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

HRID 1021061Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1021061
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

Komponenten

5

Edukt 2

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

Produkt 2

HCID 59318451Sacubitril Impurity 3HCID 68714094HCID 68714094, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 7915Isopropyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
55 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-deb7b6df6baf483abf0ad98376dc0651
Quelldatensatz
uspto-grants-2014_05
Patentnummer
US08716495B2

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