Lithium Hexamethyldisilazide → 2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-hydroxy-3-(6-methoxy-[1,5]naphthyridin-4-yl)-propionic acid ethyl ester

HRID 1666101Notes

Reaction equation

HRID 1666101 reaction equation
[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][O:28][C:29]1[N:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[C:32]2[CH:39]=[O:40]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH:39]([OH:40])[C:32]1[C:31]2[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[N:30]=2)[N:35]=[CH:34][CH:33]=1)[CH3:2]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 15700391Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetateHCID 665231381,5-Naphthyridine-4-carboxaldehyde, 6-methoxy-

Product 1

HCID 674459192-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-hydroxy-3-(6-methoxy-[1,5]naphthyridin-4-yl)-propionic acid ethyl esterYield 68%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-40 °C

Procedure

To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester (3.6 g, 15.77 mmol) in THF (50 mL) cooled to −78° C. was added LiHMDS (1M in THF, 18.1 mL) under argon. The resulting solution was stirred for 1 h at −40° C., then recooled to −78° C. 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (3.56 g, 18.92 mmol; prepared according to WO 2006/032466) was added portionwise and stirring was continued for 30 min at −78° C. The reaction mixture was quenched by the addition of aq. NH4Cl. The two layers were separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 1-2→EA) to afford a diastereoisomeric 1:1 mixture of the title compound as a pale yellow oil (4.44 g, 68% yield).

Workup

  1. customrecooled to −78° C
  2. stirringstirring
  3. waitwas continued for 30 min at −78° C
  4. customThe reaction mixture was quenched by the addition of aq. NH4Cl
  5. customThe two layers were separated
  6. extractionthe aq. layer was extracted with EA
  7. washlayers were washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated to dryness
  11. customThe residue was chromatographed (Hept-EA 1-2→EA)
  12. customto afford

Sources & evidence

ORD record
ord-6bb909b2560c479ba6e6ca643f285bbf
Source dataset
uspto-grants-2011_10
Patent number
US08044044B2

Reaction notes

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