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【结 构 式】 
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【分子编号】46732 【品名】(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 【CA登记号】 |
【 分 子 式 】C59H81N3O15 【 分 子 量 】1072.30336 【元素组成】C 66.09% H 7.61% N 3.92% O 22.38% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(VII)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 |