Dimethylacetamide → 6-((3,5-Dimethylisoxazol-4-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-4-carbonitrile

HRID 926619Notes

Reaction equation

HRID 926619 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[C:75]([N:77](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn]>[CH3:26][C:21]1[C:20]([C:12]([OH:13])([C:14]2[N:18]([CH3:19])[N:17]=[N:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[C:2]3[C:75]#[N:77])=[C:24]([CH3:25])[O:23][N:22]=1

Participants

7

Reactant 3

HCID 31374DimethylacetamideHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 118006262(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(3,5-dimethylisoxazol-4-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

Product 1

HCID 1180063706-((3,5-Dimethylisoxazol-4-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-4-carbonitrile

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
125 °C

Procedure

(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(3,5-dimethylisoxazol-4-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (180 mg, 0.32 mmol, Example 93), zinc cyanide (77 mg, 0.66 mol), X-phos (45 mg, 0.94 mmol), Pd2(dba)3 (50 mg, 0.055 mmol) and zinc metal (3 mg, 0.19 mmol) were added to a large microwave vial. DMA (4 mL, sparged with argon for 35 minutes) was added and the vial was sealed and evacuated. The mixture was heated to 125° C. in a preheated aluminum heating mantle. After 1 hour, the mixture was allowed to cool to room temperature and then was filtered through a Celite® pad and rinsed with EtOAc-MeOH (10:1). The effluent was concentrated under reduced pressure and the crude material was chromatographed directly on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as an off white solid. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.1 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.40 (dd, J=8.8, 2.2 Hz, 1H), 6.92 (s, 1H), 5.38 (s, 1H), 4.43-4.29 (m, 2H), 4.12 (s, 3H), 4.01 (s, 3H), 1.95 (s, 3H), 1.82 (s, 3H); MS (ESI): mass calc. for Chemical Formula: C28H23F3N6O3; Exact Mass: 548.2. m/z found 549.0 (M+H).

Workup

  1. customthe vial was sealed
  2. customevacuated
  3. temperatureto cool to room temperature
  4. filtrationwas filtered through a Celite® pad
  5. washrinsed with EtOAc-MeOH (10:1)
  6. concentrationThe effluent was concentrated under reduced pressure
  7. customthe crude material was chromatographed directly on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc)

Sources & evidence

ORD record
ord-ef930aff73ff4c74aa66e0086e0178d5
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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