Toluene → HCID 57699513, compound

HRID 883791Notes

Reaction equation

HRID 883791 reaction equation
[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.[C:24]([O-:27])(O)=[O:25].[Na+].[C:29](Cl)(Cl)=[O:30].[C:33]1([CH3:39])[CH:38]=CC=C[CH:34]=1.Cl.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:44][CH:43]=1.C(N(CC)CC)C>C(Cl)Cl.ClCCCl.C(Cl)Cl.O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:49][CH2:50][N:51]([C:29]([N:15]([CH3:16])[C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:24]([O:27][C:33]([CH3:39])([CH3:38])[CH3:34])=[O:25])[C@@H:2]([CH3:1])[CH2:7]4)=[CH:14][CH:13]=3)=[O:30])[CH2:52][CH2:53]2)=[CH:44][CH:43]=1

Participants

10

Reactant 6

HCID 1140TolueneHCID 6371PhosgeneHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 218981684-(4-Fluoro-phenyl)-piperidine hydrochlorideHCID 592621311,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate

Product 1

HCID 57699513HCID 57699513, compound

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent2×HCID 21908982Water methylene chlorideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D23) (100 mg, 0.31 mmol) in DCM (5 ml) was added saturated aqueous NaHCO3 solution (5 ml) and the mixture stirred vigorously for 10 min at 0° C. The mixture was allowed to stand and a solution of phosgene in toluene (0.327 ml, 20% in toluene, 0.63 mmol) was injected into the DCM layer of the reaction mixture. The mixture was stirred for a further 10 min and the DCM layer was separated and the aqueous extracted with DCM. The combined organics were dried and concentrated to give a colourless oil. This whole was dissolved in 1,2-DCE (5 ml) and 4-(4-fluorophenyl)piperidine hydrochloride (74 mg, 0.34 mmol) and triethylamine (0.083 ml, 0.63 mmol) were added. The mixture was heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was diluted with DCM/water and the organic layer separated, dried (Na2SO4) and concentration gave a crude colourless oil (189 mg). Column chromatography eluting with 0-10% EtOAc/petrol gave the title compound as a colourless oil (156 mg), MS (ES): MH+ 525.3.

Workup

  1. stirringThe mixture was stirred for a further 10 min
  2. customthe DCM layer was separated
  3. extractionthe aqueous extracted with DCM
  4. customThe combined organics were dried
  5. concentrationconcentrated
  6. customto give a colourless oil
  7. temperatureThe mixture was heated to 120° C. in a microwave reactor for 30 minutes
  8. customthe organic layer separated
  9. customdried
  10. concentration(Na2SO4) and concentration
  11. customgave a crude colourless oil (189 mg)
  12. washColumn chromatography eluting with 0-10% EtOAc/petrol

Sources & evidence

ORD record
ord-2e1043425c654534b7adf9a30f437c33
Source dataset
uspto-grants-2012_08
Patent number
US08236953B2

Reaction notes

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