Acetone cardice → (4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)bis(1-methyl-1H-1,2,3-triazol-5-yl)methanol

HRID 926578Notes

Reaction equation

HRID 926578 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[C:10]2[Cl:30].ClC1C2C(=CC=C(C(C3C(C)=NC(C)=CC=3)O)C=2)N=C(OC)C=1CC1C=CC(C(F)(F)F)=CC=1.[CH3:65][N:66]1[C:70]([C:71]([C:73]2[N:77]([CH3:78])[N:76]=[N:75][CH:74]=2)=[O:72])=[CH:69][N:68]=[N:67]1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:71]([C:70]3[N:66]([CH3:65])[N:67]=[N:68][CH:69]=3)([C:73]3[N:77]([CH3:78])[N:76]=[N:75][CH:74]=3)[OH:72])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1

Participants

7

Reactant 5

HCID 18522661Acetone cardiceHCID 867156276-Bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolineHCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanolHCID 86715669bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 118006507(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)bis(1-methyl-1H-1,2,3-triazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

n-BuLi (1.63 M in hexane, 0.139 mL, 0.226 mmol) was added dropwise over 1 minute to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (90.1 mg, 0.209 mmol, Intermediate 12: step d in THF (2.1 mL) at ˜−70° C. under argon. After 2 additional minutes, a homogeneous solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (41.4 mg, 0.215 mmol, Intermediate 13) in THF (2.1 mL) was added dropwise over 1 minute, and the resulting solution was allowed to warm to room temperature overnight as the dry ice/acetone bath expired. The resulting homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL), dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=2.02 Hz, 1H), 7.99 (br. s., 1H), 7.91 (d, J=8.59 Hz, 1H), 7.65 (d, J=8.08 Hz, 2H), 7.41-7.51 (m, 3H), 7.19 (s, 2H), 4.36 (s, 2H), 4.04 (s, 3H), 3.84 (s, 6H); MS m/e 544.1 [M+H]+.

Workup

  1. customat ˜−70° C.
  2. customThe resulting homogeneous yellow reaction
  3. customwas then quenched with 5 M aqueous NH4Cl (0.06 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customThe residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout)
  8. dry with materialThe organic layer was dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-9e5ff0731b4f41ccb5ad6dccceb3ce9b
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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