Triethylamine → Methyl 3-(6-(4,4,4-trifluoro-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoate

HRID 2407005Notes

Reaction equation

HRID 2407005 reaction equation
[F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.Cl.[NH2:55][CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59].CCN=C=NCCCN(C)C>CO>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:55][CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1

Participants

8

Reactant 6

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 181649HOAtHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 86667304Methyl 6-(4,4,4-trifluoro-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate

Product 1

HCID 86667305Methyl 3-(6-(4,4,4-trifluoro-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoateYield 63.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Methyl 6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (18 mg, 0.037 mmol) was dissolved in 1 mL methanol. 500 μL 1N aqueous sodium hydroxide was added. The resulting solution was stirred overnight at room temperature then at 50° C. for 1 h. The solution was concentrated under reduced pressure and the residue partitioned between dichloromethane and 1N aqueous HCl. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in 2 mL dichloromethane. Triethylamine (20 μL, 0.14 mmol), HOAt (10 mg, 0.073 mmol), and methyl 3-aminopropionate hydrochloride (10 mg, 0.072 mmol) were added. EDCI (10 mg, 0.052 mmol) was added and the resulting solution stirred 72 h at room temperature. The reaction solution was washed with water and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give a pale yellow oil. Purification by silica gel chromatography provided methyl 3-(6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoate (13 mg, 63%) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.6 Hz, 2.4 Hz, 1H), 7.61-7.69 (m, 4H), 7.54-7.59 (m, 2H), 7.39-7.43 (m, 2H), 6.56-6.63 (m, 1H), 6.30 (d, J=8.6 Hz, 1H), 5.14 (d, J=7.8 Hz, 1H), 4.91-4.99 (m, 1H), 3.62-3.70 (m, 5H), 2.57-2.63 (m, 2H), 2.07-2.32 (m, 4H).

Workup

  1. waitat 50° C. for 1 h
  2. concentrationThe solution was concentrated under reduced pressure
  3. customthe residue partitioned between dichloromethane and 1N aqueous HCl
  4. dry with materialThe organic layer was dried over MgSO4
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in 2 mL dichloromethane
  7. stirringthe resulting solution stirred 72 h at room temperature
  8. washThe reaction solution was washed with water
  9. extractionthe aqueous layer extracted with dichloromethane
  10. dry with materialThe combined organic layers were dried over MgSO4
  11. concentrationconcentrated
  12. customto give a pale yellow oil
  13. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-be47d92d91384b61b5f2ff80b95592d5
Source dataset
uspto-grants-2014_08
Patent number
US08809342B2

Reaction notes

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