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【结 构 式】 
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【分子编号】68882 【品名】4-(chloromethyl)-7-hydroxychromen-2-one;4-(chloromethyl)-7-hydroxy-2H-1-Benzopyran-2-one;4-(Chloromethyl)-7-hydroxycoumarin;4-Chloromethyl-7-hydroxy-2H-chromen-2-one;7-Hydroxy-4-(chloromethyl)coumarin 【CA登记号】25392-41-0 |
【 分 子 式 】C10H7ClO3 【 分 子 量 】210.61648 【元素组成】C 57.03% H 3.35% Cl 16.83% O 22.79% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) is synthesized as follows:
Cyclization of resorcinol (XI) with ethyl 4-chloroacetoacetate (XII) by means of H2SO4 gives 4-(chloromethyl)-7-hydroxychromen-2-one (XIII), which by treatment with NaOH at reflux affords (6-hydroxybenzofuran-3-yl)acetic acid (XIV). Esterification of carboxylic acid (XIV) with MeOH in the presence of H2SO4 at reflux yields the corresponding methyl ester (XV), which is hydrogenated over Pd/C in MeOH to provide (±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (XVI) . Finally, the (S)-enantiomer (VII) is isolated by preparative HPLC .
Alternatively, intermediate (XV) can be reduced by H2 in the presence of bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate and (S,S)-Et-ferrotane in the presence of NaOMe in MeOH .
| 【1】 Negoro, N., Sasaki, S., Mikami, S. et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010, 1: 290-4. |
| 【2】 Yasuma, T., Negoro, N., Yamashita, M., Itou, M. (Takeda Pharmaeutical Co., Ltd.). Fused cyclic compounds. CA 2656003, EP 2041123, EP 2248812, JP 2009280585, JP 2009542580, US 2010004312, US 7732626, WO 2008001931. |
| 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) | 68881 | methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 | |
| (XI) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (XII) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XIII) | 68882 | 4-(chloromethyl)-7-hydroxychromen-2-one;4-(chloromethyl)-7-hydroxy-2H-1-Benzopyran-2-one;4-(Chloromethyl)-7-hydroxycoumarin;4-Chloromethyl-7-hydroxy-2H-chromen-2-one;7-Hydroxy-4-(chloromethyl)coumarin | 25392-41-0 | C10H7ClO3 | 详情 | 详情 |
| (XIV) | 68883 | (6-hydroxybenzofuran-3-yl)acetic acid;2-(6-hydroxybenzofuran-3-yl)acetic acid | C10H8O4 | 详情 | 详情 | |
| (XV) | 68884 | methyl 2-(6-hydroxybenzofuran-3-yl)acetate | C11H10O4 | 详情 | 详情 | |
| (XVI) | 68885 | methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate；(±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 |