NK-3201
N-[1-苄基-2,3-二氧基-6-(2-吡啶氧基)己基]-2-[5-(甲酰胺)-6-氧基-2-苯基-1,6-二氢嘧啶-1-基]乙酰胺Chemical Name: N-[1-Benzyl-2,3-dioxo-6-(2-pyridyloxy)hexyl]-2-[5-(formylamino)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetamide
CAS No. 204460-24-2
项目整合开发状态: Preclinical
项目研究机构: Nippon Kayaku (Originator)
合成路线:Hydroxy amino ester (I) was protected as the oxazolidine (III) upon heating with 2,2-dimethoxypropane (II) in the presence of p-toluenesulfonic acid.Conversion of the ester group of (III) into aldehyde (V) was accomplished by reduction to alcohol (IV) with LiAlH4,followed by NaOCl oxidation catalyzed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr.Addition of 3-(benzyloxy)propylmagnesium bromide (VI) to aldehyde (V) furnished carbinol (VII),which was further protected as the silyl ether (VIII) by treatment with tert-butyldimethylsilyl chloride and imidazole.After hydrogenolysis of the O-benzyl protecting group of (VIII),the resultant primary alcohol (IX) was converted to bromide (X) employing the N-bromosuccinimide/triphenylphosphine reagent.
合成路线:Alkylation of 2-hydroxypyridine (XI) with bromide (X) produced a mixture of the N-alkylated pyridone (XII) and the pyridyl ether (XIII),which were separated by column chromatography.The required minor regioisomer (XIII) was desilylated with tetrabutylammonium fluoride,and the resultant alcohol (XIV) was oxidized under Swern conditions to the ketone (XV).Acidic hydrolysis of the cyclic aminal function of (XV) furnished amino alcohol (XVI).This was then coupled with the pyrimidinylacetic acid (XVII) to yield amide (XVIII).The free hydroxyl group of (XVIII) was subsequently esterified with acetic anhydride giving ester (XIX).
合成路线:Acidic Boc group cleavage from (XIX) produced amine (XX).This was converted to formamide (XXI) upon treatment with in situ-generated formic acetic anhydride.Selective hydrolysis of the acetate ester of (XXI) was then achieved by treatment with K2CO3 in MeOH.The resultant keto alcohol (XXII) was finally oxidized to the title diketone employing DMSO in the presence of EDC and pyridinium trifluoroacetate
📌 参考资料/链接：
参考文献标题:Novel acetamide derivs.and protease inhibitors
文献作者:Suzuki,Y.; Ishida,K.(Nippon Kayaku Co.,Ltd.)
参考来源:EP 0936216; US 6271238; WO 9809949
📄 详细内容
合成路线:Hydroxy amino ester (I) was protected as the oxazolidine (III) upon heating with 2,2-dimethoxypropane (II) in the presence of p-toluenesulfonic acid.Conversion of the ester group of (III) into aldehyde (V) was accomplished by reduction to alcohol (IV) with LiAlH4,followed by NaOCl oxidation catalyzed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr.Addition of 3-(benzyloxy)propylmagnesium bromide (VI) to aldehyde (V) furnished carbinol (VII),which was further protected as the silyl ether (VIII) by treatment with tert-butyldimethylsilyl chloride and imidazole.After hydrogenolysis of the O-benzyl protecting group of (VIII),the resultant primary alcohol (IX) was converted to bromide (X) employing the N-bromosuccinimide/triphenylphosphine reagent.
合成路线:Alkylation of 2-hydroxypyridine (XI) with bromide (X) produced a mixture of the N-alkylated pyridone (XII) and the pyridyl ether (XIII),which were separated by column chromatography.The required minor regioisomer (XIII) was desilylated with tetrabutylammonium fluoride,and the resultant alcohol (XIV) was oxidized under Swern conditions to the ketone (XV).Acidic hydrolysis of the cyclic aminal function of (XV) furnished amino alcohol (XVI).This was then coupled with the pyrimidinylacetic acid (XVII) to yield amide (XVIII).The free hydroxyl group of (XVIII) was subsequently esterified with acetic anhydride giving ester (XIX).
合成路线:Acidic Boc group cleavage from (XIX) produced amine (XX).This was converted to formamide (XXI) upon treatment with in situ-generated formic acetic anhydride.Selective hydrolysis of the acetate ester of (XXI) was then achieved by treatment with K2CO3 in MeOH.The resultant keto alcohol (XXII) was finally oxidized to the title diketone employing DMSO in the presence of EDC and pyridinium trifluoroacetate
参考文献标题:NK-3201
文献作者:Doggrell,S.A.; Castar,J.
参考来源:Drugs Fut 2003,28(4),323
产品链接: CAS No. 204460-24-2››