Triethylamine → N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((2-(dimethylamino)-N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778006Notes

Reaction equation

HRID 1778006 reaction equation
[C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]

Participants

6

Reactant 3

HCID 8471Triethylamine3×HCID 70103442-(Dimethylamino)acetyl chloride2×HCID 118036812N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide2×

Product 1

HCID 118036786N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((2-(dimethylamino)-N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 516892Sodium BicarbonateSolvent

Procedure

To a solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 191, 212 mg, 0.466 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.103 ml, 0.746 mmol) and 2-(dimethylamino)acetyl chloride (91 mg, 0.49 mmol) and the reaction mixture was stirred for 75 min. Additional NEt3 (0.103 ml, 0.746 mmol) was added and the reaction was continued to stir at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and a total of NEt3 (0.206 ml, 1.486 mmol) and 2-(dimethylamino)acetyl chloride (273 mg, 1.469 mmol) and DCM (2 ml) were added stepwise during the next 22 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (3-10%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 540.3 [M+H]+. 1H NMR (600 MHz, CDCl3) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.92 (s, 0.6H), 13.83 (s, 0.4H), 8.31-8.26 (m, 1H), 7.90-7.85 (m, 1H), 7.38 (s, 0.6H), 7.23 (s, 0.4H), 5.38 (s, 0.6H), 5.33 (s, 0.4H), 4.83-4.72 (m, 3H), 4.02-3.93 (m, 2H), 3.44 (s, 2.4H), 3.42 (s, 3.6H), 3.18 (s, 1.2H), 3.08 (s, 0.8H), 2.92 (s, 1.8H), 2.87 (s, 1.2H), 2.79-2.72 (m, 2H), 2.34 (s, 3.6H), 2.26 (s, 2.4H), 1.98-1.88 (m, 2H), 1.41-1.34 (m, 6H).

Workup

  1. stirringto stir at 0° C. for 30 min
  2. customPhases were separated
  3. extractionthe water phase was extracted with DCM (2×), organic phases
  4. customdried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified
  8. washeluting with a gradient of MeOH (3-10%) in DCM
  9. additionFractions containing the product
  10. customevaporated

Sources & evidence

ORD record
ord-daed44edebf64260903a13b4ce3beb00
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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