Synthesis
Preparation of Example A4-3: 2-cyano-2-methylpropionyl chloride; To a solution of commercially available ethyl 2-cyano-2-methylpropionate (3.5 g, 24.8 mmol) in methanol (10 ml) was added lithium hydroxide (LiOH, 900 mg, 37.2 mmol) and water (0.5 ml) and the reaction was stirred for 1 hour at 37°C. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, followed by acidification by addition of 1N hydrochloric acid (HCl, 50 ml) and extraction with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to give 2-cyano-2-methylpropionic acid (2.67 g, 95% yield). The compound (2.5 g, 22 mmol) was dissolved in dichloromethane (DCM, 7 ml) and the reaction was carried out as described in Step B of Preparation Example A4-1, resulting in the target product 2-cyano-2-methylpropionyl chloride (2.5 g, 86.3% yield).
References
[1] Patent: WO2008/7930, 2008, A1. Location in patent: Page/Page column 30-31
[2] Synthesis, 2005, # 4, p. 569 - 574
[3] Patent: US2018/282328, 2018, A1. Location in patent: Paragraph 0832; 0833
[4] Chemische Berichte, 1932, vol. 65, p. 432,441
[5] Journal of the American Chemical Society, 1916, vol. 38, p. 911
