1,2-dimethyl-1H-imidazole-5-carbaldehyde → {2-Azetidin-1-yl-4-chloro-3-[4-(trifluoromethyl)benzyl]quinolin-6-yl}(1,2-dimethyl-1H-imidazol-5-yl)methanol

HRID 1507324Notes

Reaction equation

HRID 1507324 reaction equation
[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][N:34]1[C:38]([CH:39]=[O:40])=[CH:37][N:36]=[C:35]1[CH3:41]>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:39]([C:38]4[N:34]([CH3:33])[C:35]([CH3:41])=[N:36][CH:37]=4)[OH:40])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 31596101,2-dimethyl-1H-imidazole-5-carbaldehydeHCID 1180060532-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline2×HCID 178418339Butyllithium

Product 1

HCID 118006138{2-Azetidin-1-yl-4-chloro-3-[4-(trifluoromethyl)benzyl]quinolin-6-yl}(1,2-dimethyl-1H-imidazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.00 g, 2.19 mmol, Intermediate 16) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (0.30 g, 2.4 mmol) in THF (20 mL) was added via cannula and stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH; MeOH in DCM) to provide the title compound. MS (ESI): mass calcd. for C26H24ClF3N4O, 500.2; m/z found, 501.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.15-8.11 (m, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.26-7.21 (m, 2H), 7.59-7.55 (m, 1H), 6.52 (d, 1H), 5.97 (s, 1H), 4.35 (s, 2H), 4.13 (t, J=7.5 Hz, 4H), 3.49 (s, 3H), 2.33 (s, 3H), 2.28-2.20 (m, 2H).

Workup

  1. stirringstirred for 10 minutes at −78° C
  2. customThe dry ice bath was then removed
  3. customreplaced with an ice water bath
  4. stirringstirred at 0° C. for approximately one hour
  5. customThe reaction was then quenched with a saturated, aqueous NH4Cl solution
  6. customtransferred to a separatory funnel with EtOAc
  7. extractionThe organic phase was extracted with a saturated, aqueous NH4Cl solution
  8. customseparated
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH

Sources & evidence

ORD record
ord-d61968708b614b068bac94fd02b8e975
Source dataset
uspto-grants-2015_12
Patent number
US09221804B2

Reaction notes

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