Trimethyl orthoformate → [4-(2-Chloro-phenyl)-pyridin-3-yl]-methyl-amine

HRID 379381Notes

Reaction equation

HRID 379381 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].[CH:15](OC)(OC)OC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15]

Participants

4

Reactant 2

HCID 9005Trimethyl orthoformateHCID 184033604-(2-Chlorophenyl)pyridin-3-amine

Product 1

HCID 18403335[4-(2-Chloro-phenyl)-pyridin-3-yl]-methyl-amineYield 77%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidCatalyst

Procedure

A solution of 14.9 g (72.8 mmol) 4-(2-chloro-phenyl)-pyridin-3-ylamine in 80 ml trimethyl orthoformate and 5 drops trifluoroacetic acid was heated for 2.5 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 130 ml tetrahydrofuran and 220 ml (220 mmol) of 1 M borane-tetrahydrofuran complex were added dropwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated, cooled to 0° C. and 130 ml 5 N hydrochloric acid solution in ethanol were added carefully. The solution was refluxed for 1 h, cooled to room temperature again and crushed ice was added. The aqueous phase was washed with three 100 ml portions diethyl ether and the organic layers were extracted with 100 ml 1 N hydrochloric acid solution. The combined aqueous layers were adjusted to pH 8-9 by addition of concentrated sodium hydroxide solution and were extracted with three 500 ml portions ethyl acetate. The combined organic extracts were dried (magnesium sulfate), evaporated and the solid residue was recrystallized from hexane/ethyl acetate to give 12.3 g (77%) of the title compound as white crystals.

Workup

  1. customThe reaction mixture was evaporated
  2. customdried in vacuo for 30 min
  3. dissolutionThe residual oil was dissolved in 130 ml tetrahydrofuran
  4. addition220 ml (220 mmol) of 1 M borane-tetrahydrofuran complex were added dropwise under ice cooling
  5. customthe reaction mixture was evaporated
  6. temperaturecooled to 0° C.
  7. addition130 ml 5 N hydrochloric acid solution in ethanol were added carefully
  8. temperatureThe solution was refluxed for 1 h
  9. temperaturecooled to room temperature again
  10. customcrushed ice
  11. additionwas added
  12. washThe aqueous phase was washed with three 100 ml portions diethyl ether
  13. extractionthe organic layers were extracted with 100 ml 1 N hydrochloric acid solution
  14. additionThe combined aqueous layers were adjusted to pH 8-9 by addition of concentrated sodium hydroxide solution
  15. extractionwere extracted with three 500 ml portions ethyl acetate
  16. dry with materialThe combined organic extracts were dried (magnesium sulfate)
  17. customevaporated
  18. customthe solid residue was recrystallized from hexane/ethyl acetate

Sources & evidence

ORD record
ord-5b6468c3e47c41f186836528dac49fe5
Source dataset
uspto-grants-2001_10
Patent number
US06297375B1

Reaction notes

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