Lithium Hexamethyldisilazide → N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778053Notes

Reaction equation

HRID 1778053 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:38][CH3:39])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:24](OC2C=CC=CC=2)=[O:25])=[CH:16][C:15]=1[N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.[NH2:40][C:41]1[CH:48]=[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])[C:44]([C:45]#[N:46])=[CH:43][N:42]=1>C1COCC1>[C:45]([C:44]1[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:48][C:41]([NH:40][C:24]([N:21]2[C:22]3[C:17](=[CH:16][C:15]([N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)=[C:14]([CH:13]([O:12][CH3:11])[O:38][CH3:39])[N:23]=3)[CH2:18][CH2:19][CH2:20]2)=[O:25])=[N:42][CH:43]=1)#[N:46]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 1180364137-(Dimethoxymethyl)-3,4-dihydro-6-(1H-imidazol-1-yl)-1,8-naphthyridine-1(2h)-carboxylic acid phenyl ester2×HCID 1180369516-Amino-4-(2-methoxyethylamino)pyridine-3-carbonitrile2×

Product 1

HCID 118036788N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-65 °C

Procedure

A solution of LHMDS (1M in THF, 260 μL, 0.260 mmol) was added to suspension of phenyl 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 320, 49.7 mg, 0.126 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 25 mg, 0.130 mmol) in THF (1 ml) at −70° C. and the reaction mixture was stirred at −65° C. for 90 min. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate and water. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (2-3%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.79 min; ESI-MS 493.1 [M+H]+.

Workup

  1. customThe reaction mixture was quenched with saturated aqueous NH4Cl
  2. additiondiluted with ethyl acetate and water
  3. customLayers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by silica gel column chromatography
  10. washeluting with a gradient of MeOH (2-3%) in DCM
  11. additionProduct containing fractions
  12. customevaporated
  13. customdried

Sources & evidence

ORD record
ord-efba41be51f248e49525aed90bbb269e
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

Loading…