Hydrochloric Acid → 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl] benzoic Acid

HRID 1867161Notes

Reaction equation

HRID 1867161 reaction equation
[Br:1][C:2]1[C:3](=[O:33])[N:4]([C:19]2[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])[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].[OH-].[Na+].Cl.C(#N)C.O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:33])[N:4]([C:19]2[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])[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

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 18373917Acetonitrile--water (1/1)HCID 22050249methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate

Product 1

HCID 220508892-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl] benzoic Acid

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a room temperature solution of methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate (1.05 g, 2.02 mmol) in THF (10.0 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 3.5 mL, 10 mmol). The reaction was then heated to 60° C. for 8.0 hours. The resulting suspension was then diluted with 500 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (2.0 N, 5.0 mL, 10 mmol). The resulting biphasic solution was separated and the resulting aqueous layer was further extracted with ethyl acetate (2×200 mL). The resulting combined organic extracts were Na2SO4 dried, filtered and concentrated in vacuo to a volume of 50 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (806 mg, 78%). 1H NMR (400 MHz, d7-DMF) δ 13.19 (s, 1H), 8.63 (app d, J=4.5 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.0, 1.6 Hz, 1H), 7.71-7.67 (m, 2H), 7.34 (app dt, J=9.6, 1.6 Hz, 1H), 7.16 (app dt, J=8.7, 1.8 Hz, 1H), 6.66 (s, 1H), 5.33 (s, 2H), 3.29 (s, 3H), 1.92 (s, 3H); LC/MS C-18 column, tr=2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0344 (M+H calcd for C22H18BrF2N2O5 requires 507.0362).

Workup

  1. customThe resulting biphasic solution was separated
  2. extractionthe resulting aqueous layer was further extracted with ethyl acetate (2×200 mL)
  3. customdried
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo to a volume of 50 mL
  6. customto form
  7. customto sit until precipitation
  8. custom(approximately 1.0 hour)
  9. customThe precipitate was collected
  10. customdried in vacuo (1.0 mm Hg)
  11. customto furnish the solid acid as an intermediate (806 mg, 78%)

Sources & evidence

ORD record
ord-dce7855171ea40ed8c7932bb0f13112f
Source dataset
uspto-grants-2009_12
Patent number
US07629363B2

Reaction notes

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