Bromotrichloromethane → 5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one

HRID 1817363Notes

Reaction equation

HRID 1817363 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=O)[N:11](C)[C:12]=2C(O)=O)[C:7]1=[O:23].C(Cl)(=O)C(Cl)=O.CC(N=NC(C#N)(C)C)(C#N)C.[N+]1([O-])C(S)=CC=CC=1.[Br:54]C(Cl)(Cl)Cl>ClCCl.CN(C=O)C.ClC(Cl)C>[Br:54][C:12]1[N:11]=[CH:10][C:9]([O:21][CH3:22])=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH2:5][C:4]1[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=1)[C:7]2=[O:23]

Participants

9

Reactant 5

HCID 6383BromotrichloromethaneHCID 6547AzobisisobutyronitrileHCID 65578Oxalyl chlorideHCID 690633856-(3-Chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acidHCID 178526253HCID 178526253, compound

Product 1

HCID 866139085-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 63651,1-DichloroethaneSolvent

Procedure

A suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (3.5 g, 9.59 mmol; Example 12, step 12) in anhydrous dichloromethane (60 mL) and anhydrous DMF (0.45 mL) at room temperature was treated with oxalyl chloride (1.7 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. A solution of the residue and AIBN (0.47 g, 2.88 mmol) in anhydrous dichloromethane (30 mL) was added portionwise to a solution of 2-pyridinethiol-N-oxide (2.4 g, 19.2 mmol) in a mixture of bromotrichloromethane (90 mL) and dichloroethane (30 mL) at 100° C. over a period of 20 minutes (Barton et al, Tetrahedron Lett., 5939, 1985). The mixture was heated at the same temperature for 20 minutes, cooled to room temperature, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the titled compound.

Workup

  1. concentrationconcentrated under vacuum
  2. temperatureThe mixture was heated at the same temperature for 20 minutes
  3. temperaturecooled to room temperature
  4. concentrationconcentrated under vacuum
  5. customCollection and concentration of appropriate fractions

Sources & evidence

ORD record
ord-d7b85aad73d74754b8dafb142121bfba
Source dataset
uspto-grants-2009_10
Patent number
US07598264B2

Reaction notes

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