Citric Acid → ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate

HRID 1867172Notes

Reaction equation

HRID 1867172 reaction equation
[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])C(O)=O)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(Cl)(=O)C(Cl)=O.[C:36]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:37][C:38]([O-])=[O:39].C([Mg]Cl)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([C:38](=[O:39])[CH2:37][C:36]([O:42][CH2:43][CH3:44])=[O:41])[CH:25]=[CH:26][C:27]=2[CH3:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]

Participants

9

Reactant 5

HCID 311Citric AcidHCID 65578Oxalyl chlorideHCID 3595298Propanedioic acid, monoethyl esterHCID 220504653-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoic acidHCID 178418918HCID 178418918, compound

Product 1

HCID 22050332ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

In an oven-dried round bottom flask, 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 487) (0.75 g, 1.62 mmol), DCM (2.00 mL), and oxalyl chloride (0.97 mL, 1.94 mmol) were combined under argon. DMF (3-5 drops) was added to aid in dissolution. Stirred at RT overnight. Solvent was removed and the crude acid chloride was coevaporated with DCM (3-5 mL×3) and dried in vacuo to give an orange solid. In a separate oven-dried flask, in an argon atmosphere, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in THF (3.00 mL) was cooled to −78° C. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stirred for 30 min at −78° C. The acid chloride prepared as described above was added dropwise as a solution in THF. The reaction was warmed to RT. After 30 min, the reaction was cooled (0° C.) and 10% citric acid (5.0 mL) added. The crude product was extracted in EtOAc, washed with 5% NaHCO3, dried over Na2SO4, filtered, and concentrated to a crude brown oil. Recrystallization from DCM and hexane. Filtered a beige solid, dried in vacuo (0.41 g, 47%). 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J=9.2 Hz), 6.66 (s, 1H), 5.36 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H), 1.99 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ESHRMS m/z 534.0744 and 536.0746 (M+H calculated for C25H23BrF2NO5 requires 534.0722 and 536.0706).

Workup

  1. customSolvent was removed
  2. customdried in vacuo
  3. customto give an orange solid
  4. customIn a separate oven-dried flask
  5. stirringThe solution was stirred for 30 min at −78° C
  6. temperatureThe reaction was warmed to RT
  7. waitAfter 30 min
  8. additionadded
  9. extractionThe crude product was extracted in EtOAc
  10. washwashed with 5% NaHCO3
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated to a crude brown oil
  14. customRecrystallization from DCM and hexane
  15. filtrationFiltered a beige solid
  16. customdried in vacuo (0.41 g, 47%)

Sources & evidence

ORD record
ord-3f24c3ea0328458592752332986adff7
Source dataset
uspto-grants-2009_12
Patent number
US07629363B2

Reaction notes

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