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【结 构 式】 
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【药物名称】FMA-199 【化学名称】11-Deoxy-3-des(cladinosyl)-11-[2-[N-methyl-N-(3-pyridylmethyl)amino]ethylamino]-3-O-(2-pyridylacetyl)-6-O-methylerythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】208455-50-9 【 分 子 式 】C47H71N5O11 【 分 子 量 】882.11682 |
【开发单位】Taisho (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Macrolides |
合成路线1
The acetylation of clarithromycin (I) with acetic anhydride gives the diacetate (II), which is acylated with CDI yielding the 12-O-(imidazolylcarbonyl compound (III). The cyclization of (III) with ethylenediamine (IV) affords the cyclic carbamate (V), which is alkylated by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 to give the secondary amine (VII). The methylation of this amine with formaldehyde and NaBH(OAc)3 yields the corresponding tertiary amine (VIII), which is treated with aqueous HCl to provide the descladinosyl compound (IX). Finally, this compound is acylated with 2-(2-pyridyl)acetic acid (X) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), and deacetylated with methanol to afford the target compound.
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 【2】 Ishii, T.; Tanikawa, T.; Matsuura, A.; Sugimoto, T.; Asaka, T.; Kashimura, M. (Taisho Pharmaceutical Co., Ltd.); Erythromycin A derivs.. EP 0945459; WO 9823628 . |
| 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) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (II) | 35359 | C43H75NO14 | 详情 | 详情 | ||
| (III) | 35360 | C47H75N3O14 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (V) | 35361 | C46H79N3O14 | 详情 | 详情 | ||
| (VI) | 35374 | 5,6-dihydro-3-pyridinecarbaldehyde | C6H7NO | 详情 | 详情 | |
| (VII) | 35375 | C52H84N4O14 | 详情 | 详情 | ||
| (VIII) | 35376 | C53H86N4O14 | 详情 | 详情 | ||
| (IX) | 35377 | C43H70N4O10 | 详情 | 详情 | ||
| (X) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
合成路线2
The selective hydrolysis of clarithromycin (I) with aqueous HCl, followed by acylation with acetic anhydride gives the monoacetylated descladinosyl compound (XI), which by reaction with trichloromethyl chloroformate (TCF) yields the cyclic carbonate (XII). The reaction of (XII) with 1,1,3,3-tetramethylguanidine (TMG) affords intermediate (XIII), which is selecti-ely acylated with 2-(2-pyridyl)acetic acid (X) and WSC giving the 3-O-acylated compound (XIV). The activation of (XIV) with CDI affords the 12-O-imidazolylcarbonyl derivative (XV), which is cyclized with ethylenediamine (IV) providing the carbamate (XVI). The alkylation of the primary amine of (XVI) by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 gives the secondary amine (XVII).
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 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) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VI) | 35374 | 5,6-dihydro-3-pyridinecarbaldehyde | C6H7NO | 详情 | 详情 | |
| (X) | 35369 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,13S,14R)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-6-yl]oxy]-4-methylcyclohexyl acetate | C33H57NO9 | 详情 | 详情 | |
| (XI) | 35367 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-methylcyclohexyl acetate | C33H59NO10 | 详情 | 详情 | |
| (XII) | 35368 | (1R,2R,4R,6S)-2-[[(3aR,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxododecahydro-4H-[1,3]dioxolo[4,5-c]oxacyclotetradecin-10-yl]oxy]-6-(dimethylamino)-4-methylcyclohexyl acetate | C34H57NO11 | 详情 | 详情 | |
| (XIII) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
| (XIV) | 35370 | (3R,4S,5R,6R,7R,9R,13S,14R)-6-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-4-yl 2-(2-pyridinyl)acetate | C40H62N2O10 | 详情 | 详情 | |
| (XV) | 35371 | (2R,3S,7R,9R,10R,11R,12S,13R)-10-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-[[2-(2-pyridinyl)acetyl]oxy]oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C44H64N4O11 | 详情 | 详情 | |
| (XVI) | 35372 | C43H68N4O11 | 详情 | 详情 | ||
| (XVII) | 35378 | C49H73N5O11 | 详情 | 详情 |
合成路线3
Finally, the secondary amine of (XVII) is methylated with formaldehyde and NaBH(OAc)3 and deacetylated with methanol to afford the target compound.
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 35378 | C49H73N5O11 | 详情 | 详情 |