1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R,E)-ethyl 4-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobut-2-enoate

HRID 70843노트

반응식

HRID 70843 반응식
Cl.[NH2:2][C@H:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]([O:31][C:32](=[O:38])/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH3:30].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]([O:31][CH2:29][CH3:30])=[O:38])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1

참가 물질

8

반응물 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 5358902Monoethyl fumarateHCID 86648193(R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride

생성물 1

HCID 59607676(R,E)-ethyl 4-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobut-2-enoate

시약·촉매·용매 2

HCID 962Water용매HCID 6228Dimethylformamide용매

실험 절차

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).

후처리

  1. extractionthe products are extracted with EtOAc
  2. washThe organic layer is washed with NH4OH, 1M HCl aq and brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give crude
  7. customThe obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)

출처 및 근거

ORD 기록
ord-dc8fc25085554fb8aeb09112820f6db6
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822534B2

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