1,1'-Carbonyl-di-(1,2,4-triazole) → (racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1777995Notes

Reaction equation

HRID 1777995 reaction equation
[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[Si:27]([O:34][CH:35]([C:37]1[CH:38]=[C:39]2[C:44](=[N:45][C:46]=1[CH:47]([O:50][CH3:51])[O:48][CH3:49])[NH:43][CH2:42][CH2:41][CH2:40]2)[CH3:36])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[Si:27]([O:34][CH:35]([C:37]1[CH:38]=[C:39]2[C:44](=[N:45][C:46]=1[CH:47]([O:50][CH3:51])[O:48][CH3:49])[N:43]([C:20]([NH:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[O:21])[CH2:42][CH2:41][CH2:40]2)[CH3:36])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]

Participants

5

Reactant 3

HCID 43939611,1'-Carbonyl-di-(1,2,4-triazole)HCID 1180369516-Amino-4-(2-methoxyethylamino)pyridine-3-carbonitrile2×HCID 131734797(Racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine2×

Product 1

HCID 131734796(racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
0 °C

Procedure

A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 524 mg, 2.73 mmol) in DMF (1.5 mL) was added drop wise to a cooled suspension of di(1H-1,2,4-triazol-1-yl)methanone (448 mg, 2.73 mmol) in DMF (1.5 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C., after which it was allowed to warm to room temperature. A solution of (racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 185, 500 mg, 1.364 mmol) in DMF (2.0 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (100 mL) and solid precipitates were filtered off. Solvents were concentrated and the crude material was purified by silica gel column chromatography eluting with a gradient of MeOH (0-4%) in DCM, followed by re-purification with a gradient of EtOAc (0-40%) in heptane. Fractions containing the product were combined to yield the title compound as a waxy solid. (UPLC-MS 3) tR 1.66 min, ESI-MS 585.3 [M+H]+.

Workup

  1. temperatureto warm to room temperature
  2. stirringthe reaction mixture was stirred at room temperature overnight
  3. customThe reaction mixture was quenched with MeOH (100 mL) and solid
  4. customprecipitates
  5. filtrationwere filtered off
  6. concentrationSolvents were concentrated
  7. customthe crude material was purified by silica gel column chromatography
  8. washeluting with a gradient of MeOH (0-4%) in DCM
  9. customfollowed by re-purification with a gradient of EtOAc (0-40%) in heptane
  10. additionFractions containing the product

Sources & evidence

ORD record
ord-d06b10aeb21645c894b02c828fecf51b
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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