Ethanol → HCID 49764010, compound

HRID 1256214Notes

Reaction equation

HRID 1256214 reaction equation
FC(F)(F)C(O)=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[C:19]2[NH:28][N:29]=[C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:34][CH2:33]3)[C:18]=2[N:17]=1.C(O)C.[OH-].[Na+].P([O-])(O)(O)=O.[K+]>C1COCC1>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]1[C:25]2[CH:24]=[C:23]([C:26]([NH2:27])=[O:4])[CH:22]=[CH:21][C:20]=2[C:19]2[NH:28][N:29]=[C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:39])=[O:40])[CH2:34][CH2:33]3)[C:18]=2[N:17]=1

Participants

6

Reactant 4

HCID 702EthanolHCID 14798Sodium HydroxideHCID 516951Monobasic potassium phosphateHCID 67494404HCID 67494404, compound

Product 1

HCID 49764010HCID 49764010, compoundYield 38.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 992 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile trifluoroacetate, 63 ml of ethanol, 30 ml of THF and 10 ml of 9.3N sodium hydroxide. After 3 h at reflux, the mixture is cooled and poured into 250 ml of a 1M aqueous solution of potassium dihydrogen phosphate. The mixture is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. The crude solid is dissolved in 20 ml of DMF, and then 1 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 323 mg of 1-hydroxybenzotriazole (HOBT), 170 mg of ammonium chloride and 1 ml of N,N-diisopropylethylamine (DIPEA) are added. After 2 h of stirring at RT, the reaction mixture is poured into water, extracted with AcOEt, washed with a 1M aqueous solution of potassium dihydrogen phosphate and then with saturated aqueous NaCl solution. Drying over MgSO4, filtering and concentration under RP are followed by purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM, methanol and 4N methanolic ammonia (90/10/1 by vol.), to give 321 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (lemon yellow solid). MS (E/I): m/z=500 (M+); 1H NMR: 1.68 (m, 2H); 2.11 (m, 2H); 2.88 (s, 3H); 2.90 (m, 2H); 3.56 (m, 2H); 3.80 (m, 1H); 6.09 (d, J=8.0 Hz, 1H); 7.33 (t, J=8.0 Hz, 2H); 7.57 (broad s, 1H); 7.69 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.36 (broad d, J=8.5 Hz, 1H); 8.45 (d, J=8.5 Hz, 1H); 12.85 (s, 1H).

Workup

  1. customA 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum
  2. temperatureAfter 3 h at reflux
  3. temperaturethe mixture is cooled
  4. extractionThe mixture is extracted with AcOEt
  5. washwashed with saturated aqueous NaCl solution
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness under RP
  9. dissolutionThe crude solid is dissolved in 20 ml of DMF
  10. addition1 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 323 mg of 1-hydroxybenzotriazole (HOBT), 170 mg of ammonium chloride and 1 ml of N,N-diisopropylethylamine (DIPEA) are added
  11. additionthe reaction mixture is poured into water
  12. extractionextracted with AcOEt
  13. washwashed with a 1M aqueous solution of potassium dihydrogen phosphate
  14. dry with materialDrying over MgSO4
  15. filtrationfiltering
  16. concentrationconcentration under RP
  17. customare followed by purification by flash chromatography on silica gel (40-63 μm)
  18. washeluting with a mixture of DCM, methanol and 4N methanolic ammonia (90/10/1 by vol.)

Sources & evidence

ORD record
ord-3fa652f1e0e8492c95d92c66a1459077
Source dataset
uspto-grants-2013_06
Patent number
US08461175B2

Reaction notes

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