Synthesis Technology Research On Dasatinb

Chronic granulocytic leukemia，which Accounts for20%of the adult leukemia, is amalignant tumor that can influence blood and bone marrow seriously. Its characteristic is toproduce a large number of immature white blood cells, which gathered themselves inside inbone marrow, and inhibit the hematopoiesis of the normal bone marrow. And can diffusionthrough the blood, leading to anemia patients easy to bleeding, infection, organ infiltrationand so on. Chronic myeloid leukemia can be divided into chronic phase, acceleration phaseand snap phase. Hydroxycarbamide and busulfan are the drugs that first used in the treatmentof chronic myeloid leukemia. The therapies such as hematopoietic stem cell transplantation,interferon, cytarabine have been used as the first-line therapy, until the emergence of tyrosinekinase inhibitor. Tyrosine kinase inhibitor is a kind of small molecular targeted drugs.According to the listed time and mechanisms, they can be roughly divided into threecategories: Mesylate imatinib is representative drug of the first generation of tyrosine kinaseinhibitors and still holds a large market share; Dasatinib is representative drug of the secondgeneration of tyrosine kinase inhibitor, this kind of medicine got a higher affinity than the firstgeneration of tyrosine kinase inhibitor and is the key of our reseach. The third generation oftyrosine kinase inhibitors is still under development.Dasatinib(N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate), whose trade name is sprycel,is an Oral tyrosine kinase inhibitor, which is developed by Bristol-Myers Squibb Company.The indication of Dasatinib is the adult patient, that have the drug resistance of Mesylateimatinib or all disease period (chronic phase, accelerated phase, lymphocyte blastic phase) ofchronic myelocytic leukemia (CML) that cannot tolerate. In the meanwhile, FDA alsoauthorizes Dasatinib to cure the adult patients, that have the drug resistance of other therapyor the acute lymphoblasticleukemia cannot tolerant positive Philadelphia chromosome. Thefirst year after Dasatinib was listed, it generated outstanding sales. The sales revenue of the first quarter of2010got a growth of40%over the same period, achieve131million dollars.Themarket sales of the year of2011jumped to803million dollars. State Food and drugadministration (SFDA) approved of Sprycel (Dasatinib) used for chronic myelogenousleukemia treatment of the second line. This product has a patent in rejected state. At thepresent stage, Only a few companies is the development of this product in domestic. In addi-tion, It is an early stage of development. Therefore, It has the significant practical value toresearch the synthesis technology of DasatinibThe mechanism and development of Dasatinib is described briefly in this paper. Ourresearch focuses on the synthetic methods of Dasatinib. After investigation of a series ofsynthetic routes of Dasatinib, the target compound Dasatinib was obtained via reaction of theEthyl2-aminothiazole-5-carboxylate Amino protection, Hydrolysis esters, ammonia shrinkage,deprotectio，Nucleophilic substitution，substitution, using Ethyl2-aminothiazole-5-carboxylate,Ditertbutyl dicarbonate, Phenylphosphonic dichloride(PDCP),3-chloro-2-methylaniline,trifluoroacetic acid,4,6-Dichloro-2-methylpyrimidine, N-(2-Hydroxyethyl)piperazine asraw materials. Further improved methods were investigated for the synthesis of severalimportant intermediates, while developing quality control methods for the key intermediates.We focused on the synthesis of Cope-5, and finally, the synthesis method, using the reactionof Cope-4and2,4-Dichloro-6-methylaniline under the Catalytic conditions of amide shrinkmixture of Phenylphosphonic dichloride, was determined. Using this method, we canreduce the requirements of the reaction conditions (If we use the method of the condensationreaction of Cinnamyi chloride and ammonia, the anhydrous conditions must be strictedcontrolled.), simplify the operation of the reaction greatly, and the reaction yield wasincreased from the original80.6%to98%. Furthermore, We also focused on the synthesis ofCope-6, the synthesis method, using the reaction of Cope-5and trifluoroacetic acid under thecondition of25℃for determinating protecting groups. Using this method, we can get theCope-6of high purity, the side effects is the least of all, and the reaction yield can increased to91%. In conclusion, we have developed a stable, mild, easy to get raw materials, inexpensiveand simple strategy for the synthetic route. The intermediates are all solid, easy to be purifiedand handled. Except for the final product Dasatinib requiring recrystallization, the otherintermediate can be applied directly to the next step reaction. Thus, the route was suitable forindustrial production. Finally we got Dasatinib with the purity over98.5%identified byHPLC, and total yield42%, higher than those of the reference, the product has been qualifiedby1H-NMR.