Enprofylline, D-4028, -Drug Synthesis Database

【结构式】

【药物名称】Enprofylline, D-4028

【化学名称】3-Propylxanthine
　　　　　　3,7-Dihydro-3-propyl-1H-purine-2,6-dione

【CA登记号】41078-02-8

【分子式】C₈H₁₀N₄O₂

【分子量】194.1945

【开发单位】AstraZeneca (Originator), Merck & Co. (Originator)

【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Ohtsuka, Y.; Oxazolopyrimidines. VI. Formation of 3-substituted xanthines via 7-(6H)-iminooxazolopyrimidines. Bull Chem Soc Jpn 1973, 46, 2, 506-509.
【2】 Sneddon, J.M.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Enprofylline. Drugs Fut 1982, 7, 9, 623.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	23923	1-propanamine	107-10-8	C₃H₉N	详情	详情
(I)	37129	5-amino-1,3-oxazole-4-carbonitrile		C₄H₃N₃O	详情	详情
(II)	37130	methyl trimethoxymethyl ether; tetramethoxymethane	1850-14-2	C₅H₁₂O₄	详情	详情
(III)	37131	4-cyano-5-[(dimethoxymethylene)amino]-1,3-oxazole		C₇H₇N₃O₃	详情	详情
(IV)	37132	5-methoxy-6-propyl[1,3]oxazolo[5,4-d]pyrimidin-7(6H)-imine		C₉H₁₂N₄O₂	详情	详情

合成路线2

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.

参考文献中间体

【1】 Ohtsuka, Y.; Oxazolopyrimidines. VI. Formation of 3-substituted xanthines via 7-(6H)-iminooxazolopyrimidines. Bull Chem Soc Jpn 1973, 46, 2, 506-509.
【2】 Kjellin, P.G.; Persson, C.G.A. (Draco Läkemedel AB); Method and pharmaceutical preparation for treating chronic obstructive airway disease and cardiac disease, and intermediates for the preparation of therapeutically active xanthine derivs.. EP 0011609 .
【3】 Sneddon, J.M.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Enprofylline. Drugs Fut 1982, 7, 9, 623.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	37133	N-propylurea		C₄H₁₀N₂O	详情	详情
(VI)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(VII)	37134	N-(2-cyanoacetyl)-N'-propylurea		C₇H₁₁N₃O₂	详情	详情
(VIII)	37135	N-[2-cyano-2-(hydroxyimino)acetyl]-N'-propylurea		C₇H₁₀N₄O₃	详情	详情
(IX)	37136	N-[2-cyano-2-(formylamino)acetyl]-N'-propylurea		C₈H₁₂N₄O₃	详情	详情
(X)	37137	6-amino-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinylformamide		C₈H₁₂N₄O₃	详情	详情
(XI)	37138	6-amino-1-propyl-2,4(1H,3H)-pyrimidinedione		C₇H₁₁N₃O₂	详情	详情
(XII)	37139	6-amino-5-nitroso-1-propyl-2,4(1H,3H)-pyrimidinedione		C₇H₁₀N₄O₃	详情	详情
(XIII)	20546	5,6-diamino-1-propyl-2,4(1H,3H)-pyrimidinedione		C₇H₁₂N₄O₂	详情	详情

Extended Information