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

HRID 915998Notes

Reaction equation

HRID 915998 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 was 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 was 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-be47a60a616549509a9f42981e5bf5ae
Source dataset
uspto-grants-2007_09
Patent number
US07268153B2

Reaction notes

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