Phosphorus oxychloride → HCID 178501046, compound

HRID 244085Notes

Reaction equation

HRID 244085 reaction equation
[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH:13]([C:30]2[C:35]([Cl:36])=[N:34][CH:33]=[CH:32][N:31]=2)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)=[O:4].O=P(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:31]3[CH:32]=[CH:33][N:34]=[C:35]([Cl:36])[C:30]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178501153HCID 178501153, compound

Product 1

HCID 178501046HCID 178501046, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A CH2Cl2 solution (2 mL) of trans-4-{[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid methyl ester (2.3 g, 4.5 mmol) in a round bottom flask equipped with a condenser was charged with POCl3 (15 mL) and stirred at 80° C. for 72 h. The reaction mixture was concentrated in vacuo to a foam, cooled to 0° C., and charged with cold 2M NH3 in isopropanol to basic pH. The mixture was concentrated in vacuo to solids and partitioned between EtOAc and water. The organic layer was washed with water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a brown oil. The resulting residue was purified by silica gel chromatography (CH2Cl2 to 1%˜7N NH3 in MeOH/CH2Cl2) to provide the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H), 7.39 (d, 1H, J=5.2 Hz), 7.45-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.61 (d, 1H, J=5.2 Hz), 7.85-7.93 (m, 3H), 8.19 (d, 2H, J=7.6 Hz), 8.27 (d, 1H, J=8.4 Hz), 8.50 (s, 1H); MS (ES+): m/z 496.9 [MH+]; HPLC: tR=3.6 min (Micromass Platform II, nonpolar—5 min).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo to a foam
  2. temperaturecooled to 0° C.
  3. additioncharged with cold 2M NH3 in isopropanol to basic pH
  4. concentrationThe mixture was concentrated in vacuo to solids
  5. custompartitioned between EtOAc and water
  6. washThe organic layer was washed with water (1×), brine (1×)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to a brown oil
  10. customThe resulting residue was purified by silica gel chromatography (CH2Cl2 to 1%˜7N NH3 in MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-a336f2f9a0104e6095b0901269402088
Source dataset
uspto-grants-2014_02
Patent number
US08653268B2

Reaction notes

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