1. Diazotization: 5-nitro-2-chloroaniline (50.0 g, 0.289 mol) was dissolved in 30% sulfuric acid (300 ml) and stirred at room temperature for 2 hours. A solution of sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0 °C and kept at this temperature for 15 min. The diazotization solution was slowly added to a 50% dilute sulfuric acid (250 ml) at 110°C and stirring was continued for 15 minutes. After cooling to room temperature, ice water was added and extracted with ethyl acetate, washed sequentially with water and brine and dried over Na2SO4. After concentration, the product was purified by column chromatography to give 12.0 g in 24.0% yield.
2. Methylation reaction: To a solution of K2CO3 (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in acetonitrile (100 ml) was added iodomethane (19.60 g, 0.138 mol) at 0 °C. The reaction mixture was warmed to room temperature. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and extracted with ethyl acetate, the organic layer was washed sequentially with water and brine and dried over Na2SO4. After concentration, the product was purified by column chromatography to give 6.0 g in 55.55% yield.
3. Reduction reaction: 2-chloro-5-nitroanisole (6.0g, 0.032mol) solution in methanol (45ml) was slowly added to stannous chloride (15.1g, 0.08mol) in concentrated hydrochloric acid (110ml). The temperature was slowly raised to 50°C and stirring was continued for 2 hours. After cooling to room temperature, it was alkalized with 50% NaOH solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine and dried over Na2SO4. After concentration, the product was purified by column chromatography to give 4.0 g in 79.36% yield.
4. Protection reaction: Trimethylacetyl chloride (2.75 g, 0.022 mol) was slowly added to a solution of triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4-chloroaniline (3.0 g, 0.0190 mol) in benzene (50 ml) at 0 °C. The solution was heated to room temperature and stirred. Warmed to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over Na2SO4 and concentrated to give 3.7 g of product in 80.43% yield.
5. Nucleophilic addition reaction: To a solution of N-trimethylacetyl-3-methoxy-4-chloroaniline (1.50 g, 0.0062 mol) in THF (30 ml) was added n-butyllithium (1.0 g, 0.0156 mol) at 0 °C and stirred for 2 hours. After cooling to -70 °C, a THF (12 ml) solution of methyl isonicotinate (1.3 g, 0.0094 mol) was slowly added. Warmed to room temperature and stirred overnight, quenched with water and extracted with ether. The aqueous layer was further extracted and the combined ether layers were washed sequentially with water and brine and dried over Na2SO4. After concentration, the product was purified by column chromatography to give 0.50 g in 23.25% yield.
6. Deprotection reaction: The product of step 5 (0.500 g, 0.0014 mol) was suspended in concentrated HCl (5 ml), heated to 95 °C and stirred overnight. After cooling to room temperature, it was alkalized with 20% NaOH solution and extracted with DCM. The combined organic layers were washed sequentially with water and brine and dried over Na2SO4. After concentration, it was purified by basic alumina column chromatography to afford the title compound (0.140 g, 37.33%).
