新产品编号:886429
Chemical Name: N-(1,3-Benzodioxol-5-ylmethyl)-3-(3,5-difluorophenyl)-N-[3-(perhydroazepin-1-yl)propyl]isoxazol-5-amine
CAS No. 359418-53-4, 359418-52-3 (hydrochloride), 359418-54-5 (trifluoroacetate)
项目整合开发状态: Biological Testing
项目研究机构: Merck & Co. (Originator)
合成路线:The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III),which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V).Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine.The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX),which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X).Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate.Alternatively,the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)
📌 参考资料/链接：
参考文献标题:Isoxazole thrombin receptor antagonists
文献作者:Freidinger,R.M.; Selnick,H.G.; Connolly,T.; Barrow,J.C.; Nantermet,P.G.(Merck & Co.,Inc.)
参考来源:GB 2356198
📄 详细内容
合成路线:The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III),which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V).Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine.The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX),which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X).Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate.Alternatively,the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)
参考文献标题:Discovery of a nonpeptide small molecule antagonist of the human platelet thrombin receptor (PAR-1)
文献作者:Nantermet,P.G.; Barrow,J.C.; Lundell,G.F.; Pellicore,J.M.; Rittle,K.E.; Young,M.; Freidinger,R.M.; Connolly,T.M.; Condra,C.L.; Karczewski,J.; Bednar,R.A.; Gaul,S.L.; Gould,R.J.; Prendergast,K.; Selnick,H.G.
参考来源:Bioorg Med Chem Lett 2002,12(3),319