Acetic Acid → HCID 69624834, compound

HRID 1386914Notes

Reaction equation

HRID 1386914 reaction equation
[CH3:1][O:2][C:3]1[C@@H:8]([CH:9]([CH3:11])[CH3:10])[N:7]=[C:6]([O:12][CH3:13])[CH2:5][N:4]=1.[Li]CCCC.[CH3:19][O:20][C:21]1[CH:32]=[CH:31][C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C(O)(=O)C>C1COCC1.CCOCC>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C@@H:25]([C@H:5]1[C:6]([O:12][CH3:13])=[N:7][C@H:8]([CH:9]([CH3:11])[CH3:10])[C:3]([O:2][CH3:1])=[N:4]1)[C:24]1[CH:31]=[CH:32][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 641297(E)-Methyl 3-(4-methoxyphenyl)acrylateHCID 736066(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazineHCID 178418339Butyllithium

Product 1

HCID 69624834HCID 69624834, compoundYield 81.3%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

To a solution of (R)-2,5-dimethoxy-3-isopropyl-3,6-dihydropyrazine (18.4 g, 100 mmol) in 250 mL of dry THF at −70° C. (internal temperature) was added dropwise a solution of n-BuLi (1.6 M in hexane, 63 mL, 100 mmol) over 3 hours so as to maintain the internal temperature below −70° C. After addition, the solution was stirred at −70° C. for 40 min. To the solution was then added 90 mL of a THF solution of methyl trans-4-methoxycinnamate (21.2 g, 110 mmol) over 1 hour. The resulting solution was stirred at −70° C. for additional 4 hours. The reaction was quenched by the addition of acetic acid (6.1 mL, 100 mmol) at −70° C. and the resulting suspension was warmed to room temperature to give a yellow solution. The solution was diluted with ether to 1000 mL and the organic layer was washed with water (3×80 mL) and brine (3×80 mL) and dried over MgSO4. After removal of the solvent, the residue (44.3 g) was purified by HPLC on silica gel, eluting with ethyl acetate/hexane (1:5.5) to give 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanoic acid methyl ester (30.6 g, 81.3 mmol, 81.3%). TLC: Rf=0.3, ethyl acetate/hexane (1/5). HRMS, obs. 377.2071, calc. 377.2076. Anal. cacld for C20H26N2O5: C, 64.16; H, 7.00; N, 7.48. Found: C, 64.05; H, 7.28; N, 7.37.

Workup

  1. temperatureto maintain the internal temperature below −70° C
  2. additionAfter addition
  3. stirringThe resulting solution was stirred at −70° C. for additional 4 hours
  4. temperaturethe resulting suspension was warmed to room temperature
  5. customto give a yellow solution
  6. washthe organic layer was washed with water (3×80 mL) and brine (3×80 mL)
  7. dry with materialdried over MgSO4
  8. customAfter removal of the solvent
  9. customthe residue (44.3 g) was purified by HPLC on silica gel
  10. washeluting with ethyl acetate/hexane (1:5.5)

Sources & evidence

ORD record
ord-4fef29c3e1a64adea95dc4f62cb044bd
Source dataset
uspto-grants-2001_07
Patent number
US06265572B1

Reaction notes

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