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【结 构 式】 
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【药物名称】HMR-3562 【化学名称】11-Deoxy-3-des(hexopyranosyloxy)-2-fluoro-11-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamino]-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】193752-41-9 【 分 子 式 】C43H64FN5O10 【 分 子 量 】830.01543 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
Direct fluorination of telithromycin (I) at position 2 by means of N-fluorosulfonimide and NaH afforded the title compound in low yield, along with a geater amount of the N-demethylated analogue. In a modified procedure, protection of the 2' hydroxyl group of (I) as the trimethylsilyl ether (II), followed by fluorination with N-fluorosulfonimide in the presence of potassium tert-butoxide provided fluoroketolide (III). Subsequent desilylation of (III) by means of tetrabutylammonium fluoride then furnished the title compound in high yield.
| 【1】 Bonnefoy, A.; Denis, A.; Novel fluoroketolides: Synthesis and antibacterial activity. Drugs Fut 2001, 26, 10, 975. |
| 【2】 Fromentin, C.; Denis, A.; Piltan, G.; Bretin, F.; Bonnet, A.; Agouridas, C.; Bonnefoy, A.; beta-Keto-ester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides. Bioorg Med Chem Lett 2000, 10, 17, 2019. |
| 【3】 Spinnewyn, B.; Auguet, M.; Denis, A.; et al.; Synthesis and antibacterial activity of 2-halogeno, 2-methyl, and 2,3 enol-ether ketolides using beta-keto-ester chemistry. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2152. |
| 【4】 Agouridas, C.; Bretin, F.; Chantot, J.-F. (Aventis Pharma SA); Erythromycin derivs., their production and their use as medicaments. EP 0799833; JP 1997176182; US 5747467 . |
| 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) | 33652 | (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-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C43H65N5O10 | 详情 | 详情 | |
| (II) | 33653 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C46H73N5O10Si | 详情 | 详情 | |
| (III) | 33654 | (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-10-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-4-ethyl-7-fluoro-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C46H72FN5O10Si | 详情 | 详情 |
合成路线2
In an alternative synthesis, compound (IV) was protected as the silyl ether (V) and then fluorinated by means of N-fluorosulfonimide and potassium tert-butoxide. The resulting fluorinated derivative (VI) was desilylated by means of tetrabutylammonium fluoride to yield (VII), which was further protected as the 2'-acetate ester (VIII). Treatment of (VIII) with 1,1'-carbonyl diimidazole produced the acyl imidazole (IX). Subsequent condensation of (IX) with amine (X) gave rise to the corresponding 11,12-cyclic carbamate, which was finally deacetylated upon treatment with MeOH.
| 【1】 Bonnefoy, A.; Denis, A.; Novel fluoroketolides: Synthesis and antibacterial activity. Drugs Fut 2001, 26, 10, 975. |
| 【2】 Fromentin, C.; Denis, A.; Piltan, G.; Bretin, F.; Bonnet, A.; Agouridas, C.; Bonnefoy, A.; beta-Keto-ester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides. Bioorg Med Chem Lett 2000, 10, 17, 2019. |
| 【3】 Spinnewyn, B.; Auguet, M.; Denis, A.; et al.; Synthesis and antibacterial activity of 2-halogeno, 2-methyl, and 2,3 enol-ether ketolides using beta-keto-ester chemistry. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2152. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 33655 | (3R,5R,6R,7R,9R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C30H51NO9 | 详情 | 详情 | |
| (V) | 33656 | (3R,5R,6R,7R,9R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C33H59NO9Si | 详情 | 详情 | |
| (VI) | 33657 | (3S,5R,6R,7R,9R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-3-fluoro-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C33H58FNO9Si | 详情 | 详情 | |
| (VII) | 33658 | (3S,5R,6R,7R,9R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-3-fluoro-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C30H50FNO9 | 详情 | 详情 | |
| (VIII) | 33659 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3S,5R,6R,7R,9R,13S,14R)-14-ethyl-3-fluoro-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H52FNO10 | 详情 | 详情 | |
| (IX) | 33660 | (2R,3S,7R,9R,10R,11R,13S)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-13-fluoro-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C36H54FN3O11 | 详情 | 详情 | |
| (X) | 17162 | 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamine; 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanamine | 173838-63-6 | C12H16N4 | 详情 | 详情 |