1-Benzyl-3,3-dimethylpiperidin-4-one

Oxidation A solution of 0.40 mL (5.6 mMol) dimethylsulfoxide in 5 mL dichloromethane was cooled to -78°C. To this solution was added 0.35 mL (2.48 mMol) trifluoroacetic anhydride dropwise and the resulting solution stirred for 30 minutes. A solution of 0.25 gm (1.14 mMol) 1-benzyl-3, 3-dimethyl-4-hydroxypiperidine in 2 mL dichloromethane was added dropwise and the reaction mixture was stirred for 1 hour. To the solution was then added 1.0 mL (7.2 mMol) triethylamine and the reaction mixture was warmed to 0°C. After stirring for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing from 0-20percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.20 gm (79percent) of the title compound.A solution of 0.40 mL (5.6 mMol) dimethylsulfoxide in 5 mL dichloromethane was cooled to -78°C. To this solution was added 0.35 mL (2.48 mMol) trifluoroacetic anhydride dropwise and the resulting solution stirred for 30 minutes. A solution of 0.25 gm (1.14 mMol) 1-benzyl-3, 3-dimethyl-4-hydroxypiperidine in 2 mL dichloromethane was added dropwise and the reaction mixture was stirred for 1 hour. To the solution was then added 1.0 mL (7.2 mMol) triethylamine and the reaction mixture was warmed to 0°C. After stirring for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing from 0-20percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.20 gm (79percent) of the title compound.In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4percent. MS(ion spray)=218.3 (M+1)(step 1) In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 mL of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics were concentrated under vacuum to give 225 g of red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4percent. MS(ion spray)=218.3(M+1).Preparation 6 [0126] Preparation of N-Benzyl-3, 3-dimethyl-4-piperidone. [CHEMMOL-00028] [0127] In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4percent. MS(ion spray)=218.3(M+1)In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4percent. MS(ion spray)=218.3(M+1)In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 mL of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisbpropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics were concentrated under vacuum to give 225 g of red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4percent. [00110] MS (ion spray)=218.3 (M+1).In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37percent weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution is cooled in an ice-water bath to 10°C, and benzylamine (109 mL, 1mole) is added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06mole) dissolved in 500ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution is quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics are concentrated under vacuum to give 225 g of red oil. The crude oil is dissolved in 1 liter of methylene chloride. This solution is carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel is washed with 4 L of methylene chloride. The methylene chloride is concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4percent.In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37percent weight solution of formaldehyde (168.5 ML, 2.25 mole) dissolved in 500 ML of absolute ethanol.. Formaldehyde (18.26 g, 225.00 mmol, 2.25 eq) was dissolved in ethanol (100.00 mL) and the benzylamine (10.72 g, 100.00 mmol, 1.00 eq) was added slowly to the solution. Preparation 43; 1-Benzyl-3, 3-dimethylpiperidin-4-one; To a solution of formaldehyde (16.9 mL, 0.23 mmol) in ethanol (50 ml.) cooled to 10°C was added benzylamine (10.9 mL, 0.10 mmol) dropwise over 1 h. The resulting solution was added over 2 h to a refluxing solution of 3-methylbutan-2-one in ethanol (50 mL) followed by concentrated hydrochloric acid (9.2 mL). The reaction mixture was heated at reflux overnight, cooled to room temperature before NSodium hydride (4.20 g, 175.0 mmol) was suspended in THF (200 mL), and a solution of the piperidone (18.9 g, 99.9 mmol) and methyl iodide (17.9 g, 126.1 mmol) in THF (20 mL) was added dropwise at room temperature over 5 minutes. The mixture was then heated to 60 °C and stirred for 5 hours. The reaction was then filtered and the filtrate concentrated. The concentrate was poured into 150 mL of water and extracted with 120 mL portions of EtOAc three times. The extract was washed with brine, dried, and concentrated. The crude product was purified by column chromatography (gradient: 12percent EtOAc in hexanes to 50percent EtOAc in hexanes over 1200 mL). Both mono and di methylation occurred. Separation of both isomers by chromatography was quite facile. 3.53 g of the dimethylated product (16percent) was obtained. MS (EI) : m/z 218.1 (M + 1). 