1-Methyl-1H-1,2,3-triazole → (4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol

HRID 926616Notes

Reaction equation

HRID 926616 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=1

Participants

5

Reactant 3

HCID 1401191-Methyl-1H-1,2,3-triazoleHCID 118006338(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 118006254(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-43 °C

Procedure

To a flask containing 1-methyl-1H-1,2,3-triazole (100 mg, 1.2 mmol) was added THF (10 mL) and the colorless solution was cooled to −43° C. using a CH3CN—CO2 bath. Then, n-BuLi (2.5 M in hexanes, 490 μL, 1.23 mmol) was added dropwise which afforded an opaque mixture. The mixture was stirred at −40° C. for 30 minutes, then a homogeneous solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (255 mg, 0.54 mmol, Intermediate 80: step b) in 2 mL THF was introduced. After 5 minutes, the reaction mixture was then placed in an ice-water bath. The reaction was quenched after 20 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×30 mL) and EtOAc:THF (1:1, 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with MeOH and filtered to give a yellow filtrate which was concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.41-7.35 (m, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 6.22 (s, 1H), 4.29 (s, 2H), 4.07 (s, 3H), 3.89 (s, 3H), 3.41 (s, 3H). MS (ESI): mass calcd. for Chemical Formula: C26H22ClF3N6O2; Exact Mass: 542.14. m/z found 542.9 [M+H]+.

Workup

  1. customafforded an opaque mixture
  2. waitAfter 5 minutes
  3. customthe reaction mixture was then placed in an ice-water bath
  4. customThe reaction was quenched after 20 minutes with aqueous NH4Cl solution
  5. extractionthe aqueous portion was extracted with EtOAc (3×30 mL) and EtOAc:THF (1:1, 30 mL)
  6. washThe combined organics were washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe solid was triturated with MeOH
  11. filtrationfiltered
  12. customto give a yellow filtrate which
  13. concentrationwas concentrated
  14. customchromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH)

Sources & evidence

ORD record
ord-281f7ed3897848068d5624917df61863
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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