3,3-DIMETHYLGLUTARIMIDE

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: 8.8 g (22.1 mmol) of rac-cis-1-[4-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione hydrochloride were mixed well with 100 g of pyridine hydrochloride and stirred under an argon atmosphere in an oil bath for 4 hours at an oil bath temperature of 180°. After cooling the mixture was treated with ice-water, whereupon the brown solution was made alkaline with ammonium hydroxide solution and then extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel. The uniform eluates obtained in a thin-layer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The oil obtained crystallized after treatment with hexane. There were obtained 5.5 g (65%) of rac-cis-1-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione in the form of yellowish crystals of m.p. 131°-132°. After cooling the mixture extracted with methylene chloride The organic phase was washed with water dried over magnesium sulphate evaporated The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel The uniform eluates obtained in a thin-layer chromatogram evaporated The oil obtained crystallized after treatment with hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and 4,4-dimethylpiperidine-2,6-dione (54 mg), and the mixture was stirred at 80° C. overnight and then at 100° C. for one day. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (3.5 mg, yield 5%). at 100° C. for one day The reaction solution was cooled to room temperature the mixture was extracted with chloroform The chloroform layer was washed with water was then dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by thin layer chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and 4,4-dimethylpiperidine-2,6-dione (54 mg), and the mixture was stirred at 80° C. overnight and then at 100° C. for one day. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (3.5 mg, yield 5%). at 100° C. for one day The reaction solution was cooled to room temperature the mixture was extracted with chloroform The chloroform layer was washed with water was then dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by thin layer chromatography

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

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

Procedure: A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (20.0 g; 0.07 mole [prepared from 3,3-dimethylglutarimide using the method of Example 2]); piperazine (31.0 g; 0.36 mole); K2CO3 (29.8 g; 0.22 mole); and KI (0.1 g) was refluxed in 250 mL acetonitrile for 18 hr. The mixture was filtered, concentrated and the unreacted piperazine removed by vacuum sublimation. The residual material was distilled to yield 17.2 g (85%) product, b.p. 170°-178° C. at 0.01 mm. The mixture was filtered concentrated the unreacted piperazine removed by vacuum sublimation The residual material was distilled

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4,4-dimethylpiperidine-2,6-dione (2.0 g, 14.2 mmol) in acetone (50 mL) was added K2CO3 (3.92 g, 28.3 mmol) followed by (bromomethyl)benzene (1.85 mL, 15.6 mmol). The reaction mixture was heated at 50° C. for 4 h then cooled to room temperature and stirred overnight. The thick white precipitate present was removed via filtration, rinsing with acetone. The filtrate was concentrated and purified by SiO2 chromatography (10% to 50% EtOAc/hexanes) to afford 3.0 g (92%) of 1-benzyl-4,4-dimethylpiperidine-2,6-dione as a white solid. then cooled to room temperature The thick white precipitate present was removed via filtration rinsing with acetone The filtrate was concentrated purified by SiO2 chromatography (10% to 50% EtOAc/hexanes)

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

Procedure: A solution is prepared from 240 parts of methanol, 14 parts of 3,3-dimethylglutarimide, and 6.5 parts of potassium hydroxide. The solvent is evaporated to leave a residual syrup which is mixed with 95 parts of dimethylformamide, Then, a solution of 32 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate in 190 parts of dimethylformamide is added. The mixture becomes dark green-black immediately. It is then stirred and warmed at 90°-110° C. for about 1 hour before it is cooled and diluted slowly to a total volume of 100 parts with toluene. The precipitate which forms is removed by filtration and washed. The solvent is evaporated from the toluene-dimethylformamide filtrate under reduced pressure and the residue is dissolved in 80 parts of acetone, diluted with 280 parts of ether, mixed with charcoal, and filtered. The solvent is evaporated from the filtrate under reduced pressure and the residual oil is diluted with 140 parts of ether and made to crystallize. The precipitate which forms is separated by filtration and dried. The solid is then dissolved in an excess of warm acetone and treated with charcoal. The resulting filtrate is diluted with 35 parts of ether and crystallization is initiated. The precipitate which forms is separated by filtration, washed with ether and then with acetone. The resulting filtrate is then concentrated to a volume of 40 parts and cooled. The precipitate which forms is separated by filtration, washed, and then dried to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3,3-dimethylglutarimide melting at about 153°-154.5° C. The solvent is evaporated to leave a residual syrup which warmed at 90°-110° C. for about 1 hour before it is cooled The precipitate which forms is removed by filtration washed The solvent is evaporated from the toluene-dimethylformamide filtrate under reduced pressure the residue is dissolved in 80 parts of acetone diluted with 280 parts of ether mixed with charcoal filtered The solvent is evaporated from the filtrate under reduced pressure the residual oil is diluted with 140 parts of ether to crystallize The precipitate which forms is separated by filtration dried The solid is then dissolved in an excess of warm acetone treated with charcoal The resulting filtrate is diluted with 35 parts of ether and crystallization The precipitate which forms is separated by filtration washed with ether The resulting filtrate is then concentrated to a volume of 40 parts cooled The precipitate which forms is separated by filtration washed dried

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

Procedure: Reaction of 4-(4′-fluorophenyl)-phenyl methyl sulfone with ethyl 3,3-dimethylglutarimideacetate (prepared from 3,3-Dimethylglutarimide and ethyl bromoacetate (as in Example 120A) following the procedures of Example 126A, followed by reduction as described in Example 126B afforded the two title products which were chromatographically separated to give the desired products. afforded the two title products which were chromatographically separated

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

Procedure: The following are prepared analogously by displacement of A-3b with the anion derived from deprotonation of the amide or sulfonamide in parentheses: I-29 (pyrrolidine-2,5-dione), I-34 (N-phenyl-methanesulfonamide), I-16 ([1,2]thiazinane 1,1-dioxide), I-23 (piperidin-2-one), I-88 (4,4-dimethyl-piperidine-2,6-dione), I-89 (PhNHAc) and I-39 (3,3-diethyl-1H-pyridine-2,4-dione). The following are prepared analogously by displacement of A-3b with the anion

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

Procedure: 8.8 g (22.1 mmol) of rac-cis-1-[4-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione hydrochloride were mixed well with 100 g of pyridine hydrochloride and stirred under an argon atmosphere in an oil bath for 4 hours at an oil bath temperature of 180°. After cooling the mixture was treated with ice-water, whereupon the brown solution was made alkaline with ammonium hydroxide solution and then extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel. The uniform eluates obtained in a thin-layer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The oil obtained crystallized after treatment with hexane. There were obtained 5.5 g (65%) of rac-cis-1-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione in the form of yellowish crystals of m.p. 131°-132°. After cooling the mixture extracted with methylene chloride The organic phase was washed with water dried over magnesium sulphate evaporated The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel The uniform eluates obtained in a thin-layer chromatogram evaporated The oil obtained crystallized after treatment with hexane