Hydrochloric Acid → Alisertib

HRID 241540Notes

Reaction equation

HRID 241540 reaction equation
Cl.[NH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1)=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28](=O)[C:29](=[CH:42]N(C)C)[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1.Cl>O.CO>[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28]3[N:2]=[C:3]([NH:5][C:6]4[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=4)[N:4]=[CH:42][C:29]=3[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 67389390HCID 67389390, compoundHCID 178493226HCID 178493226, compound

Product 1

HCID 24771867AlisertibYield 80%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
52.5 °C

Procedure

Into a reactor was added 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), 9 (5.27 kg, 14.1 mol) and methanol (63 L). The suspension was warmed to 50 to 55° C. and stirred for a minimum of 24 h until ≧96.0% conversion was obtained by HPLC analysis. Methanol (10 L) and water (37 L) were added while maintaining the temperature between 50 and 55° C. The pH of the mixture was adjusted to 3.0 to 4.0 using 7% w/w HCl (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55° C. The suspension was cooled to 20 to 25° C. over a minimum of 1 h and stirred for at least 60 min. The resulting suspension was filtered and washed with water (2×26.3 L) at 50 to 55° C. and methanol (2×10 L) at 20 to 25° C. The wet cake was dried at 45 to 50° C. under vacuum to provide 5.85 kg (80% yield) of Formula (II). 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=2.4, 8.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z MS (ESI) m/z 517.2 (M−H+, 45%).

Workup

  1. customwas obtained by HPLC analysis
  2. temperaturewhile maintaining the temperature between 50 and 55° C
  3. temperaturewhile maintaining the temperature between 50 and 55° C
  4. temperatureThe suspension was cooled to 20 to 25° C. over a minimum of 1 h
  5. stirringstirred for at least 60 min
  6. filtrationThe resulting suspension was filtered
  7. washwashed with water (2×26.3 L) at 50 to 55° C.
  8. customat 20 to 25° C
  9. customThe wet cake was dried at 45 to 50° C. under vacuum

Sources & evidence

ORD record
ord-12de47599e724cc2a72dfa71cc526192
Source dataset
uspto-grants-2014_02
Patent number
US08653064B2

Reaction notes

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