Studies On Greener Process For Gabapentin Synthesis

Gabapentin, which could be used to treat epilepsy, was developed by Warner-Lambert Company firstly and began to be marketed in British at 1993. Except for its quick assimilation, this medicine is also advantageous for its good tolerance, less side effect, good treatment effect and so on. Therefore, Gabapentin came into one of the most popular medicines soon after its marketing. However, there still exist plenty of problems in the corresponding production process, such as heavy pollution, severe corrosion on its production facility and so on. Obviously, it is quite urgent that suitable measurements and improvements could be made in the synthetic process to increase the degree of greenness and resolve related negative problems.In our study, two contributions were made in greening production process of Gabapentin. As we all know,1,1-cyclohexanediacetic acid is the important intermediate product and a large number of concentrated sulfuric acid is added as the catalyst during the production process. Consequently, plenty of black acid waste water (15-20 tons of waste water for each ton of product) would be generated afterwards and this water needs a large quantity of calcined lime to be neutralized. Besides, the acid would also result in severe corrosion on the equipment. Consequently, reducing the usage of employed sulfuric acid appears very important. In our study, different initial concentration, reaction temperature and employed sulfuric-acid concentration were all investigated systematically in the synthesis of 1,1-cyclohexanediacetic acid. Subsequently, the result showed that the 1,1-cyclohexanediacetimide,α,α'-dicyano-compd with ammonia could hydro lyze into 1,1-cyclohexanediacetic acid in the high-temperature liquid water(HTLW) and high yield would been achieved even at low concentration of sulfuric acid. The optimal reaction condition was found that the highest yield of the targeted 1,1-cyclohexanediacetic acid could reach 88.31% at the reaction temperature of 220℃, sulfuric-acid concentration of 15% and initial mass concentration of 0.05 g·mL-1.As we all know, it is easy to generate the highly toxic 3,3-pentamethylene-4-butyrolactam through the cyclization reaction in the synthesis of Gabapentin and the content of 3,3-pentamethylene-4-butyrolactam in the product is apt to exceed the standard by taking advantage of the current production technology. Therefore, different technological parameters were considered in this study to investigate the stability of Gabapentin. Generally speaking, systematic studies in temperature, concentration, solvents, mass ratio of different solvents, buffer solution, ionic strength and pH value have been made to study their influence on stability. The results showed that the reaction temperature, mass ratio between different solvents and pH value were the key influences on the stability of product. Consequently, the adjustment in the reaction concentration, mass ratio of different solvents and pH value can be made to reduce the cyclization of Gabapentin and improve the quality of final product.