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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information