Trifluoroacetic acid → HCID 178422791, compound

Temperature

110 °C

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 23.1, 128 mg, 0.329 mmol), K3PO4 (140 mg, 0.658 mmol) and Pd(PPh3)4 (15.22 mg, 0.013 mmol) were added to a solution of (R)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 20.1, 80 mg, 0.165 mmol) in toluene (1.5 mL) under an argon atmosphere. and the RM was heated at 110° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (4 mL) and treated with TFA (0.507 mL, 6.58 mmol) and stirred at RT for 2 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10-20% to 80% B in 20 min). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was crystallized from DCM/n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=6.41 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=463 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.84 (s, 1H) 2.16-2.30 (m, 3H) 2.74 (d, J=10.56 Hz, 1H) 3.04-3.33 (m, 3H) 4.14-4.23 (m, 1H) 4.76-4.87 (m, 1H) 6.07 (s, 1H) 6.73-6.86 (m, 1H) 7.29 (d, J=8.21 Hz, 2H) 7.78-7.90 (m, J=8.99 Hz, 4H) 10.07 (s, 1H) 12.34-12.56 (m, 1H).

1. customThe solvent was evaporated off under reduced pressure
2. dissolutionthe residue was dissolved in DCM (4 mL)
3. extractionextracted with EtOAc
4. washThe combined extracts were washed with brine (20 mL)
5. dry with materialdried over Na2SO4
6. customthe solvent was evaporated off under reduced pressure
7. customto give a crude product which
8. customwas purified by preparative HPLC (Condition 10-20% to 80% B in 20 min)
9. additionFractions containing pure product
10. additiontreated with sat. aq. Na2CO3
11. customthe MeCN was evaporated off under reduced pressure
12. extractionThe aq. residue was extracted with DCM
13. dry with materialthe combined extracts were dried over Na2SO4
14. filtrationfiltered
15. customthe filtrate was evaporated off under reduced pressure
16. customto give a residue which
17. customwas crystallized from DCM/n-hexane

ORD record

ord-5420a9cbf4404a379c0ed48f80966395

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08829195B2