2,6-Lutidine → tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate

HRID 926631Notes

Reaction equation

HRID 926631 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Li]CCCC.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[C:30]3[Cl:50])=[O:26])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=2)=[C:30]3[Cl:50])([C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:8])=[CH:5][CH:6]=2)[OH:26])[CH2:24]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 86715662Tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate2×HCID 178418339Butyllithium

Product 1

HCID 118006162tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A flask containing 2,6-dimethylpyridine (277 mg, 1.49 mmol) and THF (5 mL) was cooled to −78° C. and then n-BuLi (2.5 M in hexanes, 0.610 mL, 1.52 mmol) was added dropwise producing a homogeneous orange solution. After 3 minutes, tert-butyl 3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (505 mg, 0.94 mmol, Intermediate 61: step b) in 3 mL THF was introduced. After 5 minutes, the −78° C. bath was replaced with an ice-water bath. After 30 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. This material was combined with a batch from a duplicate experiment for chromatography on silica gel (5% acetone-DCM increasing to 30% acetone with 1% MeOH) which provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.7, 1.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.37 (dd, J=25.7, 8.4 Hz, 4H), 7.05 (d, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.12-4.02 (m, 5H), 3.93-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.59-3.49 (m, 1H), 2.70 (s, 1H), 2.51 (s, 3H), 2.14 (s, 3H), 1.41 (s, 9H); MS (ESI): mass calcd. Chemical Formula: C34H35ClF3N3O4, Exact Mass: 641.2. m/z found 641.9 [M+H]+.

Workup

  1. customproducing a homogeneous orange solution
  2. waitAfter 5 minutes
  3. customthe −78° C. bath was replaced with an ice-water bath
  4. waitAfter 30 minutes
  5. customthe reaction mixture was quenched with aqueous NH4Cl solution
  6. extractionextracted with EtOAc (3×30 mL)
  7. washThe combined organics were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-d84734c18c2c4452ba4e563a374295d3
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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