3,5-Difluoropyridine → Methyl 4-chloro-1-(3,5-difluoropyridin-4-yl)isoquinoline-7-carboxylate

HRID 533402

Reaction equation

HRID 533402 reaction equation
C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=2)[C:18](OS(C(F)(F)F)(=O)=O)=[N:17][CH:16]=1>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=2)[C:18]([C:12]2[C:11]([F:13])=[CH:10][N:9]=[CH:8][C:7]=2[F:6])=[N:17][CH:16]=1

Participants

7

Reactant 3

HCID 6428203,5-DifluoropyridineHCID 86666251Methyl 4-chloro-1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylateHCID 178418339Butyllithium

Product 1

HCID 67774472Methyl 4-chloro-1-(3,5-difluoropyridin-4-yl)isoquinoline-7-carboxylateYield 20.8%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Under argon gas atmosphere, n-butyllithium (1.6 M THF solution, 0.7 mL) was added dropwise to a mixture of 3,5-difluoropyridine (123 mg) and THF (3 mL) at −78° C., followed by stirring at the same temperature for one hour. Then, zinc chloride (146 mg) was added, and stirred for an additional hour. Methyl 4-chloro-1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (330 mg) and tetrakis(triphenylphosphine)palladium (206 mg) were added thereto, followed by heating under stirring in an oil bath at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-chloro-1-(3,5-difluoropyridin-4-yl)isoquinoline-7-carboxylate (62 mg).

Workup

  1. stirringstirred for an additional hour
  2. temperatureby heating
  3. stirringunder stirring in an oil bath at 60° C. for 3 hours
  4. concentrationThe reaction mixture was concentrated under reduced pressure
  5. custompurified under silica gel column chromatography (hexane/ethyl acetate)

Sources & evidence

ORD record
ord-684a031afcaa4e1b8a4c20dd142e9d36
Source dataset
uspto-grants-2014_10
Patent number
US08853242B2

Linked notes

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