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Isonicotinic Acid Methochloride. To a slurry of 246 g of isonicotinic acid in 3.2 liters of methanol and 300 ml of water containing 88 g of sodium hydroxide has 355 g of methyl iodide added to it. Note: Isonicotinic acid can be replaced with nicotinic acid, thus producing B-pethidine, instead of demerol. There is very little difference in potency between these two drugs and the formula does not change (just use an equimolar amount of nicotinic acid), so you may use either acid. Stir and reflux the above mixture for 60 hours, then remove the methanol with vacuo. Use sodium thiosulfate to reduce iodine to iodide and add water to give a volume of 1.5 liters. Use hydrochloric acid (concd) to get a ph of 2.0.
Place a slurry of Amberlite IRA-400 (6.30 equivalents) in a glass tube 10 cm in diameter and 100 cm high. The resin is washed with 20 x 1. of 5% hydrochloric acid followed with 40 x 1. of distilled water. The yellow aqueous solution is passed through the column and the effluent, which had better be iodine free, is collected at a rate of flow of 50 ml per min. Three and one half liters of effluent is coned and the residue is dried and extracted with acetic acid. Xylene is added to the hot acetic acid solution, then cooled, and saturated with dry hydrogen chloride to give 336 g of crude product. Recrystallize from acetic acid to purify.
1-Methyl-4-carboxypiperidine Hydrochloride. Isonicotinic acid methochloride is quantitively reduced in a high pressure reaction vessel in the presence of platinum oxide in methanol at 1,000 psi, mp: 231-232°.
Note: The above two steps are somewhat difficult and can be omitted by purchasing 1-methyl-4-carboxypiperidine hydrochloride from a reputable chemical supplier.
1-Methyl-4-benzoylpiperidine. A mixture of 1-methyl-4-carboxypiperidine hydrochloride (135 g) and 200 ml of thionyl chloride is refluxed for 6 hours. After the excess thionyl chloride is removed, 800 ml of dry benzene is introduced to form a slurry. 267 g of anhydrous aluminum chloride is added with constant stirring over a period of 20 min. The dark brown mixture is stirred for an additional 1/2 hour and then is poured onto 2.50 l. of crushed ice. With cooling, add enough 50% NaOH solution to make basic, while stirring. Separate the benzene phase and extract the aqueous phase with ether. The benzene and ether solutions are combined and extracted with six 300 ml portions of 5% hydrochloric acid. This acid extract is adjusted to 11 ph with NaOH and reextracted with ether. The ether solution is dried over sodium sulphate, filtered, and evaporated to a dark, reddish brown oil. This oil is fractionally distilled to collect a light yellow oil passing over at 122° at .5 mm. Crystallization from Skelly A produced the title product.
Dissolve the above product in ether, pass hydrogen chloride (dry) through the solution, and recrystallize the resulting salt from acetone, mp: 208-209°C.
1-Methyl-4-chloro-4-benzoylpiperidine Hydrochloride. Chlorine gas is slowly passed (bubbled) into a solution of 48 g of the above product in 500 ml of glacial acetic acid for 8 hours at 70°. The volume is evaporated to 150 ml and 1 1iter of dry ether is added. The resulting white powder is recrystallized from chloroform, yielding 45 g of the hydrochloric salt, mp: 181° to 182°. This is then recrystallized from Skelly A, mp: 48-49°C.
Rearrangement of 1-Mehtyl-4-chloro-4-benzoylpiperidine. Add 50 ml of xylene (containing 3.5 g of the above product) to a stirred refluxing solution containing 200 ml dry xylene and 18 g of finely powdered, dried sodium NaOH. Stir while refluxing for 30 min, then cool, extract with 25 ml portion of water until the ph of the extracts reaches neutrality (approximately).
The combined water extracts are washed with three 25 ml portions of ether and adjusted to 8 ph with hydrochloric acid. The aqueous solution is concentrated to 50 ml (by evaporation in vacuo), filtered, and acidified to 6.5 with hydrochloric acid. The solution is cooled and the crystals are washed with water, acetone, ether, and then dried. Recrystallize from water to get fine, white needles of 1-methyl-4-phenyl-4-carboxy- piperidine. Yield: 0.8 g, mp: 309-310°. This product is then dissolved in ether and treated by passing dry hydrogen chloride through this solution and recrystallizing the resulting salt from acetic acid-benzene.
Take the above hydrochloride salt and reflux it in ethanolic hydrogen chloride to get Demerol or analog
.
