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Istradefylline, KW-6002

伊曲茶碱Chemical Name: 8-[2(E)-(3,4-Dimethoxyphenyl)vinyl]-1,3-diethyl-7-methylxanthine; 8-[(1E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
CAS No. 155270-99-8
项目整合开发状态: Phase II
项目研究机构: Kyowa Hakko (Originator)
合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.

合成路线:Acylation of 5,6-diamino-1,3-dimethyluracil (I) with 4-methoxy-2,3-dimethylcinnamic acid (II) in the presence of EDC gave amide (III).This was then cyclized under basic conditions to afford the styryltheophylline derivative (IV).Finally,methylation of (IV) with iodomethane and K2CO3 furnished the title caffeine derivative.
📌 参考资料/链接:
参考文献标题:Antidepressant
文献作者:Suzuki,F.; Shimada,J.; Ishii,A.; Nakamura,J.; Ichikawa,S.; Kitamura,S.; Koike,N.(Kyowa Hakko Kogyo Co.,Ltd.)
参考来源:EP 0628311; JP 1994502746; WO 9401114

📄 详细内容


合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.

合成路线:Acylation of 5,6-diamino-1,3-dimethyluracil (I) with 4-methoxy-2,3-dimethylcinnamic acid (II) in the presence of EDC gave amide (III).This was then cyclized under basic conditions to afford the styryltheophylline derivative (IV).Finally,methylation of (IV) with iodomethane and K2CO3 furnished the title caffeine derivative.

参考文献标题:Therapeutic agents for Parkinson's disease
文献作者:Suzuki,F.; Shimada,J.; Koike,N.; Nakamura,J.; Shiozaki,S.; Ichikawa,S.; Nonaka,H.(Kyowa Hakko Kogyo Co.,Ltd.)
参考来源:EP 0590919; JP 1994211856; US 5484920


合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.

参考文献标题:Preparation of uracil derivs.
文献作者:Miwa,K.; Ito,K.; Kato,N.; Kuge,Y.; Kousai,M.; Tomioka,S.(Kyowa Hakko Kogyo Co.,Ltd.)
参考来源:JP 1997040652


合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.

参考文献标题:Adenosine A2A antagonists with potent anti-cataleptic activity
文献作者:Shimada,J.; Koike,N.; Nonaka,H.; et al.
参考来源:Bioorg Med Chem Lett 1997,7(18),2349


合成路线:This compound has been obtained by methylation of 1,3-diethyl-8-[2(E)-(4-hydroxy-3-methoxyphenyl)vinyl]-7-methylxanthine (I) (KF-23325) with 11C methyl iodide and NaOH in DMF.

参考文献标题:Radiolabelling of KW-6002 with [11C]iodomethane for studies of the adenosine A2A receptor in vivo
文献作者:Brady,F.; Luthra,S.K.; Shimada,J.; Karasawa,A.; Brooks,D.J.; Gillies,J.; Kase,H.
参考来源:J Label Compd Radiopharm 1999,42(Suppl.1),S456


合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.

参考文献标题:KW-6002
文献作者:Leeson,P.A.; Castar,J.; Sorbera,L.A.; Mart韓,L.; Rabasseda,X.
参考来源:Drugs Fut 2001,26(1),21


合成路线:Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV).The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V),which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII).Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX),which is finally methylated with methyl iodide and K2CO3 in DMF.
参考文献标题:Reactions of 1,3-dimethyl-5,6-diaminouracil
文献作者:Blicke,F.F.; Godt,H.C.Jr.
参考来源:J Am Chem Soc 1954,762798


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