SU422144A3 - METHOD FOR PRODUCING DERIVATIVES OF PHENILPIPERIDINE OR THEIR SALTS - Google Patents

Description

one

This invention relates to the field of the preparation of new derivatives of phenylpiperidine, which can be used in the pharmaceutical industry.

By using the reaction of the interaction of primary or secondary amines with ketone and formaldehyde known in organic chemistry with respect to compounds of the piperidine row, it is possible to obtain new phenylpiperidine derivatives of the general formula

The proposed method consists in the fact that the compounds are general; formula II

ten

SN -SH-SO-TS 1

where RI denotes a tertiary butyl group, phenylgrub or monosubstituted with chlorine, bromine, fluorine, lower alkyl, methoxy or methylthio group feiilgroup.

interact with formaldehyde and ketone of general formula III

CH, -CO-R ,, III

where Ri is as defined above, in a neutral or weakly acidic medium, followed by isolation of the target product as a base or salt in a known manner.

Example 1. 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -propiophenone.

A mixture of 10.0 g of 4-benzoyl-4oxy-3-phenylpiperidine hydrochloride, 4,7-paraformaldehyde and 3.7 g of acetophenone in 250 ml of ethanol is heated for 21 hours with stirring until boiling. To free the base, treat the residue remaining after evaporation of the solvent with a solution of potassium carbonate and extract the reaction product with chloroform. The crude base obtained after evaporation of chloroform is dissolved in ethanol, the calculated amount of hydrogen bromide in glacial acetic acid is added and diluted with ether until a slight turbidity occurs. The precipitated crystallisate is recrystallized once more from eganol to obtain pure 3- (4-benzoyl-4-hydroxy-3-phenylpiperidino) hydrobromide - propiofepon with m.p. 182-184 ° C.

The starting product is molded as follows.

A. 4-Benzoyl-1 - methyl-3 - phenylpiperidine. 10.1 g of magnesium are layered with 20 ml of absolute tetrahydrofuran and etched with several iodine crystals and 0.5 ml of ethylene bromide. A solution of 65.0 g of bromobenzene in 80 ml of absolute tetrahydrofuran is then added dropwise so that the reaction does not stop. The reaction mixture is then boiled again. 2 hours under reflux, it is cooled to 5 ° C and a solution of 30.0 g of 1,2,3,6-tetrahydro-1-methyl-isonicotinic acid ethyl ester in 50 ml of absolute tetrahydrofuran is added at this temperature for 15-20 minutes. . The mixture is heated to boiling for 30 minutes, cooled to 10 ° C and, with good stirring, is poured into a solution of 60 g of ammonium chloride in 400 ml of ice water. The resulting aqueous suspension is extracted several times with methylene chloride and the extract is extracted with agitation while agitating. hydrochloric acid solution. The acidic solutions are added by adding concentrated sodium hydroxide solution to an alkaline reaction while cooling, extracted with methylene chloride, the extracts are dried over potassium carbonate and evaporated under reduced pressure. The residue is distilled under high vacuum, first separating the 1-methyl-3-phenylisonicotinic acid ethyl ester from the batch. 100-110 ° C (0.05 mm Hg. Art.) As a top product and then 4-benzoyl-1-methyl-3-phenylpiperidine at about 165-180 ° C (0.05 mm Hg.). By adding hydrogen bromide to the free base, 4-benzoyl-1methyl-3-phenylpiperidine hydrobromide is obtained with m.p. 243-244 ° C (decomposition).

B. 4-Benzoyl-4-bromo-1-methyl-3-phenylpiperidi. To a solution of 165.7 of 4-benzoyl-1-methyl-3-phenylpiperidine hydrobromide in 1700 ml of glacial acetic acid, 147 g of bromine are added over 5 hours at 100 ° C and the initial mixture is then stirred for another 1 hour at the same temperature. The reaction mixture was kept at room temperature overnight, evaporated under reduced pressure at 60 ° C and acetone was added to the residue. After crystallization in the refrigerator, pure 4-benzoyl-4-bromo-1-methyl-3-phenylpiperidine hydrobromide is obtained, m.p. 163-164 ° C (easy decomposition).

B. 4-Benzoyl-4-hydroxy-1-methyl-3-phenylpiperidine. To a solution of 23.3 g of sodium in 700 ml of methanol, 148.4 g of 4-benzoyl-4-bromo-1-methyl-3-phenylpiperidine hydrobromide was added in portions under ice cooling. The mixture is stirred at room temperature for 22 hours and, by adding concentrated hydrochloric acid, dropwise, the reaction mixture is brought to a congo-acidic reaction. Stir for a further 15 minutes and then methanol is evaporated under reduced pressure at 60 ° C. A 20% potassium carbonate solution is added to the residue and then extracted several times with chloroform. The combined chloroform extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure until crystallization begins. Stand concentrate one night in the refrigerator and get pure 4benzoyl-4-hydroxy-1-methyl - 3 - phenylpiperidine with m. Pl. 167-169 ° C.

