2,2,6,6-tetramethyl-1,3-dihydropyridine

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (1.57 mol/L solution in tetrahydrofuran, 2.0 mL) in tetrahydrofuran (23 mL) was added 2,2,6,6-tetramethylpyridine (0.57 mL) at −78° C. The temperature was raised to 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was cooled to −78° C., 2-chloropyrazine (0.22 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4-methoxybezaldehyde (0.35 mL), and the mixture was stirred for additionally 1.5 hours. To the reaction-mixture were added concentrated hydrochloric acid (1.2 mL), ethanol (1.2 mL) and tetrahydrofuran (4.8 mL), and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) to give 2-chloropyrazin-3-yl 4-methoxyphenyl methanol (0.31 g). To a suspension of the obtained 2-chloropyrazin-3-yl 4-methoxyphenyl methanol(0.13 g), sodium hydroxide (0.12 g) and potassium carbonate (0.072 g) in toluene (1 mL) were added benzyl alcohol (0.080 mL) and tris-[2-(2-methoxyethoxy)ethyl]amine (0.017 mL), and the mixture was stirred for 2,hours at 120° C. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give 2-benzyloxy-3-(4-methoxybenzyl)pyrazine (0.026 g). To a solution of the obtained 2-benzyloxy-3-(4-methoxybenzyl)-pyrazine (0.025 g) in ethanol (1 mL) was added 10% palladium carbon powder (0.0099 g), and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/3) to give 3-(4-methoxybenzyl)-1H-pyridin-2-one (0.0055 g). After the reaction mixture was cooled to −78° C. the mixture was stirred for 1 hour at the same temperature the mixture was stirred for additionally 1.5 hours the temperature was raised to room temperature the mixture was concentrated under reduced pressure After the residue was extracted with dichloromethane the organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.88 mmol butyllium in hexane (4.3 ml; 1.6M) were added dropwise at -78° C. to a solution of 1.2 ml (6.88 mmol) of 2,2,6,6-tetramethylpyridine in 14 ml of dry tetrahydrofuran. The mixture was then stirred for 30 minutes at 0° C., cooled to -70° C., and added dropwise to a solution of 1-4 g (6.23 mmol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazol-1-one in 42 ml of dry tetrahydrofuran. The mixture was stirred for 90 minutes under nitrogen at -70° C. A solution of 2.4 g (6.88 mmol) of 1-triphenylmethyl-5-methyl-1H-imidazole-4-carboxaldehyde in 14 ml of dry tetrahydrofuran was then added dropwise to the reaction mixture at -70° C., and the mixture was stirred for 2 hours at -10° C. The mixture was then cooled to -70° C. and 16.8 ml of acetic acid was added dropwise. After the temperature had raised to -10° C., 8.1 g of p-toluenesulfonic acid hydrate were added. This mixture was boiled for 18 hours and evaporated in vacuum. The residue was shaken with methylene chloride and with 2N sodium hydroxide. The organic layer was separated, washed with brine, dried and evaporated. The residue was chromatographed over silicagel using methylene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 1.2 g (60%) of 2,3,3a,4,5,6-hexahydro-2-[(5-methyl-1H-imidazol-4-yl)-methylene]-1H- pyrido[3,2,1jk]carbazol-1-one were obtained. This product dissolved in 100 ml of ethanol and hydrogenated at room temperature at 1 atmosphere with palladium on carbon as a catalyst. The catalyst was removed by filtration after disappearance of the starting material, the filtrate was evaporated in vacuum, and the residue was purified by flash chromatography over silicagel using methyene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 0.49 g of the desired compound were obtained after evaporating the desired fractions. cooled to -70° C. The mixture was stirred for 90 minutes under nitrogen at -70° C the mixture was stirred for 2 hours at -10° C The mixture was then cooled to -70° C. After the temperature had raised to -10° C. This mixture was boiled for 18 hours evaporated in vacuum The residue was shaken with methylene chloride and with 2N sodium hydroxide The organic layer was separated washed with brine dried evaporated The residue was chromatographed

