Succinic anhydride → (R)-4-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid

HRID 881806Notes

Reaction equation

HRID 881806 reaction equation
Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1

Participants

5

Reactant 3

HCID 7922Succinic anhydrideHCID 81531DiisopropylethylamineHCID 86648190(R)-ethyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride

Product 1

HCID 49822224(R)-4-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acidYield 54%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (400 mg, 1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPEA (0.237 mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(3′-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (255 mg). HPLC retention time=1.15 minutes (condition B); MS (m+1)=418.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.08 Hz, 3 H) 2.46-2.58 (m, 4 H) 2.64-2.67 (m, 2 H) 2.87 (A of ABX, Jab=13.6 Hz, Jbx=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 4.12-4.24 (m, 2 H) 4.47-4.55 (m, 1 H) 6.50 (br d, J=8.8 Hz, 1 H) 7.24-7.37 (m, 4 H) 7.43-7.46 (m, 1 H) 7.48-7.52 (m, 2H) 7.55-7.56 (m, 1 H).

Workup

  1. customThe reaction is quenched with 1 M aqueous HCl
  2. extractionextracted with dichloromethane
  3. customThe organic layer is separated
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue is purified by preparative HPLC

Sources & evidence

ORD record
ord-18c30df7f85f44768d9f8b17ef8c669b
Source dataset
uspto-grants-2015_03
Patent number
US08993631B2

Reaction notes

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