1-Piperidinecarboxaldehyde → 8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl chloride

HRID 577435Notes

Reaction equation

HRID 577435 reaction equation
C(N1CCCCC1)=O.S(Cl)(Cl)=O.[Cl:13][C:14]1[C:15]2[N:16]([CH:24]=[C:25]([C:27]([OH:29])=O)[N:26]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.COC(C1N=C2C([Cl:42])=CC(C(F)(F)F)=CN2C=1)=O>CO.C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:15]2[N:16]([CH:24]=[C:25]([C:27]([Cl:42])=[O:29])[N:26]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1

Participants

7

Reactant 4

HCID 174291-PiperidinecarboxaldehydeHCID 24386Thionyl ChlorideHCID 39288178-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid2×HCID 867296498-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester

Product 1

HCID 867296488-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl chloride

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a 3000 mL three-neck round bottom flask equipped with an overhead stirrer, thermo pocket, addition funnel and nitrogen tube was charged toluene (1000 mL), N-formyl piperidine (3.54 g, 0.031 mol) and thionyl chloride (67 g, 0.559 moles) at 23° C. under nitrogen atmosphere. The resultant reaction mass was heated to 82° C. and to this 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (100 g, 0.373 moles) (prepared as in WO 2010/129500) was charged lot wise (5 lots) over a period of 60 min. The walls of the reactor were rinsed with 500 mL toluene. After addition, the resultant reaction mass was stirred at 90° C. for 75 min and the progress of the reaction was monitored by HPLC. For this, 0.5 mL of the reaction mass was diluted with 3 mL of methanol and the formation of acid chloride was analyzed indirectly by detecting its corresponding methyl ester by HPLC). After 2 hours, HPLC analysis indicated about 0.35 a % of unreacted 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid and about 99.0 a % of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester. The resultant reaction mass was further heated to 140° C. (oil bath temperature) and distilled at about 109° C. (mass temperature) and 105-107° C. (vapor temperature) at atmospheric pressure over a period of 2.5 hours to remove toluene (about 600 mL) and excess thionyl chloride present in the reaction mass. After distillation, the reaction mass was gradually cooled to 30° C. over a period of 60 min. The concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid was about 0.07 a % and the concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester about 99.2 a % as measured by HPLC at 230 nm.

Workup

  1. customTo a 3000 mL three-neck round bottom flask equipped with an overhead stirrer
  2. additionthermo pocket, addition funnel and nitrogen tube
  3. customThe resultant reaction mass
  4. additionwas charged lot wise (5 lots) over a period of 60 min
  5. washThe walls of the reactor were rinsed with 500 mL toluene
  6. additionAfter addition
  7. customthe resultant reaction mass
  8. waitAfter 2 hours
  9. customThe resultant reaction mass
  10. temperaturewas further heated to 140° C. (oil bath temperature)
  11. distillationdistilled at about 109° C. (mass temperature) and 105-107° C. (vapor temperature) at atmospheric pressure over a period of 2.5 hours
  12. customto remove toluene (about 600 mL) and excess thionyl chloride present in the reaction mass
  13. distillationAfter distillation
  14. temperaturethe reaction mass was gradually cooled to 30° C. over a period of 60 min

Sources & evidence

ORD record
ord-f8d99cb9a9504af39fd3737c45a46686
Source dataset
uspto-grants-2015_05
Patent number
US09040554B2

Reaction notes

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