Diisopropylethylamine → N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,2-benzisothiazole-3-carboxamide

HRID 600657Notes

Reaction equation

HRID 600657 reaction equation
[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH2:33])[CH2:29]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.CN(C)C=O>[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH:33][C:10]([C:3]1[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=1)=[O:12])[CH2:29]2

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 945121,2-Benzisothiazole-3-carboxylic acidHCID 27759288-methyl-8-azabicyclo[3.2.1]octan-3-amine DihydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 44183688N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,2-benzisothiazole-3-carboxamideYield 20%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of benzisothiazole-3-carboxylic acid (0.93 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (2.87 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.99 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (1.00 mmol) was added. After 18 h, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using a mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent, thus providing the product in 20% yield. Alternatively, the residues were purified by preparative HPLC. 1H NMR (CD3OD) δ 8.79 (dd, J=8.3, 1.0, 1H), 8.10-8.06 (m, 1H), 7.63-7.49 (m, 2H), 4.39-4.32 (m, 0.5H), 4.17-4.15 (m, 0.5H), 3.33-3.27 (m, 2H), 2.35 (s, 1.5H), 2.34 (s, 1.5H), 2.31-1.75 (m, 8H); LC/MS (EI) tR 3.76 min, m/z 302 (M++1).

Workup

  1. customthe reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol
  2. extractionThe aqueous layer was extracted with 95/5 dichloromethane/methanol (2×)
  3. washthe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel flash column chromatography
  8. additiona mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent
  9. customthus providing the product in 20% yield
  10. customAlternatively, the residues were purified by preparative HPLC

Sources & evidence

ORD record
ord-bfbefd32b4924e9ab8fefafd8e13ae0c
Source dataset
uspto-grants-2011_03
Patent number
US07902217B2

Reaction notes

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