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

HRID 2046287
Notes
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Reaction equation

HRID 2046287 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[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]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.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>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[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:30][CH:29]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 54739212N-{[2-[(2-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Product 1

HCID 54739204N-{[2-[(4'-fluoro-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine
Yield 53.7%

Reagents, catalysts & solvents 3

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

Procedure

To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 4-fluorobenzeneboronic acid (24.74 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 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 dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-[(4′-fluoro-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (42 mg, 0.095 mmol, 53.5% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 15.83 (s, 1H), 12.95 (s, 1H), 10.08 (t, J=5.68 Hz, 1 H), 7.44 (ddd, J=11.94, 5.37, 2.91 Hz, 2H), 7.31-7.38 (m, 2H), 7.22-7.30 (m, 3H), 7.11-7.19 (m, 1H), 5.24 (s, 2H), 4.07 (d, J=5.81 Hz, 2H), 3.13 (sept, J=6.82 Hz, 1H), 1.12 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.

Workup

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. extractionextracted with ethyl acetate (20 ml)
  3. dry with materialThe organic phase was dried over MgSO4
  4. filtrationfiltered
  5. customsolvents removed under reduced pressure
  6. customThe crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA))

Sources & evidence

ORD record
ord-072c249ad2144ac2921964b70b77adc9
Source dataset
uspto-grants-2013_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
USRE044613E1

Reaction notes

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