi Farmaceutici SpA); 1,2,3,4-Tetrahydronaphthaline derivs., process for their preparation and pharmaceutical compsns. containing them. DE 3320936; GB 2123410 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 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 | |
| (XIV) | 37386 | 5,6-dimethoxy-3,4-dihydro-2(1H)-naphthalenone | C12H14O3 | 详情 | 详情 |
合成路线4
Intramolecular acylation of amino acid (IV), with simultaneous deprotection of the hydroxyl groups using concentrated HBr furnished amino tetralone (IX). The keto group of (IX) was then reduced by hydrogenation in the presence of Pd/C.
| 【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 . |