Hydrochloric Acid → Ly-2584702

HRID 419756Notes

Reaction equation

HRID 419756 reaction equation
Cl.C(Cl)(=O)C.C(OC([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[N:20]([CH3:35])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C.Cl[C:44]1[N:49]=[CH:48][N:47]=[C:46]2[NH:50][N:51]=[CH:52][C:45]=12>CO.O.CS(C)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[N:23]=[C:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:44]4[N:49]=[CH:48][N:47]=[C:46]5[NH:50][N:51]=[CH:52][C:45]=45)[CH2:18][CH2:17]3)[N:20]([CH3:35])[CH:21]=2)=[CH:25][C:26]=1[C:31]([F:33])([F:32])[F:34]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 2210954-Chloro-1H-pyrazolo[3,4-d]pyrimidineHCID 666499314-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 25118925Ly-2584702Yield 99.6%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolvent2×HCID 887MethanolSolvent2×HCID 962WaterSolvent2×

Conditions

Temperature
20 °C

Procedure

Prepare an anhydrous HCl solution by slow addition of acetyl chloride (193.14 mL; 2.71 moles, 4.00 eq) to methanol (1160 mL) over 45 minutes at <5° C. Add the resulting solution to a separate flask containing a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (290 g; 678.46 mmoles) in methanol (2320 mL) over 90 minutes at 20° C. Stir the reaction mixture at 20° C. overnight. Concentrate the reaction mixture under vacuum at 30° C. Add dimethyl sulfoxide (1080 mL; 15.20 moles; 1.08 L; 1.19 kg) and the distillation continues until the internal temperature reaches 50° C. at a pressure of 20 mm Hg. Add DMSO until the total volume is 2030 mL. Then add triethylamine (473 mL; 3.39 moles, 5 eq) via addition funnel over 30 minutes. Charge solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (110.29 g; 713.58 mmoles, 1.05 eq) in equal portions equally spaced over 30 minutes. Stir the resulting slurry at 20° C. overnight. Heat the slurry to 80° C. Add water (229 mL) to afford a clear solution. Seed the reaction and add more water (1273 mL) slowly over 4 hours to fully crystallize the product. Cool the slurry to 50° C. and filter the solid. Wash the cake with 30% water in DMSO (2×290 mL), then water (290 mL). Dry the solids under vacuum at 60° C. to afford 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (301 g, 99%) as an off white solid.

Workup

  1. additionAdd the resulting solution to a separate flask
  2. concentrationConcentrate the reaction mixture under vacuum at 30° C
  3. customreaches 50° C. at a pressure of 20 mm Hg
  4. waitequally spaced over 30 minutes
  5. stirringStir the resulting slurry at 20° C. overnight
  6. temperatureHeat the slurry to 80° C
  7. customthe reaction
  8. customto fully crystallize the product
  9. temperatureCool the slurry to 50° C.
  10. filtrationfilter the solid
  11. washWash the cake with 30% water in DMSO (2×290 mL)
  12. customDry the solids under vacuum at 60° C.

Sources & evidence

ORD record
ord-47a5ce4019d042158c2ef96b051bb1b5
Source dataset
uspto-grants-2012_01
Patent number
US08093383B2

Reaction notes

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