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 526850Notes

Reaction equation

HRID 526850 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH:31]([CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)=[O:32]>C1COCC1>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([CH:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:5]3[Cl:25])[OH:32])[CH2:34]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]

Participants

5

Reactant 3

HCID 10726182Tert-butyl 3-formylazetidine-1-carboxylateHCID 867156276-Bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline2×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 8028TetrahydrofuranSolvent

Conditions

Temperature
-75 °C

Procedure

To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 5: step d) was added THF (30 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −75° C. and then n-BuLi (2.5 M in hexanes, 1.08 mL, 2.69 mmol) was added dropwise. After 2 minutes, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol in 3 mL THF) was introduced. After 5 minutes, the reaction mixture was transferred to an ice-water bath and stirring was continued for 30 minutes. The reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as a white solid.

Workup

  1. customresulted in a colorless homogeneous mixture
  2. waitAfter 5 minutes
  3. customthe reaction mixture was transferred to an ice-water bath
  4. waitwas continued for 30 minutes
  5. customThe reaction mixture was quenched with aqueous NH4Cl solution
  6. extractionthe aqueous portion was extracted with EtOAc (5×40 mL)
  7. washThe combined organics were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated to dryness
  11. customThe crude material was chromatographed on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc)

Sources & evidence

ORD record
ord-ed11f03cb02146079895c154e700091b
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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