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 926544Notes

Reaction equation

HRID 926544 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-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

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 12: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.08 mL, 2.69 mmol) was added dropwise. The color of the solution became a dark opaque reddish-brown color. After 2 minutes, a THF solution of tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 minutes, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 minutes at which time the mixture was quenched with aqueous 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 afford the title compound as a white solid.

Workup

  1. customresulting in a colorless homogeneous mixture
  2. waitAfter 5 minutes
  3. customthe reaction mixture was placed in an ice-water bath
  4. customwas quenched with aqueous 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-50857fdec50a4ae9bb3df4a1040168e0
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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