Lithium Hydroxide → 5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-amino}-thiophene-2-carboxylic acid

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A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (63 mg, 0.141 mmol) and pyridine-2-carbonyl chloride HCl salt (33 mg, 0.184 mmol) in DCM (2 mL) was treated with DIEA (124 μL, 0.7 mmol). After 30 min, NaHCO3 (saturated aqueous solution, 4-8 mL) was added to the mixture, followed by brine (20 mL), and the crude product was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated and the crude material was dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide (42 mg, 1 mmol,) and heated to 60 deg C. for 2 hours. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 40 mg of the title compound as its TFA salt: MS (m/z): 536.9 [M−H]+; HPLC retention time: 4.17 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

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