1,2-Dichloroethane → 5-(2,2-Difluoro-1-hydroxyethyl)-2',4'-difluoro-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]biphenyl-3-carboxamide

HRID 888414Notes

Reaction equation

HRID 888414 reaction equation
[F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19](O)=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4].[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19]([NH:31][C@@H:29]([C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)[CH3:30])=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4]

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 28948822(R)-1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethan-1-amineHCID 684984575-(2,2-Difluoro-1-hydroxyethyl)-2',4'-difluorobiphenyl-3-carboxylic acid

Product 1

HCID 426030345-(2,2-Difluoro-1-hydroxyethyl)-2',4'-difluoro-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]biphenyl-3-carboxamideYield 59.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 5-(2,2-difluoro-1-hydroxyethyl)-2′,4′-difluorobiphenyl-3-carboxylic acid (0.25 g, 0.80 mmol) in N,N-dimethylformamide (2.7 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (0.18 g, 0.88 mmol), EDC (0.27 g, 1.39 mmol), HOAT (51.1 mg, 0.40 mmol) and triethylamine (0.67 mL, 4.77 mmol). The mixture was stirred at 50 C. After 2 h, saturated sodium bicarbonate was added the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→85% dichloromethane/methanol). Product obtained was not pure therefore it was purified again by reverse phase chromatography (C-18, 95% water/acetonitrile→30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (201 mg). HRMS 424.1283 (M+1). 1H NMR δ (ppm) (DMSO-d6): 9.28 (1H, d, J=7.3 Hz), 8.01 (2H, s), 7.76 (1H, s), 7.66 (1H, dd, J=15.6, 9.0 Hz), 7.43 (1H, m), 7.26 (1H, m), 6.11 (1H, dt, J=11.2, 0.7 Hz), 5.40 (1H, m), 4.93 (1H, m), 2.33 (3H, s), 1.61 (3H, d, J=7.3 Hz).

Workup

  1. extractionwas extracted with dichloromethane (3×)
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by silica gel chromatography (100% hexanes→85% dichloromethane/methanol)
  7. customProduct obtained
  8. customit was purified again by reverse phase chromatography (C-18, 95% water/acetonitrile→30% water/acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-b3d71b8535744724bee68b844a5003f8
Source dataset
uspto-grants-2012_08
Patent number
US08247401B2

Reaction notes

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