تفاعل #160915

معادلة التفاعل

5-bromo-6-chloro-nicotinic acid

SOCl2

4-(trifluoromethoxy)aniline

DIPEA

→

title compound

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

المذيبات

toluene

DMF

THF

ظروف التفاعل

المعالجة

1. 1
   أخرىThe solvent was evaporated off under reduced pressure
2. 2
   workup.DISSOLUTIONthe residue was dissolved in THF (3.1 L)
3. 3
   درجة الحرارةcooled to −25° C.
4. 4
   أخرىAfter 30 min at 10° C. the solvent was evaporated off under reduced pressure
5. 5
   workup.DISSOLUTIONthe residue was dissolved in TBME (4 L)
6. 6
   غسيلwashed with 1N HCl (2×1 L)
7. 7
   تجفيفa sat. solution of NaHCO3 (1 L) and brine (2×200 mL) and dried over Na2SO4
8. 8
   أخرىThe solvent was evaporated off under reduced pressure
9. 9
   أخرىthe product was crystallized from EtOAc/n-heptane

الإجراء التجريبي

A stirred solution of 5-bromo-6-chloro-nicotinic acid (375 g, 1.586 mol) and DMF (37 mL) in toluene (3.1 L) was treated dropwise with SOCl2 (347 mL, 4.758 mol) at RT and then stirred at 85° C. for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (3.1 L), cooled to −25° C., treated firstly with DIPEA (543 mL, 3.172 mol) and then by the dropwise addition of a solution of 4-(trifluoromethoxy)aniline (295 g, 1.665 mol) in THF (3.1 L), After 30 min at 10° C. the solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (4 L), washed with 1N HCl (2×1 L), a sat. solution of NaHCO3 (1 L) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/n-heptane to give the title compound as a beige crystalline solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=393/395/397 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 8.73 (d, J=2.20 Hz, 1H) 8.92 (d, J=2.20 Hz, 1H) 10.69 (s, 1H).

المصدر