Hydrochloric Acid → (R)-ethyl 3-amino-4-(2',5'-dichlorobiphenyl-4-yl)butanoate hydrochloride
Reaction equation
C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]Participants
Procedure
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate (1.09 g, 2.33 mmol) is added a solution of 4 M HCl in 1,4-dioxane (5.81 mL, 23.3 mmol) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate hydrochloride. Next, a solution of the product, succinic anhydride (280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (15 mL) is allowed to stir for 2 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-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (553 mg) as a white solid; HPLC retention time=1.02 minutes (condition B); MS (m+1)=452.14; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.2 Hz, 3 H) 2.47-2.67 (m, 6 H) 2.89 (A of ABX, Jab=13.7 Hz, Jax=7.8 Hz, 1 H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.7 Hz, 1 H) 4.12-4.24 (m, 2 H) 4.49-4.57 (m, 1 H) 6.53 (br d, J=8.8 Hz, 1 H) 7.23-7.26 (m, 3 H) 7.32-7.40 (m, 4 H).
Workup
- concentrationthe reaction mixture is concentrated under reduced pressure
Sources & evidence
- ORD record
- ord-1315decb98b94ea685b56f29e05d30c9
- Source dataset
- uspto-grants-2014_09
- Patent number
- US08822534B2
Reaction notes
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