Tert-butyl 3-formylazetidine-1-carboxylate → tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylate

HRID 928828Notes

Reaction equation

HRID 928828 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.C(C1CN([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C1)=O>C1COCC1>[C:49]([O:48][C:46]([N:16]1[CH2:15][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)=[C:2]3[Cl:1])[OH:13])[CH2:19]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]

Participants

5

Reactant 3

HCID 10726182Tert-butyl 3-formylazetidine-1-carboxylateHCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol2×HCID 178418339Butyllithium

Product 1

HCID 86715660tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylateYield 76.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-70 °C

Procedure

To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 47: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5M in hexanes, 1.08 mL, 2.69 mmol)) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 min, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 min, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 min at which time the mixture was quenched with NH4Cl solution. The contents were diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a yellow foam. The crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc) to give the title compound (950 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.6, 1.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.99 (dd, J=8.0, 3.3 Hz, 1H), 4.35 (s, 2H), 4.05 (bs, 2H), 3.82 (t, J=8.7 Hz, 1H), 3.74-3.67 (m, 1H), 2.99-2.90 (m, 1H), 2.20-2.15 (m, 1H), 1.41 (s, 9H). MS (ESI): mass calcd. for C27H28ClF3N2O4: 536.98, m/z found 537.2 [M+H]+.

Workup

  1. customresulting in a colorless homogeneous mixture
  2. waitAfter 5 min
  3. customthe reaction mixture was placed in an ice-water bath
  4. customwas quenched with NH4Cl solution
  5. additionThe contents were diluted further with water
  6. extractionextracted with EtOAc (5×40 mL)
  7. washThe combined organics were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto provide a yellow foam
  12. customThe crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc)

Sources & evidence

ORD record
ord-9a84162d3027463f8895e2658ada77bb
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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