Réaction #156109

Équation de réaction

K3PO4

5-bromo-N-(cyclopropylmethyl) nicotinamide

5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

bis(pinacolato)diboron

KOAc

→

N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide

Rendement 90.0%

Solvants

water

DMF

Conditions de réaction

Traitement

1. 1
   Autrepurged again with nitrogen
2. 2
   Températurethe solution was cooled to r.t
3. 3
   AutreThe solution was purged with nitrogen
4. 4
   Températureheated at 90° C. for 3 h
5. 5
   Concentrationconcentrated under reduced pressure
6. 6
   workup.DISSOLUTIONThe residue was dissolved in DCM
7. 7
   Lavagewashed with water and brine
8. 8
   Séchagedried over MgSO4
9. 9
   Autreevaporated under vacuum
10. 10
    AutreThe crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM)

Mode opératoire

A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) (1.068 g, 3.0 mmol), bis(pinacolato)diboron (0.914 g, 3.6 mmol), KOAc (0.883 g, 9.0 mmol) and dry DMF (20 mL) was purged with nitrogen. PdCl2(dppf)2 was added to the reaction and purged again with nitrogen. The solution was heated at 80° C. for 2 h. Once TLC showed the disappearance of (I), the solution was cooled to r.t. To this solution was added K3PO4 (0.955 g, 4.5 mmol), 5-bromo-N-(cyclopropylmethyl) nicotinamide (XVII) (0.765 g, 3.0 mmol), Pd(PPh3)4 (104 mg, 0.09 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90° C. for 3 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and then evaporated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXI) as a yellow solid (1.09 g, 2.7 mmol, 90% yield), 1H NMR (DMSO-d6) δ ppm 0.20-0.31 (m, 2H), 0.35-0.57 (m, 2H), 1.65 (m, 2H), 1.74-1.87 (m, 1H), 2.10 (d, J=12.06 Hz, 2H), 2.35-2.44 (m, 1H), 3.10-3.27 (m, 3H), 3.78-3.99 (m, 2H), 6.14 (d, J=7.35 Hz, 1H), 7.90-8.14 (m, 2H), 8.50 (d, J=12.5, 2H), 9.05 (dd, J=14.60, 1.98 Hz, 2H), 10.25 (s, 1H); ESIMS found C23H24N4O3 m/z 405 (M+H).

Source