Acetic Acid → Fluazaindolizine

HRID 524442Notes

Reaction equation

HRID 524442 reaction equation
C(O[C:4]([C:6]1[N:7]=[C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]2[CH:19]=1)=[O:5])C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[S:29]([NH2:32])(=[O:31])=[O:30].[Cl-].C([Al+]CC)C.C(O)(C)C.C(O)(=O)C>CCCCCl>[Cl:14][C:13]1[C:8]2[N:9]([CH:19]=[C:6]([C:4]([NH:32][S:29]([C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[Cl:20])(=[O:31])=[O:30])=[O:5])[N:7]=2)[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:12]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 3776IsopropanolHCID 3140422-Chloro-5-methoxybenzene-1-sulfonamideHCID 737427Ethyl 8-chloro-6-(trifluoromethyl)imidazo(1,2-a)pyridine-2-carboxylateHCID 16686102Diethyl aluminum chloride2×

Product 1

HCID 46944253FluazaindolizineYield 85.2%

Reagents, catalysts & solvents 1

HCID 8005Butyl ChlorideSolvent2×

Conditions

Temperature
70 °C

Procedure

A stirred slurry of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester (3.0 g, 10.3 mmol) and 2-chloro-5-methoxybenzenesulfonamide (2.39 g, 10.8 mmol, 1.05 equiv) in n-chlorobutane (45 mL) was heated to 50° C. under nitrogen. To this slurry was added neat diethylaluminum chloride (1.40 mL, 11.3 mmol). After complete addition of diethylaluminum chloride the temperature of the reaction mixture was adjusted to 65-70° C. and was held at this temperature for 4.5 h. An additional portion of n-chlorobutane (12 mL) was added and heating at 70° C. was continued for an additional 1.5 h. Iso-propanol (1.6 mL, 20.5 mmol, 2 equiv) was added at 70° C. and the resulting mixture stirred for 5 min. Aqueous 10% acetic acid (15 mL, 25.6 mmol, 2.5 equiv) was then added over a period of 10 min at 60-65° C. The reaction was allowed to cool to room temperature and then stirred overnight. The resulting solid was filtered, washed with water (12 mL) followed by n-chlorobutane (12 mL), and suction-dried. The solid product was further dried in a vacuum oven at 50-60° C. to give the title compound (4.09 g, 85.2%). Powder X-ray diffraction data conformed with Form A of Compound 1 as in Characterization Example 2.

Workup

  1. customwas adjusted to 65-70° C.
  2. waitwas continued for an additional 1.5 h
  3. temperatureto cool to room temperature
  4. stirringstirred overnight
  5. filtrationThe resulting solid was filtered
  6. washwashed with water (12 mL)
  7. customsuction-dried
  8. customThe solid product was further dried in a vacuum oven at 50-60° C.

Sources & evidence

ORD record
ord-71c99da0daf84aeaa8522161ea62f061
Source dataset
uspto-grants-2016_05
Patent number
US09340541B2

Reaction notes

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