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【结 构 式】 
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【分子编号】36586 【品名】7-benzyl 3-ethyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate 【CA登记号】 |
【 分 子 式 】C28H34N4O7 【 分 子 量 】538.60072 【元素组成】C 62.44% H 6.36% N 10.4% O 20.79% |
合成路线1
该中间体在本合成路线中的序号：(X)Reduction of N-(benzyloxycarbonyl)-4-hydroxyproline (I) with boranedimethylsulfide complex in THF provided the corresponding diol, which was selectively protected at the primary hydroxyl group as the tert-butyldimethylsilyl ether (II). Swern oxidation of the remaining secondary alcohol of (II) afforded ketone (III). This was converted to alkene (IV) by Wittig olefination with methylene triphenylphosphorane. The 1,3-dipolar cycloaddition of (IV) with the nitrile oxide generated from chlorooxime (V) and Et3N furnished spirocycle (VI) as a diastereomeric mixture. Deprotection of the silyl ether of (VI) by treatment with tetrabutylammonium fluoride, followed by Swern oxidation of the resulting alcohol provided aldehyde (VII). Reductive amination of (VII) with 2-aminopyridine (VIII) gave amine (IX), which was protected as the tert-butyl carbamate (X) using Boc2O.
| 【1】 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 . |
| 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) | 36579 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | 13504-85-3 | C13H15NO5 | 详情 | 详情 |
| (II) | 36580 | benzyl (2S,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C19H31NO4Si | 详情 | 详情 | |
| (III) | 36581 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C19H29NO4Si | 详情 | 详情 | |
| (IV) | 36582 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C20H31NO3Si | 详情 | 详情 | |
| (V) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (VI) | 36583 | 7-benzyl 3-ethyl 8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C24H36N2O6Si | 详情 | 详情 | |
| (VII) | 36584 | 7-benzyl 3-ethyl 8-formyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C18H20N2O6 | 详情 | 详情 | |
| (VIII) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (IX) | 36585 | 7-benzyl 3-ethyl 8-[(2-pyridinylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C23H26N4O5 | 详情 | 详情 | |
| (X) | 36586 | 7-benzyl 3-ethyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C28H34N4O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)After ester (X) hydrolysis with LiOH, the free acid (XI) was coupled with tert-butyl (S)-3-amino-2-(2,4,6-trimethylphenylsulfonylamino)propionate (XII) to yield amide (XIII). Finally, the tert-butyl and Boc protecting groups of (XIII) were cleaved by treatment with trifluoroacetic acid.
| 【1】 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 36586 | 7-benzyl 3-ethyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C28H34N4O7 | 详情 | 详情 | |
| (XI) | 36587 | 7-[(benzyloxy)carbonyl]-8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid | C26H30N4O7 | 详情 | 详情 | |
| (XII) | 36588 | tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate | C16H26N2O4S | 详情 | 详情 | |
| (XIII) | 36589 | benzyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate | C42H54N6O10S | 详情 | 详情 |