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【结 构 式】 
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【分子编号】53089 【品名】(2S,3S,4R,6R)-6-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate 【CA登记号】n/a |
【 分 子 式 】C42H73NO15 【 分 子 量 】832.03936 【元素组成】C 60.63% H 8.84% N 1.68% O 28.84% |
合成路线1
该中间体在本合成路线中的序号：(XII)A related synthetic procedure started from 2',4''-bis-O-acetyl-6-O-methylerythromycin A (XII). Treatment of diol (XII) with carbonyldiimidazole in the presence of DBU generated the anhydro imidazolide (XIII). Reaction of (XIII) with hydrazine gave rise to the N-amino cyclic carbamate (XIV). Selective cleavage of the cladinose moiety at position 3 under acidic conditions afforded (XV). The keto group of (XV) was then converted to the oxime (XVI) upon treatment with O-methyl hydroxylamine. Reductive alkylation of (XVI) with aldehyde (IX) in the presence of NaBH(OAc)3 provided adduct (XVII). Then, Swern oxidation of the 3-hydroxy group of (XVII) to the corresponding ketone, followed by hydrolysis of the acetate ester, furnished the title ketolide as a diastereomeric mixture.
| 【1】 Kaneko, T.; McMillen, W.T.; McLaughlin, R.W.; Ripin, D.H.B.; Vanerplas, B.C. (Pfizer Inc.); Synthesis of carbamate ketolide antibiotics. EP 1088828; JP 2001151792 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 53087 | 3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal | n/a | C12H13N3O | 详情 | 详情 |
| (XII) | 53089 | (2S,3S,4R,6R)-6-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | n/a | C42H73NO15 | 详情 | 详情 |
| (XIII) | 53090 | (2R,3S,7R,9R,10R,11R,12S,13R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2R,4R,5S,6S)-5-(acetyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | n/a | C46H73N3O15 | 详情 | 详情 |
| (XIV) | 53091 | (2S,3S,4R,6R)-6-[((3aS,4R,7R,8S,9R,10R,11R,13R,15R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-amino-4-ethyl-11-methoxy-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 | n/a | C43H73N3O15 | 详情 | 详情 |
| (XV) | 53092 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-1-amino-4-ethyl-8-hydroxy-11-methoxy-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 | n/a | C33H57N3O11 | 详情 | 详情 |
| (XVI) | 53093 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-1-amino-4-ethyl-8-hydroxy-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6-dioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | n/a | C34H60N4O11 | 详情 | 详情 |
| (XVII) | 53094 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-4-ethyl-8-hydroxy-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6-dioxo-1-({3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl}amino)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | n/a | C46H73N7O11 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Alkylation of clarithromycin diacetate (I) with allyl t-butyl carbonate (II) in the presence of palladium catalyst affords the 11-O-allyl ether (III). Subsequent metathesis reaction between ally ether (III) and 1-butenyl-4-phenylimidazole (IV) employing Grubb's catalyst provides adduct (V). Finally, methanolysis of the 2'-acetate ester of (V) gives rise to the target compound.
| 【1】 Niu, D.; Phan, L.T.; Haley, T.; Polemeropoulos, A.; Or, Y.; Syntheses and antibacterial activities of novel 11-O-substituted macrolide and ketolide derivatives. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1666. |
| 【2】 Or, Y.S.; Phan, L.T.; Niu, D. (Enanta Pharmaceuticals, Inc.); 11-O-Substd. macrolides and their descladinose derivs.. US 2003114396; US 6673774; WO 0347600 . |
| 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) | 53089 | (2S,3S,4R,6R)-6-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | n/a | C42H73NO15 | 详情 | 详情 |
| (II) | 62295 | allyl tert-butyl carbonate | C8H14O3 | 详情 | 详情 | |
| (III) | 62680 | (2S,3S,4R,6R)-6-{[(3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-(allyloxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy}-4- | C45H77NO15 | 详情 | 详情 | |
| (IV) | 62681 | 1-(3-butenyl)-4-phenyl-1H-imidazole | C13H14N2 | 详情 | 详情 | |
| (V) | 62682 | (2S,3S,4R,6R)-6-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-12-{[(E)-5-(4-phenyl-1H-imidazol-1-yl)-2- | C56H87N3O15 | 详情 | 详情 |