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

Procedure: A solution of N-BOC-4(S)-hydroxy-2-methyl-(L)-proline, methyl ester (Step A, 2.2 g, 8.5 mmol), tert-butyldimethylsilyl chloride (1.8 g, 12 mmol), and imidazole (1.1 g, 17 mmol) in 40 mL of anhydrous DMF was stirred at rt overnight. The reaction mixture was partitioned between Et2O and water, and the product was extracted with Et2O (2×200 mL). The combined extracts were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (15 mL), and was added with 2,6-dimethyllutidine (3.0 mL, 26 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.9 mL, 17 mmol) at rt. After stirring for 2 h, the reaction mixture was cooled by an ice-water bath, and was added potassium fluoride (1.4 g, 24 mmol) in 20 mL of water. After stirring at 0° C. for 2 h, the reaction mixture was partitioned between ether and water. The product was extracted with Et2O (3×50 mL), and the organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was azeotroped with toluene and was dissolved in CH2Cl2 (10 mL) and THF (10 mL). The solution was cooled with an ice water bath, and was added DIPEA (4.4 mL, 25 mmol), 4-DMAP (0.10 g, 0.85 mmol) and 3-chlorobenzenesulfonyl chloride (2.7 g, 12 mmol). The reaction was allowed to warm to rt overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tert-butyldimethylsilyl ether of the title compound, which was used immediately. Thus, to a solution-of the silyl ether in acetonitrile (40 mL) at 0° C. was added aqueous HF (48%, 4 mL), and the reaction was allowed to warm up to rt overnight. The reaction mixture was partitioned between 5 N aqueous NaOH, brine and EtOAc, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound (3.0 g, 96% from the product of Step A). The reaction mixture was partitioned between Et2O and water the product was extracted with Et2O (2×200 mL) The combined extracts were dried with anhydrous MgSO4 filtered concentrated in vacuo The residue was dissolved in anhydrous CH2Cl2 (15 mL) the reaction mixture was cooled by an ice-water bath After stirring at 0° C. for 2 h the reaction mixture was partitioned between ether and water The product was extracted with Et2O (3×50 mL) the organic extracts were dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was azeotroped with toluene was dissolved in CH2Cl2 (10 mL) The solution was cooled with an ice water bath The reaction mixture was concentrated to dryness the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc

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

Procedure: A solution of N-BOC-4(S)-hydroxy-2-methyl-(L)-proline, methyl ester (Step A, 2.2 g, 8.5 mmol), tert-butyldimethylsilyl chloride (1.8 g, 12 mmol), and imidazole (1.1 g, 17 mmol) in 40 mL of anhydrous DMF was stirred at rt overnight. The reaction mixture was partitioned between Et2O and water, and the product was extracted with Et2O (2×200 mL). The combined extracts were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (15 mL), and was added with 2,6-dimethyllutidine (3.0 mL, 26 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.9 mL, 17 mmol) at rt. After stirring for 2 h, the reaction mixture was cooled by an ice-water bath, and was added potassium fluoride (1.4 g, 24 mmol) in 20 mL of water. After stirring at 0° C. for 2 h, the reaction mixture was partitioned between ether and water. The product was extracted with Et2O (3×50 mL), and the organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was azeotroped with toluene and was dissolved in CH2Cl2 (10 mL) and THF (10 mL). The solution was cooled with an ice water bath, and was added DIPEA (4.4 mL, 25 mmol), 4-DMAP (0.10 g, 0.85 mmol) and 3-chlorobenzenesulfonyl chloride (2.7 g, 12 mmol). The reaction was allowed to warm to rt overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tert-butyldimethylsilyl ether of the title compound, which was used immediately. Thus, to a solution-of the silyl ether in acetonitrile (40 mL) at 0° C. was added aqueous HF (48%, 4 mL), and the reaction was allowed to warm up to rt overnight. The reaction mixture was partitioned between 5 N aqueous NaOH, brine and EtOAc, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound (3.0 g, 96% from the product of Step A). The reaction mixture was partitioned between Et2O and water the product was extracted with Et2O (2×200 mL) The combined extracts were dried with anhydrous MgSO4 filtered concentrated in vacuo The residue was dissolved in anhydrous CH2Cl2 (15 mL) the reaction mixture was cooled by an ice-water bath After stirring at 0° C. for 2 h the reaction mixture was partitioned between ether and water The product was extracted with Et2O (3×50 mL) the organic extracts were dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was azeotroped with toluene was dissolved in CH2Cl2 (10 mL) The solution was cooled with an ice water bath The reaction mixture was concentrated to dryness the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (1.57 mol/L solution in tetrahydrofuran, 2.0 mL) in tetrahydrofuran (23 mL) was added 2,2,6,6-tetramethylpyridine (0.57 mL) at −78° C. The temperature was raised to 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was cooled to −78° C., 2-chloropyrazine (0.22 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4-methoxybezaldehyde (0.35 mL), and the mixture was stirred for additionally 1.5 hours. To the reaction-mixture were added concentrated hydrochloric acid (1.2 mL), ethanol (1.2 mL) and tetrahydrofuran (4.8 mL), and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) to give 2-chloropyrazin-3-yl 4-methoxyphenyl methanol (0.31 g). To a suspension of the obtained 2-chloropyrazin-3-yl 4-methoxyphenyl methanol(0.13 g), sodium hydroxide (0.12 g) and potassium carbonate (0.072 g) in toluene (1 mL) were added benzyl alcohol (0.080 mL) and tris-[2-(2-methoxyethoxy)ethyl]amine (0.017 mL), and the mixture was stirred for 2,hours at 120° C. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give 2-benzyloxy-3-(4-methoxybenzyl)pyrazine (0.026 g). To a solution of the obtained 2-benzyloxy-3-(4-methoxybenzyl)-pyrazine (0.025 g) in ethanol (1 mL) was added 10% palladium carbon powder (0.0099 g), and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/3) to give 3-(4-methoxybenzyl)-1H-pyridin-2-one (0.0055 g). After the reaction mixture was cooled to −78° C. the mixture was stirred for 1 hour at the same temperature the mixture was stirred for additionally 1.5 hours the temperature was raised to room temperature the mixture was concentrated under reduced pressure After the residue was extracted with dichloromethane the organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.88 mmol butyllium in hexane (4.3 ml; 1.6M) were added dropwise at -78° C. to a solution of 1.2 ml (6.88 mmol) of 2,2,6,6-tetramethylpyridine in 14 ml of dry tetrahydrofuran. The mixture was then stirred for 30 minutes at 0° C., cooled to -70° C., and added dropwise to a solution of 1-4 g (6.23 mmol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazol-1-one in 42 ml of dry tetrahydrofuran. The mixture was stirred for 90 minutes under nitrogen at -70° C. A solution of 2.4 g (6.88 mmol) of 1-triphenylmethyl-5-methyl-1H-imidazole-4-carboxaldehyde in 14 ml of dry tetrahydrofuran was then added dropwise to the reaction mixture at -70° C., and the mixture was stirred for 2 hours at -10° C. The mixture was then cooled to -70° C. and 16.8 ml of acetic acid was added dropwise. After the temperature had raised to -10° C., 8.1 g of p-toluenesulfonic acid hydrate were added. This mixture was boiled for 18 hours and evaporated in vacuum. The residue was shaken with methylene chloride and with 2N sodium hydroxide. The organic layer was separated, washed with brine, dried and evaporated. The residue was chromatographed over silicagel using methylene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 1.2 g (60%) of 2,3,3a,4,5,6-hexahydro-2-[(5-methyl-1H-imidazol-4-yl)-methylene]-1H- pyrido[3,2,1jk]carbazol-1-one were obtained. This product dissolved in 100 ml of ethanol and hydrogenated at room temperature at 1 atmosphere with palladium on carbon as a catalyst. The catalyst was removed by filtration after disappearance of the starting material, the filtrate was evaporated in vacuum, and the residue was purified by flash chromatography over silicagel using methyene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 0.49 g of the desired compound were obtained after evaporating the desired fractions. cooled to -70° C. The mixture was stirred for 90 minutes under nitrogen at -70° C the mixture was stirred for 2 hours at -10° C The mixture was then cooled to -70° C. After the temperature had raised to -10° C. This mixture was boiled for 18 hours evaporated in vacuum The residue was shaken with methylene chloride and with 2N sodium hydroxide The organic layer was separated washed with brine dried evaporated The residue was chromatographed

