Citric Acid → (S)-Methyl 2-((R)-2-ethyl-4-nitrobutanamido)-3-phenylpropanoate

HRID 476309Notes

Reaction equation

HRID 476309 reaction equation
[CH2:1]([C@H:3]([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[C:4]([OH:6])=O)[CH3:2].CCN=C=N[CH2:17][CH2:18][CH2:19][N:20](C)C.CCN(C(C)C)C(C)C.[C:32](O)(=O)[CH2:33][C:34]([CH2:39][C:40](O)=O)(C(O)=O)O.C[CH2:46][O:47][C:48](C)=[O:49]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:3]([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[C:4]([NH:20][C@@H:19]([CH2:18][C:17]1[CH:32]=[CH:33][CH:34]=[CH:39][CH:40]=1)[C:48]([O:47][CH3:46])=[O:49])=[O:6])[CH3:2]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 8857Ethyl AcetateHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 44464031(R)-2-Ethyl-4-nitrobutanoic acid

Product 1

HCID 44464033(S)-Methyl 2-((R)-2-ethyl-4-nitrobutanamido)-3-phenylpropanoateYield 90%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

Nitro acid 3 (0.483 g, 3 mmol) was dissolved in dry CH2Cl2 (30 mL) and treated with L-Ph-OMe.HCl (0.78 g, 3.6 mmol), EDCI (0.69 g, 3.6 mmol), DIEA (0.64 mL, 3.6 mmol) and catalytic amount of DMAP. The reaction mixture was stirred for 24 h, diluted with EtOAc, acidified with 10% citric acid and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The crude residue was purified by chromatography (hexanes/EtOAc, v/v, 8:1 to 2:1) to afford pure product 7 (0.87 g, 90%) as a white solid. An analytical sample was purified by recrystallization (hexanes/EtOAc): m.p. 86.2-87.8° C., TLC Rf=0.66 (EtOAc/hexanes, v/v, 1:1), 1H NMR (300 MHz, CDCl3) δ 7.34-7.22 (m, 3H), 7.17-7.14 (m, 2H), 6.12 (bd, J=8.1 Hz, 1H), 4.99 (dt, J=5.1, 8.0 Hz, 1H), 4.22-4.14 (m, 1H), 4.00-3.90 (m, 1H), 3.76 (s, 3H), 3.23, 2.98 (AB of ABX, JAB=14.0 Hz, JAX=5.2 Hz, JBX=7.9 Hz, 2H), 2.17-2.01 (m, 3H), 1.70-1.56 (m, 1H), 1.52-1.38 (m, 1H), 0.89 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.61, 172.23, 136.09, 129.40, 128.92, 127.46, 73.54, 52.98, 52.67, 45.70, 38.32, 29.77, 26.20, 11.79; HRMS m/z (ESI): calc. for C16H22N2O5H [M+H]+323.1602, found 323.1609. Optical rotation: [α]rtD+14.3 (c 1.23, CHCl3).

Workup

  1. extractionextracted with EtOAc (3×)
  2. washThe combined organic layers were washed with saturated NaHCO3 and brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. customThe crude residue was purified by chromatography (hexanes/EtOAc, v/v, 8:1 to 2:1)

Sources & evidence

ORD record
ord-b87e94e19c504bc5a18f466110c10520
Source dataset
uspto-grants-2014_01
Patent number
US08637696B2

Reaction notes

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