Hydrochloric Acid → 3-Fluoro-4-[[2-(2-pyridinylamino)-5-thiazolyl]thio]-2-pyridinecarboxylic acid

HRID 1685337Notes

Reaction equation

HRID 1685337 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=[O:9])[C:3]=1[F:12].O.[SH2:14].[Na].Br[C:17]1[S:21][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:19][CH:18]=1.C[O-].[Na+].Cl>CO.O.CN(C=O)C>[F:12][C:3]1[C:4]([C:8]([OH:10])=[O:9])=[N:5][CH:6]=[CH:7][C:2]=1[S:14][C:17]1[S:21][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:19][CH:18]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 53294005-bromo-N-(pyridin-2-yl)thiazol-2-amineHCID 10942334Sodium MethoxideHCID 53442613Sodium hydrogen sulfide hydrateHCID 59200355HCID 59200355, compound

Product 1

HCID 592004233-Fluoro-4-[[2-(2-pyridinylamino)-5-thiazolyl]thio]-2-pyridinecarboxylic acidYield 4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
37 °C

Procedure

A DMF (3 mL) solution of methyl 4-chloro-3-fluoropicolinate (0.3 g, 1.58 mmol) was bubbled 10 min with argon, then sodium hydrogensulfide hydrate (0.146 g, 1.98 mmol, 1.25 eq) was added and the mixture was gently heated to 37° C. The mixture was diluted with methanol then 5-bromo-N-(pyridin-2-yl)thiazol-2-amine (0.404 g, 1.58 mmol, 1 eq, described in the synthesis of thiazoles Example A) was added, followed by a solution of sodium methoxide 25% (0.725 mL, 3.16 mmol, 2 eq). The mixture was heated at 65° C. for 1 h, cooled to 23° C., diluted with water (5 ml) and stirred 5 days. The mixture was neutralized with HCl 1N, concentrated to dryness, suspended in water, sonicated and the resulting solid was collected by filtration. The solid was purified on preparative HPLC (TFA/water/acetonitrile) and the fractions were concentrated on speedvac to give the title compound as a solid (0.023 g, 4%). The compound was used as such in the next step.

Workup

  1. additionwas added
  2. temperatureThe mixture was heated at 65° C. for 1 h
  3. temperaturecooled to 23° C.
  4. concentrationconcentrated to dryness
  5. customsonicated
  6. filtrationthe resulting solid was collected by filtration
  7. customThe solid was purified on preparative HPLC (TFA/water/acetonitrile)
  8. concentrationthe fractions were concentrated on speedvac

Sources & evidence

ORD record
ord-1a1e0633fe2c483aa04d02d5c3a5f72b
Source dataset
uspto-grants-2012_04
Patent number
US08148400B2

Reaction notes

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