Cesium carbonate → HCID 67279846, compound

Participants

Reaction Steps

A degassed solution of 9-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (150 mg, 0.34 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (155 mg, 0.51 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Cs2CO3 (225 mg, 0.69 mmol) in a mixture of 1,4-dioxane (6 mL) and water (3 mL) was subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to give 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one as a crude oil. Aqueous NaOH (12.5 M, 0.4 mL) was added to a solution of 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 90 min, and then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to afford a sticky solid. The solid was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 99:1 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 90:10 to 5:95) to afford 116 as a white solid (72 mg, 40%). LCMS: RT=5.05 min, [M+H]+=519.2. 1H NMR (CDCl3, 400 MHz): δ 8.69-8.64 (m, 1H); 8.45 (s, 1H); 8.15 (d, J=2.7 Hz, 1H); 7.44-7.40 (m, 1H); 7.30-7.22 (m, 3H); 5.91 (s, 1H); 4.17 (s, 2H); 4.08-4.03 (m, 4H); 3.94-3.89 (m, 4H); 3.85 (s, 2H); 3.26 (d, J=2.6 Hz, 2H); 2.78-2.69 (m, 2H); 2.47 (t, J=11.2 Hz, 2H); 1.96 (d, J=13.8 Hz, 2H); 1.77-1.67 (m, 2H)

Provenance & Evidence