Optimized Synthesis Process Of Anticoagulants Ticagralor Intermediates

Ticagrelor,which is a novel small molecule compound of cyclopentane triazophos pyrimidine with selective and reversible,is also the first oral anticaking agent drugs.In this paper,the synthesis process of three key intermediates of synthesizing ticagrelor was summarized,respectively.The appropriate routes were selected to optimize and improve process,whose basis of the technology was completed.The intermediate Ⅰ is trans-（1R,2S）-2-（3,4-Difluorophenyl）cyclopropanamine.In this paper,two synthetic routes by considering two starting materials of 3,4-Difluo-robenzaldehyde and 1,2-Difluorobenzene was studied.The first one:Trans-（1R,2R）-2-（3,4-difluorophenyl）-1-amino trimethylene was synthesized by the starting materials of 3,4-difluorobenzaldehyde,and condensation reaction,acylation reaction,esterification,asymmetric cyclopropanation and Hofmann degradation.Finally,the intermediate I was reacted with D-mandelic acid to achieve the purpose of separation.Through improvement of synthetic route and post-processing technology,ultimate product was obtained via 7 steps goals,and the total yield after salification reached32.5%,and increased by 62.5%than the literature reported（20%）.The second one:The synthesis of the first intermediates mandelate from 1,2-Difluorobenzene by Friedel-Crafts reaction,ester reaction,asymmetric reduction,and cyclization,cyclopropane,hydrolysis,amination,and hofman rearrangement and salification reaction was described,each step yield of this process was over 80%and the total yield was 41.3%.Compared with the above two routes,the former is easy to generate racemic form,need to split,but the whole operation process is simple and easy to control reaction conditions;the latter has good antipoda selectivity,and does not need to split.The total yield is higher and the cost is relatively lower,and the raw material is inexpensive.However,the route is need to the asymmetric reduction reaction.Via comprehensive comparison,the second route has lower raw material cost,stable process,and easier industrialization.The intermediate Ⅱ is 2-{[（3aR,4S,6R,6aS）-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}ethanol.The target product was prepared from D-ribose by the methylation reaction,hydroxyl protection,iodine generation reaction,ring opening,hydroxylamine reactions,cyclization,hydrogenation open loop,benzyl reaction,amino protective reaction,etherified side chain reaction,hydrogenation protective reaction,salification reaction.The yield of this route was 18.6%.“One-pot”adopted in the syntheses process was carried out to shorten the process steps.Meanwhile,in view of the oily compound,crystallization method was able to instead of column purification.When the samples of the last four steps were post-processed,the reaction liquid after simple processing was directly into the next step reaction,which simplifies the operation.In addition,a crystallization process of salification was considered to purify the end-product,and the results were significant.Compared with processes in literatures,this paper studies the process cost is low,raw materials have the rich source,and the synthesis process of the operation is simple and able to meet the requirements of the industrialization.The intermediate Ⅲ is 4,6-dichloro-2-propylthiopyrimidine-5-amine.The thirdly intermediate was prepared from diethyl acetamidomalonate and thiocarbamide.Under the condition of alkaline,diethyl acetamidomalonate and thiocarbamide occur the cyclization reaction,and then reacted to acetyl amino pyrimidine intermediate with1-Bromopropane,it would be chlorinated by tamoxifen phosphonic and triphosgene work together.Finally,hydrolysis reaction was made to obtain the target product.As innovation route,it not only shortened the process,but avoids the usage of azide compounds.The only shortage,at present,is that the sample purity is only 78.0%and contains some impurities,and the study of further purification of the sample is still very necessary.Finally,the influence factors of changing the separation results of intermediates I despun enantiomer had been discussed in this paper,including the types of the split agent,recrystallization solvent,temperature and stoichiometric of the split agent.The best separation conditions are that D-mandelic acid is as resolution agent,the mole ratio of despun（3,4-Difluorophenyl）cyclopropanamine and split agent is 1:0.6,and ethyl acetate is considered as a solvent,and the temperature of resolution is 30℃and the cooling temperature is 25℃.The split yield of target product is 67.3%.The specific rotation of the product recrystallied with ethyl acetate is[?]_D²⁵)82(-964.^?（c.1,methanol）and the purity is 99.9%.