Tetrahydrofuran → Gamma-secretase modulators

HRID 16352Notes

Reaction equation

HRID 16352 reaction equation
O.[OH-].[Li+].O1CCCC1.C(OP([CH:17]1[C:26](=[O:27])[N:25]2[C@H:20]([CH2:21][O:22][CH2:23][C@H:24]2[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[CH2:19][CH2:18]1)(=O)OCC)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1)[CH:42]=O>O.C(OCC)(=O)C.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1)/[CH:42]=[C:17]1\[CH2:18][CH2:19][C@@H:20]2[N:25]([C:26]\1=[O:27])[C@H:24]([C:28]1[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=1)[CH2:23][O:22][CH2:21]2

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 168937Lithium hydroxide, monohydrateHCID 272824453-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehydeHCID 86612713diethyl[(4R,9aS)-6-oxo-4-(3,4,5-trifluorophenyl)octahydropyrido[2,1-c][1,4]oxazin-7-yl]phosphonate

Product 1

HCID 24781184Gamma-secretase modulatorsYield 38.2%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Lithium hydroxide monohydrate (63.4 mg) was added to a solution mixture of tetrahydrofuran (6 mL) and ethanol (2 mL) of [(4R,9aS)-6-oxo-4-(3,4,5-trifluorophenyl)octahydropyrido[2,1-c][1,4]oxazin-7-yl]phosphonic acid diethyl ester (372 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (229 mg) at room temperature. The resulting reaction solution was stirred at room temperature for 2 hr, and ethyl acetate and water were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate system) to give 163.2 mg of the title compound. The physical property values of this compound were as follows:

Workup

  1. customThe resulting reaction solution
  2. customThe organic layer was separated
  3. washwashed with saturated saline
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate system)

Sources & evidence

ORD record
ord-421593376c09495a9ee94f0957f8f9d6
Source dataset
uspto-grants-2010_06
Patent number
US07737141B2

Reaction notes

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