Hydrochloric Acid → (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)acrylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid (1 eq, from Example 3), 1-[({4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]phenyl}amino)carbonyl]cyclopentanaminium chloride (1.3 eq.) and DIPEA (4 eq) in anhydrous DMF (0.025 M) was treated with HATU (1.3 eq.) and stirred overnight at 40° C. The reaction mixture was then diluted with EtOAc, washed with aqueous HCl (1M solution), aqueous NaHCO3 (saturated solution) and brine. The foregoing compound (1 eq.) was dissolved in THF/MeOH/H2O (4:1:1, 0.025 M) and treated with LiOH.H2O (2 eq) at RT for 3 h. The acidified (1N HCl) reaction mixture was purified by RP-HPLC (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min) to afford, after freeze-drying, the title compound (0.16 eq) as a colourless powder. 1H NMR (400 MHz, DMSO, 300 K, δ) 12.36 (bs, 1H), 10.02 (bs, 1H), 9.68 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.92-7.47 (m, 9H), 6.40 (d, J 15.8, 1H), 4.47-4.39 (m, 2H), 4.02-3.15 (m, 4H, partially hidden by H2O signal), 3.07 (s, 3H), 2.50 (m, 1H, hidden by the DMSO signal), 2.38-1.05 (m, 18H); MS (ES+) m/z 651 (M)+.

Provenance & Evidence