抗白血病药物克拉屈滨的合成

doi:10.11944/j.issn.1000-0518.2016.11.160027

摘要/Abstract

摘要：

报道了抗白血病药物克拉屈滨的合成新方法:在NaH作用下,廉价易得的6-氯嘌呤高选择性地在β位和1-氯-2-脱氧-3,5-二-O-对氯苯甲酰基-D-核糖缩合;β-缩合物的2位在三氟乙酸酐和四丁基硝酸铵作用下引入硝基;在NH₄Cl/EtOH作用下,2-硝基转化为2-氯;最后在饱和NH₃/CH₃OH溶液中完成保护基脱除和6-氯氨解两步反应,以4步共43.5%的总收率得到抗白血病药物克拉屈滨。该方法完全避免了α异构体的生成,原料廉价易得,分离纯化不需柱层析,且反应扩大到100 g规模时,收率无下降,具有较好的应用前景。

关键词: 氯嘌呤, 克拉屈滨, 硝化反应, 规模合成

Abstract:

Cladribine, an anti-leukemia drug, was synthesized in 43.5% total yield by 4 steps. Readily available 6-chloropurine was glycosylated with 1-chloro-3,5-di-O-p-benzoyl-D-ribose with good selectivity for β anomer in the presence of NaH. The C2-H of β-glycosylated product was converted into C2-NO₂ using 2,2,2-trifluoroacetic anhydride and tetrabutylammonium nitrate, followed by the transformation of C2-NO₂ into C2-Cl in NH₄Cl/EtOH solution. The deprotection step and ammonolysis of C6-Cl were accomplished in NH₃/CH₃OH. The separation of α-anomer, expensive starting materials and chromatography are not required. Moreover, cladribine could be produced on a 100 gram scale with maintained yield, indicating good potential in industrial applications.

Key words: chloropurine, cladribine, nitration reaction, scalable synthesis

夏然, 孙莉萍, 渠桂荣, 陈磊山. 抗白血病药物克拉屈滨的合成[J]. 应用化学, 2016, 33(11): 1274-1278.

XIA Ran, SUN Liping, QU Guirong, CHEN Leishan. Synthesis of Anti-leukemia Drug Cladribine[J]. Chinese Journal of Applied Chemistry, 2016, 33(11): 1274-1278.

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