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

Participants

Reaction Steps

A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (412 mg, 0.90 mmol) and N-Methyl-N-pyridin-2-yl-hydrazine (222 mg, 1.8 mmol) in DCE (6 mL) was treated with AcOH (200 μL, 3.0 mmol) followed by NaBH(OAc)3 (300 mg, 4.08 mmol) in two or three portions. 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 (20 mL), treated with lithium hydroxide (4.5 mmol, 188 mg) 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 189 mg (37% yield) of the title compound as its trans isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.39 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid) and 71 mg (14% yield) of the title compound as its cis isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.52 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Provenance & Evidence