上市新药伊曲茶碱(Istradefylline)合成检索总结报告

上市新药伊曲茶碱（Istradefylline）合成检索总结报

告

一、伊曲茶碱（Istradefylline）简介

伊曲茶碱（Istradefylline）于2013年5月1日在日本上市，2019年8月27日在美国上市，主要作为左旋多巴／卡比多巴的一种辅助疗法，用于治疗关闭期的帕金森病成人患者。伊曲茶碱（Istradefylline）是一种腺苷A2A受体拮抗药，具体作用机制尚不清楚。伊曲茶碱（Istradefylline）不良反应有运动障碍，头晕，便秘，恶心，幻觉和失眠。

伊曲茶碱（Istradefylline）分子结构式如下：

CAS：155270-99-8

英文名称：Istradefylline

中文名称：伊曲茶碱

化学名：(E)-8-(3，4-二甲氧基苯乙烯基)-

1，3-二乙基-7-甲基-3，7二氢-1H-嘌呤-2,6-二酮

二、伊曲茶碱（Istradefylline）合成路线

三、伊曲茶碱（Istradefylline ）合成检索总结报告(一)伊曲茶碱（Istradefylline ）中间体3

的合成序号

实验步骤参考文献1In a 20L four-necked flask equipped with nitrogen flow protection,oil bath,condenser and mechanical stirring and drying,7000mL acetic anhydride was turned on,followed by 3400g of 1,3-diethylurea 2and 2740g of cyanoacetic acid 1.Oil bath slowly warmed to 75~85o C,incubated for 2hours.Liquid phase control showed that the raw material residue 1.6%.The reaction solution was concentrated to remove the solvent,and approximately 7000mL of solvent was distilled off.50L glass reactor into ice-water was cooled to 5-10o C,at temperature below 20dropwise 34L has a good mass percent concentration with a 5%aqueous sodium hydroxide addition was complete and was cooled to 5~10o C for 1hour.Filtered,the filter cake was washed with a small amount of ice water wet products,wet products in a forced air oven at 65for 24hours to obtain 5000g Yellow solid 6-amino-1,3-diethyl-1H-pyrimidine-

CN107141290;(2017);(A)Chinese

Dione 3,purity:95%;yield:93.3%.2

180

g 1,3-diethylformamide 2,125g cyanoacetic acid 185ml acetic anhydride for ring-forming reaction,The reaction conditions were refluxed at 78o C for 2h,the reaction was completed by adding sodium hydroxide,PH adjusted to neutral after filtration,washed three times,the resulting white solid is Compound 106496227;(2017);(A)Chinese 3

12.69grams (0.14mol)of diethylurea 2and 11.90grams (0.14mol)of cyanoacetic acid were heated in acetic anhydride at 60o C for 3hours,under dry atmosphere.Thereafter,the acetic anhydride and remaining cyanoacetic acid were evaporated,5%sodium hydroxide was added and the mixture was stirred and cooled.20grams of 6-amino-l,3-diethyluracil 3were obtained as a precipitate.WO2007/110868;(2007);(A2)English 4To N,N-diethylurea 2(3.20g,27.6mmol)in acetic anhydride (10mL)was added cyanoacetic acid 1(2.58g,30.3mmol)and the solution heated at 80°C for 2h.Solvent was removed in vacuo at 80°C,then water (10mL)added and evaporated off.The solution was then basified by rapid addition of 70%sodium hydroxide solution.A white precipitate formed,was filtered,washed with water,and dried at 110°C to reveal a white solid which was recrystallised from water to give the title compound 3as colourless needles (4.17g,83%),mp:120-122°C Bioorganic and Medicinal Chemistry Letters ;vol.23;nb.11;(2013);p.3427-3433

(二)伊曲茶碱（Istradefylline ）中间体4的合成序号

实验步骤参考文献1To a solution of 1,3-diethyl-6-aminouracil 3(800mg,4.37mmol)in 50%acetic acid (15mL)at 50-60°C,sodium nitrite (361mg,5.24mmol)was added over 15min.The mixture was cooled to room temperature,then refrigerated overnight.The ensuing orange solid was filtered,washed with cold water (50mL),then dried at 110°C overnight to reveal the title compound 4as bright purple prisms (795mg,86%),mp:205°C

Bioorganic and Medicinal Chemistry Letters ;vol.23;nb.11;(2013);p.3427-343311.8grams of sodium nitrite in 70ml water were then