Isonicotinic Acid Methochloride. To a slurry of 246 g of isonicotinic acid in 3.2 liters of methanol and 300 ml of water containing 88 g of sodium hydroxide has 355 g of methyl iodide added to it. Note: Isonicotinic acid can be replaced with nicotinic acid, thus producing B-pethidine, instead of demerol. There is very little difference in potency between these two drugs and the formula does not change (just use an equimolar amount of nicotinic acid), so you may use either acid. Stir and reflux the above mixture for 60 hours, then remove the methanol with vacuo. Use sodium thiosulfate to reduce iodine to iodide and add water to give a volume of 1.5 liters. Use hydrochloric acid (concd) to get a ph of 2.0.
Place a slurry of Amberlite IRA-400 (6.30 equivalents) in a glass tube 10 cm in diameter and 100 cm high. The resin is washed with 20 x 1. of 5% hydrochloric acid followed with 40 x 1. of distilled water. The yellow aqueous solution is passed through the column and the effluent, which had better be iodine free, is collected at a rate of flow of 50 ml per min. Three and one half liters of effluent is coned and the residue is dried and extracted with acetic acid. Xylene is added to the hot acetic acid solution, then cooled, and saturated with dry hydrogen chloride to give 336 g of crude product. Recrystallize from acetic acid to purify.
1-Methyl-4-carboxypiperidine Hydrochloride. Isonicotinic acid methochloride is quantitively reduced in a high pressure reaction vessel in the presence of platinum oxide in methanol at 1,000 psi, mp: 231-232°.
Note: The above two steps are somewhat difficult and can be omitted by purchasing 1-methyl-4-carboxypiperidine hydrochloride from a reputable chemical supplier.
1-Methyl-4-benzoylpiperidine. A mixture of 1-methyl-4-carboxypiperidine hydrochloride (135 g) and 200 ml of thionyl chloride is refluxed for 6 hours. After the excess thionyl chloride is removed, 800 ml of dry benzene is introduced to form a slurry. 267 g of anhydrous aluminum chloride is added with constant stirring over a period of 20 min. The dark brown mixture is stirred for an additional 1/2 hour and then is poured onto 2.50 l. of crushed ice. With cooling, add enough 50% NaOH solution to make basic, while stirring. Separate the benzene phase and extract the aqueous phase with ether. The benzene and ether solutions are combined and extracted with six 300 ml portions of 5% hydrochloric acid. This acid extract is adjusted to 11 ph with NaOH and reextracted with ether. The ether solution is dried over sodium sulphate, filtered, and evaporated to a dark, reddish brown oil. This oil is fractionally distilled to collect a light yellow oil passing over at 122° at .5 mm. Crystallization from Skelly A produced the title product.
Dissolve the above product in ether, pass hydrogen chloride (dry) through the solution, and recrystallize the resulting salt from acetone, mp: 208-209°C.
1-Methyl-4-chloro-4-benzoylpiperidine Hydrochloride. Chlorine gas is slowly passed (bubbled) into a solution of 48 g of the above product in 500 ml of glacial acetic acid for 8 hours at 70°. The volume is evaporated to 150 ml and 1 1iter of dry ether is added. The resulting white powder is recrystallized from chloroform, yielding 45 g of the hydrochloric salt, mp: 181° to 182°. This is then recrystallized from Skelly A, mp: 48-49°C.
Rearrangement of 1-Mehtyl-4-chloro-4-benzoylpiperidine. Add 50 ml of xylene (containing 3.5 g of the above product) to a stirred refluxing solution containing 200 ml dry xylene and 18 g of finely powdered, dried sodium NaOH. Stir while refluxing for 30 min, then cool, extract with 25 ml portion of water until the ph of the extracts reaches neutrality (approximately).
The combined water extracts are washed with three 25 ml portions of ether and adjusted to 8 ph with hydrochloric acid. The aqueous solution is concentrated to 50 ml (by evaporation in vacuo), filtered, and acidified to 6.5 with hydrochloric acid. The solution is cooled and the crystals are washed with water, acetone, ether, and then dried. Recrystallize from water to get fine, white needles of 1-methyl-4-phenyl-4-carboxy- piperidine. Yield: 0.8 g, mp: 309-310°. This product is then dissolved in ether and treated by passing dry hydrogen chloride through this solution and recrystallizing the resulting salt from acetic acid-benzene.
Take the above hydrochloride salt and reflux it in ethanolic hydrogen chloride to get Demerol or analog
.
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