Dimethylformamide → HCID 74221074, compound

HRID 928848Notes

Reaction equation

HRID 928848 reaction equation
[N:1]1([C:6]2[CH:42]=[CH:41][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([C:24]3[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:43]1[CH2:46][CH2:45][CH2:44]1.CN(C)C=O>C(OCC)(=O)C>[N:1]1([C:6]2[CH:42]=[CH:41][C:9]([CH2:10][C:11]3[C:12]([N:43]4[CH2:46][CH2:45][CH2:44]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([C:24]3[CH:25]=[N:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 10422AzetidineHCID 74221463(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

Product 1

HCID 74221074HCID 74221074, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a 5 mL sealed tube was added (3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.33 mmol, 1 equivalent, Example 23, free base), azetidine (93.7 mg, 1.64 mmol, 5 equivalents) and dimethylformamide (2 mL). The reaction vessel was sealed and heated in a 100° C. oil bath. After two days, the vessel was cooled and contents transferred to a separatory funnel with ethyl acetate dilution. The organic phase was extracted with saturated aqueous ammonium chloride solution and deionized water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide racemic (3-(4-(1H-pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-4-chloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol. MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.2, 2.1 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.65-7.62 (m, 2H), 7.57 (dd, J=8.9, 2.2 Hz, 1H), 7.24-7.18 (m, 2H), 6.51-6.49 (m, 1H), 6.47 (s, 1H), 4.38 (s, 2H), 4.25-4.20 (m, 4H), 3.53 (s, 3H), 2.30-2.21 (m, 2H). Racemic (3-(4-(1H-pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-4-chloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol was purified on a chiralcel OD column (20 um, Diacel) with ethanol/heptanes to provide two enantiomers. The first eluting enantiomer was Example 68B: MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.12 (dd, J=2.5, 0.4 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.2, 2.1 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.70 (m, 2H), 7.69-7.66 (m, 1H), 7.64-7.58 (m, 2H), 7.56 (dd, J=8.8, 2.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 6.48 (dd, J=2.4, 1.9 Hz, 1H), 6.35 (d, J=0.8 Hz, 1H), 4.32 (s, 2H), 4.20-4.14 (m, 4H), 3.48 (s, 3H), 2.25-2.15 (m, 2H), and the second eluting enantiomer was Example 68C: MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.15-8.11 (m, 1H), 8.05 (d, J=2.0 Hz, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.76-7.70 (m, 2H), 7.68 (d, J=1.5 Hz, 1H), 7.64-7.59 (m, 2H), 7.56 (dd, J=8.9, 2.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 6.48 (dd, J=2.4, 1.9 Hz, 1H), 6.35 (s, 1H), 4.32 (s, 2H), 4.17 (t, J=7.6 Hz, 4H), 3.48 (s, 3H), 2.24-2.17 (m, 2H).

Workup

  1. customTo a 5 mL sealed tube
  2. customThe reaction vessel was sealed
  3. temperaturethe vessel was cooled
  4. extractionThe organic phase was extracted with saturated aqueous ammonium chloride solution
  5. customThe organic phase was separated
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated to dryness under reduced pressure
  9. customThe crude material was purified via reverse phase chromatography

Sources & evidence

ORD record
ord-ff8f7e187d7a466a97abf6a9649317a2
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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