294190-18-4

The general procedure for the synthesis of methyl 3-amino-5-chloro-2-methylbenzoate from methyl 2-methyl-3-nitro-5-chlorobenzoate was as follows: to a stirred solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (5.0 g, 21.78 mmol) in ethyl acetate (150 mL) was added stannous (II) chloride dihydrate (20 g, 89 mmol). The reaction mixture was heated to reflux (oil bath temperature was maintained at 85 °C) and stirred continuously for 3 h until the reaction solution became a clarified solution. The completion of the reaction was confirmed by LCMS. Upon completion of the reaction, the reaction mixture was cooled to room temperature and slowly poured into 1N Na2CO3 solution (200 mL). The resulting suspension was stirred for 30 minutes and subsequently filtered through a diatomaceous earth pad (slowly filtered using a large filter funnel) and washed with ethyl acetate (EtOAc). The filtrate was transferred to a partitioning funnel to separate the organic phase (EtOAc phase), washed sequentially with water and brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure. Purification was carried out by silica gel column chromatography (Analogix, SF40-120 g, elution gradient 0 to 30% ethyl acetate/hexane) to afford the target product methyl 3-amino-5-chloro-2-methylbenzoate (4.05 g, 20.29 mmol, 93% yield) as a yellow oil. The structure of the product was confirmed by 1H NMR (400 MHz, DMSO-d6) and mass spectrometry (ES) [M + H]+ 200.0.

[1] Patent: WO2013/173441, 2013, A2. Location in patent: Page/Page column 108; 109
[2] Patent: WO2012/142513, 2012, A1. Location in patent: Page/Page column 264-265
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1556 - 1564