Dimethylformamide → Ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate

HRID 2046300Notes

Reaction equation

HRID 2046300 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:28])[CH3:27])=[N:14]1.OC1C(C(C)C)=NNC(=O)[C:31]=1[C:40]([O:42]CC)=[O:41].[H-].[Na+].BrCC1C=CC(C(F)(F)F)=CC=1F.C[N:61](C)C=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([NH:61][CH2:31][C:40]([OH:42])=[O:41])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:28])[CH3:27])=[N:14]1.[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:27])[CH3:28])=[N:14]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 27375702-Fluoro-4-(trifluoromethyl)benzyl bromideHCID 68813739Ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylateHCID 68815345Ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate

Product 2

HCID 54739180N-{[2-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycineHCID 68813739Ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylateYield 33.9%

Procedure

Ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 14(a), 0.5 g, 2.210 mmol) in N,N-Dimethylformamide (DMF) (50 ml) at 0° C. was added sodium hydride (0.133 g, 3.32 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (0.568 g, 2.210 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (2 ml) and diluted with water (10 ml). The aqueous solution was extracted with ethyl acetate (2×30 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (5-100% ethyl acetate in hexanes) to provide the title compound (ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (335 mg, 0.749 mmol, 33.9% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) dppm 12.36 (s, 1H), 7.67-7.73 (m, 1H), 7.58 (d, J=8.84 Hz, 1H), 7.45 (t, J=7.58 Hz, 1H), 5.27 (s, 2H), 4.27 (q, J=7.07 Hz, 2H), 3.15 (sept, J=6.78 Hz, 1H), 1.26 (t, J=7.07 Hz, 3H), 1.13 (d, J=6.82 Hz, 6H). MS (ES+) m/e 403 [M+H]+.

Workup

  1. temperaturecooled back to 0° C.
  2. stirringThe mixture was stirred at ambient temperature for 2.5 hours
  3. customthen quenched with 1N HCl (2 ml)
  4. additiondiluted with water (10 ml)
  5. extractionThe aqueous solution was extracted with ethyl acetate (2×30 ml)
  6. washwashed with water (100 ml) and brine (100 ml)
  7. dry with materialdried over Magnesium sulfate
  8. filtrationfiltered
  9. customsolvents removed with rotary evaporation
  10. customThe crude oil was purified by flash column chromatography (5-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-ae5aabbdd070466c89e634f6041e88f8
Source dataset
uspto-grants-2013_11
Patent number
USRE044613E1

Reaction notes

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