Synthesis Of Pramipexole Oxide

Pramipexole dihydrochloride monohydrate,developed as a second-generation nonergot dopamine D2 receptor agonist by Boehringer Ingelheim,is the active substance in the anti-Parkinson drug Mirapex,can effectively improve the early stage and late stage Parkinson's disabling dyskinesias and motor fluctuations.Pramipexole can delay and reduce the incidence and extent of levodopa related motor complications,and lessen the depressive symptoms associated with Parkinson's disease.It is used to monotherapy or adjuvant therapy for Parkinson's disease.For now,up to 10 products caused by oxidation,degradation and condensation of pramipexole have been detected and identified.The synthesis of each compound is essential for the quality control of pramipexole APIs and tablets.At the same time,the activity test of its related substances also has very important significance in the study of its further pharmacological activity.Based on study on reported synthetic routes and with our novel design,three routes were attempted to synthesize the target compounds in this paper.1,3-cyclohexanedione was used as raw material via bromination,reduction,cyclization,azide,hydrogenation,nucleophilic substitution,and Borch reduction and series of reactions to make the target compound.This paper also explored and optimized both reactions,work up,isomer separation and chiral separation methods.The target compound BI-II546CL was made with total yield 13.77%,SND1117BS with 35.59%and BI-II820BS with 38.48%.For the synthesis of compound A2,we chose Br2-H2O system with a higher yield and easier post-treatment than the Br2-CH3COOH system.We used the thiourea-pyridine-methanol system,and obtained great reaction results for compuond A3.We tried two different routes to synthesis compound A8:route A and route B.The route B is easily generate a large number of by-product,and the yield is severely low.Although the route A is longer,but the yield is higher,and the successful separation of isomers reduced the difficulty of chiral separation.As the compound BI-II546CL was not stable in its free state,we chose its hydrochloride salt,and got its stable state and increased the yield.All chemical structure of intermediates were confirmed by 1H-NMR and MS.The structure of target compound was confirmed by 1HNMR,13CNMR,HSQC,HMBC,HMQC,NOESY,MS.