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

HRID 2046281Notes

Reaction equation

HRID 2046281 reaction equation
[Br:1][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]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]1.OC1C(C(C)C)=NNC(=O)[C:27]=1[C:36]([O:38]CC)=[O:37].[H-].[Na+].BrC1C=CC=CC=1CBr.C[N:53](C)C=O>>[Br:1][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: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]1.[Br:1][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]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 769652-Bromobenzyl bromideHCID 68813242Ethyl 2-[(2-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 54739212N-{[2-[(2-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycineHCID 68813242Ethyl 2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylateYield 22.32%

Procedure

Ethyl 2-[(2-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 2-bromobenzylbromide (3.31 g, 13.26) 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 solid was triturated with ether and filtered. The solid material was 100% starting material (1 g). The filtrate was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the title compound (ethyl 2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (1.3 g, 2.96 mmol, 22.32% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) d ppm 12.33 (br. s., 1H), 7.66 (dd, J=8.08, 1.26 Hz, 1H), 7.35 (td, J=7.52, 1.14 Hz, 1H), 7.25 (td, J=7.58, 1.77 Hz, 1H), 7.03 (dd, J=7.83, 1.52 Hz, 1H), 5.20 (s, 2H), 4.28 (q, J=7.07 Hz, 2H), 3.15 (sept, J=6.82 Hz, 1H), 1.26 (t, J=7.07 Hz, 3H), 1.11 (d, J=6.82 Hz, 6 H). 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 solid was triturated with ether
  11. filtrationfiltered
  12. customThe filtrate was purified by flash column chromatography (10-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-263e83b20a3a4624a4a8e35a09d5f382
Source dataset
uspto-grants-2013_11
Patent number
USRE044613E1

Reaction notes

Loading…