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

HRID 661002Notes

Reaction equation

HRID 661002 reaction equation
[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]

Participants

8

Reactant 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

Product 1

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

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-6f30d0d762464e72990f78a842f93085
Source dataset
uspto-grants-2011_12
Patent number
US08084489B2

Reaction notes

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