Citric Acid → HCID 69679961, compound

HRID 353398Notes

Reaction equation

HRID 353398 reaction equation
[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14]/[C:15](=[CH:19]\[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:24]([CH3:34])[CH:23]=1)/[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(N)CCCCC1>CO.O>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:24]([CH3:34])[CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:10])([CH3:11])[CH3:9]

Participants

6

Reactant 3

HCID 311Citric AcidHCID 7965CyclohexylamineHCID 69679989HCID 69679989, compound

Product 1

HCID 69679961HCID 69679961, compoundYield 65%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
22.5 °C

Procedure

A stirred solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoic acid cyclohexylamine salt (1.1 Kg, 2.3 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (2.2 g, 2.4 mmol) in methanol (8.2 liters) and water (2.8 liters) was heated to 60° C., under hydrogen (60 p.s.i.), for 40 hours and then allowed to cool to 20-25° C. (enantiomeric excess=88%). The mixture was concentrated in vacuo to a volume of 3 liters and then ethyl acetate (5 liters) was added. The mixture was distilled at constant volume of ethyl acetate until water droplets appeared in the distillate. The mixture was then cooled to 20-25° C. and then demineralised water (2.9 liters) and citric acid (485 g, 2.5 mol) were added. The organic phase was separated and washed with demineralised water (1.1 liter) and then dried azeotropically by distillation at a constant volume of 8.25 liters. Methylethyl ketone (8.25 liters) was added and the mixture was warmed to 40° C. Cyclohexylamine (228 g, 2.28 mol) was added in one portion and the mixture was allowed to cool to 20-25° C., then was stirred for 16 hours. The mixture was filtered and the residue was washed with a mixture of ethyl acetate (55 ml) and methylethyl ketone (55 ml) and then dried in vacuo at 45° C. to leave the title compound as a colourless solid (0.71 Kg, 65% yield, enantiomeric excess=98.6%, 99% pure by HPLC).

Workup

  1. concentrationThe mixture was concentrated in vacuo to a volume of 3 liters
  2. additionethyl acetate (5 liters) was added
  3. distillationThe mixture was distilled at constant volume of ethyl acetate until water droplets
  4. temperatureThe mixture was then cooled to 20-25° C.
  5. customThe organic phase was separated
  6. washwashed with demineralised water (1.1 liter)
  7. customdried azeotropically by distillation at a constant volume of 8.25 liters
  8. additionMethylethyl ketone (8.25 liters) was added
  9. temperaturethe mixture was warmed to 40° C
  10. temperatureto cool to 20-25° C.
  11. filtrationThe mixture was filtered
  12. washthe residue was washed with a mixture of ethyl acetate (55 ml) and methylethyl ketone (55 ml)
  13. customdried in vacuo at 45° C.

Sources & evidence

ORD record
ord-19f440e21c2f4ae889b1fc8db92c2f74
Source dataset
uspto-grants-2004_06
Patent number
US06750363B2

Reaction notes

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