Preparation
Step 1: 2-(3-(3-chlorophenyl)acrylamido)acetic acid (E) methyl ester
Anhydrous dimethylformamide (DMF) (0.08 mL, 1.0 mmol) was added to (E)-3-(3-chlorophenyl)acrylic acid (1.0 g, 5.48 mmol) in dichloromethane (10 mL). The solution was cooled to 0 °C, and then oxaloyl dichloride (0.57 mL, 6.53 mmol) was added dropwise. The reaction was heated to room temperature. After two hours, the reaction mixture was cooled back to 0 °C. A mixture of glycine methyl ester HCl salt (1.38 g, 10.99 mmol) and diisopropylethylamine (DIEA, 3.8 mL, 21.92 mmol) was cooled to 0 °C, and dichloromethane (10 mL) was slowly added. The reaction was stirred overnight at room temperature.
The solvent was removed under vacuum to obtain the crude product, which was then purified by rapid chromatography (AcOEt/Hex 10-100%) to give 1.19 g (86%) of the title compound. ESI-MS (m/z): 254, [M+1]+. Step 2. (E)-2-(3-(3-(3-chlorophenyl)acrylamido)acetic acid Add 2.0 NNaOH (6.2 mL, 12.4 mmol) to a solution of (E)-2-(3-(3-(3-chlorophenyl)acrylamido)methyl methyl acetate (1.553 g, 6.14 mmol) in MeOH (10 mL). Stir the mixture at room temperature for 1 h. Analytical HPLC then indicates the reaction is complete. Acidify the mixture with 1 N HCl solution, remove the solvent under vacuum, and obtain the crude product, which can be used in the next step without further purification. ESI-MS (m/z): 240, [M+1]+. Step 3. ML264 DIEA (52 mg, 0.4 mmol) and HATU (50 mg, 0.13 mmol) were added to a mixture of (E)-2-(3-(3-chlorophenyl)acrylamido)acetic acid (31.5 mg, 0.13 mmol) in DMF (1 mL). The mixture was stirred for 5 minutes, and then 4-(methylamino)tetrahydro-2H-thiaran 1,1-dioxide hydrochloride (26 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction was monitored by analytical HPLC until completion. The solvent was removed under vacuum to obtain a crude product, which was purified by preparative HPLC (acetonitrile/MeOH (1:1)/water 40–100%) to give 24.6 mg (49%) of the title compound ML264.
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