Hydrochloric Acid → (R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride

HRID 70842Notes

Reaction equation

HRID 70842 reaction equation
[NH2:1][C@H:2]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.O1CCOCC1>>[ClH:27].[NH2:1][C@H:2]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:19][CH:20]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]

Participants

4

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 59607598(R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate

Product 1

HCID 86648193(R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride

Procedure

To (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate (87.6 mg, 0.183 mmol) is added a solution of HCl in 1,4-dioxane (0.456 mL, 1.825 mmol) at room temperature. After stirring for 3 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride. A mixture of (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride, fumaric acid monoethyl ester (33.4 mg, 0.220 mmol), EDCI (63.3 mg, 0.330 mmol), DIPEA (0.058 ml, 0.330 mmol) and HOAt (44.9 mg, 0.330 mmol) in DMF (1.8 ml) is allowed to stir at room temperature for 3 hour. The reaction mixture is diluted with water, and then the products are extracted with EtOAc. The organic layer is washed with NH4OH, 1M HCl aq and brine, dried over Na2SO4, filtered, and concentrated to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R,E)-ethyl 4-(4-(benzyloxy)-1-(3′-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobut-2-enoate (72.9 mg); HPLC retention time=1.40 minutes (condition B); MS (m+1)=506.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3 H) 2.58 (A of ABX, Jab=16.4 Hz, Jax=5.3 Hz, 1 H) 2.6 (B of ABX, Jab=16.4 Hz, Jbx=5.1 Hz, 1 H) 2.88 (A of ABX, Jab=13.6 Hz, Jax=8.1 Hz, 1 H) 3.03 (B of ABX, Jab=13.6 Hz, Jbx=6.3 Hz, 1 H) 4.24 (q, J=7.1 Hz, 2 H) 4.56-4.64 (m, 1 H) 5.12 (A of AB, J=12.1 Hz, 1 H) 5.18 (B of AB, J=12.1 Hz, 1 H) 6.57 (br d, J=9.1 Hz, 1 H) 6.77 (A of AB, J=15.4 Hz, 1 H) 6.81 (B of AB, J=15.4 Hz, 1 H) 7.19 (br d, J=8.1 Hz, 2 H) 7.29-7.47 (m, 10 H) 7.53-7.54 (m, 1 H).

Workup

  1. concentrationthe reaction mixture is concentrated under reduced pressure

Sources & evidence

ORD record
ord-a41b84375db74edd9d373e1575ed3f3f
Source dataset
uspto-grants-2014_09
Patent number
US08822534B2

Reaction notes

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