1,1'-Carbonyl-di-(1,2,4-triazole) → N-(4-(tert-butylamino)-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1777999Notes

Reaction equation

HRID 1777999 reaction equation
[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])[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:49][CH3:50])[C:30]1[C:39]([CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]2=[O:48])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:11]([NH:10][C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:3]=[C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]4=[O:48])=[C:30]([CH:29]([O:49][CH3:50])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])[CH:9]=1)([CH3:14])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 43939611,1'-Carbonyl-di-(1,2,4-triazole)HCID 1180366581-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one2×HCID 1180366976-Amino-4-(tert-butylamino)nicotinonitrile2×

Product 1

HCID 118036720N-(4-(tert-butylamino)-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)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-(tert-butylamino)nicotinonitrile (intermediate 197, 402 mg, 1.794 mmol) in anhydrous DMF (3 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (327 mg, 1.794 mmol) and DMF (3 ml) cooled at 0° C. After stirring for 45 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 300 mg, 0.897 mmol) in DMF (3 ml) was added. The reaction mixture was stirred for approximately 7 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 brine, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-3%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.93 min, ESI-MS 551.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.68 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 5.42 (s, 1H), 4.89 (s, 1H), 4.85 (s, 2H), 4.05-4.00 (m, 2H), 3.48 (s, 6H), 3.30 (br s, 2H), 3.25 (br s, 2H), 2.82 (t, 2H), 2.66 (br s, 2H), 2.39 (br s, 3H), 2.00-1.93 (m, 2H), 1.50 (s, 9H).

Workup

  1. temperatureto warm to room temperature
  2. stirringThe reaction mixture was stirred for approximately 7 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 brine
  11. customdried
  12. filtrationfiltered
  13. customevaporated
  14. customThe crude product was purified
  15. washeluting with a gradient of MeOH (0-3%) in DCM
  16. additionFractions containing the product
  17. customevaporated

Sources & evidence

ORD record
ord-9edde04e66914e349966d1243e3967bd
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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