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【结 构 式】 
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【分子编号】58954 【品名】sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate 【CA登记号】 |
【 分 子 式 】C35H45N4NaO10 【 分 子 量 】704.753028 【元素组成】C 59.65% H 6.44% N 7.95% Na 3.26% O 22.7% |
合成路线1
该中间体在本合成路线中的序号：(XXII)Coupling between the Boc-aminoacid (VIII) and dipeptide ester (XV) affords the linear tripeptide (XVI). Macrocyclization of (XVI) to produce (XVII) is accomplished by intramolecular olefin metathesis in the presence of Hoveyda's catalyst. Subsequent catalytic hydrogenation of (XVII) leads to a mixture of the desired saturated macrocycle (XIX) and compound (XVIII), produced by hydrogenolysis of the cyclopropane ring. Mitsunobu coupling of (XIX) with methyl 4-hydroxy-7-methoxyquinoline-2-carboxylate (XX) gives rise to quinolinyl ether (XXI). The quinoline carboxylate group of (XXI) is then selectively hydrolyzed by NaOH to furnish the sodium carboxylate salt (XXII).
| 【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 58938 | (2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid | C14H25NO4 | 详情 | 详情 | |
| (XV) | 58947 | methyl (1R,2S)-1-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)-2-vinylcyclopropanecarboxylate | C12H18N2O4 | 详情 | 详情 | |
| (XVI) | 58948 | methyl (1R,2S)-1-{[((2S,4R)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoyl}-4-hydroxypyrrolidinyl)carbonyl]amino}-2-vinylcyclopropanecarboxylate | C26H41N3O7 | 详情 | 详情 | |
| (XVII) | 58949 | methyl (2R,6S,13aS,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate | C24H37N3O7 | 详情 | 详情 | |
| (XVIII) | 58950 | methyl (13S,17R,18aS)-13-[(tert-butoxycarbonyl)amino]-17-hydroxy-1,14-dioxooctadecahydropyrrolo[1,2-a][1,4]diazacyclohexadecine-3-carboxylate | C24H41N3O7 | 详情 | 详情 | |
| (XIX) | 58951 | methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate | C24H39N3O7 | 详情 | 详情 | |
| (XX) | 58952 | methyl 4-hydroxy-7-methoxy-2-quinolinecarboxylate | C12H11NO4 | 详情 | 详情 | |
| (XXI) | 58953 | methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-{[7-methoxy-2-(methoxycarbonyl)-4-quinolinyl]oxy}-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate | C36H48N4O10 | 详情 | 详情 | |
| (XXII) | 58954 | sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate | C35H45N4NaO10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)The sodium carboxylate (XXII) is activated as the mixed anhydride (XXIII) by treatment with isobutyl chloroformate and triethylamine. Subsequent addition of diazomethane to the mixed anhydride (XXIII) leads to diazo ketone (XXIV), which is further transformed into bromo ketone (XXV) upon treatment with HBr. Cyclization of bromo ketone (XXV) with N-acetyl thiourea (XXVI) produces the thiazole derivative (XXVII). The methyl ester group of (XXVII) is finally hydrolyzed by means of LiOH to the target carboxylic acid.
| 【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 58954 | sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate | C35H45N4NaO10 | 详情 | 详情 | |
| (XXIII) | 58955 | C40H54N4O12 | 详情 | 详情 | ||
| (XXIV) | 58956 | C36H46N6O9 | 详情 | 详情 | ||
| (XXV) | 58957 | methyl (2R,6S,13aR,16aS)-2-{[2-(2-bromoacetyl)-7-methoxy-4-quinolinyl]oxy}-6-[(tert-butoxycarbonyl)amino]-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate | C36H47BrN4O9 | 详情 | 详情 | |
| (XXVI) | 58958 | 1-Acetyl-2-thiourea; N-Acetylthiourea | 591-08-2 | C3H6N2OS | 详情 | 详情 |
| (XXVII) | 58959 | methyl (2R,6S,13aR,16aS)-2-({2-[2-(acetylamino)-1,3-thiazol-4-yl]-7-methoxy-4-quinolinyl}oxy)-6-[(tert-butoxycarbonyl)amino]-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate | C39H50N6O9S | 详情 | 详情 |