Sodium hydride → 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

HRID 716378Notes

Reaction equation

HRID 716378 reaction equation
[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH:16]=[CH:17][CH:18]=[C:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CO.O>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH:16]=[CH:17][CH:18]=[C:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1

Participants

7

Reactant 3

HCID 24758Sodium hydrideHCID 21226445Aluminium lithium hydrideHCID 58324498Methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate

Product 1

HCID 583244823-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-oneYield 48.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (2.0 g, 8.22 mmol) was suspended in THF (Volume: 27.4 ml) under nitrogen atmosphere and cooled to 0° C. Sodium hydride (0.658 g, 16.45 mmol) was added in several portions over 7 min. The reaction mixture was stirred at 0° C. for 10 min, at room temperature for 20 min and cooled to below −50° C. Lithium aluminum hydride (7.40 ml, 14.80 mmol) was added over the period of 5 min and the reaction was kept at a temperature between −30 and −20° C. for 1 h. The mixture was cooled to below −40° C. and MeOH (6 mL) was added. Water (5 mL) was added and then more MeOH (50 mL). The reaction mixture was stirred at rt for 10 min. The resulting precipitate was filtered, suspended in MeOH (100 mL) and filtered again. The solid was suspended with heating overnight in MeOH:DCM (1:1, 200 mL) and filtered hot. This solid was dissolved in MeOH/DCM (100 mL, 3:1) and loaded onto silica gel (12 g) then purified by flash column chromatography on silica gel (220 g SiO2, gradient DCM:MeOH 100:1-85:15) to give 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (854 mg, 3.97 mmol, 48.3% yield) as a white solid. 1H NMR (DMSO-d6) δ 11.36 (br. s., 1H), 8.14 (d, J=1.8 Hz, 1H), 8.10 (dd, J=2.8, 1.5 Hz, 1H), 7.61-7.66 (m, 1H), 7.09 (dd, J=3.8, 1.5 Hz, 1H), 6.71 (dd, J=3.7, 2.9 Hz, 1H), 5.42 (br. s., 1H), 4.53-4.64 (m, 2H). [M+H] calc'd for C11H9N3O2, 216. found, 216.

Workup

  1. temperaturecooled to below −50° C
  2. waitthe reaction was kept at a temperature between −30 and −20° C. for 1 h
  3. temperatureThe mixture was cooled to below −40° C.
  4. stirringThe reaction mixture was stirred at rt for 10 min
  5. filtrationThe resulting precipitate was filtered
  6. filtrationfiltered again
  7. temperaturewith heating overnight in MeOH:DCM (1:1, 200 mL)
  8. filtrationfiltered hot
  9. dissolutionThis solid was dissolved in MeOH/DCM (100 mL, 3:1)
  10. customthen purified by flash column chromatography on silica gel (220 g SiO2, gradient DCM:MeOH 100:1-85:15)

Sources & evidence

ORD record
ord-42a6d8de4a2b4bda8fe5d6aaf6775009
Source dataset
uspto-grants-2015_11
Patent number
US09187497B2

Reaction notes

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