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【结 构 式】 
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【分子编号】26672 【品名】(3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone 【CA登记号】 |
【 分 子 式 】C6H11NO2 【 分 子 量 】129.15888 【元素组成】C 55.8% H 8.58% N 10.84% O 24.77% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III), which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV). The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI), which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride, BuLi and TEA in THF giving the acylated thiazolidine (VIII). The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X), which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI). The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII), which is debenzylated by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Deal, J.G.; Bender, S.L.; Chong, W.K.M.; et al.; Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's). 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 197. |
| 【2】 Bender, S.L.; Castelhano, A.L.; Chong, W.K.M.; Abreo, M.A.; Billedeau, R.J.; Chen, J.J.; Deal, J.G. (Agouron Pharmaceuticals, Inc.; Syntex (USA), Inc.); Heteroaryl succinamides and their use as metalloproteinase inhibitors. EP 0937042; JP 2000511201; US 6008243; WO 9817643 . |
| 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) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (II) | 16517 | 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane | 13411-42-2 | C7H16S2Si | 详情 | 详情 |
| (III) | 26665 | 3-(1,3-dithian-2-ylidenemethyl)-2,5-dimethoxytetrahydrofuran | C11H18O3S2 | 详情 | 详情 | |
| (IV) | 26666 | methyl 2-(2,5-dimethoxytetrahydro-3-furanyl)acetate | C9H16O5 | 详情 | 详情 | |
| (V) | 26667 | 4'-amino[1,1'-biphenyl]-4-carbonitrile | 4854-84-6 | C13H10N2 | 详情 | 详情 |
| (VI) | 26668 | methyl 2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]acetate | C20H16N2O2 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 26669 | 4'-(3-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]-1H-pyrrol-1-yl)[1,1'-biphenyl]-4-carbonitrile | C29H23N3O3 | 详情 | 详情 | |
| (IX) | 26670 | benzyl (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutanoate | C38H31N3O5 | 详情 | 详情 | |
| (X) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XI) | 26671 | (2S)-4-(benzyloxy)-2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutyric acid | C28H22N2O4 | 详情 | 详情 | |
| (XII) | 26672 | (3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone | C6H11NO2 | 详情 | 详情 | |
| (XIII) | 26673 | benzyl (3S)-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-[[(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl]amino]-4-oxobutanoate | C34H31N3O5 | 详情 | 详情 |