1-butylpyrrole-2,5-dione

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 (0.1 mol) of 2,6-di-tert-butyl-phenol and 15.31 g (0.1 mol) of N-n-butylmaleimide in dimethyl sulfoxide. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene. The heptane extract is concentrated to 150 ml and the resultant solid collected by filtration. The crude product is recrystallized from cyclohexane to give 1.03 g (4%) of a white solid: mp 151°-153° C. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene The heptane extract is concentrated to 150 ml the resultant solid collected by filtration The crude product is recrystallized from cyclohexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 (0.1 mol) of 2,6-di-tert-butyl-phenol and 15.31 g (0.1 mol) of N-n-butylmaleimide in dimethyl sulfoxide. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene. The heptane extract is concentrated to 150 ml and the resultant solid collected by filtration. The crude product is recrystallized from cyclohexane to give 1.03 g (4%) of a white solid: mp 151°-153° C. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene The heptane extract is concentrated to 150 ml the resultant solid collected by filtration The crude product is recrystallized from cyclohexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium tert-butoxide prepared from 2.40 g (0.1 mol) of sodium hydride and 135 ml of tert-butyl alcohol is added dropwise a solution of 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol in 100 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature for 150 minutes and then to the resultant green solution is added dropwise over 120 minutes a solution of 15.31 g (0.1 mol.) of N-n-butylmaleimide in 50 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature overnight and is then mixed with 10 ml of glacial acetic acid. The reaction mixture is poured into 1.5 1 of water and the resultant mixture is extracted twice with chloroform. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash chromatography (3:1 heptane:toluene eluent) to give 4.25 g (12%) of a white solid: mp 109°-112° C.; The reaction mixture is stirred at room temperature overnight the resultant mixture is extracted twice with chloroform dried over anhydrous sodium sulfate The solvent is removed in vacuo the residue is purified by flash chromatography (3:1 heptane:toluene eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium tert-butoxide prepared from 2.40 g (0.1 mol) of sodium hydride and 135 ml of tert-butyl alcohol is added dropwise a solution of 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol in 100 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature for 150 minutes and then to the resultant green solution is added dropwise over 120 minutes a solution of 15.31 g (0.1 mol.) of N-n-butylmaleimide in 50 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature overnight and is then mixed with 10 ml of glacial acetic acid. The reaction mixture is poured into 1.5 1 of water and the resultant mixture is extracted twice with chloroform. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash chromatography (3:1 heptane:toluene eluent) to give 4.25 g (12%) of a white solid: mp 109°-112° C.; The reaction mixture is stirred at room temperature overnight the resultant mixture is extracted twice with chloroform dried over anhydrous sodium sulfate The solvent is removed in vacuo the residue is purified by flash chromatography (3:1 heptane:toluene eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 (0.1 mol) of 2,6-di-tert-butyl-phenol and 15.31 g (0.1 mol) of N-n-butylmaleimide in dimethyl sulfoxide. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene. The heptane extract is concentrated to 150 ml and the resultant solid collected by filtration. The crude product is recrystallized from cyclohexane to give 1.03 g (4%) of a white solid: mp 151°-153° C. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene The heptane extract is concentrated to 150 ml the resultant solid collected by filtration The crude product is recrystallized from cyclohexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium tert-butoxide prepared from 2.40 g (0.1 mol) of sodium hydride and 135 ml of tert-butyl alcohol is added dropwise a solution of 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol in 100 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature for 150 minutes and then to the resultant green solution is added dropwise over 120 minutes a solution of 15.31 g (0.1 mol.) of N-n-butylmaleimide in 50 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature overnight and is then mixed with 10 ml of glacial acetic acid. The reaction mixture is poured into 1.5 1 of water and the resultant mixture is extracted twice with chloroform. