Triethylamine → HCID 118207373, compound

HRID 1507260Notes

Reaction equation

HRID 1507260 reaction equation
Br[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH3:8])[C:3]1=[O:16].[F:17][C:18]1([F:31])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>>[F:31][C:18]1([F:17])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([CH:2]2[CH2:6][CH2:5][N:4]([C@H:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH3:8])[C:3]2=[O:16])[CH2:19]1

Participants

4

Reactant 3

HCID 8471TriethylamineHCID 66960321HCID 66960321, compoundHCID 105426874HCID 105426874, compound

Product 1

HCID 118207373HCID 118207373, compound

Conditions

Temperature
120 °C

Procedure

To a mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.134 g, 0.47 mmol, from Example 50, step B) and 4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a from Example 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and the resulting mixture was heated at 120° C. for 1 h. After cooling, the reaction was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via preparative HPLC (method B) to yield the homochiral Examples 56 P-3 and P-4 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one diastereomers. The relative and absolute configurations of Examples 56 P-3 and P-4 were not determined and are arbitrarily named P-3 and P-4 based on the order of elution during the HPLC purification. Data for P-3: 11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (d, J=7.2, 3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m, 2H), 2.57-2.64 (q, 1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H), 3.33-3.42 (m, 2H), 3.67 (t, J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.37-7.41 (m, 2H); 19F NMR δ ppm-102.515, -103.158, -114.576, -115.216, -117.070. Data for P-4: 13.7 mg pale yellow solid; LCMS (method O) RT 1.215 min (100% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m, 3H), 2.53 (t, 1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43 (m, 1H), 3.64 (t, J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m, 2H), 7.09-7.16 (m, 4H), 7.35-7.38 (m, 2H); 19F NMR δ ppm-102.632, -103.271, -115.162, -115.801, -116.989.

Workup

  1. temperatureAfter cooling
  2. customthe reaction was partitioned between ethyl acetate and water
  3. customThe layers were separated
  4. washthe organic phase was washed with water and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified via preparative HPLC (method B)
  9. customto yield the homochiral Examples 56 P-3
  10. washbased on the order of elution during the HPLC purification
  11. custom11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0 (M+H+)
  12. customLCMS (method O) RT 1.215 min (100% AP), m/z 419.0 (M+H+)

Sources & evidence

ORD record
ord-4fe9410a64ed4643a5d913c7edec0853
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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