Phosphoric Acid → Sacubitril Impurity 72

HRID 1525637Notes

Reaction equation

HRID 1525637 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)[CH:11]=[C:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]1CCCC1.[OH-].[Li+].P(=O)(O)(O)O>C(OCC)(=O)C>[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])/[CH:11]=[C:10](/[CH3:26])\[C:9]([OH:28])=[O:27])=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 1004Phosphoric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 66584503HCID 66584503, compound

Product 1

HCID 56847899Sacubitril Impurity 72

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

2.7 g (R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) is added to tetrahydrofuran (20 ml). Aqueous lithium hydroxide solution (10 ml, 3 M) is added and the mixture is stirred for 20 h at ambient temperature. The mixture is acidified by addition of phosphoric acid and subsequently diluted by addition of ethyl acetate. The phases are separated and the organic phase is washed with water and then concentrated under reduced pressure. Isopropyl acetate is added to the residue and the mixture is filtered to afford (Z)—(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1=Boc, R2=H, R3=CO2H). 1H NMR (DMSO): 1.28 (9H), 1.85 (3H), 2.78 (2H), 5.07 (1H), 5.92 (1H), 6.96 (1H), 7.30 (2H), 7.35 (1H), 7.46 (2H), 7.56 (2H), 7.63 (2H), 12.65 (1H).

Workup

  1. customThe phases are separated
  2. washthe organic phase is washed with water
  3. concentrationconcentrated under reduced pressure
  4. additionIsopropyl acetate is added to the residue
  5. filtrationthe mixture is filtered

Sources & evidence

ORD record
ord-adcebcaf1c5346f398faecf3c78a7822
Source dataset
uspto-grants-2015_07
Patent number
US09085529B2

Reaction notes

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