Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate → Sacubitril Impurity 3

HRID 1500447Notes

Reaction equation

HRID 1500447 reaction equation
Cl.C([O:4][C:5](=[O:24])[C@@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)C.C(OC(=O)[C@H](C)C[C@H:31]([N:45]1[C:49](=O)[CH2:48][CH2:47][C:46]1=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C>C(OC(C)C)(=O)C>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]([CH2:9][C@H:8]2[NH:22][C:5](=[O:4])[C@@H:6]([CH3:23])[CH2:7]2)=[CH:11][CH:12]=1.[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]2[N:22]([CH2:31][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7]2)=[CH:15][CH:14]=1

Participants

5

Reactant 2

HCID 66739220Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoateHCID 66739279HCID 66739279, compound

Product 2

HCID 59318451Sacubitril Impurity 3HCID 68714094HCID 68714094, compound

Reagents, catalysts & solvents 1

HCID 7915Isopropyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

To a mixture of (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-b, R1=R2=H, R3=Et) [9:1 diastereoisomer mixture [(2S,4S):(2R,4S)]] (840 mg) in isopropyl acetate (10 ml) triethylamine (418 mg) is added. The mixture is then stirred at 55° C. for 1 h and then filtered. The filtrate is heated at reflux for 24 hours. To the mixture is added saturated ammonium chloride solution and the phases are separated. The organic layer is concentrated to dryness. The residue is purified by chromatography, eluting first with IPA/Heptane 2:1 then with a mixture 1:1 to afford (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1=H) and (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H). Ratio of diastereoisomers determined by 1H NMR to be 9:1 [(3S,5S):(3R,5S)]. 1H NMR (CDCl3) for (2-b, R1=H): 1.15 (3H), 1.38 (1H), 2.42 (2H), 2.63 (1H), 2.82 (1H), 3.75 (1H), 5.51 (1H), 7.17 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H). Spectroscopic data for (2-a, R1=H) as in Example 6.

Workup

  1. filtrationfiltered
  2. temperatureThe filtrate is heated
  3. temperatureat reflux for 24 hours
  4. additionTo the mixture is added saturated ammonium chloride solution
  5. customthe phases are separated
  6. concentrationThe organic layer is concentrated to dryness
  7. customThe residue is purified by chromatography
  8. washeluting first with IPA/Heptane 2:1

Sources & evidence

ORD record
ord-b56fec75b34648b5970666d736f199bb
Source dataset
uspto-grants-2015_12
Patent number
US09206116B2

Reaction notes

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