新产品编号:191931
Chemical Name: (3S,4R)-4-[N''-(4-Chlorophenyl)-N'-cyanoguanidino]-3-hydroxy-N,N-bis(isobutyl)-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-6-sulfonamide; (3S,4R)-N-(4-Chlorophenyl)-N'-cyano-N''-[6-(diisobutylsulfamoyl)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]guanidine
CAS No. 186180-70-1
项目整合开发状态: Preclinical
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:Treatment of 2-methyl-3-butyn-2-ol (I) with trifluoroacetic anhydride and DBU gave trifluoroacetate (II),which was condensed with 4-bromophenol (III) in the presence of CuCl2 to afford propargyl ether (IV).Cyclization of (IV) in N,N-diethylaniline at 185 C produced benzopyran (V).The required sulfonyl group was introduced in (V) by lithium-bromine exchange,followed by reaction with sulfur dioxide to give the lithium sulfinate (VI),and then oxidation to the sulfonyl chloride (VII) by means of sulfuryl chloride (1).Subsequent treatment of (VII) with diisobutylamine yielded sulfonamide (VIII).Asymmetric epoxidation of (VIII) using sodium hypochlorite and (S,S)(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) chloride (Jacobsen's catalyst) gave rise to epoxide (IX),which was opened with ammonium hydroxide to furnish the trans aminoalcohol (X).Finally,coupling of (X) with N-chlorophenyl-N'-cyanothiourea (XI) in the presence of EDC provided the title cyanoguanidine derivative.
📌 参考资料/链接：
参考文献标题:Sulfonamido substd.benzopyran potassium channel activators
文献作者:Ding,C.Z.; Atwal,K.S.(Bristol-Myers Squibb Co.)
参考来源:CA 2178353; EP 0747374; JP 1997003035; US 5869478
📄 详细内容
合成路线:Treatment of 2-methyl-3-butyn-2-ol (I) with trifluoroacetic anhydride and DBU gave trifluoroacetate (II),which was condensed with 4-bromophenol (III) in the presence of CuCl2 to afford propargyl ether (IV).Cyclization of (IV) in N,N-diethylaniline at 185 C produced benzopyran (V).The required sulfonyl group was introduced in (V) by lithium-bromine exchange,followed by reaction with sulfur dioxide to give the lithium sulfinate (VI),and then oxidation to the sulfonyl chloride (VII) by means of sulfuryl chloride (1).Subsequent treatment of (VII) with diisobutylamine yielded sulfonamide (VIII).Asymmetric epoxidation of (VIII) using sodium hypochlorite and (S,S)(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) chloride (Jacobsen's catalyst) gave rise to epoxide (IX),which was opened with ammonium hydroxide to furnish the trans aminoalcohol (X).Finally,coupling of (X) with N-chlorophenyl-N'-cyanothiourea (XI) in the presence of EDC provided the title cyanoguanidine derivative.
参考文献标题:Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers.6.Effect of modifications at C6 of benzopyranyl cyanoguanidines
文献作者:Ding,C.Z.; Rovnyak,G.C.; Misra,R.N.; Grover,G.J.; Miller,A.V.; Ahmed,S.Z.; Kelly,Y.; Normandin,D.E.; Sleph,P.G.; Atwal,K.S.
参考来源:J Med Chem 1999,42(18),3711