Sodium Hydroxide → 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanol

To a solution of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.20 g, 0.54 mmol) in dry THF (20 mL) at 0° C. was added 2-chloroethanesulfonyl chloride (65 μL, 0.6 mmol) and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further 2-chloroethanesulfonyl chloride (1304) was added and the reaction mixture was stirred at RT for 18 hours. An aqueous sodium hydroxide solution (8M, 3.38 mL, 27 mmol) was added and the mixture was heated at 40° C. for 18 hours then concentrated in vacuo. The resultant residue was extracted several times with 10% MeOH in DCM and the combined extracts concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-20% MeOH in DCM) followed by preparative HPLC (Gemini C18 column, gradient 5-95% MeOH in H2O+0.1% HCO2H) to give 394 (58 mg, 23%). LCMS: RT=8.45 min, [M+H]+=476. 1H NMR δ (ppm) (DMSO-d6, 80° C.): 8.22 (1H, d, J=2.31 Hz), 8.01 (1H, s), 7.33 (1H, dd, J=8.34, 2.39 Hz), 7.08 (1H, d, J=8.32 Hz), 5.81-5.73 (1H, m), 4.53 (2H, s), 4.37 (2H, t, J=5.09 Hz), 4.22 (3H, s), 3.57 (2H, t, J=6.26 Hz), 3.43 (2H, t, J=5.09 Hz), 2.79 (2H, t, J=6.37 Hz), 1.59 (6H, d, J=6.61 Hz). 1 Exchangeable proton not observed

1. temperatureThe reaction mixture was cooled to 0° C.
2. stirringthe reaction mixture was stirred at RT for 18 hours
3. temperaturethe mixture was heated at 40° C. for 18 hours
4. concentrationthen concentrated in vacuo
5. extractionThe resultant residue was extracted several times with 10% MeOH in DCM
6. concentrationthe combined extracts concentrated in vacuo
7. customThe residue was purified by flash chromatography (SiO2, 0-20% MeOH in DCM)

ORD record

ord-c91b88dfcbf04e68a6173b65d44b1dd1

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09175009B2