4-Methylanisole → 7-Cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid 2-tert-butyl ester

HRID 857897Notes

Reaction equation

HRID 857897 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1C=CC([O:27][CH3:28])=CC=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:43]([C:46]#[N:47])[C:44](I)=[C:38]2[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[C]=[O:55].[OH-].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)C>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:43]([C:46]#[N:47])[C:44]([C:28]([OH:27])=[O:55])=[C:38]2[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]

Participants

9

Reactant 5

HCID 77314-MethylanisoleHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 688913777-cyano-8-iodo-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid 2-tert-butyl esterHCID 178418416HCID 178418416, compound

Product 1

HCID 688892417-Cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid 2-tert-butyl ester

Reagents, catalysts & solvents 3

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
80 °C

Procedure

A mechanically stirred mixture of bis(triphenylphosphine)palladium (II) chloride (425 mg), triphenylphosphine (425 mg), 4-methylanisole (125 mL) and poly(ethylene glycol) (Average Mn ca 4600, 850 g) was treated with 7-cyano-8-iodo-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid 2-tert-butyl ester (7.5 g, Reference Example 20), then placed under a blanket of carbon monoxide. The reaction mixture was heated to 80° C. and then treated with a solution of sodium hydroxide (10.6 g) in water (125 mL) dropwise over 30 minutes whilst maintaining the temperature at 80° C. After vigorously stirring at 80° C. for a further 6 hours the reaction mixture was allowed to cool to room temperature and then left to stand overnight. The reaction mixture was treated with diethyl ether, the layers separated and the basic aqueous fraction filtered through celite. The filtrate was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (4.40 g) as an off white solid, m.p. 212–215° C. 1H NMR [(CD3)2SO]: δ 7.62–7.50 (m, 5H), 4.83 (s, 2H), 3.95 (t, 2H), 3.68 (t, 2H) and 1.45 (s, 9H).

Workup

  1. temperaturewhilst maintaining the temperature at 80° C
  2. temperatureto cool to room temperature
  3. waitleft
  4. waitto stand overnight
  5. customthe layers separated
  6. filtrationthe basic aqueous fraction filtered through celite
  7. extractionextracted with ethyl acetate
  8. extractionThe organic extract
  9. dry with materialwas dried over magnesium sulfate
  10. customevaporated
  11. customThe residue was triturated with diethyl ether

Sources & evidence

ORD record
ord-e9a9b1e3089c41219117b0a3d4472287
Source dataset
uspto-grants-2006_12
Patent number
US07148215B2

Reaction notes

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