一种新的合成氯法拉滨的方法

A New Method for the Synthesis of Clofarabine

氯法拉滨是临床上唯一可以特异性地治疗儿童白血病的药物,2004年被美国食品和药物管理局批准上市.由于现有合成方法存在路线长、收率低和α/β异构体难以分离等问题,限制了该药物的广泛使用和进一步研究.以廉价且商品化的2-氯腺苷为原料,通过乙酸酐保护糖环上的3个羟基,在水合肼和乙酸作用下,选择性地脱除2'位的乙酰基.然后,以商品化的氟代试剂二乙胺基三氟化硫(DAST)进行2'位羟基的氟代反应,再使用NH3/MeOH饱和溶液脱除乙酰基可得氯法拉宾.这4步反应的总收率为49%,且得到的产品全部为β构型.同时,还发现2位取代基的位阻越大,越有利于选择性脱除2'位的乙酰基.本方法可以在克级规模上进行生产,收率无下降,同时中间体及产物的纯化不需要通过柱层析分离,显示出良好的应用前景?.

Clofarabine is the active ingredient in the anti-pediatric leukemia drug, which was approved by U.S. Food and Drug Administration in 2004. However, the previous reported methods have long steps, low yield and difficult separation of α/β anomers, which restrict the wide use of the drug. In this manuscript, the cheap and commercial available2-chloroadenosine was chose as the starting material to synthesize the clofarabine. By using acetic acid and hydrazine, the selective deprotection of acetyl group in 2＇-position was accomplished. Subsequently, the fluorination step was realized by diethylaminosulfurtrifluoride（DAST）. The clofarabine was synthesized with 4 steps in 49% total yield as a pure β-anomer. Meanwhile, the strong steric hindrance of 2-substitution was favorable for the 2＇-deacetylation. Notably, the clofarobine could be synthesized at a gram scale using this method, which showed the good future of industrial application.