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【结 构 式】 
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【分子编号】16636 【品名】ethyl 3-(7-hydroxy-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoate 【CA登记号】 |
【 分 子 式 】C17H24O4 【 分 子 量 】292.37516 【元素组成】C 69.84% H 8.27% O 21.89% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The Eastern fragment (XIV) was derived from 2',4'-dihydroxy-3'-propylacetophenone (VII). This material could be converted into (X) using identical procedures to those developed in house for the synthesis of SC-41930. (X) was resolved into its two homochiral components using enzymatic methods (Amano lipase AK, pH 7.4 buffer followed by selective methylation [CH3l, KHCO3, DMSO] and recrystallization. The overall yield for this process was 33% [based on a resolution yield of 40%]) and afforded the desired (-)-isomer (XII) in > 99% e.e. This material was silylated (TBDMS chloride, DMF, imidazole) and reduced to the primary carbinol with DIBAL-H. Conversion to the Eastern fragment (XIV) was accomplished by an efficient 3-step process involving triflation (Tf2O, CH2Cl2), homologation with lithium tert-butyl acetate and protective group removal/transesterification with ethanolic hydrogen chloride (92% for the three steps). The overall yield of Eastern fragment (> 99% e.e.) was 17% based on 2',4'-dihydroxy-3'-propylacetophenone (VII) as starting material.
| 【1】 Smith, P.F.; Paulson, S.K.; Tsai, B.S.; Fretland, D.J.; Dygos, J.H.; Yu, S.S.; Djuric, S.W.; SC-53228. Drugs Fut 1994, 19, 12, 1093. |
| 【2】 Yu, S.; Docter, S.; Djuric, S.; et al.; Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity. Bioorg Med Chem Lett 1994, 4, 6, 811-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 13137 | 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone | 40786-69-4 | C11H14O3 | 详情 | 详情 |
| (VIII) | 16630 | methyl 4-(2,4-dihydroxy-3-propylphenyl)-2,4-dioxobutanoate | C14H16O6 | 详情 | 详情 | |
| (IX) | 16631 | methyl 7-hydroxy-4-oxo-8-propyl-4H-chromene-2-carboxylate | C14H14O5 | 详情 | 详情 | |
| (X) | 16632 | methyl 7-hydroxy-8-propyl-2-chromanecarboxylate | C14H18O4 | 详情 | 详情 | |
| (XI) | 16633 | 7-hydroxy-8-propyl-2-chromanecarboxylic acid | C13H16O4 | 详情 | 详情 | |
| (XII) | 16632 | methyl 7-hydroxy-8-propyl-2-chromanecarboxylate | C14H18O4 | 详情 | 详情 | |
| (XIII) | 16635 | (7-[[tert-butyl(dimethyl)silyl]oxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl)methanol | C19H32O3Si | 详情 | 详情 | |
| (XIV) | 16636 | ethyl 3-(7-hydroxy-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoate | C17H24O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The synthesis of SC-53228 was finally consummated (Scheme 3) through the coupling of Eastern (XIV) and Western (VI) fragments in a 2-step process involving intermolecular alkylation (K2CO3, DMF) followed by lithium hydroxide-mediated ester hydrolysis.
| 【1】 Yu, S.; Docter, S.; Djuric, S.; et al.; Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity. Bioorg Med Chem Lett 1994, 4, 6, 811-6. |
| 【2】 Smith, P.F.; Paulson, S.K.; Tsai, B.S.; Fretland, D.J.; Dygos, J.H.; Yu, S.S.; Djuric, S.W.; SC-53228. Drugs Fut 1994, 19, 12, 1093. |