EMD-122946
Chemical Name: 2-(2,1,3-Benzothiadiazol-5-yl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-2(Z)-butenoic acid sodium salt
项目整合开发状态: Preclinical
项目研究机构: Merck KGaA (Originator)
合成路线:The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride,followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II),which is reduced at the nitro group,and cyclized with SOCl2 yielding the benzothiadiazole (III).The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V),which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII).Finally,this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.
📌 参考资料/链接：
参考文献标题:2,1,3-Benzothia(oxa)diazole derivs.having an endothelin receptor antagonistic effect
文献作者:Dorsch,D.; Osswald,M.; Mederski,W.; Wilm,C.; Schmitges,C.; Christadler,M.; Anzali,S.(Merck Patent GmbH)
参考来源:DE 19607096; EP 0882030; WO 9730982
📄 详细内容
合成路线:The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride,followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II),which is reduced at the nitro group,and cyclized with SOCl2 yielding the benzothiadiazole (III).The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V),which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII).Finally,this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.
参考文献标题:Endothelin antagonists: Evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster
文献作者:Mederski,W.W.K.R.; Osswald,M.; Dorsch,D.; Anzali,S.; Christadler,M.; Schmitges,C.J.; Wilm,C.
参考来源:Bioorg Med Chem Lett 1998,8(1),17
合成路线:The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride,followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II),which is reduced at the nitro group,and cyclized with SOCl2 yielding the benzothiadiazole (III).The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V),which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII).Finally,this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.
参考文献标题:3.Endothelin antagonists: Discovery of EMD 122946,a highly potent and orally active ETA selective antagonist
文献作者:Mederski,W.W.K.R.; Dorsch,D.; Osswald,M.; Anzali,S.; Christadler,M.; Schmitges,C.J.; Schelling,P.; Wilm,C.; Fluck,M.
参考来源:Bioorg Med Chem Lett 1998,8(13),1771