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【结 构 式】 
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【分子编号】53181 【品名】12-(tert-butyl) 8-methyl (8S,11R,12S)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate 【CA登记号】n/a |
【 分 子 式 】C33H41F3N2O7 【 分 子 量 】634.6930296 【元素组成】C 62.45% H 6.51% F 8.98% N 4.41% O 17.65% |
合成路线1
该中间体在本合成路线中的序号：(XXI)Condensation of carbonate (XIV) with N-alpha-Cbz-lysine methyl ester (XV) afforded the carbamate (XVI). The benzyl ester and N-Cbz protecting groups of (XVI) were then removed by catalytic hydrogenolysis, yielding amino acid (XVII), which was subjected to intramolecular cyclization in the presence of BOP to furnish the macrocyclic compound (XVIII). After conversion of the phenolic hydroxyl of (XVIII) to the aryl triflate (XIX), Suzuki coupling with 2-(trifluoromethyl)phenylboronic acid (XX) provided the biphenyl derivative (XXI).
| 【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 53175 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate | n/a | C39H41NO10 | 详情 | 详情 |
| (XV) | 35087 | methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate | C15H22N2O4 | 详情 | 详情 | |
| (XVI) | 53176 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-18-[4-(benzyloxy)phenyl]-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaoctadecane-5,16,17-tricarboxylate | n/a | C48H58N2O11 | 详情 | 详情 |
| (XVII) | 53177 | (2R,3S)-6-[({[(5S)-5-amino-6-methoxy-6-oxohexyl]amino}carbonyl)oxy]-3-(tert-butoxycarbonyl)-2-(4-hydroxybenzyl)hexanoic acid | n/a | C26H40N2O9 | 详情 | 详情 |
| (XVIII) | 53178 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-11-(4-hydroxybenzyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | n/a | C26H38N2O8 | 详情 | 详情 |
| (XIX) | 53179 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-2,10-dioxo-11-(4-{[(trifluoromethyl)sulfonyl]amino}benzyl)-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | n/a | C27H38F3N3O9S | 详情 | 详情 |
| (XX) | 53180 | 2-Trifluoromethylbenzeneboronic acid; 2-Trifluoromethylphenylboronic acid; o-Trifluoromethylphenylboronic acid | 1423-27-4 | C7H6BF3O2 | 详情 | 详情 |
| (XXI) | 53181 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | n/a | C33H41F3N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)Saponification of the methyl ester (XXI) using LiOH gave the carboxylic acid (XXII). This was coupled with the glycine amide (XXIII) to produce adduct (XXIV). The desired hydroxamic acid was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XXIV), followed by coupling of the resulting carboxylic acid (XXV) with hydroxylamine.
| 【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 53181 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | n/a | C33H41F3N2O7 | 详情 | 详情 |
| (XXII) | 53182 | (8S,11R,12S)-12-(tert-butoxycarbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid | n/a | C32H39F3N2O7 | 详情 | 详情 |
| (XXIII) | 35094 | 2-amino-1-(4-morpholinyl)-1-ethanone | C6H12N2O2 | 详情 | 详情 | |
| (XXIV) | 53183 | tert-butyl (8S,11R,12S)-8-({[2-(4-morpholinyl)-2-oxoethyl]amino}carbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-12-carboxylate | n/a | C38H49F3N4O8 | 详情 | 详情 |
| (XXV) | 53184 | (8S,11R,12S)-8-({[2-(4-morpholinyl)-2-oxoethyl]amino}carbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-12-carboxylic acid | n/a | C34H41F3N4O8 | 详情 | 详情 |