2,6-Dimethylnicotinaldehyde → {2-Azetidin-1-yl-4-chloro-3-[4-(trifluoromethyl)benzyl]quinolin-6-yl}(2,6-dimethylpyridin-3-yl)methanol

HRID 1507325Notes

Reaction equation

HRID 1507325 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][C:34]1[C:39]([CH:40]=[O:41])=[CH:38][CH:37]=[C:36]([CH3:42])[N:35]=1>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:40]([C:39]4[C:34]([CH3:33])=[N:35][C:36]([CH3:42])=[CH:37][CH:38]=4)[OH:41])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 27847532,6-DimethylnicotinaldehydeHCID 1180060532-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline2×HCID 178418339Butyllithium

Product 1

HCID 118005807{2-Azetidin-1-yl-4-chloro-3-[4-(trifluoromethyl)benzyl]quinolin-6-yl}(2,6-dimethylpyridin-3-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 (1.09 g, 2.40 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 2,6-dimethyl-pyridine-3-carbaldehyde (0.36 g, 2.6 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, 0-100% DCM/(10% of a 2 M NH3 MeOH in DCM)) to afford the title compound. MS (ESI): mass calcd. for C28H25ClF3N3O, 511.2; m/z found, 512.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.44 (dd, J=8.7, 2.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 6.09 (s, 1H), 4.34 (s, 2H), 4.12 (t, J=7.6 Hz, 4H), 2.74 (s, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.29-2.18 (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. customthen transferred 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, 0-100% DCM/(10% of a 2 M NH3 MeOH in DCM))

Sources & evidence

ORD record
ord-89d30a7d6cf541f880c6225418d97571
Source dataset
uspto-grants-2015_12
Patent number
US09221804B2

Reaction notes

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