HCID 178469223, compound → HCID 178470320, compound

HRID 1670678Notes

Reaction equation

HRID 1670678 reaction equation
[OH:1][C:2]1[CH:3]([CH3:14])[NH:4][C:5]([CH3:13])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1>C(Cl)Cl.CCOC(C)=O.CCCC(C)C.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][C:3]=1[CH3:14]

Participants

5

Reactant 1

HCID 178469223HCID 178469223, compound

Product 1

HCID 178470320HCID 178470320, compoundYield 72.6%

Reagents, catalysts & solvents 3

HCID 178418406HCID 178418406, compoundCatalyst2×HCID 6344DichloromethaneSolventHCID 21882781Isohexane ethyl acetateSolvent

Conditions

Temperature
35 °C

Procedure

A solution of 2M Hydrochloric acid in 1,4-dioxane (1177 mL, 4709.97 mmol) was added to Intermediate 1-6 (745 g, 2354.99 mmol) and stirred at room temperature for 15 minutes then warmed to 40° C. for a further 40 minutes. Pyridine (6500 mL) was then slowly added and then the reaction was heated to 80° C. for 2 hours in the presence of air. The reaction was then allowed to cool to ambient temperature and evaporated to dryness to afford a viscous oil. This was suspended in DCM (2.5 L) and washed water (1.5 L). The DCM was then dried over MgSO4, filtered and concentrated to afford an orange semi-solid, which was triturated with 1:1 EtOAc/iso-hexane (250 mL) to afford ethyl 6-hydroxy-3,5-dimethyl-1,4-dihydropyrazine-2-carboxylate (127 g, 27.1%) as a cream solid. The mother liquors were then purified by flash silica chromatography (gradient from 20% ethyl acetate/iso-hexane to 80% ethyl acetate/iso-hexane). Fractions containing the desired product were concentrated and the residue was triturated with a small volume of 1:1 EtOAc/iso-hexane to afford the title compound (9.00 g, 1.948%). Manganese dioxide (150 g) was added to a suspension of ethyl 6-hydroxy-3,5-dimethyl-4,5-dihydropyrazine-2-carboxylate (121 g, 610.44 mmol) in DCM (1.8 L) at ambient temperature giving rise to a 2° C. exotherm. The reaction was stirred for 10 minutes then warmed to 35° C. for 1 hour. The reaction was incomplete so an additional 115 g of Manganese dioxide was added and the reaction stirred for 1 hour at 35° C. then stirred to cool to ambient temperature. The reaction was filtered through a short bed of silica and washed through with 2 L of 1:1 EtOAc/iso-hexane and finally 2×2 L EtOAc. The fractions were then combined and reduce in-vacuo to give an orange solid, which was slurried in 300 mL of 1:1 EtOAc/iso-hexane, filtered and washed with iso-hexane to afford the title compound (87 g, 72.6%) as an orange solid.

Workup

  1. customThe mother liquors were then purified by flash silica chromatography (gradient from 20% ethyl acetate/iso-hexane to 80% ethyl acetate/iso-hexane)
  2. additionFractions containing the desired product
  3. concentrationwere concentrated
  4. customthe residue was triturated with a small volume of 1:1 EtOAc/iso-hexane
  5. customto afford the title compound (9.00 g, 1.948%)
  6. customgiving rise to a 2° C. exotherm
  7. additionwas added
  8. stirringthe reaction stirred for 1 hour at 35° C.
  9. stirringthen stirred
  10. temperatureto cool to ambient temperature
  11. filtrationThe reaction was filtered through a short bed of silica
  12. washwashed through with 2 L of 1:1 EtOAc/iso-hexane and finally 2×2 L EtOAc
  13. customto give an orange solid, which
  14. filtrationfiltered
  15. washwashed with iso-hexane

Sources & evidence

ORD record
ord-fc4c3ee3a335469fad35cb877ccba6d9
Source dataset
uspto-grants-2011_08
Patent number
US07994179B2

Reaction notes

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