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【结 构 式】 
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【分子编号】35362 【品名】3-quinolinecarbaldehyde 【CA登记号】13669-42-6 |
【 分 子 式 】C10H7NO 【 分 子 量 】157.17172 【元素组成】C 76.42% H 4.49% N 8.91% O 10.18% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(VI)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 quinoline-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) | 35362 | 3-quinolinecarbaldehyde | 13669-42-6 | C10H7NO | 详情 | 详情 |
| (VII) | 35363 | C56H86N4O14 | 详情 | 详情 | ||
| (VIII) | 35364 | C57H88N4O14 | 详情 | 详情 | ||
| (IX) | 35365 | (1R,2R,4R,6S)-2-[((3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-[2-[methyl(3-quinolinylmethyl)amino]ethyl]-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-6-(dimethyl | C47H72N4O10 | 详情 | 详情 | |
| (X) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)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 selectively 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 quinoline-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) | 35362 | 3-quinolinecarbaldehyde | 13669-42-6 | C10H7NO | 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) | 35373 | C53H75N5O11 | 详情 | 详情 |