Nitrogen → Onalespib

HRID 241827Notes

Reaction equation

HRID 241827 reaction equation
C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.N#N.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27]

Participants

6

Reactant 3

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 57990219(2,4-Bis-benzyloxy-5-isopropenyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone

Product 1

HCID 11955716OnalespibYield 94%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 3776IsopropanolSolvent

Procedure

The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N2 10% Pd/C (90 g) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2×0.8 L) and dried at 40° C. to constant weight to give the title compound 588 g (94% yield).

Workup

  1. additionwere added
  2. filtrationfiltered
  3. additionTo the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg)
  4. concentrationthe solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol)
  5. additionWater (0.45 L) was added to the solution and concentration
  6. customhad been removed)
  7. washThe aqueous phase was washed with EtOAc (4.61 L)
  8. additiondiluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg)
  9. customthe solid was removed by filtration
  10. washThe residue was washed with acetonitrile (2×0.8 L)
  11. customdried at 40° C. to constant weight

Sources & evidence

ORD record
ord-3b384b6901a64b8fb9efb2144869f4f7
Source dataset
uspto-grants-2014_02
Patent number
US08653084B2

Reaction notes

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