Synthesis
Step 1: (R)-2-Amino-2-(4-hydroxyphenyl)acetic acid (D-4-hydroxyphenylglycine, 10.0 g, 60.1 mmol) was dissolved in methanol (200 mL) and thionyl chloride (8 mL) was added slowly and dropwise. The reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction, the solvent was removed by vacuum concentration and the residue was washed twice with ether to afford methyl (R)-2-amino-2-(4-hydroxyphenyl)acetate (D-4-hydroxyphenylglycine methyl ester, 13.0 g, 60.0 mmol, 100% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 3.68 (s, 3H) 5.07 (s, 1H), 6.85 (d, J=8.5Hz, 2H), 7.29 (d, J=8.6Hz, 2H), 9.03 (s, 3H), 10.02 (s, 1H).
Step 2: Methyl (R)-2-amino-2-(4-hydroxyphenyl)acetate (D-4-hydroxyphenylglycine methyl ester, 0.302 g, 1.39 mmol) was dissolved in freshly prepared glyoxalic acid (1.27 g, 13.8 mmol) and copper(II) sulfate pentahydrate (0.35 g, 1.40 mmol) in 2.5 M pyridine buffer and 0.5 M acetic acid in an aqueous solution. The reaction mixture was stirred at room temperature for 10 hours. Upon completion of the reaction, it was extracted with dichloromethane (10 mL x 3), the organic layers were combined, washed with 0.5 M HCl (20 mL x 3), dried, filtered and concentrated in vacuum. The residue was purified by flash column (silica gel, chloroform elution) to afford methyl 2-(4-hydroxyphenyl)-2-oxoacetate (0.109 g, 6.06 mmol, 44% yield) as a clear oil.1H NMR (300 MHz, CDCl3) δ 3.99 (s, 3H), 5.41 (br s, 1H), 6.95 (d, J=8.8 Hz, 2H), 8.00 (d, J=8.8Hz, 2H).
References
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3946 - 3952
[2] Patent: WO2013/33093, 2013, A1. Location in patent: Page/Page column 137; 138
