SU124444A3 - The method of preparation of the esters of aryl-2-piperidylmethanol - Google Patents

Description

The proposed method allows to obtain aryl-2-piperidylcarbinol esters of the general formula

where Ar is phenyl unsubstituted or containing one or more substituents, and R is lower alkyl. The proved compounds can exist in forms A and B, they can be distinguished by their infrared spectrum. In the present case, Form B is described as racemic NLI optically active isomers, which can be obtained by the method described in the following examples.

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Lo 124444

Example 1. A mixture of 19.5 g of phenyl- (1-benzylpiperidyl-2) -carbinol. in form B and 2.9 g of sodium amide in 450 ml of absolute toluene are heated to reflux in a flask and kept at this temperature and stirring for 2 hours. After cooling, 20 g of methyl iodide is added and the reaction mixture is again heated for 2 hours at boiling point. After cooling, the base is extracted with semi-normal hydrochloric acid (5 times 50 ml each). The aqueous solutions are washed with ether, then basified with caustic sodium. The free base is extracted with ether as ether. The ether extracts are washed with water, dried and evaporated, and it is obtained in the residue 12.5 g of an orange oil, which is dissolved in 200 ml of acetic acid. This compound is debenzylated by hydrogenation in the presence of 1.3 g of coal with 5% palladium at 80 ° under a pressure of 20 / cg / l; the catalyst is filtered off and the acetic acid is evaporated under vacuum, dissolve the residue in water and alkalize the resulting solution. Extracted debenzylated bases are extracted with chloroform. The chloroform solutions are washed with water, dried and evaporated in vacuo. The oil remains, which is treated with 20 ml of petroleum ether. em is a phenyl- (piperidyl-2) -carbinol in B, i.e. the non-esterified product, in an amount of 2, .32

C1 iltrate is dissolved in 30 ml of a solution of hydrogen chloride in ether with a concentration of 150 g / l. The precipitated solid phase is recrystallized from a mixture of 215 ml of ethyl acetate and 10 ml of alcohol. At the same time, get 2.8 g of phenyl methoxy- (piperidyl-2) -methanum hydrochloride in the form of B with m. Pl. 219 °.

By concentrating the mother liquor, it is possible to obtain another 1.7 For such a product with mp. 217 °.

The starting phenyl- (1-benzylpiperidyl-2) -carbinol can be obtained by benzylating the phenyl- (piperidyl-2) -carbinol with benzyl chloride. After recrystallization from hexane, it melts at 91 °.

Example 2. The experiment was carried out in the same manner as in the previous example, but with the replacement of methyl iodide with ethyl iodide. Pr, 1 this get the hydrochloride phenyl-ethoxy- (piperidyl-2) -methane in the form of B with so pl. 234 °.

PRI me R 3. A mixture of 193 g of phenyl- (1-benzylpiperidyl-2) -carbinol, form B with m. Pl. 91 ° and 29.5 g of sodium amide in 3.75 liters of absolute benzene are heated for 4 hours to reflux. A solution of 180 g of ethyl para-toluenesulfonate in 150 ml of absolute benzene is poured slowly over 30 minutes and boiling is continued for 3 hours. The cooled reaction mixture is washed with water and extracted with dilute hydrochloric acid at 50 ° (5 times, 100 ml each). This results in the hydrated phenylethoxy- (1-benzylpiperidyl-2) -methanum in form B, which is insoluble in dilute hydrochloric acid. After filtration and drying, this precipitate melts at 110. Its total amount is 179 g. The base is squeezed out of it with caustic, alkaline and extracted with ether to obtain 140 g of a colorless oil, which is dissolved in 1.1 l of pure acetic acid. by hydra in an autoclave at 70 ° under a pressure of 20 kg / cc in the presence of 15 g of carbon with 3.2%, palladium for 3 hours. The catalyst is filtered, twice, washed with 50 ml of acetic acid and the filtrate is evaporated under vacuum at a temperature not exceeding 50 ° - The residue from evaporation is dissolved in 500 ml of distilled water, 250 ml of sodium soda solution (d-7.55) are alkalinized, and the free base is extracted with 1.5 l of eff. (3 x 0.5 l) After washing with water and drying the ether extracts, the latter are evaporated, and an oil remains, which is redissolved in 120 ml of ether and containing about 15% hydrogen hloristothe. The precipitate is recrystallized from 1.7 l of ethyl acetate with a content of 20% alcohol. A total of 74 g of phenylethoxy- (piperidyl-2) -carbinol in the form of B, with a melting point of 234-235 °, are obtained. By evaporation of the mother liquor from recrystallization, an additional 16 g of the substance can be obtained with mp. 23G.

