Acetyl chloride → cis-4-(acetylamino)-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide

HRID 846803Notes

Reaction equation

HRID 846803 reaction equation
[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>ClC(Cl)Cl.CN(C)C1C=CN=CC=1>[C:40]([NH:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1)(=[O:42])[CH3:41]

Participants

6

Reactant 3

HCID 6367Acetyl chloride4×HCID 8471TriethylamineHCID 53110474-amino-5-chloro-N-[(3R,4S)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide

Product 1

HCID 15096838cis-4-(acetylamino)-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamideYield 25.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6212ChloroformSolvent2×

Procedure

10 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide were dissolved in 225 parts of hot trichloromethane. After cooling to room temperature, 3.6 parts of N,N-diethylethanamine were added. Then there was added dropwise a solution of 1.7 parts of acetyl chloride in 30 parts of trichloromethane:exothermic reaction. The whole was stirred and refluxed for 22 hours. After cooling to room temperature, 0.6 parts of acetyl chloride were added and stirring was continued overnight at reflux. Another 0.6 parts of acetyl chloride were added and stirring was continued overnight at reflux. After cooling again to room temperature, there were added successively 0.6 parts of acetyl chloride and a small amount of N,N-dimethyl-4-pyridinamine. Stirring was continued for 22 hours at reflux. The reaction mixture was cooled to room temperature and washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized twice from acetonitrile, yielding 2.78 parts (25.5%) of cis-4-(acetylamino)-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 175.6° C. (compound 233).

Workup

  1. customexothermic reaction
  2. temperaturerefluxed for 22 hours
  3. temperatureAfter cooling to room temperature
  4. stirringstirring
  5. temperatureat reflux
  6. stirringstirring
  7. waitwas continued overnight
  8. temperatureat reflux
  9. temperatureAfter cooling again to room temperature
  10. stirringStirring
  11. waitwas continued for 22 hours
  12. temperatureat reflux
  13. temperatureThe reaction mixture was cooled to room temperature
  14. washwashed with water
  15. customThe organic phase was dried
  16. filtrationfiltered
  17. customevaporated
  18. customThe residue was crystallized twice from acetonitrile

Sources & evidence

ORD record
ord-3307574dfc4d4a2493c8e16f3bb0b59b
Source dataset
uspto-grants-1992_08
Patent number
US05137896

Reaction notes

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