تفاعل #1011289

معادلة التفاعل

water

(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(5-(trifluoromethyl)pyridin-3-yl)boronic acid

Cs2CO3

Water

→

title product

(R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5′-(trifluoromethyl)-[3,3′-bipyridine]-5-carboxamide

المذيبات

dioxane

ظروف التفاعل

المعالجة

1. 1
   أخرىwas evacuated/purged with argon
2. 2
   أخرىThe solvent was evaporated off under reduced pressure
3. 3
   أخرىto give a residue that
4. 4
   استخلاصextracted with EtOAc
5. 5
   غسيلThe combined extracts were washed with water and brine
6. 6
   تجفيفdried over MgSO4/charcoal
7. 7
   ترشيحfiltered
8. 8
   أخرىthe filtrate was evaporated off under reduced pressure
9. 9
   أخرىto give a residue that
10. 10
    أخرىwas purified by flash chromatography (Silica gel column, 25 g, EtOAc)
11. 11
    أخرىPalladium was removed
12. 12
    workup.DISSOLUTIONThe residue was dissolved in EtOAc
13. 13
    workup.ADDITIONn-heptane was added
14. 14
    تركيزThe solution was concentrated
15. 15
    workup.STIRRINGthe resulting suspension was stirred
16. 16
    ترشيحfiltered
17. 17
    غسيلThe solid was washed with n-hexane
18. 18
    أخرىthen dried under HV at 45° C.

الإجراء التجريبي

A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 112 mg, 0.25 mmol), (5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial was evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol) was added and the vial sealed. Water (0.6 mL) was added and the RM was stirred at 65° C. for 3.5 h. The solvent was evaporated off under reduced pressure to give a residue that was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4/charcoal, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (Silica gel column, 25 g, EtOAc). Palladium was removed using a SPE PL-Thiol MP cartridge (StratoSpheres™). The residue was dissolved in EtOAc and n-heptane was added. The solution was concentrated under reduced and the resulting suspension was stirred and filtered. The solid was washed with n-hexane then dried under HV at 45° C. to afford the title product as an amorphous white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H) 10.19 (s, 1H).

المصدر