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【结 构 式】

【分子编号】35292

【品名】 

【CA登记号】

【 分 子 式 】C44H75NO15

【 分 子 量 】858.07724

【元素组成】C 61.59% H 8.81% N 1.63% O 27.97%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF, followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H, gives 6-O-allylerythromycin A (III), which is acylated with acetic anhydride in acetonitrile, yielding the diacetate (IV). Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V), which is cyclized with NH4OH in acetonitrile / THF, giving the cyclic carbamate (VI). Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII), which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions, palladium acetate, tris(o-tolyl)phosphine and Et3N in acetonitrile, and finally deprotected with MeOH 60-80%.

1 Ma, Z.; et al.; Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens. J Med Chem 2001, 44, 24, 4137.
2 Or, Y.; Clark, R.F.; Ma, Z.; Design, synthesis, and characterization of ABT-773: A novel ketolide highly active against multidrug-resistant pathogens. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2133.
3 Ewing, P.; Or, Y.S.; Nilius, A.M.; Wang, S.; Clark, R.F.; Alder, J.; Chu, D.T.W.; Mitten, M.; Flamm, R.K.; Ma, Z.; Design, synthesis, and antimicrobial activity of 6-O-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 2000, 43, 6, 1045-49.
4 Rabasseda, X.; Sorbera, L.A.; Castañer, J.; ABT-773. Drugs Fut 2000, 25, 5, 445.
5 Adachi, T.; Sekiguchi, K.; Sota, K.; Asaka, T.; Matsunaga, T.; Morimoto, S.; Watanabe, Y.; Kashimura, M. (Taisho Pharmaceutical Co., Ltd.); Erythromycin A derivs.. EP 0272110; US 4990602 .
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) 35291   C52H100N2O14Si2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 28391 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-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 C40H71NO13 详情 详情
(IV) 35292   C44H75NO15 详情 详情
(V) 35293   C48H75N3O15 详情 详情
(VI) 35294   C45H74N2O15 详情 详情
(VII) 35295   C35H56N2O11 详情 详情
(VIII) 28432 3-bromoquinoline 5332-24-1 C9H6BrN 详情 详情
Extended Information