Phosphoric Acid → (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid

HRID 588295Notes

Reaction equation

HRID 588295 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].P(=O)(O)(O)[OH:31]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][C:10](=[CH2:26])[C:9]([OH:27])=[O:31])=[CH:15][CH:16]=1

Participants

7

Reactant 3

HCID 1004Phosphoric AcidHCID 3939Lithium HydroxideHCID 46193438(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester

Product 1

HCID 46193439(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (27.7 g) is dissolved in THF (270 ml) at room temperature. Tetrabutylammonium bromide (0.24 g) is added followed with water (10 ml). The mixture is then cooled to 10° C. A solution of lithium hydroxide (7.3 g) in water (92 ml) is added over 2 h. Phosphoric acid (37 g, 85%) is added until pH 3. Phases are then separated. The organic phase is diluted with toluene (100 ml) and washed with brine. Phases are separated. The organic phase is then concentrated in vacuo. The residue is dissolved in acetonitrile (350 ml) at 80° C. and azeotropically distilled. Further acetonitrile is added (150 ml) and the mixture cooled to 0° C. The solid is collected by filtration and dried, to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) (25.7 g). δH (400 MHz, DMSO) 1.30 (9H), 2.29 (1H), 2.50 (1H), 2.75 (2H), 3.91 (8H), 5.62 (1H), 6.09 (1H), 6.66 (1H), 7.28 (2H), 7.33 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H).

Workup

  1. customPhases are then separated
  2. additionThe organic phase is diluted with toluene (100 ml)
  3. washwashed with brine
  4. customPhases are separated
  5. concentrationThe organic phase is then concentrated in vacuo
  6. dissolutionThe residue is dissolved in acetonitrile (350 ml) at 80° C.
  7. distillationazeotropically distilled
  8. additionFurther acetonitrile is added (150 ml)
  9. temperaturethe mixture cooled to 0° C
  10. filtrationThe solid is collected by filtration
  11. customdried

Sources & evidence

ORD record
ord-49a56b7f75334966824c2f60d5ebccca
Source dataset
uspto-grants-2016_01
Patent number
US09227934B2

Reaction notes

Loading…