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

Procedure: A solution of N-BOC-4(S)-hydroxy-2-methyl-(L)-proline, methyl ester (Step A, 2.2 g, 8.5 mmol), tert-butyldimethylsilyl chloride (1.8 g, 12 mmol), and imidazole (1.1 g, 17 mmol) in 40 mL of anhydrous DMF was stirred at rt overnight. The reaction mixture was partitioned between Et2O and water, and the product was extracted with Et2O (2×200 mL). The combined extracts were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (15 mL), and was added with 2,6-dimethyllutidine (3.0 mL, 26 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.9 mL, 17 mmol) at rt. After stirring for 2 h, the reaction mixture was cooled by an ice-water bath, and was added potassium fluoride (1.4 g, 24 mmol) in 20 mL of water. After stirring at 0° C. for 2 h, the reaction mixture was partitioned between ether and water. The product was extracted with Et2O (3×50 mL), and the organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was azeotroped with toluene and was dissolved in CH2Cl2 (10 mL) and THF (10 mL). The solution was cooled with an ice water bath, and was added DIPEA (4.4 mL, 25 mmol), 4-DMAP (0.10 g, 0.85 mmol) and 3-chlorobenzenesulfonyl chloride (2.7 g, 12 mmol). The reaction was allowed to warm to rt overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tert-butyldimethylsilyl ether of the title compound, which was used immediately. Thus, to a solution-of the silyl ether in acetonitrile (40 mL) at 0° C. was added aqueous HF (48%, 4 mL), and the reaction was allowed to warm up to rt overnight. The reaction mixture was partitioned between 5 N aqueous NaOH, brine and EtOAc, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound (3.0 g, 96% from the product of Step A). The reaction mixture was partitioned between Et2O and water the product was extracted with Et2O (2×200 mL) The combined extracts were dried with anhydrous MgSO4 filtered concentrated in vacuo The residue was dissolved in anhydrous CH2Cl2 (15 mL) the reaction mixture was cooled by an ice-water bath After stirring at 0° C. for 2 h the reaction mixture was partitioned between ether and water The product was extracted with Et2O (3×50 mL) the organic extracts were dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was azeotroped with toluene was dissolved in CH2Cl2 (10 mL) The solution was cooled with an ice water bath The reaction mixture was concentrated to dryness the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc