Istradefylline, KW-6002, -Drug Synthesis Database

【结构式】

【药物名称】Istradefylline, KW-6002

【化学名称】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

【CA登记号】155270-99-8

【分子式】C₂₀H₂₄N₄O₄

【分子量】384.43868

【开发单位】Kyowa Hakko (Originator)

【药理作用】Antidepressants, Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Adenosine A2A Antagonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Blicke, F.F.; Godt, H.C. Jr.; Reactions of 1,3-dimethyl-5,6-diaminouracil. J Am Chem Soc 1954, 76, 2798.
【2】 Leeson, P.A.; Castañer, J.; Sorbera, L.A.; Martín, L.; Rabasseda, X.; KW-6002. Drugs Fut 2001, 26, 1, 21.
【3】 Shimada, J.; Koike, N.; Nonaka, H.; et al.; Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg Med Chem Lett 1997, 7, 18, 2349.
【4】 Suzuki, F.; Shimada, J.; Ishii, A.; Nakamura, J.; Ichikawa, S.; Kitamura, S.; Koike, N. (Kyowa Hakko Kogyo Co., Ltd.); Antidepressant. EP 0628311; JP 1994502746; WO 9401114 .
【5】 Suzuki, F.; Shimada, J.; Koike, N.; Nakamura, J.; Shiozaki, S.; Ichikawa, S.; Nonaka, H. (Kyowa Hakko Kogyo Co., Ltd.); Therapeutic agents for Parkinson's disease. EP 0590919; JP 1994211856; US 5484920 .
【6】 Miwa, K.; Ito, K.; Kato, N.; Kuge, Y.; Kousai, M.; Tomioka, S. (Kyowa Hakko Kogyo Co., Ltd.); Preparation of uracil derivs.. JP 1997040652 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	43818	N,N'-diethylurea	623-76-7	C₅H₁₂N₂O	详情	详情
(II)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(III)	43819	6-amino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione		C₈H₁₃N₃O₂	详情	详情
(IV)	43820	6-amino-1,3-diethyl-5-nitroso-2,4(1H,3H)-pyrimidinedione		C₈H₁₂N₄O₃	详情	详情
(V)	28567	5,6-diamino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione		C₈H₁₄N₄O₂	详情	详情
(VI)	33601	(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl chloride		C₁₁H₁₁ClO₃	详情	详情
(VII)	28568	(E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid	2316-26-9	C₁₁H₁₂O₄	详情	详情
(VIII)	43821	(E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-3-(3,4-dimethoxyphenyl)-2-propenamide		C₁₉H₂₄N₄O₅	详情	详情
(IX)	28569	8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-dione		C₁₉H₂₂N₄O₄	详情	详情

合成路线2

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.

参考文献中间体

【1】 Brady, F.; Luthra, S.K.; Shimada, J.; Karasawa, A.; Brooks, D.J.; Gillies, J.; Kase, H.; Radiolabelling of KW-6002 with [11C]iodomethane for studies of the adenosine A2A receptor in vivo. J Label Compd Radiopharm 1999, 42, Suppl. 1, S456.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	43485	8-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-7-methyl-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione		C₂₁H₂₆N₄O₄	详情	详情

Extended Information