Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → (R)-ethyl 4-(5'-fluoro-2'-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate

HRID 70840Notes

Reaction equation

HRID 70840 reaction equation
[O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.Cl.[NH2:10][C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C@@H:11]([NH:10][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=2)[CH:30]=1

Participants

6

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 163405571,3-Oxazole-5-carboxylic acidHCID 68423640(R)-ethyl 3-amino-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoate hydrochloride

Product 1

HCID 59607772(R)-ethyl 4-(5'-fluoro-2'-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of oxazole-5-carboxylic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg, 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-ethyl 4-(5′-fluoro-2′-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time=1.50 minutes (condition A); MS (m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.2 Hz, 3 H) 2.46-2.62 (m, 2 H) 2.86 (dd, J=13.6, 8.1 Hz, 1 H) 3.02 (dd, J=13.6, 6.1 Hz, 1 H) 3.67 (s, 3 H) 4.05-4.15 (m, 2 H) 4.52-4.69 (m, 1 H) 6.76-6.82 (m, 1 H) 6.83-6.96 (m, 2 H) 7.11-7.21 (m, 3 H) 7.37 (d, J=8.1 Hz, 2 H) 7.61 (s, 1 H) 7.80 (s, 1 H)

Workup

  1. customthe reaction is quenched with H2O
  2. additionthe crude is diluted with EtOAc
  3. washthe organic layer is washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN)

Sources & evidence

ORD record
ord-f9b07090c4864583bd1718fb5270ea08
Source dataset
uspto-grants-2014_09
Patent number
US08822534B2

Reaction notes

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