Dimethylformamide → 1,8-Naphthyridine-1(2H)-carboxamide, 7-(dimethoxymethyl)-3,4-dihydro-6-(hydroxymethyl)-N-[5-(trifluoromethyl)-2-pyridinyl]-

HRID 1777860Notes

Reaction equation

HRID 1777860 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.CN([CH:38]=[O:39])C.[BH4-].[Na+]>C1COCC1.CO.C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[CH2:38][OH:39]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 4311764Sodium borohydrideHCID 118036953HCID 118036953, compound2×HCID 178418339Butyllithium

Product 1

HCID 1180362361,8-Naphthyridine-1(2H)-carboxamide, 7-(dimethoxymethyl)-3,4-dihydro-6-(hydroxymethyl)-N-[5-(trifluoromethyl)-2-pyridinyl]-

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 100 mg, 0.210 mmol) in THF (2 ml) at −78° C. under argon was treated drop wise with n-BuLi (1.5 M in hexane, 0.309 ml, 0.463 mmol). The resulting brown solution was stirred for 2 min and then DMF (0.1 ml, 1.29 mmol) was added. The resulting yellow solution was stirred at −78° C. for 15 min. The reaction mixture was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the 7-(dimethoxymethyl)-6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated to give a white solid. This material was dissolved in MeOH (2 ml) and DCM (1 ml), treated at room temperature with NaBH4 (6.36 mg, 0.168 mmol) and stirred for 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.10 min; ESI-MS 421.0 [M+H]+.

Workup

  1. stirringThe resulting yellow solution was stirred at −78° C. for 15 min
  2. customThe reaction mixture was quenched by addition of sat. aq. NH4Cl
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the 7-(dimethoxymethyl)-6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions
  9. concentrationwere concentrated
  10. customto give a white solid
  11. stirringstirred for 0.5 h
  12. customThe reaction mixture was quenched with sat. aq. NH4Cl
  13. extractionextracted with DCM (3×)
  14. dry with materialThe combined organic layers were dried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated under reduced pressure
  17. customThe crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product
  18. additioncontaining fractions
  19. concentrationwere concentrated

Sources & evidence

ORD record
ord-9911825ad49e43189047593334af0e1b
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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