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【结 构 式】 
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【分子编号】35847 【品名】7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde 【CA登记号】 |
【 分 子 式 】C10H4F4O2 【 分 子 量 】232.1341728 【元素组成】C 51.74% H 1.74% F 32.74% O 13.78% |
合成路线1
该中间体在本合成路线中的序号：(I)The Grignard reaction of 7-fluoro-4-(trifluoromethyl)benzofuran-2-carbaldehyde (I) with vinylmagnesium bromide in ether/THF gives the expected carbinol (II), which is oxidized with MnO2 in dichloromethane yielding the propenone (III). The condensation of (III) with 4-formylbenzoic acid methyl ester (IV) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) in refluxing ethanol affords the 1,4-butanedione (V), which is cyclized with ammonium acetate in refluxing methanol to give the substituted pyrrole (VI). Finally, the ester group of (V) is hydrolyzed with NaOH in refluxing ethanol/water.
| 【1】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 | |
| (I) | 35847 | 7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde | C10H4F4O2 | 详情 | 详情 | |
| (II) | 35848 | 1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-ol | C12H8F4O2 | 详情 | 详情 | |
| (III) | 35849 | 1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-one | C12H6F4O2 | 详情 | 详情 | |
| (IV) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (V) | 35850 | methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate | C21H14F4O5 | 详情 | 详情 | |
| (VI) | 35851 | methyl 4-[5-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-1H-pyrrol-2-yl]benzoate | C21H13F4NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reaction of 2-fluoro-5-(trifluoromethyl)phenol (I) with allyl bromide (II) by means of K2CO3 in DMF gives the phenol ether (III), which is submitted to an allylic rearrangement by heating at 190 C to yield 2-allyl-6-fluoro-3-(trifluoromethyl)phenol (IV). The cyclization of (IV) by means of MCPBA and KOH affords the dihydrobenzofuran (V), which is treated with Ac2O and pyridine to provide the acetate (VI). The dehydrogenation of (VI) by means of NBS and AIBN, followed by a treatment with tBu-OK and K2CO3 in methanol, gives 1-[7-fluoro-4-(trifluoromethyl)benzofuran-2-yl]methanol (VII), which is oxidized with oxalyl chloride and TEA in DMSO to yield the corresponding carbaldehyde (VIII). The condensation of (VIII) with 4-acryloylbenzoic acid methyl ester (IX) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (BHMT) and TEA in DMF affords the 1,4-butanedione derivative (X), which is submitted to a pyrrole synthesis by cyclization with AcONH4 in refluxing ethanol to provide the disubstituted pyrrole (XI). Finally, the ester group of (XI) is hydrolyzed with NaOH in ethanol to furnish the target carboxylic acid.
| 【1】 Yoshimura, H.; et al.; Discovery of novel and potent retinoic acid receptor alpha agonists: Syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem 2000, 43, 15, 2929. |
| 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) | 50315 | 2-Fluoro-5-(trifluoromethyl)phenol | 141483-15-0 | C7H4F4O | 详情 | 详情 |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 50316 | 2-(allyloxy)-1-fluoro-4-(trifluoromethyl)benzene; allyl 2-fluoro-5-(trifluoromethyl)phenyl ether | C10H8F4O | 详情 | 详情 | |
| (IV) | 50317 | 2-allyl-6-fluoro-3-(trifluoromethyl)phenol | C10H8F4O | 详情 | 详情 | |
| (V) | 50318 | [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol | C10H8F4O2 | 详情 | 详情 | |
| (VI) | 50319 | [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl acetate | C12H10F4O3 | 详情 | 详情 | |
| (VII) | 50320 | [7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]methanol | C10H6F4O2 | 详情 | 详情 | |
| (VIII) | 35847 | 7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde | C10H4F4O2 | 详情 | 详情 | |
| (IX) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 | |
| (X) | 35850 | methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate | C21H14F4O5 | 详情 | 详情 | |
| (XI) | 35851 | methyl 4-[5-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-1H-pyrrol-2-yl]benzoate | C21H13F4NO3 | 详情 | 详情 |