Diisopropylethylamine → N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamide

HRID 2362856Notes

Reaction equation

HRID 2362856 reaction equation
[CH3:1][O:2][C:3]1[CH:14]=C[C:6]2[C:7]([C:10](O)=[O:11])=[N:8]S[C:5]=2[CH:4]=1.[CH:15](N(C(C)C)CC)(C)C.Cl.Cl.[NH2:26][C@@H:27]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O1CCCC1.C[N:65]([CH3:68])C=O>>[N:29]12[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30]1)[C@H:27]([N:26]([CH3:15])[C:10]([C:7]1[C:6]3[C:68](=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:65][N:8]=1)=[O:11])[CH2:28]2

Participants

6

Reactant 5

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12494972(R)-(+)-3-Aminoquinuclidine DihydrochlorideHCID 21974620tetrahydrofuran N,N-dimethylformamideHCID 666368056-Methoxybenzo[d]isothiazole-3-carboxylic acid

Product 1

HCID 16660032N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamideYield 75%

Conditions

Temperature
0 °C

Procedure

To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61 mg, 0.30 mmol) in a 5/1 mixture of tetrahydrofuran/N,N-dimethylformamide (12 mL) was added diisopropylethylamine (0.2 mL, 1.1 mmol) and (115 mg, 0.6 mmol) 3-(R)-aminoquinuclidine dihydrochloride. The mixture was cooled to 0° C., and HATU (115 mg, 0.3 mmol) was added in one portion. The reaction mixture was allowed to warm to rt and was maintained overnight. The mixture was partitioned between saturated aqueous potassium carbonate solution and a 95/5 mixture of dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2×), and the combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) or by preparative HPLC, thus providing the amide in 75% yield as a colorless solid.

Workup

  1. temperatureto warm to rt
  2. temperaturewas maintained overnight
  3. customThe mixture was partitioned between saturated aqueous potassium carbonate solution
  4. additiona 95/5 mixture of dichloromethane/methanol
  5. extractionThe aqueous layer was extracted with 95/5 dichloromethane/methanol (2×)
  6. washthe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customThe crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) or by preparative HPLC

Sources & evidence

ORD record
ord-ef6b728f75464df4b57c28c1a73f6161
Source dataset
uspto-grants-2014_04
Patent number
US08691841B2

Reaction notes

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