G. 4-Acetoxy-4-benzoyl-1 - methyl-3-phenylpsperidin. 197.4 g of 4-benzoyl-4-hydroxy-1-methyl-3-phenylpiperidine are dissolved in 2000 ml of acetic anhydride at 90 ° C and the solution is slowly heated to 160 ° C. The reaction mixture is cooled to about 100 ° C and distilled Excess acetic anhydride is removed by a water jet pump. The viscous residue is dissolved in chloroform and taken up by stirring with cold dilute sodium hydroxide solution. Dry the organic layer over magnesium sulfate, evaporate the solvent under reduced pressure, and recrystallize the residue once with approximately 2000 ml of ethanol. Get pure 4-acetoxy-4-benzoyl-1-methyl-3-phenylpiperidine with so pl. 158-159 ° C.

D. 4-Acetoxy-4-benzoyl-3-phenylpiperidinecarboxylic acid ethyl ester. To a solution of 206.7 g of 4-acetoxy-4-benzoyl-1-methyl-3-phenylpiperidine in 2000 ml of absolute benzene is added 392 ml of ethyl chloroformate and with stirring, the reaction mixture is heated for 16 hours until boiling. The extract is then extracted three times with water, the organic phase is dried over magnesium sulphate and evaporated to dryness. After crystallization of the residue from benzene, pure 4-acetoxy-4-benzoyl-3-phenylpiperidinecarboxylic acid ethyl ester is obtained, m.p. 125-126 ° C.

E. 4-Benzoyl-4 - hydroxy - 3 - phenylpiperidine. 216.1 g of 4-acetoxy-4-benzoyl-3-phenylpiperidinecarboxylic acid ethyl ester are suspended in a mixture of 1500 ml of concentrated hydrochloric acid and 500 ml of water and with stirring, the suspension is heated for 72 hours until boiling. The product which is separated out after cooling the reaction mixture is filtered off, it is recrystallized again from ethanol to obtain the pure 4-beisoyl-4-hydroxy-3-phenylpiperidine hydrochloride, m.p. 236-237 ° C. Example 2. 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -p-methoxypropiophenone. 4-Benzoyl-4-hydroxy-3-phenyliperidine, para-5 formaldehyde and p-methoxyacetophenone are subjected to an exchange reaction according to the method described in Example 1, mp. hydrobromide 170-172 ° C (from ethanol). Example 3.3- (4-Benzoyl-4-hydroxy-3-phenyl-I-peridino) -n-fluoropropiophenone. 4-Benzoyl-4-hydroxy-3-phenylpiperidine, paraformaldehyde and p-fluoroacetophenone are subjected to an exchange reaction as described in Example I; m.p. hydrobronide 116-118 ° С (from 15 ethanol). Example 4. 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -p-chloropropiophenone. 4-Benzoyl-4-hydroxy-3-phenylpiieridine, paraformaldehyde and p-chloroacetophenone are subjected to an exchange reaction according to the method described in Example 1; m.p. hydrobromide 119-121 ° C (from ethanol). Example 5. 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -l-bromopropiophenop.25 4-Benzoyl-4-hydroxy-3-phenylpiperidine, paraformaldehyde and p-bromoacetophenone is subjected to an exchange reaction as described in Example 1 ; m.p. 177 ° C (from ethanol). Example 6. 3- (4-Benzoyl-4-hydroxy-3-phenyl-30 piperidino) -l-methoxyG1ropiopheno 1. 1-4-Benzoyl-4-hydroxy-3-phenylpiperidine, paraformaldehyde, and w-methoxyacetophenone are subjected to an exchange reaction as described in example 1 method; m.p. hydrobromide 165-35 166.5 ° C (from ethanol). Example 7. 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) lg-methylpropiophenone. 4-Benzoyl-4-hydroxy-3-phenylpiperidine, paraformaldehyde and ./-methyl acetophenone undergo an exchange reaction as described in Example 1; m.p. hydrobromide 163-164 ° C (from ethanol - ether). Example 8. 5- (4-Benzoyl-4-hydroxy-3-fenpiperidino) -2,2-dimethyl-3-pentanone. 45 4-Benzoyl-4-hydroxy-3-phenylpiperidine, paraormaldehyde and methyl tert-butyl ketone are subjected to peaKuiiii exchange as described in example 1; m.p. hydrobromide 187-188.5 ° C (from ethanol). The subject of the invention. A process for the preparation of phenylpiperidine derivatives, i.e. of the formula I, is CH CHCH -CO-Ht I, where RI denotes a tertiary butyl group, a phenyl group or is monosubstituted with chlorine, bromine, fluorine, lower alkyl, methoxy, or methylthio, phenyl, or their salts, about one l and h and y p; and with the fact that the compound of formula P is reacted with formaldehyde and ketone of general formula P1 CH3-CO-R, P1 where RI has the above values in neutral or weakly acidic medium, followed by isolation of the target product as an NLP base by converting it to salt known methods.