Diphenyl carbonate → 7-(Dimethoxymethyl)-3,4-dihydro-6-(1H-imidazol-1-yl)-1,8-naphthyridine-1(2h)-carboxylic acid phenyl ester

HRID 1778054Notes

Reaction equation

HRID 1778054 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:29][CH3:30])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][NH:21]2)=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[C:31]1([O:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:30][O:29][CH:13]([O:12][CH3:11])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:38]([O:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1

Participants

5

Reactant 3

HCID 7597Diphenyl carbonateHCID 2733832Lithium Hexamethyldisilazide2×HCID 1180367227-(Dimethoxymethyl)-1,2,3,4-tetrahydro-6-(1H-imidazol-1-yl)-1,8-naphthyridine2×

Product 1

HCID 1180364137-(Dimethoxymethyl)-3,4-dihydro-6-(1H-imidazol-1-yl)-1,8-naphthyridine-1(2h)-carboxylic acid phenyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-25 °C

Procedure

A solution of LHMDS in THF (1M, 500 μL, 0.500 mmol) was added drop wise to a solution of 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 321, 130 mg, 0.474 mmol) and diphenylcarbonate (105 mg, 0.490 mmol) in THF (2.2 ml) at −25° C. The reaction mixture was stirred for 85 minutes at −25° C., then warmed to room temperature and stirred for 45 min, placed in a fridge and stored over the weekend at 4° C. The reaction mixture was then cooled to −65° C. and further LHMDS (500 μl, 0.500 mmol) was added and it was allowed to warm to −45° C. to −35° C. and stirred for 80 min. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and water. Phases were separated and the water phase 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 (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.78 min; ESI-MS 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.44-7.34 (m, 3H), 7.25-7.15 (m, 5H), 5.11 (s, 1H), 4.04-3.96 (m, 2H), 3.34 (s, 6H), 2.90 (t, 2H), 2.15-2.04 (m, 2H).

Workup

  1. temperaturewarmed to room temperature
  2. stirringstirred for 45 min
  3. customstored over the weekend at 4° C
  4. temperatureThe reaction mixture was then cooled to −65° C.
  5. temperatureto warm to −45° C. to −35° C.
  6. stirringstirred for 80 min
  7. customThe reaction mixture was quenched with saturated aqueous NH4Cl
  8. additiondiluted with ethyl acetate and water
  9. customPhases were separated
  10. extractionthe water phase was extracted with ethyl acetate
  11. washThe combined organic layers were washed with brine
  12. customdried
  13. filtrationfiltered
  14. customevaporated
  15. customThe crude product was purified by silica gel column chromatography
  16. washeluting with a gradient of MeOH (1-5%) in DCM
  17. customevaporated
  18. customdried

Sources & evidence

ORD record
ord-01e3f9770e7a45148cb7fcf51ab5a9ba
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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