Thionyl Chloride → Methyl alpha-phenyl-1-[4-[[[4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetate

HRID 1989866Notes

Reaction equation

HRID 1989866 reaction equation
S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[C:42]1([CH:37]([CH:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:10]4[CH:11]=[CH:12][C:7]([C:6]([F:5])([F:22])[F:23])=[CH:8][CH:9]=4)=[O:20])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)[C:38]([O:40][CH3:41])=[O:39])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1

Participants

8

Reactant 4

HCID 24386Thionyl ChlorideHCID 552514'-(Trifluoromethyl)(1,1'-biphenyl)-2-carboxylic acidHCID 81531DiisopropylethylamineHCID 22499374(+/-)-Methyl 1-(4-aminophenyl)-alpha-phenyl-4-piperidineacetate

Product 1

HCID 22499403Methyl alpha-phenyl-1-[4-[[[4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetateYield 59.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

Thionyl chloride (3.6 ml) was added to a clear solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.025 mol) in DMF (1 ml) and DCM (100 ml). The mixture was stirred and refluxed for one hour. The solvent was evaporated. DCM (50 ml) was added to the residue, then evaporated. The residue was dissolved in DCM (50 ml) and the solution was added dropwise to a solution of intermediate (18) (0.025 mol) in DCM (150 ml) and DIPEA (0.049 mol). The reaction mixture was stirred for 2 hours at room temperature. Water was added and this mixture was extracted twice. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in DIPE, filtered off, dried, and crystallized from 2-propanol (150 ml; later, 300 ml was added). The mixture was stirred for 2 hours at room temperature. The precipitate was filtered off, washed with 2-propanol and dried, yielding 8.58 g of methyl α-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetate (intermediate 23).

Workup

  1. temperaturerefluxed for one hour
  2. customThe solvent was evaporated
  3. additionDCM (50 ml) was added to the residue
  4. customevaporated
  5. dissolutionThe residue was dissolved in DCM (50 ml)
  6. stirringThe reaction mixture was stirred for 2 hours at room temperature
  7. extractionthis mixture was extracted twice
  8. customThe separated organic layer was dried
  9. filtrationfiltered
  10. customthe solvent evaporated
  11. stirringThe residue was stirred in DIPE
  12. filtrationfiltered off
  13. customdried
  14. customcrystallized from 2-propanol (150 ml
  15. additionlater, 300 ml was added)
  16. stirringThe mixture was stirred for 2 hours at room temperature
  17. filtrationThe precipitate was filtered off
  18. washwashed with 2-propanol
  19. customdried

Sources & evidence

ORD record
ord-6268aee8969749a1a76a49c2559504ff
Source dataset
uspto-grants-2010_01
Patent number
US07642378B2

Reaction notes

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