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

HRID 2046286Notes

Reaction equation

HRID 2046286 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]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=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>[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:33]3[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=3)=[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 23546919(2-Methoxypyridin-4-yl)boronic acidHCID 54739228N-{[2-[(4-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Product 1

HCID 54739205N-{[5-hydroxy-6-(1-methylethyl)-2-({4-[2-(methyloxy)-4-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycineYield 43.1%

Reagents, catalysts & solvents 3

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

Procedure

To a 20 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, 31 mg, 0.073 mmol), [2-(methyloxy)-4-pyridinyl]boronic acid (11.18 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 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 (4 ml) and acidified with 1N HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-2-({4-[2-(methyloxy)-4-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (15 mg, 0.031 mmol, 43.1% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.96 (br. s., 1H), 10.18 (t, J=5.56 Hz, 1H), 8.22 (d, J=5.31 Hz, 1H), 7.76 (d, J=8.34 Hz, 2H), 7.42 (d, J=8.34 Hz, 2H), 7.30 (dd, J=5.43, 1.39 Hz, 1H), 7.10 (s, 1H), 5.31 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.89 (s, 3H), 3.19 (sept, J=6.78 Hz, 1H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 453 [M+H]+.

Workup

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. filtrationthen filtered
  3. customto remove any residue
  4. customfollowed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA))

Sources & evidence

ORD record
ord-cf11c5286e974ca9a5be65abb597dfcc
Source dataset
uspto-grants-2013_11
Patent number
USRE044613E1

Reaction notes

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