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【结 构 式】 
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【药物名称】 【化学名称】(-)-2,6-Dimethyl-5-nitro-4(S)-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylic acid 2-(nitrooxy)ethyl ester 【CA登记号】250330-33-7, 250330-34-8 (enantiomer), 339528-66-4 (undefined stereochem.) 【 分 子 式 】C17H16F3N3O7 【 分 子 量 】431.32817 |
【开发单位】Dalhousie University (Originator), University of Alberta (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Calcium Channel Activators, Calcium Channel Blockers |
合成路线1
D-Threonine (I) was esterified by means of thionyl chloride in methanol, and the resultant amino ester (II) was subsequently acylated with 3,5-dinitrobenzoyl chloride (III) to afford amide (IV). Conversion of (IV) to the acetoacetate ester (VI) was effected by reaction with the diketene precursor 2,2,6-trimethyl-4H-1,3-dioxin-4-one (V) in boiling xylene. Treatment of keto ester (V) with ammonia in the presence of p-toluenesulfonic acid produced the aminocrotonate ester (VI). Dihydropyridine (IXa-b) was then obtained as a diastereomeric mixture by a modified Hantzsh condensation between enamine (VI), 2-trifluoromethylbenzaldehyde (VII) and nitroacetone. After chromatographic separation of the isomers, the chiral auxiliary group was removed by methanolysis in the presence of DBU. The desired (+)-(S)-dihydropyridinecarboxylic acid (X) was finally converted to the nitrooxyethyl ester by reaction with 2-bromoethyl nitrate (XI).
| 【1】 Shan, R.; Knaus, E.E.; Howlett, S.E.; Syntheses, calcium channel agonist-antagonist modulation activities, nitric oxide release, and voltage-clamp studies of 2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate enantiomers. J Med Chem 2002, 45, 4, 955. |
| 【2】 Knaus, E.E.; Shan, R.; The design of (-)-(S)-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate: A cardioselective positive inotropic derivative of Bay K 8644. Bioorg Med Chem Lett 1999, 9, 17, 2613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 30332 | 2-(trifluoromethyl)benzaldehyde | 447-61-0 | C8H5F3O | 详情 | 详情 |
| (IXa) | 59607 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate | C27H24F3N5O11 | 详情 | 详情 | |
| (IXb) | 59608 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4R)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate | C27H24F3N5O11 | 详情 | 详情 | |
| (I) | 28908 | L-Threonine; (2R,3S)-2-amino-3-hydroxybutyric acid | 632-20-2 | C4H9NO3 | 详情 | 详情 |
| (II) | 42026 | methyl (2S,3R)-2-amino-3-hydroxybutanoate | C5H11NO3 | 详情 | 详情 | |
| (III) | 12053 | 3,5-Dinitrobenzoyl chloride | 99-33-2 | C7H3ClN2O5 | 详情 | 详情 |
| (IV) | 59604 | methyl (2R,3S)-2-[(3,5-dinitrobenzoyl)amino]-3-hydroxybutanoate | C12H13N3O8 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 59605 | methyl (2R,3S)-3-(acetoacetyloxy)-2-[(3,5-dinitrobenzoyl)amino]butanoate | C16H17N3O10 | 详情 | 详情 | |
| (VII) | 59606 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (E)-3-amino-2-butenoate | C16H18N4O9 | 详情 | 详情 | |
| (X) | 59609 | (4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylic acid | C15H13F3N2O4 | 详情 | 详情 | |
| (XI) | 59610 | 1-bromo-2-(nitrooxy)ethane | C2H4BrNO3 | 详情 | 详情 |