4-Methylmorpholine → 1-Boc-4-(2-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine

HRID 1685139Notes

Reaction equation

HRID 1685139 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=1)=[O:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:33][CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:45])[F:46])[CH:38]=2)=[O:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 666499872-Amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Hydrochloride

Product 1

HCID 534391291-Boc-4-(2-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidineYield 70.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmol; 57.92 g) in THF (400 mL), add NMM (3 equiv; 631.52 mmol; 69.66 mL). Cool to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmol; 30.26 mL) dropwise maintaining the temperature below −5° C. After 30 min at from −5 to 10° C., add 2-amino-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmol) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min and then 1 h at RT. Partition between water and EA; wash the organic layer with water then saturated NaCl aqueous (brine), dry over anhydrous MgSO4, filter and concentrate in vacuo. Suspend the crude in MTBE and stir for 2 h. Filter the solid and dry in vacuo to give the title compound (64.44 g; 70.79%). 1H NMR (300 MHz, DMSO): 8.37-8.26 (m, 3H), 7.74-7.68 (m, 1H), 4.61 (d, J=5.5 Hz, 2H), 3.91 (d, J=12.9 Hz, 2H), 2.75-2.64 (m, 2H), 2.46-2.37 (m, 1H), 1.69-1.60 (m, 2H), 1.39 (s, 12H).

Workup

  1. custom1 h
  2. customat RT
  3. customPartition between water and EA
  4. washwash the organic layer with water
  5. dry with materialsaturated NaCl aqueous (brine), dry over anhydrous MgSO4
  6. filtrationfilter
  7. concentrationconcentrate in vacuo
  8. stirringstir for 2 h
  9. filtrationFilter the solid
  10. customdry in vacuo

Sources & evidence

ORD record
ord-4d7ddf1b00184ef6a1b3700b37e331da
Source dataset
uspto-grants-2012_04
Patent number
US08148387B2

Reaction notes

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