1-Methyl-1H-1,2,3-triazole → HCID 74221202, compound

HRID 928849Notes

Reaction equation

HRID 928849 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=1

Participants

5

Reactant 3

HCID 1401191-Methyl-1H-1,2,3-triazoleHCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol2×HCID 178418339Butyllithium

Product 1

HCID 74221202HCID 74221202, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-50 °C

Procedure

To a flask containing 1-methyl-1H-1,2,3-triazole (275 mg, 3.31 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (35 mL) and the colorless solution was cooled to −50° C. Then, n-butyllithium (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise which afforded a dark reddish-brown viscous solution. The mixture was stirred between −20 to −10° C. for 30 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (700 mg, 1.44 mmol in 4 mL THF, Intermediate 47: step f) was introduced at 0° C. The reaction mixture became a dark brown color and was allowed to warm gradually to room temperature. The mixture was stirred for 60 minutes at room temperature then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc, 3×50 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (1% MeOH-DCM increasing to 5% MeOH-DCM) provided the product as a light brown solid. MS m/e 586.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (d, J=1.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.37 (d, J=7.9 Hz, 3H), 6.93 (q, J=8.1 Hz, 2H), 6.80 (s, 1H), 5.51 (s, 1H), 4.36-4.22 (m, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H). Racemic (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 was separated into its individual enantiomers using the following conditions: Chiralcel OD, 20 uM (Diacel) using ethanol with 242 nM detection to give the first eluting enantiomer Example 77B: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H); and the second eluting enantiomer Example 77C: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H).

Workup

  1. customafforded a dark reddish-brown viscous solution
  2. temperatureto warm gradually to room temperature
  3. stirringThe mixture was stirred for 60 minutes at room temperature
  4. customthen quenched with aqueous NH4Cl solution
  5. extractionThe aqueous portion was extracted with EtOAc, 3×50 mL
  6. washThe combined organics were washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto provide a brown oil

Sources & evidence

ORD record
ord-eca68f3a428d4df797a4d86314632614
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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