Synthesis
General procedure for the synthesis of 3-methoxybenzyl chloride from m-methoxybenzyl alcohol: 3-methoxybenzyl alcohol (248 μL, 2.0 mmol) and triethylamine (335 μL, 2.4 mmol) were dissolved in dichloromethane (DCM, 7 mL). Thionyl chloride (218 μL, 3.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed with 1N HCl aqueous solution. The organic phase was dried with anhydrous magnesium sulfate (MgSO). The solvent was removed under reduced pressure to give the target product 3-methoxybenzyl chloride (313 mg, 100%) as a yellow oil.
Next, 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (Example 74, 85 mg, 0.26 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF, 1 mL), followed by addition of cesium carbonate (169 mg, 0.52 mmol) and 3-methoxybenzyl chloride ( 81 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (EtOAc) and water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried with anhydrous magnesium sulfate (MgSO). The solvent was removed under reduced pressure. The crude product was purified by fast chromatography using a mixture of cyclohexane/ethyl acetate (8:2) as eluent to afford the target product (3-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a pale yellow oil (11 mg, 9%).
Product characterization data: 1H NMR (300 MHz, CDCl) δ 2.62 (s, 3H), 2.71 (dd, J = 15.8, 2.2 Hz, 1H), 2.92 (dd, J = 15.8, 7.5 Hz, 1H), 3.31 (s, 3H), 3.37 (ddt, J = 10.0, 8.5, 3.6 Hz, 1H). 3.46 (dt, J = 10.0, 4.1 Hz, 1H), 3.70-3.79 (m, 4H), 4.13-4.23 (m, 2H), 5.04 (d, J = 12.7 Hz, 1H), 5.11 (d, J = 12.7 Hz, 1H), 6.64 (s, 1H), 6.70 (d, J = 7.5 Hz, 1H), and 6.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.16-7.23 (m, 3H). Mass spectrum (MS): [M + H] m/z 444. high-resolution mass spectrum (HRMS): calculated value of CHNCl, [M + H] 444.1578, measured value 444.1579.
References
[1] Patent: WO2016/16238, 2016, A1. Location in patent: Page/Page column 126-127
[2] Organic Process Research and Development, 2016, vol. 20, # 2, p. 568 - 573
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 19, p. 8889 - 8895
[4] Journal of Organic Chemistry, 1998, vol. 63, # 25, p. 9565 - 9568
[5] Australian Journal of Chemistry, 1992, vol. 45, # 1, p. 71 - 97
