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【结 构 式】 
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【药物名称】Remimazolam 【化学名称】3-[8-Bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4(S)-yl]propionic acid methyl ester 【CA登记号】308242-62-8 【 分 子 式 】C21H19BrN4O2 【 分 子 量 】439.305 |
【开发单位】GlaxoSmithKline (UK); licensed to PAION AG (DE), Ono Pharmaceutical Co., Ltd. (JP) and Yichang Humanwell Pharmaceutical (CN) 【药理作用】GABAA Benzodiazepine Site Receptor Agonist;Anesthetic/Sedative |
合成路线1
Condensation of 5-bromoanthranilic acid (I) with the lithium derivative of 2-bromopyridine (II) in cold THF/ethyl ether gives the diaryl ketone (III). N-Fmoc-L-glutamic acid 5-methyl ester (IV) is chlorinated with oxalyl chloride and catalytic DMF to produce the acid chloride (V), which is then coupled with the amino ketone (III) in boiling chloroform to afford amide (VI). Base-mediated deprotection of amine (VI), followed by cyclization by treatment with AcOH in dichloroethane leads to the benzodiazepinone (VII). Subsequent treatment of lactam (VII) with bis-morpholinophosphorochloridate and NaH affords the imino phosphate (VIII), which is then condensed with 1-amino-2-propanol (IX) producing amidine (X). Finally, remimazolam is obtained by Swern oxidation of the secondary alcohol of (X), followed by cyclization under acidic conditions .
| 【1】 Jung, D.K., Pacofsky, G.J., Stafford, J.A., Feldman, P.L., Kaldor, I., Tidwell, J.H. (GlaxoSmithKline plc). Short-acting benzodiazepines. EP 1183243, JP 2002544266, JP 2006151984, JP 2007197468, JP 2007197469, US 7160880, US 2007093475,US 2007135419, US 2007135420, US 2007135421, US 7435730, US 7528127, US 7473689, US 7485635, WO 2000069836 |
| 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) | 31634 | 2-amino-5-bromobenzoic acid | 5794-88-7 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (III) | 68085 | (2-amino-5-bromophenyl)(pyridin-2-yl)methanone | 1563-56-0 | C12H9BrN2O | 详情 | 详情 |
| (IV) | 68086 | (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acidN-Fmoc-L-glutamic acid 5-methyl ester | C21H21NO6 | 详情 | 详情 | |
| (V) | 68087 | (R)-methyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-chloro-5-oxopentanoate | C21H20ClNO5 | 详情 | 详情 | |
| (VI) | 68088 | (S)-methyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((4-bromo-2-picolinoylphenyl)amino)-5-oxopentanoate | C33H28BrN3O6 | 详情 | 详情 | |
| (VII) | 68089 | (S)-methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate | C18H16BrN3O3 | 详情 | 详情 | |
| (VIII) | 68090 | (S)-methyl 3-(7-bromo-2-((dimorpholinophosphoryl)oxy)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate | C26H31BrN5O6P | 详情 | 详情 | |
| (IX) | 41397 | 1-amino-2-propanol | 78-96-6 | C3H9NO | 详情 | 详情 |
| (X) | 68091 | methyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate | C21H23BrN4O3 | 详情 | 详情 |