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

HRID 2100314Notes

Reaction equation

HRID 2100314 reaction equation
[CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:18][NH:17][CH2:16]1)=[O:12].C(N(CC)CC)C.CN(C)CCN>ClCCl>[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:16][N:17]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:18]1)=[O:12]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 66053N,N-DimethylethylenediamineHCID 662791-Propanesulfonyl chlorideHCID 688270942-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide

Product 1

HCID 116770272-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide

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. customwas used without further purification
  2. customThe resulting mixture was partitioned between dichloromethane and water
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customevaporated to dryness
  6. customPurification by flash column chromatography on a silica cartridge
  7. washeluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%)

Sources & evidence

ORD record
ord-19c1fc87df6d4a5eadb2bc9bcd47a67d
Source dataset
uspto-grants-2009_08
Patent number
US07572792B2

Reaction notes

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