Diisopropylethylamine → (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate

HRID 70864Notes

Reaction equation

HRID 70864 reaction equation
[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:9]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:33])=[O:10])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:6]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 59607655(R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid

Product 1

HCID 59607897(R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoateYield 92.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (142 mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride (76 mg, 0.542 mmol), WSC hydrochloride (120 mg, 0.626 mmol), 1-hydroxy-7-azabenzotriazole (85 mg, 0.626 mmol) and DIPEA (0.219 ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room temperature under nitrogen for 13 hours. The reaction is quenched with H2O. The products are extracted with ethyl acetate, washed with aqueous 1M HCl and then with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100) to give (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (164 mg, 91%). HPLC retention time=1.59 minutes (condition A); MS (ES+)=425.4 (m); 369.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.44 (m, 2 H) 2.67-2.79 (m, 3 H) 2.89-2.96 (m, 1 H) 3.28-3.36 (m, 1 H) 3.45-3.53 (m, 1 H) 7.23 (d, J=5.8 Hz, 2 H) 7.33 (t, J=7.35 Hz, 1 H) 7.41-7.44 (m, 2 H) 7.51 (d, J=8.1 Hz, 2 H) 7.58 (d, J=7.4 Hz, 2 H).

Workup

  1. customThe reaction is quenched with H2O
  2. extractionThe products are extracted with ethyl acetate
  3. washwashed with aqueous 1M HCl
  4. dry with materialwith brine, dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100)

Sources & evidence

ORD record
ord-26aa9ff202fa4624b5c195398c148b2d
Source dataset
uspto-grants-2014_09
Patent number
US08822534B2

Reaction notes

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