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

HRID 1021061ノート

反応式

HRID 1021061 の反応式
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

参加物

5

反応物 2

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

生成物 2

HCID 59318451Sacubitril Impurity 3HCID 68714094HCID 68714094、化合物

試薬・触媒・溶媒 1

HCID 7915Isopropyl Acetate溶媒

反応条件

温度
55 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-deb7b6df6baf483abf0ad98376dc0651
出典データセット
uspto-grants-2014_05
特許番号
US08716495B2

反応ノート

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