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【结 构 式】 
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【分子编号】57661 【品名】tert-butyl (1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate 【CA登记号】 |
【 分 子 式 】C30H42N4O5 【 分 子 量 】538.68744 【元素组成】C 66.89% H 7.86% N 10.4% O 14.85% |
合成路线1
该中间体在本合成路线中的序号：(XII)Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) in the presence of NaH provides the aza diene derivative (III). Cyclization of (III) under olefin metathesis conditions, employing a ruthenium catalyst, gives rise to the tetrahydroazepine (IV). Oxidation of (IV) with m-chloroperbenzoic acid yields epoxide (V), which is subsequently converted into the trans azido alcohol (VI) upon ring opening with NaN3 and NH4Cl. Azide (VI) is reduced to the corresponding amine (VII) by using 1,3-propanedithiol. Acylation of the racemic trans amino alcohol (VII) by N-Boc-L-leucine (VIII) produces a diastereomeric mixture of amides, which are separated by column chromatography. The desired isomer (IX) is then subjected to catalytic hydrogenolysis of the N-carbobenzoxy group to afford azepine (X). Then, acylation of (X) with 3-(2-pyridyl)phenylacetic acid (XI) furnishes amide (XII).
| 【1】 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 . |
| 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) | 49723 | benzyl allylcarbamate | C11H13NO2 | 详情 | 详情 | |
| (II) | 49724 | 1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide | 1119-51-3 | C5H9Br | 详情 | 详情 |
| (III) | 49725 | benzyl allyl(4-pentenyl)carbamate | C16H21NO2 | 详情 | 详情 | |
| (IV) | 49726 | benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49727 | benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 57657 | benzyl (3S,4S)-4-azido-3-hydroxy-1-azepanecarboxylate | C14H18N4O3 | 详情 | 详情 | |
| (VII) | 57658 | benzyl (3S,4S)-4-amino-3-hydroxy-1-azepanecarboxylate | C14H20N2O3 | 详情 | 详情 | |
| (VIII) | 31819 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid | 16937-99-8 | C11H21NO4 | 详情 | 详情 |
| (IX) | 57659 | benzyl (3S,4S)-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino)-3-hydroxy-1-azepanecarboxylate | C25H39N3O6 | 详情 | 详情 | |
| (X) | 57660 | tert-butyl (1S)-1-({[(3S,4S)-3-hydroxyazepanyl]amino}carbonyl)-3-methylbutylcarbamate | C17H33N3O4 | 详情 | 详情 | |
| (XI) | 50904 | 2-[3-(2-pyridinyl)phenyl]acetic acid | C13H11NO2 | 详情 | 详情 | |
| (XII) | 57661 | tert-butyl (1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate | C30H42N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Acidic cleavage of the Boc protecting group of (XII) affords amine (XIII). This is coupled with 5-[2-(morpholin-4-yl)ethoxy]benzofuran-2-carboxylic acid (XIV) using EDC to furnish amide (XV). The azepine 3-hydroxyl group of (XV) is finally oxidized to the target ketone using DMSO in the presence of sulfur trioxide-pyridine complex.
| 【1】 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 57661 | tert-butyl (1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate | C30H42N4O5 | 详情 | 详情 | |
| (XIII) | 57662 | (2S)-2-amino-N-((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)-4-methylpentanamide | C25H34N4O3 | 详情 | 详情 | |
| (XIV) | 50913 | 5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxylic acid | C15H17NO5 | 详情 | 详情 | |
| (XV) | 57663 | N-((1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutyl)-5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxamide | C40H49N5O7 | 详情 | 详情 |