SA-862
Chemical Name: 3-(3-Amidinophenyl)-N-(2'-sulfamoylbiphenyl-4-yl)isoxazole-4-carboxamide
CAS No. 209730-58-5, 209730-59-6 (monotrifluoroacetate)
项目整合开发状态: Preclinical
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:3-Cyanobenzaldehyde oxime (I) was treated with N-chlorosuccinimide to afford hydroxyiminoyl chloride (II).Subsequent cycloaddition of the intermediate nitrile oxide,generated in situ from (II) and Et3N,with methyl methoxyacrylate (III) produced isoxazole (IV).Then,basic hydrolysis of the ester group,followed by treatment with SOCl2 provided acid chloride (V).Aminobiphenyl (VIII) was obtained by Suzuki coupling of 4-bromoaniline (VI) with boronic acid (VII) using a palladium catalyst.Condensation of (VIII) with acid chloride (V) in the presence of Et3N then gave amide (IX).Alternatively,amide (IX) was obtained by AlMe3-catalyzed condensation of ester (IV) with amine (VIII).Treatment of nitrile (IX) with HCl in MeOH-CHCl3 generated the corresponding iminoester (X) with concomitant cleavage of the N-tert-butyl group.Finally,reaction of this iminoester with methanolic ammonium carbonate afforded the target amidine.
合成路线:The reaction of 3-formylbenzonitrile (I) with methyl 2-bromoacetate (II) by means of activated Zn in hot THF gives 3-(3-cyanophenyl)-3-hydroxypropionic acid methyl ester (III),which is oxidized with activated MnO2 in hot dichloromethane yielding the oxoester (IV).The bromination of (IV) with NBS in CCl4 affords the alpha bromo derivative (V),which is cyclized with thioacetamide (VI) in hot THF affording 4-(3-cyanophenyl)-2-methylthiazole-5-carboxylic acid methyl ester (VII).The condensation of (VII) with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VIII) by means of trimethylaluminum in toluene/dichloromethane gives the corresponding amide (IX),which is treated with hot TFA to eliminate the ter-butyl protecting group yielding intermediate (X).Finally,the cyano group of (X) is treated first with anhydrous HCl in methanol,and finally with ammonium carbonate in the same solvent to obtain the target amidine.
📌 参考资料/链接：
参考文献标题:Oxygen or sulfur containing heteroaromatics as fac
文献作者:Quan,M.L.; Pinto,D.J.P.; Fevig,J.M.; Pruitt,J.R.(DuPont Pharmaceuticals Co.)
参考来源:WO 9828282
📄 详细内容
合成路线:3-Cyanobenzaldehyde oxime (I) was treated with N-chlorosuccinimide to afford hydroxyiminoyl chloride (II).Subsequent cycloaddition of the intermediate nitrile oxide,generated in situ from (II) and Et3N,with methyl methoxyacrylate (III) produced isoxazole (IV).Then,basic hydrolysis of the ester group,followed by treatment with SOCl2 provided acid chloride (V).Aminobiphenyl (VIII) was obtained by Suzuki coupling of 4-bromoaniline (VI) with boronic acid (VII) using a palladium catalyst.Condensation of (VIII) with acid chloride (V) in the presence of Et3N then gave amide (IX).Alternatively,amide (IX) was obtained by AlMe3-catalyzed condensation of ester (IV) with amine (VIII).Treatment of nitrile (IX) with HCl in MeOH-CHCl3 generated the corresponding iminoester (X) with concomitant cleavage of the N-tert-butyl group.Finally,reaction of this iminoester with methanolic ammonium carbonate afforded the target amidine.
参考文献标题:Phenyl-isoxazoles as factor Xa inhibitors
文献作者:Pinto,D.J.P.; Pruitt,J.R.; Fevig,J.M.; Quan,M.L.(DuPont Pharmaceuticals Co.)
参考来源:US 6187797
合成路线:3-Cyanobenzaldehyde oxime (I) was treated with N-chlorosuccinimide to afford hydroxyiminoyl chloride (II).Subsequent cycloaddition of the intermediate nitrile oxide,generated in situ from (II) and Et3N,with methyl methoxyacrylate (III) produced isoxazole (IV).Then,basic hydrolysis of the ester group,followed by treatment with SOCl2 provided acid chloride (V).Aminobiphenyl (VIII) was obtained by Suzuki coupling of 4-bromoaniline (VI) with boronic acid (VII) using a palladium catalyst.Condensation of (VIII) with acid chloride (V) in the presence of Et3N then gave amide (IX).Alternatively,amide (IX) was obtained by AlMe3-catalyzed condensation of ester (IV) with amine (VIII).Treatment of nitrile (IX) with HCl in MeOH-CHCl3 generated the corresponding iminoester (X) with concomitant cleavage of the N-tert-butyl group.Finally,reaction of this iminoester with methanolic ammonium carbonate afforded the target amidine.
参考文献标题:Isoxazolines and isoxazoles as factor Xa inhibitor
文献作者:Wexler,R.R.; Bostrom,L.L.; Pinto,D.J.; Wrong,P.C.; Pruitt,J.R.; Knabb,R.M.; Estrella,M.J.; Quan,M.L.
参考来源:216th ACS Natl Meet (Aug.23-27,Boston) 1998,Abst MEDI 077
合成路线:The cyclization of the chlorooxime (I) with formylacetic methyl ester (II) by means of diazomethane and TEA gives the 3-(3-cyanophenyl)isoxazole-4-carboxylic acid methyl ester (III),which is condensed with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (IV) by means of AlMe3 to yield the corresponding amide (V).The methanolysis of the cyano group of (V) with HCl and methanol affords the iminoester (VI),which is finally converted into the target amidine by reaction with ammonium carbonate.
参考文献标题:Isoxazolines and isoxazoles as factor Xa inhibitors
文献作者:Pruitt,J.R.; Pinto,D.J.; Estrella,M.J.; Bostrom,L.L.; Knabb,R.M.; Wong,P.C.; Wright,M.R.; Wexler,R.R.
参考来源:Bioorg Med Chem Lett 2000,10(8),685