Cesium carbonate → 6-(3-chloro-4-fluorobenzyl)4-[(3-chloro-4-fluorobenzyl)oxy]-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

HRID 1817323Notes

Reaction equation

HRID 1817323 reaction equation
[OH:1][C:2]1[C:3](=[O:19])[N:4]([CH3:18])[C:5]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]2[C:11]=1[C:10](=O)[NH:9][CH2:8][CH2:7]2.[C:20]([O-:23])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30]Br.[H-].[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:10][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([O:1][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:35])=[C:27]([Cl:26])[CH:28]=3)[C:3](=[O:19])[N:4]([CH3:18])[C:5]=2[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:20]1=[O:23]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 24758Sodium hydrideHCID 27575424-(Bromomethyl)-2-chloro-1-fluorobenzeneHCID 690584564-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Product 1

HCID 690581956-(3-chloro-4-fluorobenzyl)4-[(3-chloro-4-fluorobenzyl)oxy]-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A solution of 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.018 g, 0.068 mmol) in DMF (2 mL) was treated with Cs2CO3 (0.066 g, 0.2 mmol) and 3-chloro-4-fluoro benzyl bromide (0.045 g, 0.2 mmol) and heated to 40° C. The reaction mixture was then cooled to 0 degrees C., a suspension of NaH (95% dispersion in oil, 0.2 mmol) was added and the reaction was warmed to room temperature. After 1 hr the reaction was partitioned between ice water and EtOAc, the organic layer was dried with brine and Na2SO4, filtered and evaporated to give 6-(3-chloro-4-fluorobenzyl)4-[(3-chloro-4-fluorobenzyl)oxy]-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (ES MS M+1=549.9). This material was then dissolved in CH2Cl2 (3 mL) and treated with 4 drops of a 30% by weight solution of HBr in propionic acid at room temperature. After 20 minutes the solution was concentrated and purified by reverse phase chromatography to give the product.

Workup

  1. temperatureThe reaction mixture was then cooled to 0 degrees C
  2. additionwas added
  3. temperaturethe reaction was warmed to room temperature
  4. customAfter 1 hr the reaction was partitioned between ice water and EtOAc
  5. dry with materialthe organic layer was dried with brine and Na2SO4
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-a5bb6bcf145b42ff92478210191a9974
Source dataset
uspto-grants-2009_10
Patent number
US07598264B2

Reaction notes

Loading…