Acetic Acid → Sacubitril impurity 11

HRID 882516Notes

Reaction equation

HRID 882516 reaction equation
[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[ClH:27].C(O)(=[O:30])C>>[ClH:27].[NH2:12][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1)[CH2:9][C@@H:10]([CH3:20])[C:11]([OH:19])=[O:30]

Participants

4

Reactant 3

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 66738857(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one

Product 1

HCID 25017084Sacubitril impurity 11

Procedure

5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one of example 6 were mixed with a mixture of acetic acid and concentrated hydrochloric acid (50 ml ratio 1:1) and stirred under reflux for about 20 hours. The solution was then concentrated under vacuum and the residue crystallised from acetic acid/ethyl acetate to yield 4.7 g of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride (3-a, R1=R2=R3=H). 1H-NMR (DMSO): 1.10 (3H, s, CH3); 1.58 (1H, m, 3-CHH); 1.88 (1H, m, CHH); 2.64 (1H, m, 4-CH); 2.88 (1H, dd, 5-CHH); 3.01 (1H, dd, 5-CHH); 3.45 (1H, m, 2-CH); 7.38 (3H, m, aromatic); 7.47 (2H, m, aromatic); 7.66 (4H, m, aromatic); 8.07 (2H, s, NH); 12.25 (1H, s, CO2H). m/z: 284 (MH+, 100%); 267 (25); 249 (47); 221 (13); 193 (24).

Workup

  1. temperatureunder reflux for about 20 hours
  2. concentrationThe solution was then concentrated under vacuum
  3. customthe residue crystallised from acetic acid/ethyl acetate

Sources & evidence

ORD record
ord-41f7f3132a7c4d92bc387125d6029436
Source dataset
uspto-grants-2015_03
Patent number
US08993785B2

Reaction notes

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