Acetic Acid → HCID 118061090, compound

HRID 575528Notes

Reaction equation

HRID 575528 reaction equation
CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=O)=O.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].[O-]CC.[Na+].S([O-])(=O)(=O)C.C(O)(=O)C>CCO>[C:21]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 7764Ethyl cyanoacetate2×HCID 85257Methanesulfonate2×HCID 2723922Sodium ethoxideHCID 15229596tert-Butyl 4-(2-((methanesulfonyl)oxy)ethyl)piperidine-1-carboxylate

Product 1

HCID 118061090HCID 118061090, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
37.5 °C

Procedure

Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%).

Workup

  1. temperatureheating the mixture at 35-40° C. for 24 h at which time NMR analysis
  2. temperatureSlowly cool
  3. customthe reaction to RT
  4. concentrationConcentrate the mixture
  5. distillationvacuum distillation
  6. custompartition between water (25 L) and EtOAc (35 L)
  7. customSeparate the layers
  8. extractionextract the aqueous phase with EtOAc (10 L)
  9. washCombine the organic portions, wash with brine (15 L)
  10. concentrationconcentrate to a red oil
  11. customPurify the oil
  12. washeluting with hexane (40 L)
  13. custom20% EtOAc/hexane to provide a fraction (7.8 kg) that

Sources & evidence

ORD record
ord-7a8f8039da054216b2f7ff293351cdd1
Source dataset
uspto-grants-2015_05
Patent number
US09035051B1

Reaction notes

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