Acetyl chloride → 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidin-1-yl)ethanone

HRID 928864Notes

Reaction equation

HRID 928864 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[C:16]3[Cl:36])([C:7]2[N:11]([CH3:12])[N:10]=[N:9][CH:8]=2)[OH:6])[CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(Cl)(=O)C>CCN(CC)CC.ClCCl>[Cl:36][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]([OH:6])([C:7]3[N:11]([CH3:12])[N:10]=[N:9][CH:8]=3)[CH:3]3[CH2:4][N:1]([C:37](=[O:39])[CH3:38])[CH2:2]3)[CH:14]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]=1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=1

Participants

6

Reactant 3

HCID 6367Acetyl chlorideHCID 7918Acetic AnhydrideHCID 86715675azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol2×

Product 1

HCID 742212651-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidin-1-yl)ethanoneYield 58.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent2×

Procedure

To a flask containing azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (140 mg, 0.27 mmol, Intermediate 66: step d) was added dichloromethane (8 mL) which gave a suspension at room temperature. Et3N (0.13 mL, 0.9 mmol) was added, followed by acetic anhydride (0.3 mL, 0.32 mmol). After stirring at room temperature for 4 h, more Et3N (200 μL) was added along with more acetyl chloride (25 μL) and the suspension was heated to 35° C. for 18 h. The reaction was quenched with the addition of 1N NaOH (2 mL) and water (5 mL). The aqueous portion was extracted with dichloromethane (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated. The crude material was chromatographed on silica gel (5% MeOH-dichloromethane) to give the title compound (88 mg) as an off white solid. 1H NMR (500 MHz, CD3CN, racemate) δ 8.25 (dd, J=14.0, 1.9 Hz, 1H), 7.74 (dd, J=8.7, 2.6 Hz, 1H), 7.66 (d, J=4.4 Hz, 1H), 7.58-7.49 (m, 2H), 7.48-7.33 (m, 3H), 5.17 (s, 0.5H), 5.06 (s, 0.5H), 4.43-4.28 (m, 3H), 4.22-4.10 (m, 1H), 4.07-3.98 (m, 4H), 3.93 (dd, J=9.9, 6.0 Hz, 1H), 3.82 (dd, J=9.1, 5.6 Hz, 1H), 3.72 (t, J=8.6 Hz, 1H), 3.65-3.48 (m, 5H). MS (ESI) 560.1 [M+H]+.

Workup

  1. customgave a suspension at room temperature
  2. temperaturethe suspension was heated to 35° C. for 18 h
  3. customThe reaction was quenched with the addition of 1N NaOH (2 mL) and water (5 mL)
  4. extractionThe aqueous portion was extracted with dichloromethane (3×25 mL)
  5. dry with materialThe combined organics were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was chromatographed on silica gel (5% MeOH-dichloromethane)

Sources & evidence

ORD record
ord-df2f2ab03a024fd396dc90f070a260f1
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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