Acetic Anhydride → 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone

HRID 926615Notes

Reaction equation

HRID 926615 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[C:18]3[Cl:38])([C:7]2[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[OH:6])[CH2:2]1.N1CC(C(C2C(C)=NC(C)=CC=2)(O)C2C=C3C(=CC=2)N=[C:49]([OH:54])[C:48](CC2C=CC(C(F)(F)F)=CC=2)=C3Cl)C1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:38][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:5]([C:7]3[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)([OH:6])[CH:3]3[CH2:4][N:1]([C:49](=[O:54])[CH3:48])[CH2:2]3)[CH:16]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=1

Participants

6

Reactant 4

HCID 7918Acetic AnhydrideHCID 8471TriethylamineHCID 118006245Azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanolHCID 178425670HCID 178425670, compound

Product 1

HCID 1180062701-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a flask containing crude azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol and 6-(azetidin-3-yl(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)-4-chloro-3-(4-(trifluoromethyl)benzyl)-quinolin-2-ol (630 mg, 1.16 mmol, Example 126) was added DCM (20 mL) which gave a suspension at room temperature. Triethylamine (1 mL, 6.9 mmol) was added, followed by acetic anhydride (0.30 mL, 3 mmol) and the initial suspension became homogeneous after about 2 minutes. The mixture was heated to 40° C. for 4 hours then quenched with brine and extracted with DCM (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (5% MeOH-EtOAc increasing to 10% MeOH) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (dd, J=4.1, 2.0 Hz, 2H), 7.81-7.71 (m, 4H), 7.53 (d, J=8.2 Hz, 4H), 7.46-7.37 (m, 6H), 7.25-7.17 (m, 2H), 4.45-4.33 (m, 5H), 4.30-4.07 (m, 4H), 4.04 (d, J=1.3 Hz, 5H), 4.01-3.97 (m, 1H), 3.85 (t, J=8.6 Hz, 1H), 3.77-3.59 (m, 3H), 2.49 (d, J=1.6 Hz, 6H), 2.18 (s, 6H), 1.83 (d, J=13.7 Hz, 6H); MS (ESI): mass calcd. Chemical Formula: C31H29ClF3N3O3, Exact Mass: 583.2. m/z found 583.9 [M+H]+. 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone was purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO2, 25% i-PrOH (0.3% iPrNH2)) to give two enantiomers. The first eluting enantiomer was Example 87b and the second eluting enantiomer was Example 87c.

Workup

  1. customgave a suspension at room temperature
  2. customthen quenched with brine
  3. extractionextracted with DCM (3×25 mL)
  4. dry with materialThe combined organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customThe residue was purified by FCC (5% MeOH-EtOAc increasing to 10% MeOH)

Sources & evidence

ORD record
ord-cdaa8b4998084d32aff55f01dc9c14cc
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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