Reaction Steps
A solution of the acetate of cyclosporin allylic chloride from Example 35 (60 mg, 0.047 mmol) and thiomorpholine (48 mg, 0.47 mmol) in methylene chloride (3 mL) was stirred overnight at room temperature under N2 atmosphere. The mixture was concentrated in vacuo. The residue and potassium carbonate (102 mg, 0.740 mmol) were dissolved in methanol (3 mL) and allowed to stir overnight at room temperature under N2 atmosphere. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by semi-preparative HPLC to afford cyclosporine thiomorpholine (28.8 mg, 33%) as a white solid: 1H NMR (300 MHz, CD2Cl2) δ 7.96 (d, J=9.7 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 5.67 (dd, J=10.9, 4.1 Hz, 1H), 5.05-5.48 (m, 9H), 5.43 (d, J=6.6 Hz, 2H), 5.28 (d, J=3.8 Hz, 1H), 5.24 (d, J=3.8 Hz, 1H), 5.15-4.89 (m, 5H), 4.79 (t, J=14.5 Hz, 2H), 4.72 (s, 1H), 4.64 (dd, J=14.8, 5.8 Hz, 2H), 4.23 (t, J=14.5 Hz, 2H), 3.44 (s, 3H), 3.35 (s, 3H), 3.21(s, 3H), 3.09 (s, 3H), 3.08 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.50-1.40 (m, 15H), 1.27-0.70 (m, 54H): ESI MS m/z 1304 [C66H118N12O12S+H]+; HPLC>99% (AUC), tR=13.00 min.
