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【结 构 式】 
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【药物名称】Cethromycin, ABT-773, Abbott-195773 【化学名称】(3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-Ethyl- 3a,7,9,11,13,15-hexamethyl-11-[3-(3-quinolinyl)-2(E)-propenyloxy]- 10-[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylohexopyranosyloxy] octahydro-2H-oxacyclotetradecino- [4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetraone 【CA登记号】205110-48-1 【 分 子 式 】C42H59N3O10 【 分 子 量 】765.95263 |
【开发单位】Abbott; Taisho 【药理作用】ANTIBIOTICS，Macrolide/ketolide antibiotic |
合成路线1
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 |
合成路线2
Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX), which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb). The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS, then with DBU and finally with CDI and NaH, provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb), which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb). Finally, these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate, tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 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】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xb) | 28430 | (2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C39H61NO11 | 详情 | 详情 | |
| (XIb) | 28431 | (2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C39H59NO11 | 详情 | 详情 | |
| (Xa) | 35296 | (2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C34H59NO11 | 详情 | 详情 | |
| (XIa) | 35297 | (2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C34H57NO11 | 详情 | 详情 | |
| (XIIa) | 35298 | (2R,3S,7R,9S,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-9-(allyloxy)-2-ethyl-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C38H57N3O11 | 详情 | 详情 | |
| (XIIb) | 35299 | (2R,3S,7R,9S,10R,11R,13R)-9-(allyloxy)-10-[[(2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C43H59N3O11 | 详情 | 详情 | |
| (XIIIb) | 35300 | (2S,3R,4S,6R)-2-[[(3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-11-(allyloxy)-4-ethyl-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 benzoate | C40H58N2O11 | 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 | |
| (VII) | 35295 | C35H56N2O11 | 详情 | 详情 | ||
| (VIII) | 28432 | 3-bromoquinoline | 5332-24-1 | C9H6BrN | 详情 | 详情 |
| (IX) | 28249 | 2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide | C26H26N2O2 | 详情 | 详情 |
合成路线3
A new synthesis of ABT-773 has been reported: The acylation of erythromycin A 9-oxime (I) with acetic anhydride, TEA and DMAP in THF gives the 2',4'',9-tri-O-acetylerythromycin A 9-oxime (II), which is first condensed with 3-(3-quinolinyl)-2-propen-1-ol tert-butyl carbonate (III) by means of Pd2(dba)3 and dppb in toluene and then treated with NaOH to yield 2',4''-di-O-acetyl-6-O-[3-(3-quinolinyl)-2-propenyl]erythromycin A 9-oxime (IV). Reaction of oxime (IV) with NaHSO3 and HOAc in water/THF affords 4''-O-acetyl-6-O-[3-(3-quinolinyl)-2-propenyl]erythromycin A (V), which is benzoylated with benzoic anhydride and TEA in isopropyl acetate/THF to provide 4''-O-acetyl-2'-O-benzoyl-6-O-[3-(3-quinolinyl)-2-propenyl]ery- thromycin A (VI). The reaction of compound (VI) with carbonyldiimidazole (CDI), sodium hexamethyldisilazide (NaHMDS) and ammonia gas in THF/DMF gives the 11-N,12-O-cyclic carbamate erythromycin A derivative (VII). The intermediate 3-(3-quinolinyl)-2-propen-1-ol tert-butyl carbonate (III) has been obtained by Grignard condensation of quinoline-3-carbaldehyde (X) with vinylmagnesium bromide (XI) in THF to give the secondary alcohol (XII), followed by esterification and simultaneous rearrangement with Boc2O in the same solvent.
| 【1】 Process for preparing 6-O-substd. erythromycin derivs.. WO 0078773 . |
| 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) | 46726 | (3R,4R,5R,6R,7S,9R,11S,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 10-oxime | C37H68N2O13 | 详情 | 详情 | |
| (II) | 46727 | (2S,3S,4R,6R)-6-([(3R,4R,5R,6R,7S,9R,11S,12R,13S,14R)-6-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-10-[(acetoxy)imino]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradecanyl]oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C43H74N2O16 | 详情 | 详情 | |
| (III) | 46728 | tert-butyl (E)-3-(3-quinolinyl)-2-propenyl carbonate | C17H19NO3 | 详情 | 详情 | |
| (IV) | 46729 | (2S,3S,4R,6R)-6-[((3R,4R,5R,6R,7S,9R,11S,12R,13S,14R)-6-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-10-(hydroxyimino)-3,5,7,9,11,13-hexamethyl-2-oxo-7-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C53H81N3O15 | 详情 | 详情 | |
| (V) | 46730 | (2S,3S,4R)-6-[((3R,4R,5R,6R,7S,9R,11R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-7-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C51H78N2O14 | 详情 | 详情 | |
| (VI) | 46731 | (2S,3R,4S,6R)-2-[((3R,4R,5R,6R,7S,9R,11R,12R,13S,14R)-4-[[(2R,4R,5S,6S)-5-(acetoxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-7-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C58H82N2O15 | 详情 | 详情 | |
| (VII) | 46732 | (2S,3R,4S,6R)-2-[((3aS,4R,7R,8R,9R,10R,11S,13R,15R,15aR)-8-[[(2R,4R,5S,6S)-5-(acetoxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C59H81N3O15 | 详情 | 详情 | |
| (VIII) | 35362 | 3-quinolinecarbaldehyde | 13669-42-6 | C10H7NO | 详情 | 详情 |
| (IX) | 46733 | chloro(vinyl)magnesium | 3536-96-7 | C2H3ClMg | 详情 | 详情 |
| (X) | 46734 | 1-(3-quinolinyl)-2-propen-1-ol | C12H11NO | 详情 | 详情 |
合成路线4
The treatment of cyclic carbamate (VII) with HCl in ethanol produces the cleavage of the cladinosyl sugar moiety, resulting in the 3-hydroxyerythromycin derivative (VIII), which is oxidized with N-chlorosuccinimide (NCS) in dichloromethane to yield the 3-oxoerythromycin A derivative (IX). Finally, this compound is debenzoylated in refluxing methanol.
| 【1】 Process for preparing 6-O-substd. erythromycin derivs.. WO 0078773 . |
| 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) | 46732 | (2S,3R,4S,6R)-2-[((3aS,4R,7R,8R,9R,10R,11S,13R,15R,15aR)-8-[[(2R,4R,5S,6S)-5-(acetoxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C59H81N3O15 | 详情 | 详情 | |
| (VIII) | 46735 | (2S,3R,4S,6R)-2-[((3aS,4R,7R,8S,9S,10R,11S,13R,15R,15aR)-4-ethyl-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C49H65N3O11 | 详情 | 详情 | |
| (IX) | 46736 | (2S,3R,4S,6R)-2-[((3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-11-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C49H63N3O11 | 详情 | 详情 |