Acetic Acid → 10-(5-Fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one

HRID 1478448Notes

Reaction equation

HRID 1478448 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][C:10](=[O:31])[CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)[CH2:14][CH2:13]2)[CH:5]=[N:6][CH:7]=1.C(O)(=O)C.C(OCC)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:32][C:12]3([CH2:13][CH2:14][N:15]([C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:31])[CH:9]=2)[CH:5]=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 8857Ethyl AcetateHCID 897053021-(5-Fluoro-3-pyridyl)-4-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butane-1,3-dione

Product 1

HCID 8970851210-(5-Fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-oneYield 91.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 1-(5-fluoro-3-pyridyl)-4-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butane-1,3-dione (100 mg, 0.23 mmol) in acetic acid (1.7 mL, 30 mmol) was heated at 120° C. for 1 h. The reaction mixture was cooled to 25° C. and repartitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to yield 10-(5-fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (92 mg). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.61 (d, J=2.7 Hz, 1H), 7.74 (ddd, J=9.0, 2.7, 1.9 Hz, 1H), 7.28-7.24 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.09 (s, 1H), 4.58 (dt, J=12.1, 6.1 Hz, 1H), 3.42 (br s, 2H), 2.68 (s, 2H), 2.27-2.22 (m, 6H), 1.75 (m, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.20, found 439.3 (M+1)+; Retention time: 1.78 minutes (3 min run).

Workup

  1. temperatureThe reaction mixture was cooled to 25° C.
  2. customThe aqueous layer was separated
  3. extractionextracted with ethyl acetate (3×50 mL)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated to dryness
  7. customThe crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-997bd01bbb3045878443419dc0bc7f4d
Source dataset
uspto-grants-2016_08
Patent number
US09403839B2

Reaction notes

Loading…