Sodium Hydroxide → 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide

HRID 1256222Notes

Reaction equation

HRID 1256222 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.[OH-].[Na+].P([O-])(O)(O)=[O:49].[K+].[F-].[F-].[F-].[F-].[F-].[F-].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C.O.C1COCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:20])=[O:49])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1

Participants

12

Reactant 7

HCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516951Monobasic potassium phosphateHCID 66774364HCID 66774364, compoundHCID 86664929HCID 86664929, compound

Product 1

HCID 667746395-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 272 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile, 10 ml of ethanol, 5 ml of THF and 0.611 ml of 9.3N NaOH. After 2 h of reflux, the mixture is cooled, and 50 ml of a 1M aqueous solution of potassium dihydrogen phosphate are poured in. The product is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. The crude solid obtained is dissolved in 4 ml of DMF and than 275 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 84 mg of 1-hydroxybenzotriazole (HOBT), 44 mg of ammonium chloride and 2 ml of N,N-diisopropylethylamine (DIPEA) are added. After 3 h at RT, the mixture is poured into water, extracted with AcOEt, and washed with saturated aqueous NaCl solution. Drying of MgSO4, filtering and concentration under RP give 300 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide. MS (E/I): m/z=684 (M+).

Workup

  1. customA 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum
  2. temperatureAfter 2 h of reflux
  3. temperaturethe mixture is cooled
  4. extractionThe product 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. customThe crude solid obtained
  10. additionare added
  11. extractionextracted with AcOEt
  12. washwashed with saturated aqueous NaCl solution
  13. dry with materialDrying of MgSO4
  14. filtrationfiltering
  15. concentrationconcentration under RP

Sources & evidence

ORD record
ord-ed3fbfc864514a93af789e18b8184456
Source dataset
uspto-grants-2013_06
Patent number
US08461175B2

Reaction notes

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