Succinic anhydride → (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester

HRID 70820Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 70820
Cl.[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:3].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>ClCCl>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:22])=[CH:14][CH:13]=1

Komponenten

5

Edukt 3

HCID 7922Succinic anhydrideHCID 81531DiisopropylethylamineHCID 68424075(R)-ethyl 3-amino-4-(biphenyl-4-yl)butanoate hydrochloride

Produkt 1

HCID 49822223(R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (148.2 mg). HPLC retention time=1.64 minutes (condition A); MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3 H) 2.31-2.39 (m, 2 H) 2.40-2.56 (m, 4 H) 2.77-2.92 (m, 2 H) 4.08 (q, J=7.24 Hz, 2 H) 4.33-4.48 (m, 1 H) 6.62 (d, J=8.34 Hz, 1 H) 7.30 (d, J=8.08 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.41-7.49 (m, 2 H) 7.54-7.60 (m, 2 H) 7.60-7.67 (m, 2 H) 10.02 (br. s., 1 H).

Aufarbeitung

  1. customThe reaction is quenched with 10% aqueous citric acid
  2. extractionextracted with dichloromethane
  3. customThe organic layer is separated
  4. concentrationconcentrated under reduced pressure
  5. customThe obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN)

Quellen und Nachweise

ORD-Eintrag
ord-22fea9004fc54737951db776a0020cf4
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822534B2

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