3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester → 5-amino-2-(2,6-difluorophenyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide

温度

110 °C

A mixture of tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (234 mg, 0.5 mmol), potassium fluoride dihydrate (155 mg, 1.65 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol) in THF (5 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2, 60 mg, 0.05 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 110° C. for 8 hr. Water (10 mL) was added and the mixture extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel chromatography (isohexane then 0-5% MeOH/EtOAc). The resulting intermediate was dissolved in MeOH (5 mL) and treated with a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 16 hr and the solvent removed under reduced pressure. Purification via preparative HPLC gave 101 as a brown solid (37 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.05 (s, 1H), 7.38-7.26 (m, 1H), 7.06-6.97 (m, 2H), 6.13 (s, 2H), 6.03-6.00 (m, 1H), 4.41 (d, J=2.8 Hz, 1H), 4.39 (d, J=2.8 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 2.45-2.41 (m, 2H). LCMS (ES+) m/z 418 (M+1).

1. customwas degassed
2. customby bubbling nitrogen through it for 15 min
3. customthe mixture degassed for a further 10 min
4. additionWater (10 mL) was added
5. extractionthe mixture extracted with EtOAc (3×5 mL)
6. customThe combined organic layers were passed through a phase separation cartridge
7. concentrationconcentrated under reduced pressure
8. customThe residue was purified via silica gel chromatography (isohexane
9. dissolutionThe resulting intermediate was dissolved in MeOH (5 mL)
10. additiontreated with a solution of HCl in dioxane (4 M, 5 mL)
11. customthe solvent removed under reduced pressure
12. customPurification via preparative HPLC

ORDレコード

ord-6a44804d1f0f4bcca097197121bff99e

出典データセット

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09328106B2