Hydrochloric Acid → 5-(4-Methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester dihydrochloride salt

HRID 1486501Notes

Reaction equation

HRID 1486501 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]OS(C)(=O)=O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[ClH:39].CO>CC(C)=O>[ClH:39].[ClH:39].[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 887MethanolHCID 11430Potassium CarbonateHCID 531671-MethylpiperazineHCID 579902125-Methanesulfonyloxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester

Product 1

HCID 668965095-(4-Methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester dihydrochloride saltYield 65%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Conditions

Temperature
15 °C

Procedure

The solid from Step 8 (assume 0.232 mol) was dissolved in acetone (700 mL) and this solution was added over 45 mins to a cooled (internal temp 15-17° C.) suspension of K2CO3 (48 g) and N-methylpiperazine (50 mL, 0.45 mol) in acetone (330 mL). The suspension was stirred at 15° C. for 3 h (complete removal of starting material by tlc) when the solution was evaporated to a small volume and the residue partition between EtOAc (1000 mL) and a mixture of water (500 mL) and saturated brine (50 mL). The organic phase was washed with a mixture of water (500 mL) and saturated brine (150 mL) and finally washed with saturated brine (300 mL). The solution was dried (MgSO4) and filtered and to this solution was added 1M-HCl in MeOH (430 mL, 0.43 mol). The suspension was cooled (0° C. for 30 mins) and the solid removed by filtration which was washed with EtOAc and then heptane on the sinter and the solid dried (oil-pump, RT 72 h) to give crop 1 of the title compound 66.34 g (65%) as a colourless solid. 1H NMR (400 MHz, Me-d3-OD): 7.64-7.51 (m, 2H), 7.51-7.29 (m, 6H), 5.23 (s, 2H), 4.79 (dd, J=16.2, 6.1 Hz, 4H), 4.49 (s, 2H), 3.66 (s, 8H), 3.03 (s, 3H).

Workup

  1. additionthis solution was added over 45 mins to
  2. temperaturea cooled
  3. custom(complete removal of starting material by tlc) when the solution
  4. customwas evaporated to a small volume
  5. customthe residue partition between EtOAc (1000 mL)
  6. additiona mixture of water (500 mL) and saturated brine (50 mL)
  7. washThe organic phase was washed with a mixture of water (500 mL) and saturated brine (150 mL)
  8. washfinally washed with saturated brine (300 mL)
  9. dry with materialThe solution was dried (MgSO4)
  10. filtrationfiltered and to this solution
  11. temperatureThe suspension was cooled (0° C. for 30 mins)
  12. customthe solid removed by filtration which
  13. washwas washed with EtOAc
  14. dry with materialheptane on the sinter and the solid dried (oil-pump, RT 72 h)

Sources & evidence

ORD record
ord-42c054cb760b4cf7a218dbe8310eee19
Source dataset
uspto-grants-2016_08
Patent number
US09428439B2

Reaction notes

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