1-[3-(p-Fluorbenzoyl)propyl]-4-hydroxy-4-(p-tolyl)piperidiniumchlorid

1-[3-(p-fluorobenzoyl)propyl]-4-hydroxy-4-(p-tolyl)piperidinium chloride Chemische Eigenschaften,Einsatz,Produktion Methoden

• Originator

  Luvatren,Cilag

• Manufacturing Process

  A solution of 95 parts of methyl bromide in 356 parts of ether was added portionwise to a refluxing suspension of 24 parts of magnesium in 214 parts of ether. The mixture was refluxed for 2 hours, and 92 parts of 4- methylacetophenone were added in the course of 90 minutes. The refluxing was continued for 3 hours, and the mixture was stirred for 24 hours at room temperature. The Grignard complex was destroyed by the addition of ammonium chloride and 10% hydrochloric acid. The mixture was extracted with ether and the ether extracts were washed with 10% sulfuric acid and then with water. Then extracts were dried over anhydrous calcium chloride, filtered, and concentrated in vacuum to remove the solvent. About 0.5 part of hydroquinone was added to the residue, which was then heated to a temperature of 100-110°C at 50 mm. The distillate was extracted with ether and the ether extracts were dried over anhydrous calcium chloride and filtered. A small quantity of hydroquinone was added to the ether. The solution was fractionated by distillation to yield 4-methyl-α-methylstyrene boiling at about 72-74°C at 80 mm.
  A mixture of 856 parts of ammonium chloride and 3000 parts of 36% formaldehyde was stirred and heated to about 60°C. With cooling to maintain this temperature, 944 parts of 4-methyl-α-methylstyrene were added slowly. After the addition was completed, the mixture was stirred at room temperature until the temperature of the reaction mixture dropped to about 40°C. After 2000 parts of methanol were added, the stirring was continued for 20 hours. The methanol was removed in vacuum and the residue was diluted with 3000 parts of concentrated hydrochloric acid. For 4 hours, the mixture was heated with stirring at a temperature of 100°C. The mixture was cooled, diluted with 2000 parts of water, and made alkaline with 15 N sodium hydroxide solution. The reaction mixture was extracted with benzene, and the benzene extracts were dried over anhydrous potassium carbonate and filtered. The benzene was removed from the filtrate. The remaining residue was distilled in vacuum to yield 4-(p-tolyl)-1,2,3,6-tetrahydropyridine. This base was dissolved in benzene. Dry, gaseous hydrogen chloride was passed through the solution, whereupon there precipitated the hydrochloride, which was collected on a filter. The 4-(p-tolyl)-1,2,3,6-tetrahydropyridine hydrochloride boiling at about 162-170°C/10 mm Hg.
  While the temperature was being maintained at about 10-20°C, anhydrous hydrogen bromide gas was passed for 7 hours through a solution of 160 parts of 4-(p-tolyl)-1,2,3,6-tetrahydropyridine in 500 parts of acetic acid. The mixture was stirred during the addition of the hydrogen bromide gas. The mixture was then allowed to stand at room temperature of 16 hours. The acetic acid and the excess hydrogen bromide were removed in vacuum at a bath temperature of less than 40°C. The residue was treated with ether. This solution was cooled, and the product was collected on a filter to give the 4-(ptolyl)-4-bromopiperidine hydrobromide. A solution of 160 parts of above prepared hydrobromide in 3000 parts of water was treated with 100 parts of 20% sodium hydroxide solution. The resulting precipitate was recovered by filtration and washed with water. The precipitate was then dissolved in toluene, and the solution was dried over anhydrous potassium carbonate and filtered. The filtrate was cooled to 0°C. The crystalline product thus obtained was collected on a filter to yield 4-(p-tolyl)-piperidin-4-ol; MP: 136-137°C.
  To a suspension of 341 parts of aluminium chloride in 1740 parts of carbon disulphide were added 96 parts of fluorobenzene with stirring and cooling. While the temperature was maintained at about 10°C, 141 parts of γ- chlorobutyryl chloride were added. After the addition was completed, the cooling bath was removed and the stirring was continued for 2 hours. The reaction mixture was poured into ice water. The organic layer was separated, washed

• Therapeutic Function

  Neuroleptic

1-[3-(p-fluorobenzoyl)propyl]-4-hydroxy-4-(p-tolyl)piperidinium chloride Upstream-Materialien And Downstream Produkte

1-[3-(p-Fluorbenzoyl)propyl]-4-hydroxy-4-(p-tolyl)piperidiniumchlorid Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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