pyrrolidine-2,4-dione

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

Procedure: A solution of 20 g (0.102 mol) of (S)-5-cyclohexylmethyl)-2,4-pyrrolidinedione in 800 ml of 10% methanol-ethyl acetate is exposed to hydrogen gas in the presence of platinum oxide (this solution is charcoaled and filtered before reduction). After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure. The remaining white solid is triturated with 100 ml of diethyl ether, filtered and washed with diethyl ether to afford 19.3 g of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone after recrystallization from ethyl acetate; mp 141°-143° C.; [α]D23 =-19.9° (c=0.98% methanol). filtered before reduction) the catalyst is filtered the filtrate concentrated under reduced pressure The remaining white solid is triturated with 100 ml of diethyl ether filtered washed with diethyl ether

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

Procedure: A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%). The reaction solution was cooled the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%)

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

Procedure: A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%). The reaction solution was cooled the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%)

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

Procedure: A solution of 20 g (0.102 mol) of (S)-5-cyclohexylmethyl)-2,4-pyrrolidinedione in 800 ml of 10% methanol-ethyl acetate is exposed to hydrogen gas in the presence of platinum oxide (this solution is charcoaled and filtered before reduction). After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure. The remaining white solid is triturated with 100 ml of diethyl ether, filtered and washed with diethyl ether to afford 19.3 g of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone after recrystallization from ethyl acetate; mp 141°-143° C.; [α]D23 =-19.9° (c=0.98% methanol). filtered before reduction) the catalyst is filtered the filtrate concentrated under reduced pressure The remaining white solid is triturated with 100 ml of diethyl ether filtered washed with diethyl ether

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

Procedure: A solution of 20 g (0.102 mol) of (S)-5-cyclohexylmethyl)-2,4-pyrrolidinedione in 800 ml of 10% methanol-ethyl acetate is exposed to hydrogen gas in the presence of platinum oxide (this solution is charcoaled and filtered before reduction). After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure. The remaining white solid is triturated with 100 ml of diethyl ether, filtered and washed with diethyl ether to afford 19.3 g of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone after recrystallization from ethyl acetate; mp 141°-143° C.; [α]D23 =-19.9° (c=0.98% methanol). filtered before reduction) the catalyst is filtered the filtrate concentrated under reduced pressure The remaining white solid is triturated with 100 ml of diethyl ether filtered washed with diethyl ether

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

Procedure: A solution of 20 g (0.102 mol) of (S)-5-cyclohexylmethyl)-2,4-pyrrolidinedione in 800 ml of 10% methanol-ethyl acetate is exposed to hydrogen gas in the presence of platinum oxide (this solution is charcoaled and filtered before reduction). After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure. The remaining white solid is triturated with 100 ml of diethyl ether, filtered and washed with diethyl ether to afford 19.3 g of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone after recrystallization from ethyl acetate; mp 141°-143° C.; [α]D23 =-19.9° (c=0.98% methanol). filtered before reduction) the catalyst is filtered the filtrate concentrated under reduced pressure The remaining white solid is triturated with 100 ml of diethyl ether filtered washed with diethyl ether

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

Procedure: A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%). The reaction solution was cooled the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%)

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

Procedure: A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%). The reaction solution was cooled the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%)

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

Procedure: Freshly prepared 1-propyl-2,4-dioxopyrrolidine was prepared by heating together 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.16 g) (U.S. Pat. No. 4,511,568, Example 52d describes the preparation of the methoxy compound; the ethoxy compound may be prepared in a similar manner), and acetonitrile (100 ml). After heating for 1.5 hours the volatiles were removed under aspirator vacuum and the residue consisting of crude 2,4-dioxopyrrolidine was taken up in toluene (4 ml). This solution was added dropwise to a refluxing mixture of 2-amino-3-methylbenzonitrile from Example 1(0.48 g) and p-toluenesulfonic acid (36 mg) in toluene (10 ml). The refluxing mixture was surmounted with a Dean-Stark trap to collect water evolved in the reaction as the azeotrope with toluene. Following the addition of 2,4-dioxopyrrolidine (about 60 minutes), the mixture was heated for an additional 2 hours, then excess toluene was removed by distillation. After cooling to ambient temperature, the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. After separation of the layers, the ethyl acetate layer was washed once with brine, dried (MgSO4) and concentrated to leave an orange gum. Chromatographing the material over silica gel using ethyl acetate as the eluent afforded the desired product (0.70 g, 75%) as a white solid; tlc, Rf =0.21, silica gel, ethyl acetate. After heating for 1.5 hours the volatiles were removed under aspirator vacuum This solution was added dropwise to a refluxing mixture of 2-amino-3-methylbenzonitrile from Example 1(0.48 g) and p-toluenesulfonic acid (36 mg) in toluene (10 ml) to collect water evolved in the reaction as the azeotrope with toluene the mixture was heated for an additional 2 hours excess toluene was removed by distillation the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 After separation of the layers the ethyl acetate layer was washed once with brine dried (MgSO4) concentrated to leave an orange gum

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

Procedure: A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%). The reaction solution was cooled the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%)

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

Procedure: A solution of 20 g (0.102 mol) of (S)-5-cyclohexylmethyl)-2,4-pyrrolidinedione in 800 ml of 10% methanol-ethyl acetate is exposed to hydrogen gas in the presence of platinum oxide (this solution is charcoaled and filtered before reduction). After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure. The remaining white solid is triturated with 100 ml of diethyl ether, filtered and washed with diethyl ether to afford 19.3 g of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone after recrystallization from ethyl acetate; mp 141°-143° C.; [α]D23 =-19.9° (c=0.98% methanol). filtered before reduction) the catalyst is filtered the filtrate concentrated under reduced pressure The remaining white solid is triturated with 100 ml of diethyl ether filtered washed with diethyl ether