Dimethylformamide → Ethyl 2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate

HRID 1822409Notes

Reaction equation

HRID 1822409 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.OC1C(C(C)C)=NNC(=O)[C:27]=1[C:36]([O:38]CC)=[O:37].[H-].[Na+].BrC1C=C(C=CC=1)CBr.C[N:53](C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:53][CH2:27][C:36]([OH:38])=[O:37])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]2)[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 699793-Bromobenzyl bromideHCID 68813161Ethyl 2-[(3-bromophenyl)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 54739211N-{[2-[(3-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycineHCID 68813161Ethyl 2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylateYield 13.58%

Procedure

Ethyl 2-[(3-bromophenyl)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 46(a), 3 g, 13.26 mmol) in N,N-Dimethylformamide (DMF) (50 ml) at 0° C. was added sodium hydride (0.796 g, 19.89 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 3-bromobenzyl bromide (3.31 g, 13.26 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 title compound (ethyl 2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (890 mg, 1.801 mmol, 13.58% yield) as a pale yellow solid. The product isolated was a 5:1 mixture of the desired mono alkylated to the bis-alkylated(4-O-benzyl)(LCMS=564). 1H NMR (400 MHz, DMSO-d6) d ppm 12.33 (s, 1H), 7.46-7.53 (m, 2H), 7.24-7.35 (m, 2H), 5.14 (s, 2 H), 4.26 (q, J=7.07 Hz, 2H), 3.17 (sept, J=6.78 Hz, 1H), 1.26 (t, J=7.20 Hz, 3H), 1.16 (d, J=6.82 Hz, 6H). MS (ES+) m/e 396 [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)

Sources & evidence

ORD record
ord-a36fd3731a8e46a7adca8629da464f4c
Source dataset
uspto-grants-2009_10
Patent number
US07608621B2

Reaction notes

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