Dimethylformamide → N-{[2-[(4-Bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

HRID 2046261Notes

Reaction equation

HRID 2046261 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16](OCC)=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)=[C:4]([F:25])[CH:3]=1.OC1C(C(C)C)=NNC(=O)[C:28]=1[C:37]([O:39]CC)=[O:38].[H-].[Na+].BrC1C=CC(CBr)=C(F)C=1.C[N:55](C)C=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:55][CH2:28][C:37]([OH:39])=[O:38])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]2)=[C:4]([F:25])[CH:3]=1

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 27336604-Bromo-2-fluorobenzyl bromideHCID 68812816Ethyl 2-[(4-bromo-2-fluorophenyl)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 1

HCID 54747353N-{[2-[(4-Bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Procedure

Ethyl 2-[(4-bromo-2-fluorophenyl)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 (9.5 g, 42.0 mmol) in N,N-Dimethylformamide (DMF) (250 ml) at 0° C. was added sodium hydride (60% in oil, 2.52 g, 63.0 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 4-bromo-2-fluorobenzyl bromide (12.38 g, 46.2 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (10 ml) and diluted with water (30 ml). The aqueous solution was extracted with ethyl acetate (2×100 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 (10-100% ethyl acetate in hexanes) to provide the crude product (8 g, ˜75% pure, 35% yield) as a pale yellow solid. The material was purified by reverse phase HPLC (C18, 75-90% acetonitrile/0.3 M aqueous ammonium formate) to give the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6.82 Hz, 6H) 1.26 (t, J=7.20 Hz, 3H) 3.09-3.17 (m, 1H) 4.26 (q, J=7.07 Hz, 2H) 5.16 (s, 2H) 7.21 (t, J=8.08 Hz, 1H) 7.40 (dd, J=8.34, 1.77 Hz, 1H) 7.57 (dd, J=9.73,1.89 Hz, 1H) 12.31 (s, 1H). MS (ES+) m/e 413 [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 (10 ml)
  4. additiondiluted with water (30 ml)
  5. extractionThe aqueous solution was extracted with ethyl acetate (2×100 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 (10-100% ethyl acetate in hexanes)
  11. customto provide the crude product (8 g, ˜75% pure, 35% yield) as a pale yellow solid
  12. customThe material was purified by reverse phase HPLC (C18, 75-90% acetonitrile/0.3 M aqueous ammonium formate)

Sources & evidence

ORD record
ord-5b55cf69c2e24a618f1d8912749f5f77
Source dataset
uspto-grants-2013_11
Patent number
USRE044613E1

Reaction notes

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