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A convenient synthesis of gimeracil

Posted on 6. March, 2018.

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A practical three-step synthetic approach to gimeracil in a 68% overall yield is described, using 2,4-dimethoxypyridine as the starting material with 3,5-dichloro-2,4-dimethoxypyridine and 3,5-dichloro-2,4-dihydroxypyridine as intermediates. The advantages of this procedure include short reaction steps, simple operation and good yield.

The anti-cancer drug S-1 (trade name Teysuno in Japan) contains three ingredients: tegafur, gimeracil and oteracil. It is commonly used for the treatment of advanced gastric cancer. Recently, it has also been used in combination with cisplatin to treat other kinds of cancers, such as head and neck cancer, colorectal cancer and non-small-cell lung cancers in several countries. Within the drug, the molar ratio of tegafur, gimeracil and oteracil is 1:1:0.4.  Among these ingredients, tegafur is the actual chemotherapeutic agent. It is a prodrug of 5-fluorouridine (5-FU). Gimeracil can reversibly block dihydropyrimidine dehydrogenase (DPD), resulting in higher 5-FU levels and a prolonged half-life.
Gimeracil (2), 5-chloro-2,4-dihydroxypyridine, has been known for over 60 years with several synthetic methods reported. However, most of these methods have several drawbacks such as long synthetic steps, necessity of the use of special equipment (e.g. a sealed tube) and time-consuming procedures.
In this study, the authors have developed an efficient three-step preparation of gimeracil from easily available 2,4-dimethoxypyridine.

Read the full article in Journal of Chemical Research, Volume 42, Number 1, January 2018, pp. 33-34.

Authors: Xiao-lin Lia, Hao-ting Zhua, Li Zhana, Ting Liua, Guang Chengb, Ning Liub, Shan-bao Yuc, Hui Lic, Yu Luoa*, Fan Yanga and Jie Tanga
aDepartment of Chemistry, School of Chemistry and Molecular Engineering (Current address: Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering), East China Normal University, Shanghai, 200241, P.R. China
bNanjing Luye Pharmaceutical Co., Ltd., Nanjing 210061, P.R. China
cPharmaBlock Sciences (Nanjing), Inc., Nanjing 210032, P.R. China

Keywords: gimeracil, synthesis of gimeracil, S-1, protodechlorination, SNAr