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Methanol → Methyl 2-chloro-3-fluoropyridine-4-carboxylate

HRID 1180244
Notes
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Reaction equation

HRID 1180244 reaction equation
[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[F:11]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 2

HCID 887MethanolHCID 27828122-Chloro-3-fluoropyridine-4-carboxylic acid

Product 1

HCID 24820381Methyl 2-chloro-3-fluoropyridine-4-carboxylateYield 93.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 24386Thionyl ChlorideSolvent

Procedure

2-Chloro-3-fluoroisonicotinic acid (3.30 g, 18.8 mmol) was suspended in thionyl chloride (40 ml) and heated under reflux for 2.5 h. The solvent was evaporated and the residue dried by means of azeotropic removal of water with toluene (100 ml) to afford a pale yellow oil. The oil was dissolved in dichloromethane (20 ml) and cooled to 0° C. before methanol (2.42 g, 75.3 mmol) was added dropwise to the solution over 15 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was evaporated and the mixture partitioned between water (75 ml) and dichloromethane (100 ml). The aqueous phase was extracted further with dichloromethane (100 ml), the organic layers were combined, washed with brine (75 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give 2-chloro-3-fluoroisonicotinic acid methyl ester (3.32 g, 93%) as a pale yellow solid: δH (360 MHz, CDCl3) 3.99 (3H, s), 7.70 (1H, dd, J 5 and 5), 8.31 (1H, d, J 5).

Workup

  1. temperatureheated
  2. temperatureunder reflux for 2.5 h
  3. customThe solvent was evaporated
  4. dry with materialthe residue dried by means of azeotropic removal of water with toluene (100 ml)
  5. customto afford a pale yellow oil
  6. additionwas added dropwise to the solution over 15 min
  7. additionOn complete addition the mixture
  8. customThe solvent was evaporated
  9. customthe mixture partitioned between water (75 ml) and dichloromethane (100 ml)
  10. extractionThe aqueous phase was extracted further with dichloromethane (100 ml)
  11. washwashed with brine (75 ml)
  12. dry with materialdried over anhydrous sodium sulphate
  13. filtrationfiltered
  14. customevaporated

Sources & evidence

ORD record
ord-7ddd90cc31fb48abb7e16c882e98708c
Source dataset
uspto-grants-2007_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07279580B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes