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【结 构 式】 
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【分子编号】35087 【品名】methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate 【CA登记号】 |
【 分 子 式 】C15H22N2O4 【 分 子 量 】294.35076 【元素组成】C 61.21% H 7.53% N 9.52% O 21.74% |
合成路线1
该中间体在本合成路线中的序号：(XII)Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).
| 【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
| 【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (II) | 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 |
| (III) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (IV) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (V) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VII) | 35082 | (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (VIII) | 35083 | (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (IX) | 35084 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C22H32O4 | 详情 | 详情 | |
| (X) | 35085 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate | C22H34O5 | 详情 | 详情 | |
| (XI) | 35086 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate | C29H37NO9 | 详情 | 详情 | |
| (XII) | 35087 | methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate | C15H22N2O4 | 详情 | 详情 | |
| (XIII) | 35088 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate | C38H54N2O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)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 |