Hydrogen Bromide → Methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate

HRID 882006Notes

Reaction equation

HRID 882006 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]#N)[C:3]=1[Cl:12].[BrH:13].S(=O)(=O)(O)[OH:15].[C:19](=O)([O-])[O-:20].[Na+].[Na+]>C(O)(=O)C.CCOCC.CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Br:13])[N:5]=[C:4]([C:10]([O:20][CH3:19])=[O:15])[C:3]=1[Cl:12]

Participants

8

Reactant 4

HCID 260Hydrogen BromideHCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 704973794-Amino-3-chloro-5,6-difluoropicolinonitrile

Product 1

HCID 71551894Methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinateYield 75%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 4-amino-3-chloro-5,6-difluoropicolinonitrile (70 g, 0.37 mol) and 33% HBr in acetic acid (700 mL) was heated to 120° C. in a sealed, stirred reaction vessel for 2 h. After cooling to room temperature, the supernatant was separated from a large amount of a tan solid and concentrated under vacuum to give a tacky dark residue. This residue was taken into CH3OH (600 mL) and added back to the tan solids that remained in the pressure reactor. To this mixture was slowly added concentrated sulfuric acid (H2SO4; 40 g, 0.41 mol), and the reactor was again sealed and heated to 110° C. for 6 h. The cooled reaction mixture was slowly poured into satd aq sodium carbonate (Na2CO3; 2 L) and Et2O (1 L). The ether extract was dried over MgSO4, filtered and concentrated to a tan solid. This solid was purified by column chromatography to give methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (78 g, 75%) as fine white crystals: mp 119-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 2H), 3.87 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 163.54 (s, C═O), 144.63 (d, J=256.3 Hz, C5), 142.60 (d, J=4.9 Hz, C2), 140.55 (d, J=13.6 Hz, C4), 125.61 (d, J=21.0 Hz, C6), 116.65 (s, C3), 53.2 (s, OMe); 19F NMR (376 MHz, CDCl3) δ −128.86; EIMS m/z 284 (Mr). Anal. Calcd for C7H5BrClFN2O2: C, 29.66; H, 1.78; N, 9.88. Found: C, 30.03; H, 1.80; N, 9.91.

Workup

  1. customreaction vessel for 2 h
  2. temperatureAfter cooling to room temperature
  3. customthe supernatant was separated from a large amount of a tan solid
  4. concentrationconcentrated under vacuum
  5. customto give a tacky dark residue
  6. additionadded back to the tan solids that
  7. customthe reactor was again sealed
  8. temperatureheated to 110° C. for 6 h
  9. customThe cooled reaction mixture
  10. extractionThe ether extract
  11. dry with materialwas dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated to a tan solid
  14. customThis solid was purified by column chromatography

Sources & evidence

ORD record
ord-5ac676e582734469b55f86abe58551d4
Source dataset
uspto-grants-2015_03
Patent number
US08993772B2

Reaction notes

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