Chemical Properties
Off White Crystals
Uses
3-Amino-2-chloro-4-methylpyridine, also known as CAPIC, is a key intermediate in the production of nevirapine, a non-nucleosidic reverse transcriptase inhibitor that has been established to be clinically useful for the treatment of infection by HIV-1.
Preparation
An improved and commercially valuable process is developed by Ge et al. for the scalable synthesis of 2-chloro-3-amino-4-methylpyridine (CAPIC), a key intermediate of Nevirapine. The synthesis was accomplished in four steps, featuring condensation starting from 4,4-dimethoxyl-2-butanone and cyanoacetamide with ammonium acetate and acetic acid as catalysts. Specifically, a stirred solution of NaOH (15.6 g, 0.39 mol) and water (85 g) at 10 ℃ was added, 10% NaClO (96.8 g, 0.13 mol) and ethanol (80 g). 2-Chloro-3-amido-4- methylpyridine 7 (22 g, 0.13 mol) was added to the reaction mixture, stirring for 1 h. The mixture was heated to 60 ℃ and held for 3 h. After ethanol was removed in a vacuum, the mixture was cooled with an ice-water bath for 15–20 min to precipitate solid. Then, the mixture was filtered, washed with water, and dried to give 15.8 g (85.1% yield) of light yellow solid. 14.7 g of the white solid 2 was obtained via recrystallization in toluene.
Synthesis
General procedure for the synthesis of 2-chloro-3-amino-4-methylpyridine from 2-chloro-4-methylnicotinamide: 61.5 g of calcium hypochlorite was added to the reaction mixture in batches, and after the addition was completed, stirring was continued for 30 minutes at a maintained reaction temperature of 50 °C. Subsequently, 50 mL of 40 wt% aqueous calcium oxide solution was added in batches, the temperature was controlled not to exceed 10 °C, and the reaction lasted for 2 to 3 hours. Upon completion of the reaction, the cooled reaction mixture was slowly added dropwise to 150 mL of water, and the temperature was controlled not to exceed 100 °C during the dropwise addition. After the dropwise addition, the reaction was continued at 70 to 80°C for 2 hours. After the reaction solution was cooled to 5°C, the pH was adjusted to 6.5~7 with concentrated hydrochloric acid. filtration was carried out and the filter cake was washed with ice water. The filter cake was resuspended in 75 mL of water, heated to 60-70°C, stirred for 30 minutes, and then slowly cooled to 0~5°C to precipitate crystals. It was filtered again and the filter cake was washed with ice water and finally dried under vacuum. This process yielded 41.5 g of 2-chloro-3-amino-4-methylpyridine with 99.9% HPLC purity.
References
[1] Xin Ge. “A concise synthesis of 2-chloro-3-amino-4-methylpyridine.” Research on Chemical Intermediates 37 6 (2011): 599–604.
