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

HRID 629094Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 629094
Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25]C)=[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.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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>[OH: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:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])=[CH:5][N:4]=1

Komponenten

7

Edukt 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

Produkt 1

HCID 899083836-(2-hydroxyethoxy)-5-(1-(tetrahydro-2 h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 887MethanolLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 100 mg, 0.237 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.237 mmol), Pd(Ph3P)4 (27 mg, 0.024 mmol), K3PO4 (151 mg, 0.712 mmol) and toluene (1.5 mL) was stirred at 110° C. for 5 h under an argon atmosphere. 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-hydroxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, which was dissolved in DCM (0.4 mL), treated with TFA (0.25 mL, 3.24 mmol) and stirred overnight at RT. 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 was purified by preparative SFC (Column DEAP; gradient 25% to 30% in 6 min.) and lyophilized to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=0.92 min, m/z=409.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.82 (t, J=4.90 Hz, 2H) 4.48 (t, J=4.89 Hz, 2H) 6.98 (d, J=1.69 Hz, 1H) 7.37 (d, J=8.66 Hz, 2H) 7.75-7.83 (m, 1H) 7.88 (s, 2H) 8.70 (d, J=2.26 Hz, 2H) 8.79 (br. s, 1H) 10.54 (s, 1H) 12.86-13.40 (m, 1H).

Aufarbeitung

  1. filtrationfiltered through a cartridge of PL-Thiol MP-Resin
  2. customthe filtrate was evaporated to dryness under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-e84e491913da4a7ca1ba9f496e259359
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09315489B2

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