1H-Pyrazole, 1-methyl- → 1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a 5° C. solution of 5.00 mL (60.9 mmol) n-methylpyrazole in 100 ml THF was added dropwise 381 mL (60.9 mmol) 1.6M n-BuLi in hexanes. The reaction mixture was warmed to room temperature, and after 1 hr at room temperature, the reaction mixture was cooled to −78° C. 18.4 mL (79.0 mmol) isopropyl borate was added. After 1.00 h at −78° C., the reaction mixture was quenched with12.0 mL of 2N HCl. The resulting solution was concentrated in vacuo and azotroped with toluene. The resulting crude material was dissolved in 111 mL THF. 6.57 g (55.6 mmol) pincol and 1.00 g of molecular sieves were added. After 24.0 hr at room temperature, the reaction mixture was filtered and concentrated. The resulting residue was dissolved in 100 mL hexanes, washed twice with water, dried over NaSO4, filtered, and concentrated in vacuo to afford 5.90 g (51%) 1-methyl-5-(4,4,5,5-tetrarnethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (CD3OD, 400 MHz) 7.45(d, 1H, J=1.92); 7.67 (d, 2H, J=1.92 Hz); 4.04 (s, 3H); 1.35 (s, 12H). ESMS+1 for C10H17BN2O2:209.1. To a sealed vessel containing 9.20 g (19.8 mmol) 2-(4-iodophenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide, 4.95 g (23.8 mmol) 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 0.133 g (0.476 mmol) tricyclohexylphosphine, and 0.181 g (0.198 mmol) Pd2(dba)3 was added 52.8 mL dioxane and 26.5 mL of 1.27M K3PO4. After 12.0 h at 100° C., the reaction mixture was cooled to room temperature and extracted three times with CH2Cl2 and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 50-100% EtOAc:hexane). The resulting solid was recrystallized from n-butylchloride to afford 5.00 g (60%) 2-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) 8.23 (d, 1H, J=2.74 Hz); 7.51 (d, 1H, J=1.83 Hz); 7.38 (m, 4H); 7.22 (m, 2H); 6.79 (br d, 1H, J=7.15 Hz); 6.30 (d, 1H, J=2.01 Hz); 5.13 (m, 1H); 4.38 (q, 2H, J=8.05 Hz); 3.90 (s, 3H); 3.63 (s, 2H); 1.43 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H21F3N4O2: 419.1682, Found: 419.1690.

1. temperaturethe reaction mixture was cooled to −78° C
2. waitAfter 1.00 h at −78° C.
3. customthe reaction mixture was quenched with12
4. concentrationThe resulting solution was concentrated in vacuo and azotroped with toluene
5. dissolutionThe resulting crude material was dissolved in 111 mL THF
6. addition6.57 g (55.6 mmol) pincol and 1.00 g of molecular sieves were added
7. waitAfter 24.0 hr at room temperature
8. filtrationthe reaction mixture was filtered
9. concentrationconcentrated
10. dissolutionThe resulting residue was dissolved in 100 mL hexanes
11. washwashed twice with water
12. dry with materialdried over NaSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo

ORD record

ord-c5e8a708c3054404bf16b5cd3788ff95

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08263627B2