4-Piperidinecarboxamide → 1-[4'-(Trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl]piperidine-4-carboxamide

HRID 2243108Notes

Reaction equation

HRID 2243108 reaction equation
[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]2)=[O:17])=[CH:7][CH:8]=1

Participants

8

Reactant 5

HCID 37724-PiperidinecarboxamideHCID 8471TriethylamineHCID 552514'-(Trifluoromethyl)(1,1'-biphenyl)-2-carboxylic acidHCID 65578Oxalyl chlorideHCID 516892Sodium Bicarbonate

Product 1

HCID 338091521-[4'-(Trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl]piperidine-4-carboxamideYield 82.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

4′-(Trifluoromethyl)-2-biphenylcarboxylic acid (20.5 g; 77 mmol) is dissolved in 340 ml of dimethylformamide and 200 ml of dichloromethane. The reaction medium is placed at 0° C. and oxalyl chloride (1.8 eq.; 138.6 mmol; 12 ml) is added. The reaction medium is stirred at room temperature for 3 hours and then evaporated to dryness. The crude product is taken up in 270 ml of dichloromethane, followed by addition of a solution of isonipecotamide (0.97 eq.; 74.7 mmol; 9.57 g) and triethylamine (2.7 eq.; 207.9 mmol; 29 ml) in 270 ml of dichloromethane, placed at 0° C. The mixture is allowed to warm to room temperature over 12 hours, saturated aqueous sodium hydrogen carbonate solution is then added (in a 1/1 proportion) and the resulting mixture is stirred for 30 minutes. The organic phase is washed with 1M sodium hydroxide solution and then with water, dried over sodium sulfate and evaporated to dryness. The crude product is dispersed in diisopropyl ether and then filtered off and dried to give 23.09 g of coupling product.

Workup

  1. customis placed at 0° C.
  2. customevaporated to dryness
  3. customplaced at 0° C
  4. temperatureto warm to room temperature over 12 hours
  5. stirringis stirred for 30 minutes
  6. washThe organic phase is washed with 1M sodium hydroxide solution
  7. dry with materialwith water, dried over sodium sulfate
  8. customevaporated to dryness
  9. additionThe crude product is dispersed in diisopropyl ether
  10. filtrationfiltered off
  11. customdried

Sources & evidence

ORD record
ord-14d8f875e9144f7091dc88f3d92aeda2
Source dataset
uspto-grants-2010_03
Patent number
US07674803B2

Reaction notes

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