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash chromatography (3:1 heptane:toluene eluent) to give 4.25 g (12%) of a white solid: mp 109°-112° C.; The reaction mixture is stirred at room temperature overnight the resultant mixture is extracted twice with chloroform dried over anhydrous sodium sulfate The solvent is removed in vacuo the residue is purified by flash chromatography (3:1 heptane:toluene eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-proline (20 mmol), 4-nitrobenzaldehyde (20 mmol) and N-butylmaleimide (20 mmol) was heated to 80° C. in DMF (20 ml) for 24 hours. The solvent was removed in a high vacuum and the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine). (3aRS, 4SR,8aRS,8bSR)-2-Butyl-4-(4-nitro-phenyl)-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained in 32% yield as a yellow solid (Rf =0.35). This product in 50 ml of ethanol was treated with 200 mg of 10% palladium on charcoal and reduced under hydrogen within 8 hours. After filtration of the catalyst and removal of the solvent in a vacuum (3aRS,4SR,8aRS,8bSR)-4-(4-amino-phenyl)-2-butyl-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained as a pale yellow oil (Rf =0.23). 120 mg of this crude product were treated with 80 mg of 3,5-dimethyl-pyrazolyl-1-carboximidamidinium nitrate in 20 ml of DMF and heated at 80° C. for 48 hours. After removing the solvent in a vacuum the material remaining was separated on a RP-18 chromatography column with a water/methanol gradient. (3aRS,4SR,8aRS, 8bSR)-N-[4-(2-Butyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-phenyl]-guanidinium nitrate was obtained in 12% yield as a pale yellow oil. ISP-MS: 483.4 ([M+H]+, 100). The solvent was removed in a high vacuum the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-proline (20 mmol), 4-nitrobenzaldehyde (20 mmol) and N-butylmaleimide (20 mmol) was heated to 80° C. in DMF (20 ml) for 24 hours. The solvent was removed in a high vacuum and the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine). (3aRS, 4SR,8aRS,8bSR)-2-Butyl-4-(4-nitro-phenyl)-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained in 32% yield as a yellow solid (Rf =0.35). This product in 50 ml of ethanol was treated with 200 mg of 10% palladium on charcoal and reduced under hydrogen within 8 hours. After filtration of the catalyst and removal of the solvent in a vacuum (3aRS,4SR,8aRS,8bSR)-4-(4-amino-phenyl)-2-butyl-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained as a pale yellow oil (Rf =0.23). 120 mg of this crude product were treated with 80 mg of 3,5-dimethyl-pyrazolyl-1-carboximidamidinium nitrate in 20 ml of DMF and heated at 80° C. for 48 hours. After removing the solvent in a vacuum the material remaining was separated on a RP-18 chromatography column with a water/methanol gradient. (3aRS,4SR,8aRS, 8bSR)-N-[4-(2-Butyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-phenyl]-guanidinium nitrate was obtained in 12% yield as a pale yellow oil. ISP-MS: 483.4 ([M+H]+, 100). The solvent was removed in a high vacuum the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-proline (20 mmol), 4-nitrobenzaldehyde (20 mmol) and N-butylmaleimide (20 mmol) was heated to 80° C. in DMF (20 ml) for 24 hours. The solvent was removed in a high vacuum and the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine). (3aRS, 4SR,8aRS,8bSR)-2-Butyl-4-(4-nitro-phenyl)-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained in 32% yield as a yellow solid (Rf =0.35). This product in 50 ml of ethanol was treated with 200 mg of 10% palladium on charcoal and reduced under hydrogen within 8 hours. After filtration of the catalyst and removal of the solvent in a vacuum (3aRS,4SR,8aRS,8bSR)-4-(4-amino-phenyl)-2-butyl-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained as a pale yellow oil (Rf =0.23). 120 mg of this crude product were treated with 80 mg of 3,5-dimethyl-pyrazolyl-1-carboximidamidinium nitrate in 20 ml of DMF and heated at 80° C. for 48 hours. After removing the solvent in a vacuum the material remaining was separated on a RP-18 chromatography column with a water/methanol gradient. (3aRS,4SR,8aRS, 8bSR)-N-[4-(2-Butyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-phenyl]-guanidinium nitrate was obtained in 12% yield as a pale yellow oil. ISP-MS: 483.4 ([M+H]+, 100). The solvent was removed in a high vacuum the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.B)c) (3aRS,4RS,8aSR,8bSR)-4-(2-Butyl-decahydro-1,3-dioxo-pyrrolo[3,4-a]pyrrolizin-4-yl)-benzonitrile was prepared analogously to Example 4.B)g) from 4-cyano-benzaldehyde, L-proline and N-butylmaleimide. Yellow oil. 1 H-NMR (DMSO-D6): 7.74 (d, ArH); 7.49 (d, ArH); 4.22 (d, 4-H).