Hydrochloric Acid → 4'-{[5-{[(Carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-3'-fluoro-4-biphenylcarboxylic acid

HRID 1822397Notes

Reaction equation

HRID 1822397 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:20]([CH2:19][NH:18][C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:3][C:4]=2[F:27])[N:10]=[C:11]([CH:24]([CH3:26])[CH3:25])[C:12]=1[OH:23])=[O:17])([OH:22])=[O:21]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 3121834-Carboxyphenylboronic AcidHCID 54747353N-{[2-[(4-Bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Product 1

HCID 547392304'-{[5-{[(Carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-3'-fluoro-4-biphenylcarboxylic acidYield 24.1%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 75 mg, 0.17 mmol), 4-carboxybenzeneboronic acid (34 mg, 0.20 mmol), potassium carbonate (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (20 mg, 0.041 mmol, 24% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.93 (s, 1H), 13.03 (br. s., 2H), 10.15 (t, J=5.43 Hz, 1H), 8.01 (d, J=8.34 Hz, 2H), 7.83 (d, J=8.59 Hz, 2H), 7.64 (dd, J=11.37, 1.77 Hz, 1H), 7.57 (dd, J=7.96, 1.64 Hz, 1H), 7.38 (t, J=7.96 Hz, 1H), 5.35 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.19 (sept, J=6.86 Hz, 1H), 1.19 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 484 [M+H]+.

Workup

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. extractionextracted with ethyl acetate (20 ml)
  3. washThe organic phase was washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customsolvents removed under reduced pressure
  7. customThe crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA))

Sources & evidence

ORD record
ord-674fa94aa0a14468a18e90a3e1b6c4a9
Source dataset
uspto-grants-2009_10
Patent number
US07608621B2

Reaction notes

Loading…