(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone → 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-1,2,3-triazol-5-yl)ethanol

HRID 526862Notes

Reaction equation

HRID 526862 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[Li][CH3:34]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)([OH:13])[CH3:34])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1

Participants

4

Reactant 2

HCID 86715636(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone2×HCID 178418348HCID 178418348, compound

Product 1

HCID 1180065751-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-1,2,3-triazol-5-yl)ethanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 0.54 mmol, Intermediate 9: step b) was added THF (15 mL). The solution was cooled to −78° C. and MeLi (1.6 M in Et2O, 0.4 mL, 0.64 mmol) was introduced. The reaction mixture was quenched after 25 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford an off white solid. Chromatography on silica gel (10% CH3CN-DCM increasing to 30% CH3CN) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.74 (d, J=2.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.35 (m, 3H), 4.35 (s, 2H), 4.07 (s, 3H), 3.71 (s, 3H), 2.82 (br. s, 1H), 2.06 (s, 3H); MS (ESI): mass calcd. for C23H20ClF3N4O2, 476.1, m/z found 477.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-1,2,3-triazol-5-yl)ethanol was purified by chiral SFC (Stationary phase: Lux 5 m cellulose-3, 4.6 mm×250 mm, Mobile phase: 12% EtOH, 0.2% Et3N, 88% CO2) to give 2 enantiomers. The first eluting enantiomer was Example 11b and the second eluting enantiomer was Example 11c.

Workup

  1. customThe reaction mixture was quenched after 25 minutes with aqueous NH4Cl solution
  2. extractionthe aqueous portion was extracted with EtOAc (4×30 mL)
  3. washThe combined organics were washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customto afford an off white solid

Sources & evidence

ORD record
ord-c3d8c2bbeb7e4e3eb0faf3443716507c
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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