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

HRID 1377194Notes

Reaction equation

HRID 1377194 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][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]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][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]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 10946873(5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-oneHCID 21221128HCID 21221128, compound

Product 1

HCID 677093875(S)-[1(S)-(Boc-Amino)-2-cyclohexylethyl]-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 1.47 g (4.72 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-(3H)-one in 6 ml of abs. THF and 1 ml (1.65 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 space of approximately 20 min, with 9.44 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After a further 20 min at -75° C., a solution of 1.45 g (4.72 mmol) of 2,3,4-trimethoxybenzyl iodide [Example 47b)] in 3 ml of abs. THF is added dropwise to this mixture, within the space of approximately 10 min, and this mixture is allowed to react at -75° C. for a further 2.5 h. For the working up, the reaction mixture is treated with 1.76 ml of propionic acid, followed by 1.76 ml of water, and the temperature is allowed to rise to 0° C. The reaction mixture is diluted with approximately 70 ml of ethyl acetate and stirred up with 30 ml of (cold) 10% citric acid. The aqueous phase is separated off and the organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again. The combined aqueous phases are reextracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue which remains after removing the solvent is chromatographed on silica gel (toluene:ethyl acetate, 5:1). HPLC tRet =19.13 min (gradient II). FAB-MS (M+H)+ =491. IR(CH2Cl2)=inter alia 3429, 1766, 1711, 1602, 1495, 1165 und 1100 cm-1. 1H-NMR(CD3OD)=inter alia 6.86 (d, 1H); 6.70 (d, 1H); 4.37 (m, 1H); 3.87, 3.82 and 3.81 (each s, each 3H); 3.37 (m, 1H); 3.13 (dxd, 1H); 2.94 (m, 1H); 2.59 (dxd, 1H) and 1.40 (s, 9H).

Workup

  1. customto react at -75° C. for a further 2.5 h
  2. customto rise to 0° C
  3. customThe aqueous phase is separated off
  4. washthe organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again
  5. dry with materialThe combined organic phases are dried over sodium sulfate
  6. concentrationconcentrated
  7. customafter removing the solvent
  8. customis chromatographed on silica gel (toluene:ethyl acetate, 5:1)
  9. customtRet =19.13 min (gradient II)

Sources & evidence

ORD record
ord-314136cedc9345dfb8e0b007ea3844cb
Source dataset
uspto-grants-1997_09
Patent number
US05663200

Reaction notes

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