KR-31378, -Drug Synthesis Database

【结构式】

【药物名称】KR-31378

【化学名称】N-[6-Amino-2-(dimethoxymethyl)-3(S)-hydroxy-2(S)-methyl-3,4-dihydro-2H-1-benzopyran-4(R)-yl]-N'-benzyl-N''-cyanoguanidine

【CA登记号】335381-99-2, 335381-85-6 (diastereomer), 335381-86-7 (diastereomer), 335381-87-8 (diastereomer)

【分子式】C₂₂H₂₇N₅O₄

【分子量】425.49159

【开发单位】Korea Res. Inst. Chem. Technol. (Originator)

【药理作用】Acute Myocardial Infarction, Treatment of, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Antioxidants, K(ATP) Channel Activators

合成路线1 合成路线2

合成路线1

Epoxidation of the chiral benzopyran derivative (I) by means of oxone furnished the diastereomeric epoxides (II). Subsequent epoxide ring opening with ethanolic ammonia gave rise to the mixture of amino alcohols (III) and (IV). Condensation of this mixture with N-cyano-N'-benzylthiourea sodium salt (V) in the presence of EDC produced the corresponding mixture of guanidines from which the target (2S,3S,4R)-isomer (VI) was isolated by column chromatography. Finally, reduction of the nitro group of (VI) to the desired amine was accomplished by treatment with NaBH4 in the presence of cupric acetate.

参考文献中间体

【1】 Benzopyranyl guanidine derivs., process for preparation thereof, and pharmaceutical compsns. containing them. US 6323238; WO 0129023 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	51836	(2S)-2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene; methoxy[(2S)-2-methyl-6-nitro-2H-chromen-2-yl]methyl methyl ether	C₁₃H₁₅NO₅	详情	详情
(II)	51837	methoxy[(2S)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl]methyl methyl ether; (2S)-2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene	C₁₃H₁₅NO₆	详情	详情
(III)	51838	(2S,3S,4R)-4-amino-2-(dimethoxymethyl)-2-methyl-6-nitro-3,4-dihydro-2H-chromen-3-ol	C₁₃H₁₈N₂O₆	详情	详情
(IV)	51839	(2S,3R,4S)-4-amino-2-(dimethoxymethyl)-2-methyl-6-nitro-3,4-dihydro-2H-chromen-3-ol	C₁₃H₁₈N₂O₆	详情	详情
(V)	51840	sodium 1-([[(cyanoimino)(sulfido)methyl]amino]methyl)benzene	C₉H₈N₃NaS	详情	详情
(VI)	51841	N-benzyl-N''-cyano-N'-[(2S,3S,4R)-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]guanidine	C₂₂H₂₅N₅O₆	详情	详情

合成路线2

The asymmetric epoxidation of (R)-2-methyl-6-nitro-2H-1-benzopyran-2-carbaldehyde (I) with NaOCl catalyzed by the chiral catalyst Mn(III)-Salen gives the chiral epoxide (II), which is opened by means of NH3 in hot ethanol to yield the amino alcohol (III). The reaction of (III) with diphenylcyanocarbonimidate (IV) by means of TEA in DMF/isopropanol affords the N-cyano-O-phenylisourea (V), which by reaction with benzylamine (VI) in the same solvent provides the N-cyanoguanidine (VII). Finally, the nitro group of this compound is reduced with H2 over Pd/C or NaBH4 in methanol to give the target amino derivative.

参考文献中间体

【1】 Lee, S.; Yoo, S.; Yi, K.Y.; et al.; A novel anti-ischemic ATP-sensitive potassium channel (KATP) opener without vasorelaxation: N-(6-aminobenzopyranyl)-N-benzyl-N'-cyanoguanidine analogue. J Med Chem 2001, 44, 24, 4207.

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)	51836	(2S)-2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene; methoxy[(2S)-2-methyl-6-nitro-2H-chromen-2-yl]methyl methyl ether		C₁₃H₁₅NO₅	详情	详情
(II)	57013	(1aS,2S,7bS)-2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene; [(1aS,2S,7bS)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl](methoxy)methyl methyl ether		C₁₃H₁₅NO₆	详情	详情
(III)	51838	(2S,3S,4R)-4-amino-2-(dimethoxymethyl)-2-methyl-6-nitro-3,4-dihydro-2H-chromen-3-ol		C₁₃H₁₈N₂O₆	详情	详情
(IV)	25868	1-[(cyanoimino)(phenoxy)methoxy]benzene	107-37-9	C₁₄H₁₀N₂O₂	详情	详情
(V)	57014	(2S,3S,4R)-4-{[(cyanoimino)(phenoxy)methyl]amino}-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromene		C₂₁H₂₂N₄O₇	详情	详情
(VI)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(VII)	51841	N-benzyl-N''-cyano-N'-[(2S,3S,4R)-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]guanidine		C₂₂H₂₅N₅O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)