Acetic Acid → 5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(N'-methyl-N'-pyrazin-2-yl-hydrazino)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

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A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) and N-Methyl-N-pyrazin-2-yl-hydrazine (41 mg, 0.33 mmol) in DCE (2 mL) was treated with AcOH (100 μL, 1.5 mmol) followed by NaBH(OAc)3 (120 mg, 0.5 mmol) in two portions. After 5 h, NaHCO3 (saturated aqueous solution, 2 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 (20 mL), treated with lithium hydroxide (1.1 mmol, 46 mg) and heated to 60 deg C. for 1 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 11 mg of the title compound as its trans isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 26.05 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient) and 7 mg of the title compound as its cis isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 24.38 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient).

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