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

HRID 529767
Notes
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Reaction equation

HRID 529767 reaction equation
C(O[C:6](=[O:45])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=34)=[O:24])[C:19]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[O:41][CH:42]([F:44])[F:43])=[N:18]2)[CH2:13][CH2:12]1)(C)(C)C.[C:46](O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[ClH:40].[C:6]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=34)=[O:24])[C:19]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[O:41][CH:42]([F:43])[F:44])=[N:18]2)[CH2:15][CH2:16]1)(=[O:45])[CH3:46]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 6367Acetyl chlorideHCID 6422Trifluoroacetic acidHCID 118522579[3-(4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid tert-butyl ester

Product 1

HCID 131735625Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [1-[1-(3-acetylaminopropyl)piperidin-4-yl]-3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide hydrochloride
Yield 32%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

[3-(4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid tert-butyl ester (129 mg, 0.20 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction was stirred at room temperature for 1 hour and then evaporated to dryness. 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 of the basic fractions gave a residue which was dissolved in pyridine (2 mL). Acetyl chloride (21 μL, 0.30 mmol) was added and the solution was allowed to stand at room temperature for 5 days. The volatiles were evaporated and azeotroped with toluene. 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 glassy solid which was purified by HPLC (Method 3). The pure amine was dissolved in MeOH and 1.25M methanolic HCl was added. The volatiles were evaporated and the solid product was triturated with EtOAc/Et2O to give the title compound as a white solid (40 mg, 32%). LCMS (Method 5) [M+H]+=587.0, RT=2.91 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.89 (s, 1H), 9.76 (s, 1H), 9.35 (dd, 1H, J=1.5, 7.0 Hz), 8.69 (dd, 1H, J=1.6, 4.2 Hz), 8.67 (s, 1H), 8.39 (s, 1H), 8.04 (t, 1H, J=5.8 Hz), 7.67-7.61 (m, 2H), 7.46 (d, 2H, J=8.4 Hz), 7.31 (dd, 1H, J=4.2, 6.9 Hz), 7.26 (t, 1H, J=73.4 Hz), 4.64-4.54 (m, 1H), 3.64 (d, 2H, J=12.2 Hz), 3.21-3.01 (m, 6H), 2.40-2.29 (m, 4H), 1.84 (m, 5H).

Workup

  1. customevaporated to dryness
  2. dissolutionThe residue was dissolved in MeOH
  3. customAfter flushing with MeOH
  4. washthe product was eluted with 2M ammonia in MeOH
  5. customEvaporation of the basic fractions
  6. customgave a residue which
  7. waitto stand at room temperature for 5 days
  8. customThe volatiles were evaporated
  9. customazeotroped with toluene
  10. dissolutionThe residue was dissolved in MeOH
  11. customAfter flushing with MeOH
  12. washthe product was eluted with 2M ammonia in MeOH
  13. customEvaporation
  14. customgave a glassy solid which
  15. customwas purified by HPLC (Method 3)
  16. dissolutionThe pure amine was dissolved in MeOH
  17. addition1.25M methanolic HCl was added
  18. customThe volatiles were evaporated
  19. customthe solid product was triturated with EtOAc/Et2O

Sources & evidence

ORD record
ord-a329072924f74b858873b1432576cdf0
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09346815B2

Reaction notes

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