Diisopropylethylamine → 5-amino-2-(2,6-difluorophenyl)-N-(5-((5R,6S)-5,6-dihydroxyoxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

A solution of 7-(2-methyl-4-nitro-pyrazol-3-yl)oxepane-3,4-diol (Intermediate 10) (165 mg, 0.64 mmol) in MeOH (13 mL) was passed through the H-Cube (full H2 mode, 80° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure. To a solution of the resulting amine in DCM (10 mL) was added DIPEA (0.33 mL, 1.92 mmol), PyBOP (499 mg, 0.96 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (249 mg, 0.70 mmol). The mixture was stirred at room temperature for 18 hr, diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-10% MeOH/EtOAc) gave a pink solid. This solid (65 mg, 0.11 mmol) was dissolved in a solution of HCl in dioxane (4 M, 8.6 mL) and MeOH (2 mL) and stirred at room temperature for 18 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 111 as an off-white solid (28 mg, 9% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.75 (br s, 1H), 8.17 (s, 1H), 7.39-7.32 (m, 1H), 7.10-7.00 (m, 2H), 6.25 (br s, 2H), 5.14-5.10 (m, 1H), 4.23 (dd, J=13.7, 4.0 Hz, 1H), 3.90-3.85 (m, 1H), 3.79 (s, 3H), 3.75-3.56 (m, 2H), 2.12-2.00 (m, 3H), 1.76-1.70 (m, 1H). OH protons not observed. LCMS (ES+) m/z 466 (M+1).

1. customThe solvent was removed under reduced pressure
2. washwashed with water (3×5 mL)
3. customThe organic layer was passed through a phase separation cartridge
4. concentrationconcentrated under reduced pressure
5. customPurification via silica gel chromatography (0-10% MeOH/EtOAc)
6. customgave a pink solid
7. stirringstirred at room temperature for 18 hr
8. customThe solvents were removed under reduced pressure
9. customPurification via preparative HPLC

ORDレコード

ord-6330a540ed3a4a4f93bb871bba6b5eaa

出典データセット

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09328106B2