Acetone → Buparlisib Hydrochloride

HRID 709524Notes

Reaction equation

HRID 709524 reaction equation
[N:1]1([C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[CH:10]=[C:9]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)=O.[ClH:34]>C(O)(C)C>[ClH:34].[N:1]1([C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[CH:10]=[C:9]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1

Participants

5

Reactant 3

HCID 180Acetone2×HCID 313Hydrochloric AcidHCID 16654980Buparlisib

Product 1

HCID 66577015Buparlisib HydrochlorideYield 88.4%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
25 °C

Procedure

Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and 500 mL addition funnel with 51.3 g (0.125 mol, 1 eq.) of 5 and 247 g (312 mL) of acetone. Stir the slurry at 25° C. for 15 minutes. Filter through Celite (2-5 g). Wash the reactor and filter cake with 30 g (37 mL) of acetone and combine the wash with the filtrate. Rinse the reactor with methanol and dry it with heat and vacuum. Cool the reactor and re-charge the filtrate. Warm the solution to 50° C. Add a solution of 25.7 mL (0.125 mol, 1.03 eq.) of 5 N hydrogen chloride in isopropanol and 198 g (250 mL) of acetone over 2 h. Seed after the first 5% of the acid solution has been added (about 25 mL). Maintain temperature for 15 min. Cool to 10° C. and filter the solids. Wash the filter cake with 47 g (60 mL) of acetone and dry the solids at 50° C., 35 mbar for 16 h to afford 49.4 g (88.1% yield) of 6 as a yellow, crystalline solid. Following this procedure, Compound 6 is polymorph Form A of the monohydrochloride salt of the Compound of Formula A.

Workup

  1. additionCharge a nitrogen-
  2. customflushed 3 L reactor
  3. filtrationFilter through Celite (2-5 g)
  4. washWash the reactor
  5. filtrationfilter cake with 30 g (37 mL) of acetone
  6. washwash with the filtrate
  7. washRinse the reactor with methanol
  8. customdry it
  9. temperaturewith heat
  10. temperatureCool the reactor
  11. additionre-charge the filtrate
  12. temperatureWarm the solution to 50° C
  13. temperatureMaintain temperature for 15 min
  14. temperatureCool to 10° C.
  15. filtrationfilter the solids
  16. washWash the filter cake with 47 g (60 mL) of acetone
  17. customdry the solids at 50° C.

Sources & evidence

ORD record
ord-3dfb339928794f928496ac34cf0bae7a
Source dataset
uspto-grants-2015_11
Patent number
US09181215B2

Reaction notes

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