1-Hydroxybenzotriazole → 5-(4-Methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

A mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (70 mg, 0.21 mmol), EDC.HCl (49 mg, 0.25 mmol) and HOBT (34 mmol, 0.25 mmol) in DMF (2 mL) was stirred at RT for 30 min. N-hydroxy-4-(trifluoromethoxy)benzimidamide (55 mg, 0.25 mmol) was added and the reaction mixture was stirred for 1 h at RT and then at 140° C. for another 2 h. The reaction mixture was cooled to RT, diluted with H2O (5 mL) and taken into EtOAc (10 mL). The organic layer was separated, washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to give 5-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (2.0 mg, 2%). MS (ES+) C25H24F3N5O2S requires: 515, found: 516[M+H]+; 1H-NMR (500 MHz, CD3OD) δ ppm 8.24 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 8.24 (t, J=8.0 Hz, 1H), 6.94-6.92 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 4.23 (s, 2H), 3.23 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.54 (s, 3H), 2.36 (s, 3H).

1. stirringthe reaction mixture was stirred for 1 h at RT
2. waitat 140° C. for another 2 h
3. temperatureThe reaction mixture was cooled to RT
4. customThe organic layer was separated
5. washwashed with H2O (5 mL) and brine (5 mL)
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. customto afford the crude product, which
10. customwas purified by pre-HPLC (Mobile phase
11. waitGradient: B=60%-95% in 18 min

ORDレコード

ord-32fdf1582bc84236ac70a437d7a3381e

出典データセット

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09115120B2