合成路线: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.
参考文献标题:Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'--imidazolidine]-2',5'-diones
文献作者:Yamaguchi,T.; Miura,K.; Usui,T.; Unno,R.; Matsumoto,Y.; Fukushima,M.; Mizuno,K.; Kondo,Y.; Baba,Y.; Kurono,M.
参考来源:Arzneim-Forsch Drug Res 1994,44(3),344-8
合成路线: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.
合成路线:2) The cyclization of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) with KCN and ammonium carbonate in hot water (80-90 C) gives 6-fluoro-2',5'-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4'-imidazolidine]-2-carboxylic acid (X) as a (5:1)-mixture of the (RS,RS)- and (RS,SR)-diastereomers.This mixture is treated with SiCl4 and dry ammonia in pyridine,yielding the corresponding (5:1)-mixture of amides (XI),which is separated by recrystallization,affording the (RS,RS)-diastereomer (XII) as a pure compound.The optical resolution of (XII) with N-methylquininium hydroxide (XIII) and crystallization gives the (2S,4S)-isomer as the N-methylquininium salt (XIV),which is finally treated with 1N aqueous HCl in ethanol/water.
参考文献标题:SNK-860
文献作者:Mealy,N.; Castar,J.
参考来源:Drugs Fut 1996,21(3),261
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