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

HRID 1778004Notes

Reaction equation

HRID 1778004 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.[CH3:27][O:28][CH:29]([O:51][CH3:52])[C:30]1[C:39]([CH2:40][N:41]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[S:42]([CH3:45])(=[O:44])=[O:43])=[C:30]([CH:29]([O:28][CH3:27])[O:51][CH3:52])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]

Participants

5

Reactant 3

HCID 43939611,1'-Carbonyl-di-(1,2,4-triazole)HCID 118036878N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)methanesulfonamide2×HCID 1180369516-Amino-4-(2-methoxyethylamino)pyridine-3-carbonitrile2×

Product 1

HCID 118036792N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((N-(2-(dimethylamino)ethyl)methylsulfonamido)methyl)-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, 720 mg, 3.75 mmol) in anhydrous DMF (6 ml) was added dropwise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (660 mg, 3.62 mmol) and DMF (6 ml) cooled at 0° C. After stirring for 50 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)methanesulfonamide (intermediate 201, 697 mg, 1.803 mmol) in DMF (6 ml) was added. The reaction mixture was stirred for 14 h at room temperature, quenched by the addition of MeOH and concentrated. The residue was diluted with EtOAc and water, filtered to remove insoluble byproducts. Phases were separated and the aqueous layer was washed with EtOAc. The organic layers were combined, washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.81 min, ESI-MS 605.3 [M+H]+.

Workup

  1. temperatureto warm to room temperature
  2. stirringThe reaction mixture was stirred for 14 h at room temperature
  3. customquenched by the addition of MeOH
  4. concentrationconcentrated
  5. additionThe residue was diluted with EtOAc and water
  6. filtrationfiltered
  7. customto remove insoluble byproducts
  8. customPhases were separated
  9. washthe aqueous layer was washed with EtOAc
  10. washwashed with water
  11. customdried
  12. filtrationfiltered
  13. customevaporated
  14. customThe crude product was purified
  15. washeluting with a gradient of MeOH (0-5%) in DCM
  16. additionFractions containing the product
  17. customevaporated

Sources & evidence

ORD record
ord-fbc8d6f1025948ee9867d8a63aa276cd
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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