Triethylamine → HCID 118207373, compound

HRID 1507259Notes

Reaction equation

HRID 1507259 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

A mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (from Example 50, step B) (0.145 g, 0.51 mmol), 4-(3,3-difluoropiperidin-4-yl)phenol (0.06 g, 0.28 mmol, E-2a from Example 56 step B) and 0.2 mL of triethylamine (1.4 mmol) was heated at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, and then it was dried over Na2SO4, filtered, and concentrated to afford 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one as a pair of diastereomers. These diastereomers were separated via preparative HPLC (method B) to yield 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one homochiral Examples 56 P-1 (10.7 mg) and P-2 (5.5 mg). The relative and absolute configurations of Examples 56 P-1 and P-2 were not determined and are arbitrarily named P-1 and P-2 based on the order of elution during the HPLC purification. Data for P-1: pale yellow solid; LCMS (method O) RT 1.21 min (95.8% AP) m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (m, 3H) 1.78-1.90 (m, 1H), 1.90-2.01 (M, 1H), 2.1-2.2 (m, 1H), 2.21-2.35 (m, 1H), 2.49 (m, 1H), 2.80-2.99 (m, 1H), 3.01-3.10 (m, 4H), 3.33-3.38 (m, 3H), 3.63 (t, 1H), 5.40 (m, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.38-7.41 (m, 2H); 19F NMR δ ppm-76.948, -102.623, -103.262, -115.103, -115.743, -117.043. Data for P-2: solid; LCMS (methods N, O) 99% AP; 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=7.03 Hz, 3H) 1.79-1.90 (m, 1H) 2.01-2.23 (m, 3H) 2.62-2.72 (m, 1H) 2.86-3.19 (m, 5H) 3.40-3.74 (m, 2H) 4.36-4.56 (m, 1H) 5.28-5.48 (m, 1H) 6.76 (d, J=9.04 Hz, 2H) 7.08-7.19 (m, 4H) 7.30-7.42 (m, 2H); 19F NMR δ ppm-76.938, -102.480, -012.630, -103.120, -103.146, -103.269, -114.559, -115.124, -115.199, -115.763, -116.990, -117.049.

Workup

  1. customThe cooled reaction mixture
  2. customwas partitioned between water and ethyl acetate
  3. washThe organic phase was washed with water and brine
  4. dry with materialit was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-802fe490a3684139afa6d184d61d6eea
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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