Hydrochloric Acid → HCID 178511314, compound

HRID 744296Notes

Reaction equation

HRID 744296 reaction equation
C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)=[N:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl.FC1C=C2C([C:42](C3CCNCC3)=[N:43]N2)=CC=1.C([O-])(O)=O.[Na+].ClCC#N>C(O)C.C(#N)C.C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([C:11]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:42]#[N:43])[CH2:23][CH2:24]3)=[N:10][NH:9]2)=[CH:13][CH:14]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 7856ChloroacetonitrileHCID 14797Potassium HydroxideHCID 516892Sodium BicarbonateHCID 18467270HCID 18467270, compoundHCID 178505426HCID 178505426, compound

Product 1

HCID 178511314HCID 178511314, compoundYield 89.1%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6342AcetonitrileSolventHCID 21226138Dichloromethane ethylacetateSolvent

Procedure

To a suspension of 1-benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole (31.6 g, 71.3 mmol) in ethanol (500 ml) was added 50% KOH(aq.) (100 g of KOH in 100 g H2O) at room temperature. The reaction mixture was warmed to reflux for 4 hours and cooled to room temperature. After adjusting the pH to about one (to litmus) using HCl (con., 110 ml), the volatiles were removed under reduced pressure. The remaining wet solid was diluted with water and collected via filtration. The solid material was dissolved into hot water to which 50% NaOH(aq.) was added (pH was about 10, to litmus). The precipitated 4-(6-fluoro-1H-indazol-3-yl)piperidine (10.7 g) was filtered and used without further purification. To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCO3 (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149°-151° C.

Workup

  1. temperatureThe reaction mixture was warmed
  2. temperatureto reflux for 4 hours
  3. customthe volatiles were removed under reduced pressure
  4. additionThe remaining wet solid was diluted with water
  5. filtrationcollected via filtration
  6. dissolutionThe solid material was dissolved into hot water to which 50% NaOH(aq.)
  7. additionwas added (pH was about 10, to litmus)
  8. filtrationThe precipitated 4-(6-fluoro-1H-indazol-3-yl)piperidine (10.7 g) was filtered
  9. customused without further purification
  10. temperatureThe suspension was warmed
  11. temperatureto reflux for 22.5 hours
  12. temperaturecooled to room temperature
  13. filtrationsubsequently filtered
  14. washThe remaining solids were washed with DCM
  15. concentrationthe combined filtrates were concentrated
  16. dissolutionThe resulting brown oil was dissolved into EtOAc
  17. washwashed with water
  18. dry with materialThe organic phase was dried (MgSO4)
  19. filtrationfiltered
  20. concentrationconcentrated
  21. customto give a brown solid which
  22. customflushed through alumina with DCM
  23. concentrationThe eluent was concentrated

Sources & evidence

ORD record
ord-d72701907aaa45c8a57275c6458612fd
Source dataset
uspto-grants-1996_09
Patent number
US05559116

Reaction notes

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