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Diisopropylethylamine → (+/-)-3-({5-[1-(4'-Tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester

HRID 661002
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HRID 661002 반응식
[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][C:12]=2[CH3:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:26]([C:24]1[S:25][C:21]([CH:19]([O:18][C:14]2[CH:13]=[C:12]([CH3:29])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)=[C:16]([CH3:17])[CH:15]=2)[CH3:20])=[CH:22][CH:23]=1)=[O:27]
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참가 물질

8

반응물 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 67485042(+/-)-5-[1-(4'-Tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid

생성물 1

HCID 59355988
(+/-)-3-({5-[1-(4'-Tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester
수율 71.4%

시약·촉매·용매 2

HCID 962Water용매HCID 6228Dimethylformamide용매

실험 절차

To a mixture of (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.546 g, 1.34 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.204 g, 1.46 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (12.3 mL) is added N, N-diisopropylethylamine (0.70 mL, 4.01 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.333 g, 1.74 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide (±)-3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.472 g, 71%) as a white solid. MS (ES): 492.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak OD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.180 g, 98.3% ee) and Isomer 2 (0.190 g, 96.7% ee).

후처리

  1. extractionextracted with EtOAc (3×25 mL)
  2. washCombined organic extracts are washed with H2O, brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. washeluted

출처 및 근거

ORD 기록
ord-6f30d0d762464e72990f78a842f93085
출처 데이터셋
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08084489B2

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