Sodium Carbonate → 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

HRID 525715Notes

Reaction equation

HRID 525715 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:27][C:28]1[C:47](I)=[CH:46][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([Cl:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[O:33])=[CH:30][N:29]=1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:28]1[C:47]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[CH:46][C:31]([C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42]([Cl:45])([F:43])[F:44])=[CH:39][CH:40]=2)=[O:33])=[CH:30][N:29]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 867026266-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide

Product 1

HCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (9.45 g, 34.0 mmol), Na2CO3 (39.2 mL, 78 mmol) and PdCl2(dppf) (0.956 g, 1.307 mmol) were added to 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3, 12 g, 26.1 mmol) in DME (160 mL). The mixture was evacuated/purged 3 times with argon, and stirred at 80° C. for 22 h. The RM was diluted with EtOAc (350 mL), washed with water (4×150 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 850 g, EtOAc/n-hexane (1:2)) and crystallized from iPr2O/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=7.523 min, UPLC-MS (Condition 3) tR=1.22 min, m/z=483/485 [M+H]+.

Workup

  1. customThe mixture was evacuated/purged 3 times with argon
  2. additionThe RM was diluted with EtOAc (350 mL)
  3. washwashed with water (4×150 mL)
  4. extractionextracted with EtOAc
  5. dry with materialThe combined extracts were dried over Na2SO4
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give the crude product which
  8. customwas purified by flash chromatography (Silica gel column, 850 g, EtOAc/n-hexane (1:2))
  9. customcrystallized from iPr2O/EtOAc

Sources & evidence

ORD record
ord-96106d6ff22b4c09af6a4de47772c53f
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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