Fidarestat, SNK-860, Aldos, -Drug Synthesis Database

【结构式】

【药物名称】Fidarestat, SNK-860, Aldos

【化学名称】(2S,4S)-6-Fluoro-2',5'-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

【CA登记号】136087-85-9, 118803-58-0 (cis-racemic), 105300-43-4 (undefined isomer)

【分子式】C₁₂H₁₀FN₃O₄

【分子量】279.2296

【开发单位】Sanwa (Originator), Sankyo (Licensee), Japan Energy (Codevelopment), Kaken (Codevelopment)

【药理作用】Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Treatment of Diabetic Complications, Aldose Reductase Inhibitors

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

合成路线2

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.

参考文献中间体

【1】 Mealy, N.; Castaner, J.; SNK-860. Drugs Fut 1996, 21, 3, 261.
【2】 Kurono, M.; Kondo, Y.; Yamaguchi, T.; Miura, K.; Usui, T.; Terada, N.; Asano, K.; Mizuno, K.; Matsubara, A.; Kato, N.; Sawai, K.; Unno, R.; Ozawa, H.; Fukushima, M. (Sanwa Kagaku Kenkyusho Co., Ltd.); Hydantoin derivs. for treating complications of diabetes. EP 0264586; JP 1988057588; JP 1988126881; JP 1988250373; US 4861792; US 4978758; US 5447946 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	16060	6-fluoro-4-oxo-2-chromanecarboxylic acid	C₁₀H₇FO₄	详情	详情
(X)	16067	6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid	C₁₂H₉FN₂O₅	详情	详情
(XI)	16068	(rac)-(6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxamide)	C₁₂H₁₀FN₃O₄	详情	详情
(XII)	64700		C₁₂H₁₀FN₃O₄	详情	详情
(XIII)	64698	5-ethenyl-2-{hydroxy[6-(methyloxy)-4-quinolinyl]methyl}-1-methyl-1-azoniabicyclo[2.2.2]octane hydroxide	C₂₁H₂₈N₂O₃	详情	详情
(XIV)	64699		C₃₃H₃₈FN₅O₇	详情	详情
(XV)	16072	2',5'-Dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid	C₁₂H₁₀N₂O₅	详情	详情

Extended Information