Acetic Acid → Fluazaindolizine

HRID 524444Notes

Reaction equation

HRID 524444 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)(=O)C>ClCCl.CCCCCCC.C(O)(C)C>[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

8

Reactant 4

HCID 176Acetic AcidHCID 3140422-Chloro-5-methoxybenzene-1-sulfonamideHCID 737427Ethyl 8-chloro-6-(trifluoromethyl)imidazo(1,2-a)pyridine-2-carboxylate2×HCID 16686102Diethyl aluminum chloride3×

Product 1

HCID 46944253Fluazaindolizine

Reagents, catalysts & solvents 3

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolventHCID 8900HeptaneSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred slurry of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester (see PCT Patent Publication WO 2010/129500 for preparation) (3 g, 10.3 mmol) and 2-chloro-5-methoxybenzenesulfonamide (see PCT Patent Publication WO 2010/129500 for preparation) (2.4 g, 10.8 mmol, 1.05 equiv) in dichloromethane (24 mL) at 17° C. under nitrogen was added diethyl aluminum chloride (1.5 mL, 12.0 mmol, 1.16 equiv) over approximately 1 minute. The addition of diethylaluminum chloride was accompanied by ca. 13° C. temperature rise and gas evolution. After complete addition of diethylaluminum chloride the temperature of the reaction mixture was adjusted to 40° C. and the batch became an off-white slurry. The reaction mixture was held stirring for about 24 h at 40° C. HPLC analysis (after 24 h) indicated 3.6 area % of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester remaining. Iso-propyl alcohol (1.6 mL) and heptane (12 mL) were respectively added to the reaction resulting in formation of a thicker slurry. Aqueous 10% acetic acid (15 mL, 25.6 mmol, 2.5 equiv) was then added resulting in a strong exotherm. The reaction mass was held for about 1.5 h at 20-25° C. and was then filtered and the filter cake was washed with water (12 ml). The solid product was split into two portions, the larger portion was dried in a vacuum oven at 80° C. for 16 hours and the smaller portion was air-dried for 16 hours to give the title compound (2.8 g and 0.95 g respectively) in 86.8% combined yield. The vacuum-dried product conformed with polymorph Form A and the air-dried portion did not. The polymorph Form A was characterized by its powder X-ray diffraction pattern (See Characterization Example 2).

Workup

  1. customwas accompanied by ca. 13° C.
  2. customwas adjusted to 40° C.
  3. customHPLC analysis (after 24 h)
  4. customresulting in formation of a thicker slurry
  5. customresulting in a strong exotherm
  6. waitThe reaction mass was held for about 1.5 h at 20-25° C.
  7. filtrationwas then filtered
  8. washthe filter cake was washed with water (12 ml)
  9. customThe solid product was split into two portions
  10. customthe larger portion was dried in a vacuum oven at 80° C. for 16 hours
  11. customthe smaller portion was air-dried for 16 hours

Sources & evidence

ORD record
ord-6ce52f7986bb4323b71ab98100b8bdca
Source dataset
uspto-grants-2016_05
Patent number
US09340541B2

Reaction notes

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