Hydrochloric Acid → 1-Acetyl-4-(2',4'-difluorobenzoyl)piperidine

HRID 915108Notes

Reaction equation

HRID 915108 reaction equation
[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 97411,3-DifluorobenzeneHCID 24386Thionyl ChlorideHCID 1172551-Acetylpiperidine-4-carboxylic acidHCID 6451240Aluminum(III) Chloride

Product 1

HCID 27407071-Acetyl-4-(2',4'-difluorobenzoyl)piperidineYield 61%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent3×

Conditions

Temperature
60 °C

Procedure

A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL) was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL of dichloroethane and then heated to 60° C. for 30 min. Another flask containing a suspension of 8.02 mL (81.8 mmol) of 1,3-difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethane was prepared, to this was added the previously prepared acid chloride suspension in portions. The resulting suspension was refluxed for 4 h, cooled and then poured over ice and HCl. The acidic solution was extracted with CH2Cl2 (3×300 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized from hexanes to afford 9.5 g (61%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C14H15F2NO2, 267.11; m/z found, 268.1 [M+H]+, 1H NMR (CDCl3, 400 MHz): 7.87 (dt, J=8.41, 6.65 Hz 1H), 6.98 (m, 1H), 6.88 (ddd, J=10.96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32 (dtt, J=10.76, 3.91, 1.37 Hz, 1H), 3.19 (ddd, J=13.89, 11.93, 2.93 Hz, 1H), 2.79 (ddd, J=13.89, 12.24, 2.93 Hz, 1H), 2.10 (s, 3H), 1.95 (br d, J=12.91 Hz, 2H), 1.72 (br m, 1H), 1.56 (br m, 1H).

Workup

  1. additionAnother flask containing
  2. customwas prepared
  3. temperatureThe resulting suspension was refluxed for 4 h
  4. temperaturecooled
  5. extractionThe acidic solution was extracted with CH2Cl2 (3×300 mL)
  6. washthe combined organic extracts were washed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customThe crude product was recrystallized from hexanes

Sources & evidence

ORD record
ord-a80404f43ef741eab1bd4ff235c6feaa
Source dataset
uspto-grants-2007_09
Patent number
US07265102B2

Reaction notes

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