Potassium Phosphate, Tribasic → 4-(1-Methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile

HRID 922777Notes

Reaction equation

HRID 922777 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]([CH3:23])[CH2:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:24]#[N:25])[CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH2:12][N:13]4[CH2:18][C@H:17]([C:19]([F:20])([F:21])[F:22])[O:16][C@H:15]([CH3:23])[CH2:14]4)=[CH:9][CH:10]=3)[N:5]=[C:4]([C:24]#[N:25])[CH:3]=2)[CH:29]=[N:28]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 895549564-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile

Product 1

HCID 895549534-(1-Methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrileYield 67.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

4-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-7, 859 mg, 2.323 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (725 mg, 3.48 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), and X-Phos (111 mg, 0.232 mmol) were combined in THF (10 ml). To this was added 1M K3PO4 (7 ml, 7.00 mmol). The mixture was degassed (3× pump/N2) then heated to 70° C. overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (100 g, 50% EtOAc/hexanes) to afford 4-(methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-8, 650 mg, 67%) as a white solid. 1H NMR (399 MHz, CDCl3): δ 8.22 (d, J=8.7 Hz, 1H); 8.10 (s, 1H); 7.86 (s, 1H); 7.78 (s, 1H); 7.71 (dd, J=8.7, 1.7 Hz, 1H); 7.63 (s, 1H); 4.07 (m, 3H); 3.78 (m, 3H); 2.92 (d, J=11.0 Hz, 1H); 2.75 (d, J=11.4 Hz, 1H); 2.22 (t, J=10.8 Hz, 1H); 1.97 (t, J=10.8 Hz, 1H); 1.20 (d, J=6.3 Hz, 3H).

Workup

  1. customThe mixture was degassed (3× pump/N2)
  2. temperatureThe mixture was cooled to rt
  3. additiondiluted with H2O
  4. extractionextracted with EtOAc (3×)
  5. filtrationThe combined organic layers were filtered through a pad of Celite
  6. washwashing with EtOAc
  7. concentrationthen concentrated

Sources & evidence

ORD record
ord-e2bd0ce698c74c85a7adf7d409ce1b55
Source dataset
uspto-grants-2016_03
Patent number
US09278960B2

Reaction notes

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