Hydrochloric Acid → 6-(1-Methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide Hydrochloride

HRID 335282

Reaction equation

HRID 335282 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:17]=[CH:16][C:15]=2[CH3:37])=[O:12])[CH:7]=1.CC12CC1(C)OB([C:46]1[N:50]([CH3:51])[N:49]=[CH:48][CH:47]=1)O2.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)[Cl:59].Cl>COCCOC.O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.CCO>[ClH:59].[CH3:51][N:50]1[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[CH3:37])=[O:12])[CH:7]=2)=[CH:47][CH:48]=[N:49]1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 6344Dichloromethane3×HCID 10796Cesium carbonate2×HCID 712832536-Bromo-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamideHCID 866956765-(1,5-dimethyl-2,4-dioxa-3-borabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazole2×

Product 1

HCID 712833396-(1-Methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide Hydrochloride

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst3×HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 312751,4-DioxaneSolventHCID 21584252Ethanol ethylacetateSolvent

Procedure

6-Bromo-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (169 mg, 0.301 mmol), 5-(1,5-dimethyl-2,4-dioxa-3-borabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazole (75 mg, 0.391 mmol) and cesium carbonate (392 mg, 1.204 mmol) in DME (3209 μL) and water (1284 ul) were combined to give a yellow solution. PdCl2(dppf).CH2Cl2 adduct (6.15 mg, 7.52 μmol) was added and the mixture was heated using microwave radiation at 100° C. for 1 hr. A further portion of PdCl2(dppf).CH2Cl2 adduct (6.15 mg, 7.52 μmol) was added and heating continued using microwave radiation at 100° C. for 1 hr. 5-(1,5-Dimethyl-2,4-dioxa-3-borabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazole (75 mg, 0.391 mmol), PdCl2(dppf).CH2Cl2 adduct (6.15 mg, 7.52 μmol) and cesium carbonate (392 mg, 1.204 mmol) were added. The mixture was heated using microwave radiation at 100° C. for 2 hrs. The product was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM followed by a second column using 0-15% 2M NH3 in MeOH/DCM. The resulting residue was dissolved in MeOH/DCM, filtered through a glass fibre filter paper and purified by preparative chromatography eluting with 20-50% MeCN/water (0.1% TFA). The appropriate fractions were partitioned between with NaHCO3 and EtOAc and the organic portion was dried (MgSO4) and concentrated to afford a colourless oil. HCl (1 equiv.) in dioxane was added and trituration with EtOAc/EtOH afforded the title compound as a solid;

Workup

  1. customto give a yellow solution
  2. temperaturethe mixture was heated
  3. customat 100° C.
  4. customfor 1 hr
  5. temperatureheating
  6. customat 100° C.
  7. customfor 1 hr
  8. temperatureThe mixture was heated
  9. customat 100° C.
  10. customfor 2 hrs
  11. customThe product was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM
  12. dissolutionThe resulting residue was dissolved in MeOH/DCM
  13. filtrationfiltered through a glass fibre
  14. filtrationfilter paper
  15. custompurified by preparative chromatography
  16. washeluting with 20-50% MeCN/water (0.1% TFA)
  17. customThe appropriate fractions were partitioned between with NaHCO3 and EtOAc
  18. dry with materialthe organic portion was dried (MgSO4)
  19. concentrationconcentrated
  20. customto afford a colourless oil

Sources & evidence

ORD record
ord-7a2f2514068e40f582925ad91b14b7fc
Source dataset
uspto-grants-2014_11
Patent number
US08883819B2

Linked notes

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