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

HRID 2388623Notes

Reaction equation

HRID 2388623 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-6b008bc55c6c47a89e30b4d583738684
Source dataset
uspto-grants-2012_09
Patent number
US08269039B2

Reaction notes

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