Trifluoroacetic acid → 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide

HRID 2100313Notes

Reaction equation

HRID 2100313 reaction equation
[Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:9][NH:10][CH2:11]1)=[O:5]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 57798318Tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate

Product 1

HCID 688270942-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamideYield 64%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.40 g, 0.9 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.20 g, 64%) which was used without further purification. Propane-1-sulfonyl chloride (0.04 ml, 0.34 mmol) was added to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.10 g, 0.28 mmol) and triethylamine (0.08 g, 0.56 mmol) in dichloromethane (2 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on a silica cartridge eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%) led to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an off-white solid. m/z (M++H) 464, 1H NMR (500 MHz, DMSO): δ 9.34 (s, 1 H); 7.58 (t, J=6.7 Hz, 1 H); 7.43 (s, 1 H); 4.07 (t, J=12.7 Hz, 1H); 3.91 (d, J=7.8 Hz, 1 H); 3.79 (d, J=7.8 Hz, 2 H); 3.65 (d, J=8.1 Hz, 1 H); 3.53 (d, J=10.8 Hz, 1 H); 3.17 (s, 2 H); 3.05 (t, J=7.4 Hz, 2 H); 2.80 (s, 1 H); 2.56 (s, 2 H); 1.75 (s, 1 H); 1.67 (dd, J=7.8, 15.0 Hz, 5 H); 1.39 (s, 2 H); 0.96 (t, J=7.3 Hz, 3 H).

Workup

  1. customThe mixture was evaporated to dryness
  2. additionthe residue treated with saturated aqueous sodium carbonate
  3. extractionThe product was extracted into dichloromethane
  4. washThe organic phase was washed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. customevaporated

Sources & evidence

ORD record
ord-cdf5c0c8eac1499f8d6e433a31221e08
Source dataset
uspto-grants-2009_08
Patent number
US07572792B2

Reaction notes

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