Diisopropylethylamine → 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

To a solution of 2,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide (410 mg, 1.16 mmol, intermediate 83) in MeOH (20 mL) was added ammonium formate (400 mg, 6.34 mmol) and 10% Pd/C (400 mg). The mixture was heated at reflux for 5 hr then cooled to room temperature. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in IPA (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (312 mg, 1.22 mmol) and DIPEA (0.62 mL, 3.47 mmol) were then added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.61 mL, 1.28 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. Saturated aqueous NaHCO3 solution (10 mL) and DCM (20 mL) were added. The organic layer was washed with 1 N HCl (10 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) gave 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide as an oil. To a solution of this oil in IPA (2 mL), THF (2 mL) and water (1 mL) was added K2CO3 (31 mg, 0.22 mmol) and the mixture heated at 50° C. for 18 hr. More K2CO3 (300 mg, 2.2 mmol) was added and the mixture heated in a microwave at 120° C. for 2.5 hr. The reaction mixture was cooled to room temperature, filtered washing with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The residue was passed through an SCX column eluting with 0-5% 7 N NH3 in MeOH/DCM) and purified by preparative HPLC to give 178 as a colourless solid (1 mg, 0.2% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.45 (s, 2H), 8.01 (s, 1H), 7.39-7.32 (m, 1H), 7.06 (t, J=8.8 Hz, 2H), 5.82 (s, 1H), 3.98 (d, J=11.6 Hz, 2H), 3.74-3.65 (m, 5H), 2.86 (s, 2H), 0.69 (s, 3H). LCMS (ES+) m/z 465 (M+1).

1. temperatureThe mixture was heated
2. temperatureat reflux for 5 hr
3. filtrationThe suspension was filtered
4. concentrationthe filtrate concentrated under reduced pressure
5. dissolutionThe residue was dissolved in IPA (10 mL)
6. washThe organic layer was washed with 1 N HCl (10 mL)
7. customseparated
8. dry with materialdried over MgSO4
9. concentrationconcentrated under reduced pressure
10. customPurification via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM)

ORD-Eintrag

ord-63684a35e3854af39b3cffb18387b6f4

Quelldatensatz

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09328106B2