Triethylamine → (R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamide

HRID 1170915Notes

Reaction equation

HRID 1170915 reaction equation
[NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][C@@H:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:31][C@H:23]([CH3:22])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 32893(-)-AmphetamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 469351864-Amino-2-(trifluoromethyl)pyridine-3-carboxylic acid

Product 1

HCID 59553895(R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamideYield 92%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

4-amino-2-(trifluoromethyl)nicotinic acid (15 g, 61.83 mmol) was suspended in a mixture of anhydrous DMF (300 mL) and anhydrous dichloromethane (500 mL). To this was added triethylamine (30.4 mL, 216 mmol), followed by L-amphetamine hydrochloride (12.7 g, 74.2 mmol). HBTU (30.5 g, 80.4 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo to remove dichloromethane. The resultant DMF solution was poured into water, extracted with ethyl acetate (1 L). The organic layer was washed successively with 1N NaOH, saturated sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography using 40-70% ethyl acetate/heptanes as eluant to provide the product as a colorless foam (18.3 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.2-7.4 (m, 5H), 6.6 (d, 1H), 5.8 (d, 1H), 4.7 (bs, 2H), 4.5 (m, 1H), 2.9 (m, 2H), 1.25 (d, 3H). MS m/z 324.3 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customto remove dichloromethane
  3. additionThe resultant DMF solution was poured into water
  4. extractionextracted with ethyl acetate (1 L)
  5. washThe organic layer was washed successively with 1N NaOH, saturated sodium bicarbonate, water
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give an oil
  10. customThis oil was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-18c88b45ccc7421e8463f6d8a17899d0
Source dataset
uspto-grants-2010_11
Patent number
US07829572B2

Reaction notes

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