【结 构 式】 |
【药物名称】 【化学名称】11-Amino-11-deoxy-3-des(hexopyranosyloxy)-6-O-[N-[3-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-2(E)-propenyl]carbamoyl]-3-oxoerythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】 【 分 子 式 】C43H60FN5O11 【 分 子 量 】841.98295 |
【开发单位】Ortho-McNeil (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
The intermediate aldehyde (VII) has been obtained as follows: The cyclization of 2-fluoro-4-hydrazinobenzonitrile (I) with malonaldehyde (II) by means of HCl in refluxing ethanol gives 2-fluoro-4-(1-pyrazolyl)benzonitrile (III), which is reduced by means of diisobutylaluminum hydride in toluene to yield the benzaldehyde (IV). The condensation of (IV) with (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (V) by means of TDA-1 and K2CO3 in refluxing dichloromethane to afford the 3-[2-fluoro-4-(1-pyrazolyl)phenyl]-2-propenal ethylene ketal (VI), which is finally hydrolyzed with HCl in THF to provide the target intermediate aldehyde (VII).
【1】 Henninger, T.C.; Xu, X.C. (Ortho-McNeil Pharmaceutical, Inc.); 6-O-Carbamoyl ketolide derivs. of erythromycin useful as antibacterials. US 6472372; WO 0246204 . |
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) | 58667 | 2-fluoro-4-hydrazinobenzonitrile | C7H6FN3 | 详情 | 详情 | |
(II) | 58668 | 1,1,3,3-Tetramethoxypropane; Malonaldehyde bis(dimethylacetal); Malonaldehyde tetramethylacetal | 102-52-3 | C7H16O4 | 详情 | 详情 |
(III) | 58669 | 2-fluoro-4-(1H-pyrazol-1-yl)benzonitrile | C10H6FN3 | 详情 | 详情 | |
(IV) | 58670 | 2-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde | C10H7FN2O | 详情 | 详情 | |
(V) | 18641 | (1,3-dioxolan-2-ylmethyl)(triphenyl)phosphonium bromide | 52509-14-5 | C22H22BrO2P | 详情 | 详情 |
(VI) | 58671 | 1-{4-[(E)-2-(1,3-dioxolan-2-yl)ethenyl]-3-fluorophenyl}-1H-pyrazole | C14H13FN2O2 | 详情 | 详情 | |
(VII) | 58672 | (E)-3-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenal | C12H9FN2O | 详情 | 详情 |
合成路线2
The reaction of erythromycin A (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the triacetate (IX), which is treated with NaHMDS in THF to yield the unsaturated erythromycin derivative (X). The treatment of (X) with trichloroacetyl isocyanate (XI), followed by reaction with TEA and t-BuOK affords the cyclic carbamate (XII). The acylation of the 2'-OH of (XII) with Ac2O and TEA, followed by cleavage of its cladinose sugar by means of HCl in ethanol/water provides compound (XIII), which is oxidized and deacetylated to give the ketolide derivative (XIV). Finally, this compound is reductocondensed with the intermediate aldehyde (VII) by means of Tes-H and TFA in acetonitrile to yield the target substituted ketolide.
【1】 Henninger, T.; et al.; Synthesis and antibacterial activity of C6-carbamate ketolides. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1661. |
【2】 Henninger, T.C.; Xu, X.C. (Ortho-McNeil Pharmaceutical, Inc.); 6-O-Carbamoyl ketolide derivs. of erythromycin useful as antibacterials. US 6472372; WO 0246204 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 58672 | (E)-3-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenal | C12H9FN2O | 详情 | 详情 | |
(VIII) | 58673 | (3R,4S,5R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C37H67NO13 | 详情 | 详情 | |
(IX) | 58674 | (2S,3S,4R,6R)-6-[((3R,4S,5R,7R,9R,11R,12R,13S,14R)-12-(acetyloxy)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C43H73NO16 | 详情 | 详情 | |
(X) | 58675 | (2S,3S,4R,6R)-6-[((3R,4S,5R,7R,9R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-4-yl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C41H69NO14 | 详情 | 详情 | |
(XI) | 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 |
(XII) | 58676 | (2S,3S,4R,6R)-6-[((3aS,4R,7R,8S,9R,11R,13R,15S,15aR)-11-[(aminocarbonyl)oxy]-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C41H69N3O15 | 详情 | 详情 | |
(XIII) | 58677 | (2S,3R,4S,6R)-2-({(3aS,4R,7R,8S,9S,11R,13R,15S,15aR)-11-[(aminocarbonyl)oxy]-4-ethyl-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl}oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C33H55N3O12 | 详情 | 详情 | |
(XIV) | 58678 | (3aS,4R,7R,9R,11R,13R,15S,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-11-yl carbamate | C31H51N3O11 | 详情 | 详情 |