Citric Acid → (r)-2-[2-(Tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid (s)-alpha-methylbenzylamine salt

HRID 353399Notes

Reaction equation

HRID 353399 reaction equation
[C:1]([O:5][C:6](=[O:28])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH3:27])[CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C@H:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(N)CCCCC1.C(OC(=O)C[C@@H](CCCC1C=CC(C2C=CC=CC=2)=C(C)C=1)C(O)=O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH3:29][C@H:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:1]([O:5][C:6](=[O:28])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:17]([CH3:27])[CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:3])([CH3:4])[CH3:2]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 758181-Phenethylamine, (-)-2×HCID 11825126(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acidHCID 69679961HCID 69679961, compound

Product 1

HCID 86585207(r)-2-[2-(Tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid (s)-alpha-methylbenzylamine saltYield 91%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
22.5 °C

Procedure

(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoic acid can be enantiomerically upgraded as the (S)-alpha-methylbenzylamine salt. Thus, (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoic acid cyclohexylamine salt (50 g, 0.10 mol, enantiomeric excess=72%) was partitioned between ethyl acetate (750 ml) and aqueous citric acid solution (10%, 750 ml). The organic phase was separated, washed with water (500 ml), then azeotropically dried by distillation at constant volume. (S)-alpha-methylbenzylamine (13.2 ml, 0.10 mol) was added dropwise over 5 min at 40° C., the mixture was allowed to cool to 20-25° C., and was then stirred for 24 hours. The mixture was filtered and the residue was washed with ethyl acetate (100 ml) and then dried in vacuo) at 45° C. for 2 hours to leave the title compound as a colourless solid (41.0 g, 91% yield, enantiomeric excess=96.4%, 95% pure by NMR).

Workup

  1. customThe organic phase was separated
  2. washwashed with water (500 ml)
  3. customazeotropically dried by distillation at constant volume
  4. filtrationThe mixture was filtered
  5. washthe residue was washed with ethyl acetate (100 ml)
  6. customdried in vacuo) at 45° C. for 2 hours

Sources & evidence

ORD record
ord-a2d79fee135c4c0a9eb639755ae74ff2
Source dataset
uspto-grants-2004_06
Patent number
US06750363B2

Reaction notes

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