抗肿瘤药物卡巴他赛的合成方法研究  

An efficient synthesis of antitumor drug cabazitaxel

作　　者：陈明[1] 郭丰洁[1] 赵冠人[1] CHEN Ming;GUO Feng-jie;ZHAO Guan-ren(Department of Pharmacy, The 309th Hospital of PLA ,Beijing 100091, China)

机构地区：[1]中国人民解放军第309医院药剂科,北京100091

出　　处：《中国药物化学杂志》2018年第2期113-118,共6页Chinese Journal of Medicinal Chemistry

基　　金：解放军第309医院院内课题基金项目(2015MS-011)

摘　　要：目的研究抗肿瘤药物卡巴他赛的合成新方法。方法以10-脱乙酰基巴卡亭(10-DAB)和苯基异丝氨酸甲酯为原料,经过10-DAB的双甲基化、苯基异丝氨酸甲酯保护、酯解、酯化偶联、脱保护得到关键的中间体,最后再经Boc反应得到目标产物卡巴他赛。结果与结论以商品化的原料开始,共经7步反应得到卡巴他赛,总收率达到41.5%(以10-DAB计),纯度99%以上。部分中间体结构经~1H-NMR、^(13)C-NMR及HRMS表征。该合成路线操作简单、纯化方便、避免柱色谱分离,适合规模化生产。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 June2010,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 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-dimethyla-ted derivative of docetaxel.The synthetic route of cabazitaxel is similar to that of docetaxel,but more difficult. Only fewsyntheses 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,reaction with a protected（3R,4S）-β-lactam,followed by deprotection,gave cabazitaxel in 17. 8% total yield. In 2012,Zhang et al reported direct dimethylation of expensive docetaxel,which prepared from 10-DAB in fewsteps,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 this finding,we designed a newsynthetic 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 newsynthesis,characterized by the simplicity of operation and the conv

关 键 词：卡巴他赛 抗肿瘤 合成 规模化 

分 类 号：R914[医药卫生—药物化学]