1-Methyl-1H-1,2,3-triazole → tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate

HRID 926629Notes

Reaction equation

HRID 926629 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:28]3[Cl:48])=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[C:28]3[Cl:48])([OH:24])[C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]

Participants

5

Reactant 3

HCID 1401191-Methyl-1H-1,2,3-triazoleHCID 86715662Tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate2×HCID 178418339Butyllithium

Product 1

HCID 86715661tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-43 °C

Procedure

To a flask containing 1-methyl-1H-1,2,3-triazole (430 mg, 0.8 mmol) was added THF (15 mL) and the solution was cooled to −43° C. using a CH3CN—CO2 bath. Then, n-BuLi, (2.5 M in hexanes, 0.7 mL, 1.75 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30 minutes, then tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)-azetidine-1-carboxylate (430 mg, 0.8 mmol, Intermediate 61: step b) in 2 mL THF was introduced. The reaction mixture was allowed to warm to room temperature over 30 minutes, and was quenched after 45 minutes with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on Silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.7, 2.1 Hz, 1H), 4.35 (s, 2H), 4.20 (t, J=8.8 Hz, 1H), 4.07 (s, 3H), 4.00 (dd, J=9.3, 5.6 Hz, 1H), 3.92 (dd, J=8.9, 5.7 Hz, 1H), 3.67 (s, 3H), 3.62 (t, J=8.8 Hz, 1H), 3.52-3.38 (m, 1H), 1.38 (s, 9H); MS (ESI): mass calcd: Chemical Formula: C30H31ClF3N5O4; Exact Mass: 617.2. m/z found 617.8 [M+H]+.

Workup

  1. temperatureto warm to room temperature over 30 minutes
  2. customwas quenched after 45 minutes with aqueous NH4Cl solution
  3. extractionThe aqueous portion was extracted with EtOAc (3×30 mL)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-b4433750c92e4eab9b2ae7c68e022033
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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