5,5-dimethylpyrrolidine-2,4-dione

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%. The mixture is then left to reach room temperature over the course of approximately one hour extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution Drying concentration by evaporation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%. The mixture is then left to reach room temperature over the course of approximately one hour extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution Drying concentration by evaporation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, in a heat-dried apparatus, 7.4 mg of Pd(OAc), 22 mg of di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine and 0.78 g of K3PO4 in 4.8 ml of air-free dioxane are introduced as initial charge. 203 mg of 5,5-dimethylpyrrolidine-2,4-dione and 659 mg of 3-(4-chlorophenyl)-6-methylbromobenzene are added and the mixture is stirred for 16 hours under reflux. The mixture is 10 then left to cool to room temperature, diluted with ca. 6 ml of methanol and filtered, and the filter residue is after-washed with ca. 3 ml of MeOH. The combined filtrates are concentrated by evaporation on a rotary evaporator. The residue is taken up in ca. 6 ml of water and rendered weakly acidic using 1 N hydrochloric acid. The precipitated solid is filtered off with suction and washed with ca. 3 ml of water. It is then washed from the filter with acetone and the filtrate is concentrated by evaporation. This gives 0.597 g of solid. Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6% according to HPLC/MS. as initial charge under reflux then left filtered the filter residue is after-washed with ca. 3 ml of MeOH The combined filtrates are concentrated by evaporation on a rotary evaporator The precipitated solid is filtered off with suction washed with ca. 3 ml of water It is then washed from the filter with acetone the filtrate is concentrated by evaporation Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6%

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethylpyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethylpyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, in a heat-dried apparatus, 1.0 g of solid sodium hydroxide (in the form of so-called “Micropills”) and 15 ml of water- and air-free N-methylpyrrolidone (NMP) are introduced as initial charge. With stirring, 1.907 g of 5,5-dimethylpyrrolidine-2,4-dione are then added and the mixture is stirred for 20 minutes at room temperature. 1.71 g of 3-bromotoluene are then added and the reaction mixture is heated to 125° C. At this temperature, 0.328 g of triphenylphosphine and 89 mg of PdCl2 are then added. The mixture is stirred for 4 hours at 125° C., left to cool to room temperature, stirred into 20 ml of ice-water and adjusted to pH 2 using dilute hydrochloric acid. 20 ml of methylene chloride are added, the mixture is stirred, the phases are separated and the aqueous phase is extracted by shaking two more times with 10 ml of methylene chloride in each case. The combined organic phases are dried and then concentrated on a rotary evaporator. This gives 1.82 g of target product (corresponding to a yield of 84% of theory). as initial charge the mixture is stirred for 20 minutes at room temperature The mixture is stirred for 4 hours at 125° C. left to cool to room temperature the mixture is stirred the phases are separated the aqueous phase is extracted by shaking two more times with 10 ml of methylene chloride in each case The combined organic phases are dried concentrated on a rotary evaporator

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%. The mixture is then left to reach room temperature over the course of approximately one hour extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution Drying concentration by evaporation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%. The mixture is then left to reach room temperature over the course of approximately one hour extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution Drying concentration by evaporation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, in a heat-dried apparatus, 7.4 mg of Pd(OAc)2, 22 mg of di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine and 0.78 g of K3PO4 in 4.8 ml of air-free dioxane are introduced as initial charge. 203 mg of 5,5-dimethylpyrrolidine-2,4-dione and 659 mg of 3-(4-chlorophenyl)-6-methylbromobenzene are added and the mixture is stirred for 16 hours under reflux. The mixture is then left to cool to room temperature, diluted with ca. 6 ml of methanol and filtered, and the filter residue is after-washed with ca. 3 ml of MeOH. The combined filtrates are concentrated by evaporation on a rotary evaporator. The residue is taken up in ca. 6 ml of water and rendered weakly acidic using 1 N hydrochloric acid. The precipitated solid is filtered off with suction and washed with ca. 3 ml of water. It is then washed from the filter with acetone and the filtrate is concentrated by evaporation. This gives 0.597 g of solid. Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6% according to HPLC/MS. as initial charge under reflux The mixture is then left filtered the filter residue is after-washed with ca. 3 ml of MeOH The combined filtrates are concentrated by evaporation on a rotary evaporator The precipitated solid is filtered off with suction washed with ca. 3 ml of water It is then washed from the filter with acetone the filtrate is concentrated by evaporation Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6%

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethyl-pyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethyl-pyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, in a heat-dried apparatus, 1.0 g of solid sodium hydroxide (in the form of so-called “Micropills”) and 15 ml of water- and air-free N-methylpyrrolidone (NMP) are introduced as initial charge. With stirring, 1.907 g of 5,5-dimethylpyrrolidine-2,4-dione are then added and the mixture is stirred for 20 minutes at room temperature. 1.71 g of 3-bromotoluene are then added and the reaction mixture is heated to 125° C. At this temperature, 0.328 g of triphenylphosphine and 89 mg of PdCl2 are then added. The mixture is stirred for 4 hours at 125° C., left to cool to room temperature, stirred into 20 ml of ice-water and adjusted to pH 2 using dilute hydrochloric acid. 20 ml of methylene chloride are added, the mixture is stirred, the phases are separated and the aqueous phase is extracted by shaking two more times with 10 ml of methylene chloride in each case. The combined organic phases are dried and then concentrated on a rotary evaporator. This gives 1.82 g of target product (corresponding to a yield of 84% of theory). as initial charge the mixture is stirred for 20 minutes at room temperature The mixture is stirred for 4 hours at 125° C. left to cool to room temperature the mixture is stirred the phases are separated the aqueous phase is extracted by shaking two more times with 10 ml of methylene chloride in each case The combined organic phases are dried concentrated on a rotary evaporator