Citric Acid → 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,3,4-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one

HRID 2394134Notes

Reaction equation

HRID 2394134 reaction equation
[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][O:43][C:44]1[C:51]([O:52][CH3:53])=[C:50]([O:54][CH3:55])[CH:49]=[CH:48][C:45]=1[CH2:46]I.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:46][C:45]2[CH:48]=[CH:49][C:50]([O:54][CH3:55])=[C:51]([O:52][CH3:53])[C:44]=2[O:43][CH3:42])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]

Participants

10

Reactant 6

HCID 311Citric AcidHCID 1032Propionic AcidHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 2733832Lithium HexamethyldisilazideHCID 10870461tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamateHCID 212211282,3,4-Trimethoxybenzyl iodide

Product 1

HCID 152958925(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,3,4-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 1.368 g (4.48 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 5 ml of abs. THF and 0.91 ml (1.67 equivalents) of DMPU is cooled down to -75° C., under argon, and treated dropwise, at an internal temperature of below -70° C. and over the period of approximately 20 min, with 8.78 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After a further 15 min, a solution of 1.38 g (1 equivalent) of 2,3,4-trimethoxybenzyl iodide in 2.5 ml of abs. THF is added dropwise to this mixture, within the period of approximately 15 min, and the mixture is allowed to react at -75° C. for a further 2.25 h. For the working-up, the reaction mixture is treated with 1.67 ml of propionic acid and 1.67 ml of water, and the temperature is allowed to rise to 0° C. The mixture is poured onto 20 ml of (cold) 10% citric acid, and approximately 50 ml of (cold) ethyl acetate is added to this mixture. After stirring for a further 5 min, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and saline once again. The combined aqueous phases are reextracted twice with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated. The residue which remains after removing the solvent is chromatographed on silica gel (hexane:ethyl acetate, 3:1), and the title compound thereby obtained. HPLC tRet =16.49 min (gradient II). FAB-MS (M+H)+ =486 and M+ =485. IR(KBr)=inter alia, 3312, 1759, 1686, 1603, 1537, 1165 and 1104 cm-1. 1H-NMR(CD3OD)=inter alia, 7.30-7.10 (m, 5H); 6.84 and 6.66 (each d, each 1H); 3.85, 3.82 and 3.87 (each s, each 3H); 1.30 (s, 9H).

Workup

  1. customto react at -75° C. for a further 2.25 h
  2. customto rise to 0° C
  3. additionis added to this mixture
  4. customthe phases are separated
  5. washThe organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and saline once again
  6. dry with materialThe combined organic phases are dried over Na2SO4
  7. concentrationconcentrated
  8. customafter removing the solvent
  9. customis chromatographed on silica gel (hexane:ethyl acetate, 3:1)

Sources & evidence

ORD record
ord-ddac5c8eac1b47a78dc4fa3f649ac7b4
Source dataset
uspto-grants-1998_09
Patent number
US05807891

Reaction notes

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