Chlorosulfamic acid → (R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)butan-1-one

HRID 332966Notes

Reaction equation

HRID 332966 reaction equation
[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O.CCOC(C)=O>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:23](=[O:26])(=[O:25])[N:24]=1

Participants

5

Reactant 2

HCID 24499Chlorosulfamic acidHCID 86714288(R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile

Product 1

HCID 73213734(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)butan-1-oneYield 58%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

To a solution of (R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in DMA (15.0 mL) was added sulfamoyl chloride (2.68 g, 23.21 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 2 hrs and the solution was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%). The intermediate was dissolved in EtOH (25.0 mL) and aq.NaOH (2.0N, 5.0 mL) was added at room temperature. The reaction mixture was then refluxed overnight then cooled to 0° C. and neutralized carefully with 1 N HCl. The precipitate was collected by filtration and was recrystallized with 20% water/EtOH to provide the title compound as a white solid (730 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6, room temperature) δ0.86 (t, J=7.6 Hz, 3H), 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J=13.6 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, isomer), 4.50 (t, J=10 Hz, 1H), 5.16 (t, J=4.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.68 (s, isomer), 7.77 (s, 1H), 8.23 (s, 1H), 8.36 (s, isomer), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ0.88 (t, J=7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 (m, 7H), 1.77 (d, J=11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J=10 Hz, 1H), 5.00-5.03 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.81 (s, 2H), 10.64 (s, 1H). MS 381 (MH+).

Workup

  1. washwashed with water, brine
  2. dry with materialdried over Na2SO4
  3. customThe solvent was removed under reduced pressure
  4. customthe residue was purified by Biotage SP-1 (40s column)
  5. washeluting with EtOAc/Hexane (10%-70%)
  6. dissolutionThe intermediate was dissolved in EtOH (25.0 mL)
  7. additionNaOH (2.0N, 5.0 mL) was added at room temperature
  8. temperatureThe reaction mixture was then refluxed overnight
  9. temperaturethen cooled to 0° C. and neutralized carefully with 1 N HCl
  10. filtrationThe precipitate was collected by filtration
  11. customwas recrystallized with 20% water/EtOH

Sources & evidence

ORD record
ord-5078f30fc0ad46f4b9c1372638cc946b
Source dataset
uspto-grants-2014_11
Patent number
US08877922B2

Reaction notes

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