Synthesis and Impurity Profiling of a Vital Intermediate in Gabapentin and Bispidine Derivative Pathways by Response Surface Methodology

Abstract

Spiro[3, nonane-9,1′-cyclohexane]-2,4,6,8-tetrone ( 8) is an important intermediate that opens up two distinct synthetic pathways for the production of gabapentin and bispidine. This work describes the acidic hydrolysis of 2,4dioxo-3-azaspiro-1,5-dicarbonitrile (7) to obtain (8) and investigates the effect of the most important variables on its yield percentage. Box−Behnken design (BBD) as a subclass of response surface methodology (RSM) was conducted to explore the most suitable operating conditions for maximizing the yield of the product (8) and reducing the formation of the impurities. The effective factors in this process were the H 2 SO 4 concentration (X 1 ), reaction temperature (X 2 ), and reaction time (X 3 ). The optimal reaction conditions of 65.5% sulfuric acid concentration, 22 h time, and 102 °C temperature were obtained, corresponding to the maximum reaction yield. Under these conditions, the experimental yield was 89.25 ± 1.31%, which was matched with the predicted yield (90.03%). The yield of the reaction was significantly higher than that reported in most published studies, and the impurity formation reached a minimum. The optimization results showed that the reaction yield decreased at both low and high temperatures (as well as the acid concentration) owing to a lack of reaction progress and the formation of impurities. However, in the given time frame (19− 24 h), the impact of the time on the reaction efficiency was not as strong as that for the other two factors, despite being significant. In addition, 13 C and 1 H NMR analyses revealed that the formation of 2,4-dioxo-3-azaspiro[5.5]undecane-1-carboxamide (13) and 1,1cyclohexanediacetic acid (CDA)(14) was minimized.