Oxalyl chloride → 2-{[6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

HRID 639345Notes

Reaction equation

HRID 639345 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:36])[C:32]([NH2:35])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.[N-]=C=O>ClCCl>[CH3:29][O:30][C:31](=[O:36])[C:32]([NH:35][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:15])([CH3:34])[CH3:33]

Participants

7

Reactant 5

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 105034IsocyanateHCID 4186341Methyl 2-amino-2-methylpropanoateHCID 675049236-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid

Product 1

HCID 248296362-{[6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a dichloromethane (1 ml) solution of 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (0.107 g, 0.358 mmol, 1.0 eq) was added oxalyl chloride (0.136 g, 1.07 mmol, 3.0 eq). The reaction was stirred at room temperature for 3 hours after which time the solvent was removed in vacuo. The residue was re-dissolved in dichloromethane (3 ml) and added portion-wise to a dichloromethane (1 ml) solution of aminoisobutyric acid methyl ester (0.066 g, 0.429 mmol, 1.2 eq). PS—N,N-diisopropylethylamine (0.31 g, 1.04 mmol, 3.0 eq) resin was added to the reaction and the mixture stirred overnight at room temperature. PS-isocyanate (0.15 g, 0.358 mmol, 1.0 eq) and PS-aminomethyl (0.15 g, 0.358 mmol, 1.0 eq) resin were added to the reaction and the mixture stirred for a further 12 hrs at room temperature. The reaction was filtered and resin washed successfully with dichloromethane (2×3 ml). The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1) to afford 2-{[6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester. Yield=0.030 g (21%). HPLC-MS=100%; 2.52 min (MW=400; M+1=401.2).

Workup

  1. customwas removed in vacuo
  2. dissolutionThe residue was re-dissolved in dichloromethane (3 ml)
  3. stirringthe mixture stirred overnight at room temperature
  4. stirringthe mixture stirred for a further 12 hrs at room temperature
  5. filtrationThe reaction was filtered
  6. washresin washed successfully with dichloromethane (2×3 ml)
  7. concentrationThe combined filtrates were concentrated in vacuo
  8. customthe residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1)

Sources & evidence

ORD record
ord-a78dbd1c303844d8821ecf1f09ea273e
Source dataset
uspto-grants-2010_04
Patent number
US07691863B2

Reaction notes

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