(Racemic) 7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine → (racemic) N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778065Notes

Reaction equation

HRID 1778065 reaction equation
[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([C:40]#[N:41])=[CH:32][N:31]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:40]([C:33]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:35][C:30]([NH:29][C:28]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([CH:14]4[CH2:18][CH2:17][O:16][CH2:15]4)=[C:4]([CH:3]([O:2][CH3:1])[O:19][CH3:20])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:27])=[N:31][CH:32]=1)#[N:41]

Participants

6

Reactant 2

HCID 118036983(Racemic) 7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine2×HCID 125470513Phenyl (5-cyano-4-isopropoxypyridin-2-yl)carbamate2×

Product 1

HCID 118036843(racemic) N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of (racemic) 7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (Intermediate 337, 230 mg, 0.45 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (Intermediate 96, 405 mg, 1.36 mmol) and DMAP (170 mg, 1.36 mmol) in DMF (2.7 ml) was stirred at 90° C. After 1 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried over Na2SO4 and evaporated. The crude material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 100% EtOAc/heptanes. Product-containing fractions were combined and evaporated. The resulting material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 50% MeOH/DCM. Product-containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 6) tR 1.28; ESI-MS 482.3 [M+H]+.

Workup

  1. temperaturethe reaction mixture was cooled to room temperature
  2. extractionextracted with EtOAc (3×)
  3. washThe combined organic layers were washed with H2O and brine
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. custompurified by normal phase chromatography
  7. washeluting
  8. washwith eluting with a gradient from 1% to 100% EtOAc/heptanes
  9. customevaporated
  10. custompurified by normal phase chromatography
  11. washeluting
  12. washwith eluting with a gradient from 1% to 50% MeOH/DCM
  13. customevaporated

Sources & evidence

ORD record
ord-04eb3dd0a9934bdba2f3d8fbd1a91bb4
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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