An efficient synthesis of antitumor drug cabazitaxel

CHEN Ming1 GUO Feng-jie1 ZHAO Guan-ren1

(1.Department of Pharmacy, the 309th Hospital of PLA, Beijing, China 100091)

【Abstract】Patients with castration-resistant prostate cancer (CRPC) had limited therapeutic options once they became refractory to docetaxel chemotherapy, and no treatments improved survival until recently. In June 2010, the taxane anticancer drug cabazitaxel (Jevtana; Sanofi-Aventis), was approved in the US by FDA and in Europe by the EMA in combination with prednisone for the treatment of patients with CRPC whose disease progresses were after docetaxel treatment. As reported, more than 217 000 men have been diagnosed with prostate cancer and 32 000 will die of metastatic prostate cancer in the United States. Therefore, cabazitaxel will have the potential market prospect in future. Cabazitaxel is a semisynthetic taxane which possesses the same antitumor mechanism as paclitaxel and docetaxel. It is a 7,10-O-dimethylated derivative of docetaxel. The synthetic route of cabazitaxel is similar to that of docetaxel, but more difficult. Only few syntheses have been reported so far. Chattopadhyay S. K. et al. synthesized cabazitaxel in six steps with a total yield of 5.4% starting from 10-deacetylbaccatin Ⅲ (10-DAB) in 2002. In 2011, Sun et al. described dimethylation of the 7,10-OH of 10-DAB, and reaction with a protected (3R, 4S)-β-lactam, followed by deprotection, and gave cabazitaxel in 17.8% total yield. In 2012, Zhang et al. reported direct dimethylation of expensive docetaxel, which was prepared from 10-DAB in few steps, and could furnish cabazitaxel in 82% yield. Indeed, cabazitaxel could be synthesized by these methods. However, these methods, which normally needed column chromatography in purification procedure, are not suitable for scale-up. We found 2-(4-methoxy-phenyl)-4-phenyl-5-oxazoline acid ester is extremely unstable and easy to remove protection groups in acidic condition. Based on this finding, we designed a new synthetic method of cabazitaxel. The design involved seven steps and had the total yield of 41.5% with the purity of 99% started with available materials. The new synthesis, characterized by the simplicity of operation and the convenience of purification, is suitable for large-scale production.

【Keywords】 cabazitaxel; antitumor; synthesis; large-scale;


【Funds】 Foundation of the 309th Hospital of PLA (2015MS-011)

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This Article



Vol 28, No. 02, Pages 113-118

April 2018


Article Outline


  • 1 Synthetic route
  • 2 Synthetic experiments
  • 3 Results and discussion
  • References