Hydrochloric Acid → N-[(5-Hydroxy-6-(1-methylethyl)-2-{[2'-(methyloxy)-4-biphenylyl]methyl}-3-oxo-2,3-dihydro-4-pyridazinyl)carbonyl]glycine

HRID 2046276Notes

Reaction equation

HRID 2046276 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)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 27339582-Methoxyphenylboronic acidHCID 54739228N-{[2-[(4-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Product 1

HCID 54739223N-[(5-Hydroxy-6-(1-methylethyl)-2-{[2'-(methyloxy)-4-biphenylyl]methyl}-3-oxo-2,3-dihydro-4-pyridazinyl)carbonyl]glycineYield 35.1%

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-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 2-methoxyphenyl boronic acid (17.2 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, 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 (15.0 mg, 0.033 mmol, 35% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.97 (s, 1H), 10.21 (t, J=5.94 Hz, 1H), 7.41-7.47 (m, 2H), 7.31-7.37 (m, 3H), 7.26 (dd, J=7.58, 1.77 Hz, 1H), 7.10 (d, J=7.58 Hz, 1H), 7.01 (dt, J=7.45, 1.01 Hz, 1H), 5.28 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.74 (s, 3H), 3.20 (m, 1H), 1.23 (d, J=6.82 Hz, 6H). MS (ES+) m/e 452 [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-83b12d5328c3425c925beff8942c6d34
Source dataset
uspto-grants-2013_11
Patent number
USRE044613E1

Reaction notes

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