Diisopropylethylamine → N-(2-fluoro-5-(trifluoromethyl)benzyl)-2-hydroxy-2-phenylbutanamide

HRID 2358321Notes

Reaction equation

HRID 2358321 reaction equation
[OH:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:6][CH3:7])[C:3]([OH:5])=O.C(N(C(C)C)CC)(C)C.[F:23][P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.F[C:57]1[CH:58]=[C:59]([CH2:67][NH2:68])[CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=1>CN(C)C=O>[F:23][C:58]1[CH:57]=[CH:62][C:61]([C:63]([F:66])([F:65])[F:64])=[CH:60][C:59]=1[CH2:67][NH:68][C:3](=[O:5])[C:2]([OH:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH3:7]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2873222-Hydroxy-2-phenylbutanoic acidHCID 2724699PyBOPHCID 27333043-Fluoro-5-(trifluoromethyl)benzylamine

Product 1

HCID 58960068N-(2-fluoro-5-(trifluoromethyl)benzyl)-2-hydroxy-2-phenylbutanamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 2-oxo-2-phenylacetic acid (10 g, 66.6 mmol) (Acros Organics B.V.B.A., Belgium) in tetrahydrofuran (THF, 200 mL) was treated at room temperature with ethylmagnesium bromide (2.5 M, 80 mL, 200 mmol). The reaction mixture was stirred for 5 h, partitioned between ethyl acetate and 1N—HCl. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 2-hydroxy-2-phenylbutanoic acid. A solution of 2-hydroxy-2-phenylbutanoic acid (100 mg, 0.55 mmol) and diisopropylethylamine (188 uL, 1.11 mmol) in N,N-dimethylformamide (2 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 290 mg, 0.55 mmol). After 15 min, (3-fluoro-5-(trifluoromethyl)phenyl)methanamine (107 mg, 0.55 mmol) was added. The reaction mixture was stirred for 3 h, partitioned between dichloromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the racemic mixture of the amide which was resolved using the chiral column (CiralPak AD) to give the desired product (2-1); HRMS (M+H—H2O)=338.1167; 1H NMR (500 MHz, CDCl3) δ 7.59 (d, 1 H, J=7.5 Hz), 7.51 (m, 1 H), 7.42 (d, 1 H, J=5.0 Hz), 7.37 (t, 1 H, J=7.5 Hz), 7.32 (d, 1 H, J=7.0 Hz), 7.13 (t, 1 H, J=9.0 Hz), 7.01 (bs, 1 H), 4.52 (dq, 2 H, J=15.6, 6.4 Hz), 2.83 (s, 1 H), 2.36 (m, 1 H), 2.12 (m, 1 H), 0.94 (t, 3 H, J=7.2 Hz).

Workup

  1. custompartitioned between dichloromethane and 0.5N—NaOH
  2. customThe aqueous layer was removed
  3. washthe organic layer washed with 0.5N—HCl
  4. customThe aqueous layer was removed
  5. filtrationby filtering through a plastic frit
  6. customThe organic layer was evaporated in vacuo
  7. customto give

Sources & evidence

ORD record
ord-9aa7ec02b6c540a3bf6c9cffc8804e4f
Source dataset
uspto-grants-2010_07
Patent number
US07763659B2

Reaction notes

Loading…