5.91 g (29percent) of the monomethylated product was obtained. MS (EI) : m/z 204.0 (M + 1).PREPARATION 1 In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4percent. MS(ion spray)=218.3(M+1)(step 1) To a solution of formalin (61.1 mL) in ethanol (150 mL) was added dropwise benzylamine (36.4 mL) under ice-cooling, and the obtained reaction mixture was added dropwise to a solution of 3-methylbutan-2-one (30.6 g), and concentrated hydrochloric acid (31.0 mL) in ethanol (150 mL) under refluxing. The reaction solution was stirred for 16 hr under reflux, and cooled to room temperature. N-Ethyldiisopropylamine (50.2 mL) and formalin (8.15 mL) were added to the reaction solution, and the mixture was stirred under reflux for 16 hr, and cooled to room temperature. To the reaction solution was added a solution of potassium hydroxide (20.7 g) in water (70 mL), and ethanol was evaporated under reduced pressure. The resulting product was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (solvent gradient: 5'15% ethyl acetate/hexane) to give In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 mL of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics were concentrated under vacuum to give 225 g of red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%. MS(ion spray)=218.3(M+1).Preparation 6 [0126] Preparation of N-Benzyl-3, 3-dimethyl-4-piperidone. [CHEMMOL-00028] [0127] In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion spray)=218.3(M+1)In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion spray)=218.3(M+1)In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 mL of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisbpropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics were concentrated under vacuum to give 225 g of red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%. [00110] MS (ion spray)=218.3 (M+1).In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution is cooled in an ice-water bath to 10C, and benzylamine (109 mL, 1mole) is added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06mole) dissolved in 500ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution is quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics are concentrated under vacuum to give 225 g of red oil. The crude oil is dissolved in 1 liter of methylene chloride. This solution is carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel is washed with 4 L of methylene chloride. The methylene chloride is concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%.In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 ML, 2.25 mole) dissolved in 500 ML of absolute ethanol.. The resulting solution is cooled in an ice-water bath to 10C, and benzylamine (109 ML, 1mole) is added dropwise over a one hour period.. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 ML, 1.06mole) dissolved in 500ml of absolute ethanol and concentrated hydrogen chloride (92 ML, 1.11mole).. The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period.. This solution is refluxed overnight, and then cooled to ambient temperature.. diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 ML, 0.3mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature.. The solution is quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 ML of water, and then extracted with 500 ML ethyl acetate three times.. The organics are concentrated under vacuum to give 225 g of red oil.. The crude oil is dissolved in 1 liter of methylene chloride.. This solution is carefully poured over 1 kg of silica gel on a sintered glass filter.. The silica gel is washed with 4 L of methylene chloride.. The methylene chloride is concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%.Formaldehyde (18.26 g, 225.00 mmol, 2.25 eq) was dissolved in ethanol (100.00 mL) and the benzylamine (10.72 g, 100.00 mmol, 1.00 eq) was added slowly to the solution. The mixture was stirred at 15 C for 1 hour. The mixture was then slowly added to a refluxing solution of 3-methylbutan-2-one (8.61 g, 100.00 mmol, 1.00 eq) in ethanol (100.00 mL) and hydrochloric acid (9.20 mL). The mixture was stirred at 80 C for 12 hours. The mixture was then cooled to 15 C and then diisopropylamine (14.22 g, 110.00 mmol, 1.10 eq) and formaldehyde (2.44 g, 30.00 mmol, 0.30 eq) were added and the mixture was stirred at 80 C for another 7 hours. The pH of the reaction mixture was adjusted to > 10 with potassium hydroxide and then extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 30/1 to 10: 1) to deliver Preparation 43; 1-Benzyl-3, 3-dimethylpiperidin-4-one; To a solution of formaldehyde (16.9 mL, 0.23 mmol) in ethanol (50 ml.) cooled to 10C was added benzylamine (10.9 mL, 0.10 mmol) dropwise over 1 h. The resulting solution was added over 2 h to a refluxing solution of 3-methylbutan-2-one in ethanol (50 mL) followed by concentrated hydrochloric acid (9.2 mL). The reaction mixture was heated at reflux overnight, cooled to room temperature before N1N- diisopropylethylamine (19.2 mL, 0.11 mmol) and formaldehyde (2.3 mL, 0.03 mmol) were added. The mixture was heated again at reflux for 6 h, cooled to room temperature and treated with a solution of potassium hydroxide (6.2 g) in water (20 mL). The precipitate formed was dissolved in water (50 mL) and the resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine, concentrated in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane:pentane (1 :1 to 1 :0) to afford the title compound as an oil (9.63g, 44%). 