Toluene → 6-(2-methoxyethoxy)-5-(1-(tetrahydro-2 h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 629093Notes

Reaction equation

HRID 629093 reaction equation
Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:37]2[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=[CH:35][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1

Participants

7

Reactant 4

HCID 1140TolueneHCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 899074165-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 1180732896-(2-methoxyethoxy)-5-(1-(tetrahydro-2 h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolvent

Procedure

A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (49 mg, 0.172 mmol), Pd(Ph3P)4 (13 mg, 0.011 mmol) and toluene (0.5 mL) was stirred for 15 min under an argon atmosphere. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-methoxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.099 mmol), TFA (0.25 mL, 3.24 mmol) and DCM (0.4 mL) was stirred at RT for 2 h. The mixture was treated with a solution of Na2CO3 (2 M) 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 preparative SFC (Column Diol; gradient 13% to 18% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=423.3 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 3.73-3.82 (m, 2H) 4.58 (br. s, 2H) 6.90 (d, J=1.88 Hz, 1H) 7.37 (d, J=8.47 Hz, 2H) 7.83-7.87 (m, 1H) 7.89 (d, J=9.03 Hz, 2H) 8.70 (d, J=2.26 Hz, 1H) 8.77-8.90 (m, 1H) 10.55 (br. s, 1H) 13.06-13.22 (m, 1H).

Workup

  1. stirringthe RM was stirred at 110° C. for 6 h
  2. filtrationfiltered through a cartridge of PL-Thiol MP-Resin
  3. customthe filtrate was evaporated to dryness under reduced pressure

Sources & evidence

ORD record
ord-34c84dd20bf840e6b06180856d5c9eaf
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

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