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

HRID 1778049Notes

Reaction equation

HRID 1778049 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:18]([C:27]([O:29]C1C=CC=CC=1)=O)[CH2:17][CH2:16][CH2:15]2.[NH2:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:23][CH3:24])[O:25][CH3:26])[N:18]([C:27]([NH:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1)=[O:29])[CH2:17][CH2:16][CH2:15]2

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 118036767phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate2×HCID 1180369516-Amino-4-(2-methoxyethylamino)pyridine-3-carbonitrile2×

Product 1

HCID 1180366576-bromo-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 8028TetrahydrofuranSolvent

Conditions

Temperature
-25 °C

Procedure

LHMDS (1M in THF, 0.36 mL, 0.360 mmol) was added to a solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 148 mg, 0.345 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 70 mg, 0.346 mmol) in THF (3 ml) at −70° C. and stirred for 35 min. The reaction mixture was allowed to warm to −25° C., stirred for 5 min and cooled to −70° C. while stirring for 30 min. The reaction mixture was allowed to warm to −15° C., stirred for 10 min, cooled to −70° C. and quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and ethyl acetate, layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient ethyl acetate (90-100%) in heptane. Product fractions were combined, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 1.16 min, ESI-MS 505.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 5.68 (s, 1H), 5.26-5.21 (m, 1H), 4.06-4.00 (m, 2H), 3.62 (t, 2H), 3.51-3.44 (m, 8H), 3.40 (s, 3H), 2.84 (t, 2H), 2.03-1.96 (m, 2H).

Workup

  1. stirringstirred for 5 min
  2. temperaturecooled to −70° C.
  3. stirringwhile stirring for 30 min
  4. temperatureto warm to −15° C.
  5. stirringstirred for 10 min
  6. temperaturecooled to −70° C.
  7. customquenched with saturated aqueous NH4Cl
  8. additionThe reaction mixture was diluted with water and ethyl acetate, layers
  9. customwere separated
  10. extractionthe aqueous layer was extracted with ethyl acetate
  11. washThe combined organic layers were washed with water
  12. customdried
  13. filtrationfiltered
  14. customevaporated
  15. customThe crude product was purified by silica gel column chromatography
  16. washeluting with a gradient ethyl acetate (90-100%) in heptane
  17. customevaporated
  18. customdried

Sources & evidence

ORD record
ord-3648203ca4da4a48ad17ffd525b9f988
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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