Hydrochloric Acid → N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

HRID 529763Notes

Reaction equation

HRID 529763 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:37][CH2:36][C:31]4(OCC[O:32]4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:40])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:28]3[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]3)[N:9]=2)[CH:7]=1

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 118523245N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Product 1

HCID 118522668N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide (46.7 g, 79.5 mmol) in dioxane (280 mL) was cooled in an ice bath before being treated with concentrated hydrochloric acid (210 mL) at a rate which maintained an internal temperature below 22° C. On complete addition, the reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled in an ice bath, diluted with ethyl acetate and water and the pH of the aqueous phase adjusted to ˜8 by the portionwise addition of solid Na2CO3. The mixture was extracted with ethyl acetate (×4) and the combined organic extract was dried (Na2CO3) and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane as a beige solid (48.8 g, 97%). LCMS (Method 3) [M+H]+=544.2, RT=2.85 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.87 (s, 1H), 8.79 (dd, 1H, J=1.8, 7.0 Hz), 8.70 (s, 1H), 8.57 (dd, 1H, J=1.8, 4.0 Hz), 8.47 (s, 1H), 7.67 (d, 1H, J=2.8 Hz), 7.43 (dd, 1H, J=2.7, 8.7 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=4.3, 7.0 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.14 (s, 2H), 3.93 (t, 2H, J=6.2 Hz), 3.85 (t, 2H, J=6.2 Hz), 3.70 (s, 8H), 2.50 (t, 2H, J=6.2 Hz), 2.42 (t, 2H, J=6.1 Hz).

Workup

  1. temperaturewas cooled in an ice bath
  2. temperaturemaintained an internal temperature below 22° C
  3. additionOn complete addition
  4. temperatureThe reaction was cooled in an ice bath
  5. extractionThe mixture was extracted with ethyl acetate (×4)
  6. extractionthe combined organic extract
  7. dry with materialwas dried (Na2CO3)
  8. customevaporated

Sources & evidence

ORD record
ord-e79b3e7c01124e11a8f991c185e01e60
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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