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885 g thereof are dissolved in 2,250 ml of hot ethanol, the solution is allowed to cool to 50 and 300 ml of 6.5 N ethanolic hydrochloric acid are rapidly added while stirring. The precipitate formed is filtered off, washed with ethanol and dried at 60. 840 g thereof are again dissolved in 2,150 ml of ethanol at 80 and the solution allowed to cool to room temperature while stirring for 4 hours. The resulting suspension is filtered, the residue again recrystallized from 2,150 ml of ethanol and dried at 60, to yield the corresponding hydrochloride melting at 176-178;;l it is somewhat purer than that obtained according to Example 1. The starting material is prepared as follows: The mixture 268 of diphenylmethanol, 200 g of 4-hydroxypiperidine hydrochloride and 28.8 g of p-toulenesulfonic acid monohydrate is stirred and heated to 160 while reducing the pressure to 0.2 mm Hg with a vacuum pump for 3 hours. It is cooled to 80, dissolved in 500 ml of ethanol and the solution cooled to 10. The resulting suspension is filtered, the residue washed with isopropanol and dried at 60, to yield the 4-diphenylmethoxy-piperidine hydrochloride.
4
[ 67-63-0 ]
[ 65214-84-8 ]
[ 65214-86-0 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In water; acetone;
A mixture of 24 parts of ethyl 4-(diphenylmethoxy)-1-piperidinecarboxylate, 20 parts of potassium hydroxide and 120 parts of 2-propanol is stirred and refluxed for 4 hours. The 2-propanol is evaporated. Water is added to the residue and the product is extracted with methylbenzene. The extract is washed three times with water, dried, filtered and evaporated. The oily residue is converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and dried, yielding 4-(diphenylmethoxy)piperidine hydrochloride; mp. 209.8 C.
sodium hydrogencarbonate; In 4-methyl-2-pentanone; at 119.0℃; for 11.0h;
Example 5. Preparation of l-[4-(l,l-dimethylethyI)phenyI]-4-[4-(diphenyImethoxy)-l- piperidinyl]-l-butanone I"A mixture of 4-Benzhydryloxypiperidine hydrochloride IP'.HCl (15.19 g, 50 mmol), sodium hydrogen carbonate (10.08 g), methyl isobutyl ketone (24.30 g) and 4'-tert-butyl-4-chloro- butyrophenone III" (14.33 g) was heated to reflux (119 C) for 11 h (at this point, analysis indicated that an Ebastine solution of 81.94% purity had been formed, based on HPLC area- %). The reaction mixture was cooled to room temperature and water (100 mL) and sodium chloride (1 g) were added. The organic phase was washed with sodium chloride solution (2 x 100 mL) and oxalic acid (4.17 g) was added to the organic phase, the oxalate salt was isolated by filtration and washed twice with acetone to give the moist oxalate salt I".H2C204 (22.06 g). The oxalate salt was suspended in water (100 mL) and aqueous ammonia (12.5 % was added dropwise until a pH of 7-7.5 was obtained). The product was isolated by filtration and washed with water (3x 20 mL). The moist product (18.97 g) was dried to give l-[4-(l,l- dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-l-piperidinyl]-l-butanone I" (13.42 g, 57.15%). HPLC 89.2 %.
Example 5. Preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone I' A mixture of 4-Benzhydryloxypiperidine hydrochloride II'.HCl (15.19 g, 50 mmol), sodium hydrogen carbonate (10.08 g), methyl isobutyl ketone (24.30 g) and 4'-tert-butyl-4-chloro*butyrophenone III' (14.33 g) was heated to reflux (119 C) for 11 h (at this point, analysis indicated that an Ebastine solution of 81.94% purity had been formed, based on HPLC area-%). The reaction mixture was cooled to room temperature and water (100 mL) and sodium chloride (1 g) were added. The organic phase was washed with sodium chloride solution (2 x 100 mL) and oxalic acid (4.17 g) was added to the organic phase, the oxalate salt was isolated by filtration and washed twice with acetone to give the moist oxalate salt I'.H2C2O4 (22.06 g). The oxalate salt was suspended in water (100 mL) and aqueous ammonia (12.5 % was added dropwise until a pH of 7-7.5 was obtained). The product was isolated by filtration and washed with water (3x 20 mL). The moist product (18.97 g) was dried to give 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone I' (13.42 g, 57.15%). HPLC 89.2 %.
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