Hexane → 3,6-Diethoxy-2,5-dihydropyrazine

HRID 2258284Notes

Reaction equation

HRID 2258284 reaction equation
C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13].[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32]Br)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32][C@@H:16]2[C:15]([O:14][CH2:12][CH3:13])=[N:20][CH2:19][C:18]([O:21][CH2:22][CH3:23])=[N:17]2)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44].[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13]

Participants

7

Reactant 4

HCID 8058HexaneHCID 111267023,6-Diethoxy-2,5-dihydropyrazineHCID 113258232-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzeneHCID 178418339Butyllithium

Product 2

HCID 111267023,6-Diethoxy-2,5-dihydropyrazineHCID 539179532(R)-{2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]3-methylbutyl}-3,6-diethoxy-2,5-dihydro-pyrazine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-40 °C

Procedure

1 6M n-butyllithium in hexane (788 ml, 1.26 mol) is added dropwise at -40° C. under an inert atmosphere over a period of 20 minutes to a solution of 3,6-diethoxy-2,5-dihydro-pyrazine (229.8 g, 1.35 mol) in tetrahydrofuran (3.0 liters). The batch is stirred for a further 15 minutes at -40° C. and then a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide (323.4 g, 0.90 mol) in tetrahydrofuran (1.0 liter) is added dropwise thereto over a period of 20 minutes. When the addition is complete, the temperature of the mixture is allowed to rise to -20° C. and the mixture is then stirred at that temperature over a period of 18 hours. The reaction mixture is concentrated and the residue is partitioned between ethyl acetate (1 liter) and water (1 liter). The organic phase is washed with 2×1 liter of water, and the aqueous phases are each back-extracted with 1 liter of ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution (1 liter) and dried over magnesium sulfate. After concentration, the residue is dried under a high vacuum over a period of 1 hour at 35° C. The crude title compound is obtained in admixture with a small amount of epimeric 2(R)-{2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]3-methylbutyl}-3,6-diethoxy-2,5-dihydro-pyrazine (approx. 95:5 diastereoisomeric mixture) and excess 3,6-diethoxy-2,5-dihydro-pyrazine in the form of a colourless oil (472 g): Rf (ethyl acetate/hexane 1:2)=0.20. The 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide used as starting material can be prepared, for example, as described below:

Workup

  1. waitover a period of 20 minutes
  2. additionWhen the addition
  3. customto rise to -20° C.
  4. stirringthe mixture is then stirred at that temperature over a period of 18 hours
  5. concentrationThe reaction mixture is concentrated
  6. customthe residue is partitioned between ethyl acetate (1 liter) and water (1 liter)
  7. washThe organic phase is washed with 2×1 liter of water
  8. extractioneach back-extracted with 1 liter of ethyl acetate
  9. washthe combined organic phases are washed with saturated sodium chloride solution (1 liter)
  10. dry with materialdried over magnesium sulfate
  11. concentrationAfter concentration
  12. customthe residue is dried under a high vacuum over a period of 1 hour at 35° C

Sources & evidence

ORD record
ord-81bfe6fa6f4c4ba0b90ada275b7f7b19
Source dataset
uspto-grants-1997_08
Patent number
US05659065

Reaction notes

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