Tetrahydrofuran → HCID 68785259, compound

HRID 910476Notes

Reaction equation

HRID 910476 reaction equation
[C:1]([O:6]C)(=O)[CH:2]([CH3:4])[CH3:3].[CH:8]([N-:11]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:28][C@H:29]1[NH:34][CH2:33][C@H:32]([O:35][CH:36]([C:47]2[CH:48]=[CH:49][C:50]3[O:55][CH2:54][CH2:53][N:52]([CH2:56][CH2:57][CH2:58][O:59][CH3:60])[C:51]=3[CH:61]=2)S(C2C=CC(C)=CC=2)(=O)=O)[C@@H:31]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][O:69][CH2:70][C@H](OCC)C)=[CH:64][CH:63]=2)[CH2:30]1.[CH2:76]1[CH2:80][O:79][CH2:78][CH2:77]1>>[CH2:80]([O:79][C@H:78]([CH3:77])[CH2:70][O:69][CH2:68][C:65]1[CH:64]=[CH:63][C:62]([C@@H:31]2[C@@H:32]([O:35][CH2:36][C:47]3[CH:48]=[CH:49][C:50]4[O:55][CH2:54][CH2:53][N:52]([CH2:56][CH2:57][CH2:58][O:59][CH3:60])[C:51]=4[CH:61]=3)[CH2:33][NH:34][C@H:29]([CH2:28][C:2]([CH3:4])([CH3:3])[C:1]([NH:11][CH3:8])=[O:6])[CH2:30]2)=[CH:67][CH:66]=1)[CH3:76]

Participants

6

Reactant 5

HCID 8028Tetrahydrofuran2×HCID 11039Methyl isobutyrateHCID 12679HexamethylphosphoramideHCID 2724682Lithium diisopropylamideHCID 67389069HCID 67389069, compound

Product 1

HCID 68785259HCID 68785259, compound

Conditions

Temperature
-78 °C

Procedure

To a solution of 4.0 mmol of methyl isobutyrate in 2 ml of THF at −78° C. are added 4.0 mmol of lithiumdiisopropyl amide solution (0.5 M in THF) and the reaction mixture is stirred for 30 min at −78° C. Then 8.0 mmol of hexamethylphosphoramide is added at −78° C. and the mixture is stirred for 30 min. A solution of 1.0 mmol of 6-[(3R,4R,6S) -6-bromomethyl-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-1-(toluene-4-sulfonyl) -piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine in 2 ml of THF is then added dropwise to the “enolate” at −78° C. and the solution is stirred for 30 min. The reaction mixture is allowed to warm to −12° C. and stirred at this temperature for 40 min. The solution is quenched with 1M aqueous HCl and extracted with 200 ml of EtOAc (3×). The combined organic layers are washed with brine and dried with Na2SO4. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as yellow oil. Rf=0.41 (EtOAc/heptane 1:3); Rt=5.93 (gradient I).

Workup

  1. stirringthe mixture is stirred for 30 min
  2. stirringthe solution is stirred for 30 min
  3. temperatureto warm to −12° C.
  4. stirringstirred at this temperature for 40 min
  5. customThe solution is quenched with 1M aqueous HCl
  6. extractionextracted with 200 ml of EtOAc (3×)
  7. washThe combined organic layers are washed with brine
  8. dry with materialdried with Na2SO4
  9. filtrationThe organic layer is filtered
  10. customevaporated under reduced pressure
  11. customThe residue is purified by flash chromatography (SiO2 60 F)

Sources & evidence

ORD record
ord-b02c77c612144bd6b072c345c2bcf557
Source dataset
uspto-grants-2011_09
Patent number
US08022069B2

Reaction notes

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