Study On Synthesis Of Pramipexole Dihydrochloride And Related Impurities

Pramipexole dihydrochloride,a novel D₂ and D₃ non-ergot dopamine agonist with chemical name of S?-?-2-amino-6-?propylamino?-4,5,6,7-tetrahyd robenzothiazole dihydrochloride,has been used for the treatment of Parkinson's disease.As a aminobenzothiazole dopamine agonists with high selectivity and sufficient affinity to the D₂ dopamine acceptor family,it's widely used in the clinical treatment of Parkinson.Due to the clinical effects is better and its patent has expired,the studies on the synthesis and quality standards of Pramipexole dihydrochloride has great social and economic values.In the dissertation,we focused on the study in the synthesis of Pramipexole dihydrochloride and its related impurities?BI-II546CL,BI-II786BS and BI-II7828BS?.The synthetic route and process of Pramipexole dihydrochloride and related impurities are determined by taking into account the cost and stability of raw materials,the yield of products and the operability of workup.The results will provide a solid experimental foundation for the subsequent large-scale production and application of Pramipexole dihydrochloride.Studies on the synthesis of Pramipexole dihydrochloride.With the 1,4-Di-oxaspiro[4.5]decan-8-one as a starting material,a synthetic method was proposed to overcome the distanvanges,such as lower yields and complex workup involved in reported procedures.The"one-pot"method was used to improve the preparation of 2-amino-6-hydroxyl-4,5,6,7-benzothiazole which was a key intermediate for Pramipexole dihydrochlorid.It's obtained in the yield of 80.3%and with the advantages of simple operations without further separation and purification.The key parameters of preparation Pramipexole hydrochloride were controlled by optimizing the reaction conditions of azidation,reduction,resolution,alkylation and salt formation with2-amino-6-hydroxyl-4,5,6,7-benzothiazole as starting material.A stable and suitable process for the manufacture on a large scale of Pramipexole hydrochloride was obtained with a total yield of 24.9%.Studies on the synthesis of related impurities of BI-II546CL,BI-II786BS and BI-II7828BS.Based on the literatures,the synthetic methods of BI-II546CL,BI-II786BS and BI-II7828BS were proposed.The reaction conditions were optimized in order to obtain the samples that fit the requirements of declaration.BI-II546CL was obtained via the reactions of bromination,cyclization,bromination and nucleophilic substitution with the1,3-cyclohexanedione as starting material.BI-II786BS and BI-II7828BS were obtained via thirteen steps with 1,3-cyclohexanedione as starting material.The reactions were the bromination,cyclization,bromination,propionylation,azidation,reduction of carbonyl compound,reduction of azide compound,resolution with tartaric acid,neutralization,propionylation,mitsunobu reaction,hydrolysis and reductive amination.All the intermediates and final products were confirmed by ¹H NMR and¹³C NMR.