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Hydrochloric Acid → Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amide hydrochloride

HRID 529754
Notes
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Reaction equation

HRID 529754 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])[C:16]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH:39]([F:41])[F:40])=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl.CO>[ClH:37].[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([O:38][CH:39]([F:40])[F:41])=[C:31]([C:16]2[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:18][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=2)[CH:36]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 1185223724-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 131735620Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amide hydrochlorideYield 56.6%

Reagents, catalysts & solvents

2
HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester (600 mg, 0.97 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) was added. The mixture was allowed to stir at room temperature for 30 minutes. The solvent was evaporated and the residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a glass which was purified by HPLC (Method 3). Appropriate fractions were combined and evaporated to afford an off-white solid. The solid was dissolved in MeOH and 1.25M methanolic HCl (1 mL) was added. The solvent was evaporated, azeotroped three times with methanol and triturated with ethyl acetate to afford the title compound as an off-white solid (144 mg, 28%). LCMS (Method 5) [M+H]+=488.0, RT=2.93 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 8.98 (d, 1H, J=9.9 Hz), 8.69 (dd, 1H, J=1.7, 4.3 Hz), 8.67 (s, 1H), 8.38 (s, 1H), 7.65-7.62 (m, 2H), 7.30 (dd, 1H, J=4.2, 7.2 Hz), 7.26 (t, 1H, J=73.6 Hz), 4.66-4.57 (m, 1H), 3.47-3.42 (m, 2H), 3.17-3.03 (m, 2H), 2.32-2.18 (m, 4H).

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in MeOH
  3. customAfter flushing with MeOH
  4. washthe product was eluted with 2M ammonia in MeOH
  5. customEvaporation
  6. customgave a glass which
  7. customwas purified by HPLC (Method 3)
  8. customevaporated
  9. customto afford an off-white solid
  10. customThe solvent was evaporated
  11. customazeotroped three times with methanol
  12. customtriturated with ethyl acetate

Sources & evidence

ORD record
ord-0a9f0977730749cfaebdeeaf45bda262
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09346815B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes