Acetic Acid → {4-[3'-(4-Fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-ylmethyl]-5-methyl-pyrazol-1-yl}-acetic acid ethyl ester

HRID 220540Notes

Reaction equation

HRID 220540 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][N:25]1[C:29]([CH3:30])=[CH:28][CH:27]=[N:26]1)[CH3:21].[C:32](O)(=O)C.C=O>C(O)C>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][N:25]1[C:29]([CH3:30])=[C:28]([CH2:32][N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:19][CH2:18]2)[CH:27]=[N:26]1)[CH3:21]

Participants

6

Reactant 4

HCID 176Acetic Acid2×HCID 712Formaldehyde2×HCID 4039589(5-Methyl-pyrazol-1-yl)-acetic acid ethyl esterHCID 673669592-(4-Fluorophenyl)-3-(piperazin-1-yl)pyrazine

Product 1

HCID 68594551{4-[3'-(4-Fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-ylmethyl]-5-methyl-pyrazol-1-yl}-acetic acid ethyl esterYield 16.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
120 °C

Procedure

Combine 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.500 g, 1.94 mmol) with (5-methyl-pyrazol-1-yl)-acetic acid ethyl ester (0.416 g, 2.48 mmol) in ethanol (8 mL). Add acetic acid (801 μL, 14 mmol) and a 37% aqueous solution of formaldehyde (401 μL). Heat in microwave at 120° C. for 5 hr. Add acetic acid (801 μL, 14 mmol) and a 37% aqueous solution of formaldehyde (401 μL). Heat in microwave at 120° C. for 3 hr. Concentrate, add ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 methanol:ethyl acetate) to give {4-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-ylmethyl]-5-methyl-pyrazol-1-yl}-acetic acid ethyl ester (139 mg, 16%). MS (ES): m/z=439 [M+H]+.

Workup

  1. temperatureHeat in microwave at 120° C. for 3 hr
  2. concentrationConcentrate
  3. additionadd ethyl acetate and saturated aqueous sodium bicarbonate solution
  4. dry with materialExtract aqueous layer twice with ethyl acetate, dry (magnesium sulfate)
  5. filtrationfilter
  6. concentrationconcentrate
  7. custompurify (silica gel chromatography
  8. washeluting with 50:50 to 100:0 ethyl acetate

Sources & evidence

ORD record
ord-16c7a4812e794b56a0267696e02f7e97
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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