Enprofylline, D-4028

恩丙茶碱Chemical Name: 3-Propylxanthine; 3,7-Dihydro-3-propyl-1H-purine-2,6-dione
CAS No. 41078-02-8
项目整合开发状态: Phase III
项目研究机构: AstraZeneca (Originator), Merck & Co. (Originator)
合成路线:The reaction of N-propylurea (V) with cyanacetic acid (VI) in hot acetic anhydride gives N-propyl-N'-cyanacetylurea (VII),which is nitrosated with NaNO2 - HCl yielding the isonitroso derivative (VIII).The reduction and simultaneous formylation of (VIII) with Zn in formic acid affords the formylamino compound (IX),which is cyclized by treatment with NaOH to give 6-amino-5-formylamino-1-propylpyrimidine-2,4-dione (X).Finally,this compound is cyclized by treatment with refluxing formic acid.The cyclization of (VII) with NaOH in hot water gives 6-amino-1-propylpyrimidine-2,4-dione (XI),which is nitrosated with NaNO2 - HCl as usual yielding 6-amino-nitroso-1-propylpyrimidine-2,4-dione (XII).The reduction of (XII) with H2 over Pt in DMF affords 5,6-diamino-1-propylpyrimidine-2,4-dione (XIII),which is finally formylated with refluxing formic acid to (X).This compound can also be finally cyclized by treatment with NaOH in refluxing water.
📌 参考资料/链接:
参考文献标题:Method and pharmaceutical preparation for treating chronic obstructive airway disease and cardiac disease,and intermediates for the preparation of therapeutically active xanthine derivs.
文献作者:Kjellin,P.G.; Persson,C.G.A.(Draco L鋕emedel AB)
参考来源:EP 0011609

📄 详细内容


合成路线:The reaction of 5-amino-4-cyanooxazole (I) with tetramethyl orthocarbonate (II) in refluxing acetic anhydride gives 4-cyano-5-(diethoxymethyleneamino)oxazole (III),which is cyclized with propylamine (A) in refluxing ethanol yielding 5-methoxy-6-propyl-7(6H)-iminooxazolo[5,4-d]pyrimidine (IV),which is finally hydrolyzed and rearranged by treatment with NaOH in water at 100 C or with formamide at 180 C.

合成路线:The reaction of N-propylurea (V) with cyanacetic acid (VI) in hot acetic anhydride gives N-propyl-N'-cyanacetylurea (VII),which is nitrosated with NaNO2 - HCl yielding the isonitroso derivative (VIII).The reduction and simultaneous formylation of (VIII) with Zn in formic acid affords the formylamino compound (IX),which is cyclized by treatment with NaOH to give 6-amino-5-formylamino-1-propylpyrimidine-2,4-dione (X).Finally,this compound is cyclized by treatment with refluxing formic acid.The cyclization of (VII) with NaOH in hot water gives 6-amino-1-propylpyrimidine-2,4-dione (XI),which is nitrosated with NaNO2 - HCl as usual yielding 6-amino-nitroso-1-propylpyrimidine-2,4-dione (XII).The reduction of (XII) with H2 over Pt in DMF affords 5,6-diamino-1-propylpyrimidine-2,4-dione (XIII),which is finally formylated with refluxing formic acid to (X).This compound can also be finally cyclized by treatment with NaOH in refluxing water.

参考文献标题:Enprofylline
文献作者:Sneddon,J.M.; Castar,J.; Blancafort,P.; Serradell,M.N.
参考来源:Drugs Fut 1982,7(9),623


合成路线:The reaction of 5-amino-4-cyanooxazole (I) with tetramethyl orthocarbonate (II) in refluxing acetic anhydride gives 4-cyano-5-(diethoxymethyleneamino)oxazole (III),which is cyclized with propylamine (A) in refluxing ethanol yielding 5-methoxy-6-propyl-7(6H)-iminooxazolo[5,4-d]pyrimidine (IV),which is finally hydrolyzed and rearranged by treatment with NaOH in water at 100 C or with formamide at 180 C.

合成路线:The reaction of N-propylurea (V) with cyanacetic acid (VI) in hot acetic anhydride gives N-propyl-N'-cyanacetylurea (VII),which is nitrosated with NaNO2 - HCl yielding the isonitroso derivative (VIII).The reduction and simultaneous formylation of (VIII) with Zn in formic acid affords the formylamino compound (IX),which is cyclized by treatment with NaOH to give 6-amino-5-formylamino-1-propylpyrimidine-2,4-dione (X).Finally,this compound is cyclized by treatment with refluxing formic acid.The cyclization of (VII) with NaOH in hot water gives 6-amino-1-propylpyrimidine-2,4-dione (XI),which is nitrosated with NaNO2 - HCl as usual yielding 6-amino-nitroso-1-propylpyrimidine-2,4-dione (XII).The reduction of (XII) with H2 over Pt in DMF affords 5,6-diamino-1-propylpyrimidine-2,4-dione (XIII),which is finally formylated with refluxing formic acid to (X).This compound can also be finally cyclized by treatment with NaOH in refluxing water.
参考文献标题:Oxazolopyrimidines.VI.Formation of 3-substituted xanthines via 7-(6H)-iminooxazolopyrimidines
文献作者:Ohtsuka,Y.
参考来源:Bull Chem Soc Jpn 1973,46(2),506-509


产品链接: CAS No. 41078-02-8››