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【结 构 式】 
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【药物名称】CP-654743 【化学名称】3-Des(hexopyranosyloxy)-9-deoxo-11-deoxy-2-fluoro-9-(methoxyimino)-6-O-methyl-3-oxo-11-[3-[4-(3-pyridyl)imidazol-1-yl]propylhydrazino]erythromycin A 11-N1,12-O-cyclic carbamate 【CA登记号】286462-85-9 【 分 子 式 】C43H66FN7O10 【 分 子 量 】860.04477 |
【开发单位】Pfizer (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
Treatment of macrolide (I) with O-methylhydroxylamine hydrochloride produced the 9-oxime (II) with concomitant deacetylation. Reductive condensation of (II) with pyridylimidazolylpropionaldehyde (III) in the presence of NaBH3CN gave adduct (IV), which was reprotected as the acetate ester (V). Fluorination of (V) at position 2 to afford fluorolactone (VI) was achieved by treatment of the corresponding potassium enolate with 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(TM)). The title compound was finally obtained by deacetylation of (VI) in hot MeOH.
| 【1】 Bonnefoy, A.; Denis, A.; Novel fluoroketolides: Synthesis and antibacterial activity. Drugs Fut 2001, 26, 10, 975. |
| 【2】 Kaneko, T.; et al.; Synthesis and in vitro activity of C2-substituted C9-oxime ketolides. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1815. |
| 【3】 Kaneko, T.; McMillen, W.T. (Pfizer Inc.); Ketolide antibiotics. WO 0044761 . |
| 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) | 45786 | (2S,3R,4S,6R)-2-[[(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C33H55N3O11 | 详情 | 详情 | |
| (II) | 45787 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | C32H56N4O10 | 详情 | 详情 | |
| (III) | 45789 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-([3-[4-(3-pyridinyl)-1H-imidazol-1-yl]propyl]amino)octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | C43H67N7O10 | 详情 | 详情 | |
| (IV) | 45790 | (2S,3R,4S,6R)-2-[[(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6,8-trioxo-1-([3-[4-(3-pyridinyl)-1H-imidazol-1-yl]propyl]amino)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C45H69N7O11 | 详情 | 详情 | |
| (V) | 45791 | (2S,3R,4S,6R)-2-[[(3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-4-ethyl-7-fluoro-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6,8-trioxo-1-([3-[4-(3-pyridinyl)-1H-imidazol-1-yl]propyl]amino)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C45H68FN7O11 | 详情 | 详情 |