BL-3875
Chemical Name: N-(3,5-Dimethylisoxazol-4-ylcarbonyl)-L-valyl-L-proline 1(S)-(1-benzothien-3-ylmethyl)-3,3,3-trifluoro-2-oxopropylamide
CAS No. 402732-26-7
项目整合开发状态: Preclinical
项目研究机构: Dainippon Pharmaceutical (Originator)
合成路线:N-Boc-Benzothienylalanine (I) was converted to oxazolidinone (II) by treatment with paraformaldehyde in the presence of p-toluenesulfonic acid.Reaction of oxazolidinone (II) with trimethyl(trifluoromethyl)silane produced the corresponding trifluoromethyl ketone,which was subsequently reduced to alcohol (III) by using NaBH4 in MeOH (1).Cleavage of the N-Boc group of (III) under acidic conditions afforded amine (IV).This was then coupled with N-Boc-L-valyl-L-proline (V) using EDC to furnish the N-Boc-tripeptidyl alcohol (VI).Deprotection of (VI) by means of HCl in dioxane gave amine (VII),which was acylated with 3,5-dimethylisoxazole-4-carboxylic acid (VIII) to yield amide (IX).Finally,oxidation of the alcohol function of (IX) employing the Dess-Martin periodinane reagent provided the target trifluoromethyl ketone
合成路线:N-Boc-Benzothienylalanine (I) was converted to oxazolidinone (II) by treatment with paraformaldehyde in the presence of p-toluenesulfonic acid.Reaction of oxazolidinone (II) with trimethyl(trifluoromethyl)silane produced the corresponding trifluoromethyl ketone,which was subsequently reduced to alcohol (III) by using NaBH4 in MeOH (1).Cleavage of the N-Boc group of (III) under acidic conditions afforded amine (IV).This was then coupled with N-Boc-L-valyl-L-proline (V) using EDC to furnish the N-Boc-tripeptidyl alcohol (VI).Deprotection of (VI) by means of HCl in dioxane gave amine (VII),which was acylated with 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (VIII) to yield amide (IX).Finally,oxidation of the alcohol function of (IX) employing the Dess-Martin periodinane reagent provided the target trifluoromethyl ketone.
📌 参考资料/链接：
参考文献标题:Pyrrolidine derivs.and their use as chymase inhibitor
文献作者:Sato,F.; Showell,G.A.; Fujitani,B.; Deguchi,T.; Honda,Y.; Shiratake,R.; Kiyoshi,A.; Notake,M.; Boyle,R.G.; Klair,S.S.(Dainippon Pharmaceutical Co.,Ltd.)
参考来源:WO 0218378
📄 详细内容
合成路线:N-Boc-Benzothienylalanine (I) was converted to oxazolidinone (II) by treatment with paraformaldehyde in the presence of p-toluenesulfonic acid.Reaction of oxazolidinone (II) with trimethyl(trifluoromethyl)silane produced the corresponding trifluoromethyl ketone,which was subsequently reduced to alcohol (III) by using NaBH4 in MeOH (1).Cleavage of the N-Boc group of (III) under acidic conditions afforded amine (IV).This was then coupled with N-Boc-L-valyl-L-proline (V) using EDC to furnish the N-Boc-tripeptidyl alcohol (VI).Deprotection of (VI) by means of HCl in dioxane gave amine (VII),which was acylated with 3,5-dimethylisoxazole-4-carboxylic acid (VIII) to yield amide (IX).Finally,oxidation of the alcohol function of (IX) employing the Dess-Martin periodinane reagent provided the target trifluoromethyl ketone
合成路线:N-Boc-Benzothienylalanine (I) was converted to oxazolidinone (II) by treatment with paraformaldehyde in the presence of p-toluenesulfonic acid.Reaction of oxazolidinone (II) with trimethyl(trifluoromethyl)silane produced the corresponding trifluoromethyl ketone,which was subsequently reduced to alcohol (III) by using NaBH4 in MeOH (1).Cleavage of the N-Boc group of (III) under acidic conditions afforded amine (IV).This was then coupled with N-Boc-L-valyl-L-proline (V) using EDC to furnish the N-Boc-tripeptidyl alcohol (VI).Deprotection of (VI) by means of HCl in dioxane gave amine (VII),which was acylated with 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (VIII) to yield amide (IX).Finally,oxidation of the alcohol function of (IX) employing the Dess-Martin periodinane reagent provided the target trifluoromethyl ketone.
参考文献标题:Synthesis and structure-activity relationships of a novel peptidyl trifluoromethyl ketone inhibitor of human chymase
文献作者:Deguchi,T.; Shiratake,R.; Sato,F.; Fujitani,B.; Kiyoshi,A.; Honda,Y.; Notake,M.
参考来源:223rd ACS Natl Meet (April 7 2002,Orlando) 2002,Abst MEDI 61