Study On Synthesis And Optimization Of Flupirtine Derivatives

Flupirtine, is a new kind of moderate intensity of the central non-opioid analgesics, small adverse reaction, non-addictive, effective to many kinds of aches. Besides, it can be used in many indications (such as anticonvulsant, cell protection, treatment of movement disorders and rigid caused by lacking of dopamine, anti-Parkinsonian, anti-migraine, anti-inflammatory, and so on), showing a broad clinical application prospect. But it has not been registered in China, and the synthesis of flupirtine and 2,3,6-triaminopyridine derivatives has not been reported in domestic yet. Therefore, the synthesis and process optimization of Flupirtine is very significance.In this paper, A five-step procedure and optimization for synthesis of flupirtine maleate, started from 2,6-dichloro-3-nitropyridine, was developed. Ethanol replaced dioxane as solvent, the total yield of the five-step up to 81.2%. In addition, seven 2,3,6-triaminopyridine derivatives were deigned and prepared, four of them has not been reported in the literature. The test of antioxidant activity by the elimination of DPPH radical showed that the six of 2,3,6-triaminopyridine derivatives have antioxidation activity.Moreover, flupirtine maleate reference substance was prepared, and HPLC methods were empoldered and tested:λ=248 nm, pH=3.65, methanol-water (55-45); the range of concentration is 0.01-0.90 mg/ml, linear regression equation for Y = 1488842X + 89008, R~2=0.9999; the average recovery was 100. 6% (RSD=0.77%, n=9).A new route of nevirapine was studied. Found that the the selectivity of acylation between 2,3-diamino-4- methyl-pyridine and 2-chloronicotinoyl chloride was not existed, and the product ring-closured easily.