The Synthesis Technology Study Of Anticancer Drug Gemcitabine Hydrochloride

Gemcitabine hydrochloride,the chemical name is 2’-deoxy-2’,2’-difluorocytidine(β-Anome),is a new nucleoside analogue,antimetabolite, anticancer drug.Gemcitabine hydrochloride is used in various carcinomas: non-small cell lung cancer,pancreatic cancer,bladder cancer,breast cancer,and various other solid tumor.This paper introduced a new craft to synthesis gemcitabine hydrochloride depends on the present crafts which are from the literature. The new craft is started from D-mannitol,via acetalation with acetone and oxidation to produce 2,3-O-isopropylidene-d-glyceraldehyde,wich via reformatsky reaction with Ethyl bromodifluoroacetate,hydrolyzation and benzoylation,recrystallized at the mixture of CHCl2 and isopropanol (10:1) to afford 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose-3,5-dibenzoate.Then the intermediate via lithium tri-t-butoxyaluminium hydride reduction,p-toluenesulfonation to aford 2-deoxy-2,2-difiuoro-Dribofuranose -3,5-dibenzoate-1-(p-toluene)sulfonate,which was subjected to glycosylate with cytosine under the the catalyst Me3SiOTf followed by deprotection,salt formation and separative crystallization in aqueous acetone(1/12) to afford gemcitabine hydrochloride.Compare the present craft,the new craft has the following improvements:1.Reduce the cost because of choosing the cheap original material, and the intermediate 2,3-O-isopropylidene-d-glyceraldehyde via reformatsky reaction with Ethyl bromodifluoroacetate to produce the following intermediate directly,avoid the disadvantage that 2,3-O- isopropylidene-d-glyceraldehyde is easy to polymerize.2.When produce 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose-3,5-dibenzoate,the new craft chose to cyclize firstly,then benzoylation with two hydroxyl groups at one step.Compare the craft of US5223608,the new craft reduced the synthesis step and increased the efficiency.3.When produce 2-deoxy-2,2-difiuoro-D-ribofuranose-3,5-dibenzoate-1-(p-toluene)sulfonate,the new craft chose to use ptoluenesulfonyl chloride instead of methylsulfonyl chloride,and glycosylate with cytosine instead of N-Acetylcytosine.At last,the new craft gets the close effiency with the US5223608,and is better in producingβ-Anome.4.The new craft optimized the present craft,such as recycling the solvent,reducing the waste and increasing the effiency,got the optimize condition after many experiments.The new craft is more environment -friendly.