Dimethylacetamide → HCID 86715671, compound

HRID 928850Notes

Reaction equation

HRID 928850 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:28][CH3:29])[C:3]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[C:76]([N:78](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].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]>[CH3:27][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:28][CH3:29])[C:3]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)=[C:2]3[C:76]#[N:78])=[CH:25][CH:24]=[C:23]([CH3:26])[N:22]=1

Participants

7

Reactant 3

HCID 31374Dimethylacetamide2×HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 74221202HCID 74221202, compound

Product 1

HCID 86715671HCID 86715671, compound

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×

Conditions

Temperature
125 °C

Procedure

(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (250 mg, 0.44 mmol, Example 77A), zinc cyanide (90 mg, 0.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos, 40 mg, 0.084 mmol), zinc powder (8 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0), (Pd2(dba)3; 60 mg, 0.066 mmol) were added to a large microwave vial, then dimethylacetamide (7 mL, degassed with argon) was added and the vial was sealed and evacuated. The mixture was heated to 125° C. in an aluminum heating mantle. The mixture was cooled to 80° C. and then filtered through a Celite® pad and rinsed with EtOAc-MeOH (10:1, v/v) and the light brown filtrate was concentrated under vacuum to afford a brown oil. The crude material was chromatographed directly on silica gel (100% DCM increasing to 10% MeOH-DCM) which provided the product contaminated with dimethylacetamide. This material was further purified by RP-HPLC to the title compound as a white foam. MS m/e 559.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.05 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.42-7.34 (m, 2H), 7.06 (s, 1H), 4.37 (s, 2H), 4.13 (s, 3H), 3.94 (s, 3H), 2.77 (s, 3H), 2.62 (s, 3H). The racemic material was separated into its individual enantiomers using the following conditions: Chiralpack OD, 80% heptanes:20% ethanol; wavelength at 220 nM to provide the two enantiomers. The first eluting enantiomer was Example 78B and the second eluting enantiomer was Example 78C.

Workup

  1. customthe vial was sealed
  2. customevacuated
  3. temperatureThe mixture was cooled to 80° C.
  4. filtrationfiltered through a Celite® pad
  5. washrinsed with EtOAc-MeOH (10:1
  6. concentrationv/v) and the light brown filtrate was concentrated under vacuum
  7. customto afford a brown oil
  8. customThe crude material was chromatographed directly on silica gel (100% DCM increasing to 10% MeOH-DCM) which
  9. customprovided the product
  10. customThis material was further purified by RP-HPLC to the title compound as a white foam
  11. customThe racemic material was separated into its individual enantiomers
  12. customwavelength at 220 nM to provide the two enantiomers

Sources & evidence

ORD record
ord-b7f6e3b4238e4b809a2295103f4e14ae
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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