【结 构 式】 |
【分子编号】16066 【品名】(2S,4S)-6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid propyl ester 【CA登记号】 |
【 分 子 式 】C15H15FN2O5 【 分 子 量 】322.2929832 【元素组成】C 55.9% H 4.69% F 5.89% N 8.69% O 24.82% |
合成路线1
该中间体在本合成路线中的序号:(IX)1) The condensation of 4-fluoroanisole (I) with maleic anhydride (II) by means of AlCl3 in hot 1,2-dichloroethane gives (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (III), which is cyclized by means of NaHCO3 in boiling water to yield racemic 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is condensed with (S)-(-)-1-phenylethylamine (VI) affording the amide (VII) as a diastereomeric mixture (R,S + S,S), which is submitted to a fractional crystallization to give the suitable isomer (S,S)-(VII). The hydrolysis of (S,S)-(VII) with concentrated HCl in refluxing dioxane yields the corresponding acid (S)-(IV) as a pure enantiomer. The cyclization of (S)-(IV) with KCN and (NH4)2CO3 in hot water affords the acidic spiro compound (VIII), again as a diastereomeric mixture (2S,4R + 2S,4S), which is separated by fractional crystallization to obtain the desired (2S,4S)-(VIII) compound. The esterification of (2S,4S)-(VIII) with propanol/sulfuric acid affords the corresponding propyl ester (IX), which is finally treated with dry ammonia in methanol.
【1】 Mealy, N.; Castaner, J.; SNK-860. Drugs Fut 1996, 21, 3, 261. |
【2】 Yamaguchi, T.; Miura, K.; Usui, T.; Unno, R.; Matsumoto, Y.; Fukushima, M.; Mizuno, K.; Kondo, Y.; Baba, Y.; Kurono, M.; Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'--imidazolidine]-2',5'-diones. Arzneim-Forsch Drug Res 1994, 44, 3, 344-8. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
((S)-IV) | 16064 | (2S)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid | C10H7FO4 | 详情 | 详情 | |
(I) | 16057 | 4-Fluoroanisole; 4-fluorophenyl methyl ether; 1-fluoro-4-methoxybenzene; p-Fluoroanisole | 459-60-9 | C7H7FO | 详情 | 详情 |
(II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
(III) | 16059 | (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid | C10H7FO4 | 详情 | 详情 | |
(IV) | 16060 | 6-fluoro-4-oxo-2-chromanecarboxylic acid | C10H7FO4 | 详情 | 详情 | |
(V) | 16061 | 6-fluoro-4-oxo-2-chromanecarbonyl chloride | C10H6ClFO3 | 详情 | 详情 | |
(VI) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
(VII) | 16063 | (2S)-6-fluoro-4-oxo-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide | C18H16FNO3 | 详情 | 详情 | |
(VIII) | 16065 | (2S,4S)-6-fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]2-ylcarboxylic acid | C12H9FN2O5 | 详情 | 详情 | |
(IX) | 16066 | (2S,4S)-6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid propyl ester | C15H15FN2O5 | 详情 | 详情 |