Propionic Acid → 5(S)-[1(S)-(Boc-Amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]-3(R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-one

HRID 1377199Notes

Reaction equation

HRID 1377199 reaction equation
[C:1]([NH:8][C@H:9]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:38]([O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]I)=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC>C1COCC1.CN1C(=O)N(C)CCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH2:50][C:49]2[CH:52]=[CH:53][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:47][CH:48]=2)[CH2:23]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

9

Reactant 4

HCID 1032Propionic AcidHCID 2733832Lithium HexamethyldisilazideHCID 11723738p-Benzyloxybenzyl iodideHCID 541918735(S)-[1(S)-(Boc-Amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]dihydrofuran-2-(3H)-one

Product 1

HCID 701494025(S)-[1(S)-(Boc-Amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]-3(R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-one

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolventHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
0 °C

Procedure

Under an N2 atmosphere, 3,6 g (9,48 mmol) of 5(S)-[1(S)-(Boc-amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]dihydrofuran-2-(3H)-one, dissolved in 17.3 ml of THF and 1.9 ml of DMPU, are deprotonated, at -70° C., with 18.58 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and, after 15 min, alkylated with 3.07 g (9.48 mmol) of p-benzyloxybenzyl iodide (Example 1d)) in 6 ml of THF. After 30 min at -75° C., the mixture is protonated with 3.53 ml (47.4 mmol) of propionic acid and 3.53 ml of water and warmed to 0° C. The reaction mixture is diluted with 95 ml of ethyl acetate and the whole is washed with 10% citric acid solution, sat. NaHCO3 solution and saline. The aqueous phases are extracted with 2 portions of ethyl acetate. The organic phases are dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) and crystallization from ethyl acetate/hexane yields the pure title compound: TLC Rf (C)=0.38; tRet (II)=18.0 min; FAB-MS (M+H)+ =576.

Workup

  1. waitAfter 30 min at -75° C.
  2. washthe whole is washed with 10% citric acid solution, sat. NaHCO3 solution and saline
  3. extractionThe aqueous phases are extracted with 2 portions of ethyl acetate
  4. dry with materialThe organic phases are dried with Na2SO4
  5. customevaporated
  6. customColumn chromatography (SiO2, hexane/ethyl acetate, 1:1) and crystallization from ethyl acetate/hexane

Sources & evidence

ORD record
ord-8ccd6f9158fb4394ac76cfcafe329bce
Source dataset
uspto-grants-1997_09
Patent number
US05663200

Reaction notes

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