3-Amino-1-propanol → 4-(3-Hydroxypropyl)-1lambda~4~,4-thiazinan-1-one

Step 1. To a solution of 3-amino-1-propanol (1.33 g, 17.64 mmol) in water (30 ml) was added divinylsulfoxide (2.0 g, 19.6 mmol). After the reaction mixture was refluxed for 0.5 h, it was concentrated and dried in vacuo at 50° C. to afford 4-(3-hydroxypropyl)thiomorpholine 1-oxide (3.0 g, 96%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.71-1.85 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.75-2.99 (m, 6H), 3.01-3.27 (m, 2H), 3.73 (t, J=5.9 Hz, 2H), 4.22 (brs, 1H). Step 2. To a solution of OZ288 (0.50 g, 1.4 mmol), 4-(3-hydroxypropyl)thiomorpholine 1-oxide (0.50 g, 2.8 mmol), triphenylphosphine (0.74 g, 2.8 mmol), and triethylamine (0.4 ml, 2.8 mmol) in dry THF (50 ml) at 0° C. was added dropwise a solution of DIAD (0.57 g, 2.8 mmol) in THF (10 ml). After stirring at rt overnight, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with water (3×50 ml), dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 50% EtOH in EtOAc) to afford OZ466 free base (0.47 g, 65%) as a colorless solid. To a solution of OZ466 free base (0.47 g, 0.91 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.09 g, 0.91 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ466 (0.50 g, 90%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.98 (m, 22H), 2.12-2.21 (m, 2H), 2.39 (s, 3H), 2.51-2.61 (m, 1H), 3.04-3.85 (m, 10H), 4.02 (t, J=6.1 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 9.78 (brs, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 23.50, 26.01, 26.42, 31.49, 34.29, 34.45, 35.98, 36.28, 40.89, 42.13, 54.50, 64.91, 108.32, 110.73, 114.63, 127.65, 138.48, 156.68. Anal. Calcd for C30H45NO8S2: C, 58.89; H, 7.41; N, 2.29. Found: C, 57.47; H, 6.94; N, 2.23.

1. temperatureAfter the reaction mixture was refluxed for 0.5 h
2. concentrationit was concentrated
3. customdried in vacuo at 50° C.

ORD record

ord-4c9545c29b674ab4af2bcb2349f9b45b

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08067620B2