1H NMR (CDCI3, 400 MHz) delta 1.11 (s, 6H), 2.38 (s, 2H), 2.49 (t, 2H), 2.70 (t, 2H), 3.54 (s, 2H), 7.21-7.37 (m, 5H); LRMS 218 [MH+].The solution of benzylamine (12 g, 112 mmol) and paraformaldehyde (2 g, 66.6 mmol) in ethanol (30 ml) was stirred for 30 minutes at room temperature and then the mixture was added dropwise to the refluxing solution of 3- methyl-2-butanone (2.8 g, 32.5 mmol) in ethanol containing 10% HCI. The reaction mixture was refluxed for 8 hours. After completion of reaction, the mixture was cooled to room temperature and poured into water (100 ml), pH was adjusted to 7 using aqueous sodium bicarbonate solution and extracted with ethylacetate (50 ml x 3). The combined organic layers were washed with water (50 ml x 2), brine (50 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using the 2% ethyl acetate in hexane as the eluent to provide the titled compound (2 g) as brown liquid. 1HNMR (DMSOd6): delta 1.16 (6H1 s), 2.70 - 2.71 (2H, t), 2.72 - 2.77 (2H, t), 3.40 - 3.42 (2H1 s), 3.50 - 3.52 (1 H, d), 3.56 - 3.66 (1 H, d), 7.20 - 7.22 (2H1 m), 7.26 - 7.28 (3H, m) m/z: 218 (M+1)Benzylamine (214 g, 2 mol) is combined with formaldehyde (37% in water, 375 g, 4.5 mol) in ethanol (1 L) with occasional cooling. This biphasic mixture is added over a period of 90 minutes to a refluxing solution of 2-methyl-3-butanone (182 g, 2.11 mol) in anhydrous ethanol (1L) and hydrochloric acid (209 g of 37% solution, 2.1 mol). The brownish solution is heated at reflux for an additional 18 hours. Then triethylamine (310 mL, 223.8 g, 2.21 mol) and formaldehyde (50 g, 36%, 0.6 mol) are added sequentially and the reaction mixture is heated at reflux for 24 hours. The reaction mixture is then cooled to 5C and treated with potassium hydroxide (117.6 g, 2.1 mol, dissolved in 200 mL of water). The reaction mixture is then extracted with heptane (2 X 500 mL) and methyl tert-butyl ether (2 X 500 mL). The organic extracts is then combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the title compound, (339.36 g after 18% by volume of the above combined organic extracts was removed prior to concentration). This material was purified by chromatography on silica gel (methylene chloride/ethanol, 100:1) to provide purified title compound.1H NMR (CDCl3) delta 1.14 (s, 6H), 2.41 (s, 2H) , 2.52 (t, 2H), 2.72 (t, 2H), 3.57 (s, 2H), 7.2-7.4 (m, 5H).Benzylamine (214 g, 2 mol) is combined with formaldehyde (37% in water, 375 g, 4.5 mol) in ethanol (1 L) with occasional cooling.. This biphasic mixture is added over a period of 90 minutes to a refluxing solution of 2-methyl-3-butanone (182 g, 2.11 mol) in anhydrous ethanol (1L) and hydrochloric acid (209 g of 37% solution, 2.1 mol).. The brownish solution is heated at reflux for an additional 18 hours.. Then triethylamine (310 ML, 223.8 g, 2.21 mol) and formaldehyde (50 g, 36%, 0.6 mol) are added sequentially and the reaction mixture is heated at reflux for 24 hours.. The reaction mixture is then cooled to 5C and treated with potassium hydroxide (117.6 g, 2.1 mol, dissolved in 200 ML of water).. The reaction mixture is then extracted with heptane (2 X 500 ML) and methyl tert-butyl ether (2 X 500 ML).. The organic extracts is then combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the title compound, (339.36 g after 18% by volume of the above combined organic extracts was removed prior to concentration).. This material was purified by chromatography on silica gel (methylene chloride/ethanol, 100:1) to provide purified title compound.1H NMR (CDCl3) delta 1.14 (s, 6H), 2.41 (s, 2H), 2.52 (t, 2H), 2.72 (t, 2H), 3.57 (s, 2H), 7.2-7.4 (m, 5H).A mixture of 10.14 gm (46.66 mMol) A mixture of 10.14 gm (46.66 mMol) A mixture of 5.0 gm (23 MMol) Step 2 3, 3-Dimethyl-4-oxo-piperidine-1-carboxylic Acid Tert-Butyl Ester To a solution of Step 2: 3, 3-Dimethyl-4-oxo-piperidine-1-carboxylic Acid Tert-Butyl Ester To a solution of Step 2 3, 3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester To a solution of General procedure: To a solution of [Int-1.1] (1 g, (0213) 1 eq., 4.21 mmol) and tert-butyl 4-oxopiperidine-l- carboxylate (0.8 g, 1 eq., 4.21 mmol) in EtOH (15 mL) , HC1 36% (4 mL)was added. The reaction mixture was heated at 80 C and stirred for 16 h. The suspension was filtered and washed with Et20 to furnish the title compound as brown solid (0.6 g, 50%) :

Molecular Weight:217.31
XLogP3:2.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:217.146664230
Monoisotopic Mass:217.146664230
Topological Polar Surface Area:20.3
Heavy Atom Count:16
Complexity:254
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes