Tetrahydrofuran → Methyl (6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3',4':4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate

HRID 2114858Notes

Reaction equation

HRID 2114858 reaction equation
[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][NH:16][C:15](=[O:23])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44]Br>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][N:16]1[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[N:6]3[C@@H:7]([CH3:9])[CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]3=[C:12]([O:13][CH3:14])[C:11]=2[C:15]1=[O:23]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 27575424-(Bromomethyl)-2-chloro-1-fluorobenzeneHCID 86612123Methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3',4':4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate

Product 1

HCID 86612124Methyl (6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3',4':4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
-25 °C

Procedure

To a cold (−25° C.) solution of methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.96 mmol) was added. The reaction mixture was stirred at −25° C. for 25 minutes and treated with 3-chloro-4-fluorobenzyl bromide (0.27 g, 1.2 mmol; passed through activated basic alumina). The reaction mixture was stirred at 0° C. for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product.

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 40 minutes
  2. concentrationconcentrated under vacuum
  3. customThe residue was partitioned between ethyl acetate and dilute aqueous HCl
  4. extractionThe organic extract
  5. washwas washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. washeluted with ethyl acetate-hexane gradient
  10. customCollection and concentration of appropriate fractions

Sources & evidence

ORD record
ord-f6bf92154eb3497691e72c5dbcf36367
Source dataset
uspto-grants-2008_10
Patent number
US07435735B2

Reaction notes

Loading…