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【结 构 式】 
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【分子编号】53175 【品名】1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate 【CA登记号】n/a |
【 分 子 式 】C39H41NO10 【 分 子 量 】683.75528 【元素组成】C 68.51% H 6.04% N 2.05% O 23.4% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (II) | 53167 | methyl 3-[4-(benzyloxy)phenyl]propanoate | n/a | C17H18O3 | 详情 | 详情 |
| (III) | 53168 | 3-[4-(benzyloxy)phenyl]propanoic acid | 50463-48-4 | C16H16O3 | 详情 | 详情 |
| (IV) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (V) | 53169 | (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one | n/a | C26H25NO4 | 详情 | 详情 |
| (VI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VII) | 53170 | tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate | n/a | C32H35NO6 | 详情 | 详情 |
| (VIII) | 53171 | (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid | n/a | C22H26O5 | 详情 | 详情 |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 53172 | (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid | n/a | C25H30O5 | 详情 | 详情 |
| (XI) | 53173 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate | n/a | C32H36O5 | 详情 | 详情 |
| (XII) | 53174 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate | n/a | C32H38O6 | 详情 | 详情 |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XIV)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 |