Example 4. The experiment was carried out in the same manner as in Example 3, but para-toluenesulfonic acid ethyl ester was replaced with neutral n-propyl sulfate, which gave hydrated phenyln-propoxy (2-methanol) hydrochloride in form B in 84 yield. ,five%..

22.4 g of hydrochloride directly debenzylate at 20 ° in acetic acid (250 ml) under a slight excess pressure of hydrogen (about 10 cm aq. Art.) In the presence of 8 g of coal with 3.2% palladium. After evaporation of the acetic acid and washing the residue with ether, 15.8 g of phenyl-n-propoxy- (piperidyl-2) - methane hydrochloride are obtained: Form B, mp. 205 °. After recrystallization from methyl ethyl ketone, 13.2 g of product are obtained, melting at 210 °.

Example 5. Do the same as in example 4, but n. propyl sulfate is replaced with neutral n. butyl sulfate. An aqueous hydrochloride, phenyl-n, is obtained. butoxy- (1-benzylpiperidyl-2) -methane with a yield of 74%. The corresponding base in the amount of 16.5 g is squeezed out with caustic soda solution, extracted with ether, dissolved, evaporated and the residue from evaporation is debenzylated at 20 ° in acetic acid in the presence of 3.2% palladium on carbon under a slight excess pressure of hydrogen. The acetic acid is evaporated, the residue is dissolved in water, alkalinized with caustic soda and extracted with ether. After drying, the ether is evaporated and the residual, pale oil (11.5 g) is dissolved in 200 ml of ethyl acetate. With the addition of 18 ml of a 15% aqueous solution of hydrogen chloride in the air, 9.5 g of phenyl-n-butoxy- (piperidyl-2) -methane hydrochloride fall out; form B, so pl. 189 °.

Example 6. A mixture of 9.5 g of phenyl- (piperidyl-2) -carbinol in the form of B and 2.3 sodium amide in 200 ml of absolute benzene is heated to boiling in a flask for one hour under reflux. A solution of 12.6 g of ethyl p-toluenesulfonate in 30 ml of absolute benzene is added dropwise and boiling is continued for 2 hours. The cooled reaction mixture is washed with 100 ml of water and extracted three times with 100 ml of two-normal hydrochloric acid. The combined acidic extracts are washed with ether, alkalized with 30 ml of sodium hydroxide solution (, 33) and the isolated bases are extracted with chloroform. After washing the chloroform layer, it is dissolved over potassium carbonate and a semi-crystalline residue is obtained by evaporation, which is triturated with 100 ml of petroleum ether. The insoluble crystals are 4.5 g of the starting phenyl- (pileridyl-2) -carbinol, m.p. 172 °. The oil obtained by evaporation of the filtrate (4.5 g) is dissolved in 30 ml of methyl ethyl ketone and the product is extracted with 6 ml of a 15% aqueous solution of hydrogen chloride in ether. A total of 2 g of phenyl ethoxy- (piperidyl-2) -methane hydrochloride in the form of B- is obtained. This product is identical to that described in Example 2.

Example 7. A mixture of phenyl- (1-formylpiperidyl-2) -carbinol in

Form B with t-pl. 133 ° and 2.15 g of sodium amide in 300 ml of absolute benol are boiled for 3 hours in a flask with reflux. By

A solution of 9.3 g of ethyl iodide in 40 ml of absolute 3–No. 124444 is added to the solution.

No. 124444

benzene; It is then boiled again for 4 hours. After cooling, the reaction mixture is successively washed with distilled water, half normal hydrochloric acid, sodium bicarbonate solution and again with water. It is dried over calcined sodium sulphate, evaporated and 6.7 g of phenyl-ethoxy- (1-formylpiperidyl-2X-me1an in form B are obtained in this way).

This derivative, in the form of a solution of 1.35 g in 50 ml of a 6% aqueous solution of hydrogen chloride in absolute alcohol, is boiled for 24 hours with a reflux condenser, then the alcohol is evaporated. The evaporation residue is dissolved in water, washed with benzene and alkalinized with sodium hydroxide solution (specific weight 1.33). The base is extracted with ether, dried and evaporated. The residue obtained (1.2 g) is triturated with petroleum ether. The insoluble fraction melts at 150 °. The residue from evaporation of petroleum ether (0.8 g) is dissolved and after adding a solution of hydrogen chloride in ether, 0.9 g of phenyl ethoxy (piperidyl-2) -methane hydrochloride in the form of B is obtained. This compound is identical with those described in examples 3 and 6

Example 8. A mixture of phenyl- (1-formylpiperidyl-2) -carbinol, form B, so pl. 133 ° and 5.9 g of sodium amide in 500 ml of absolute benzene are boiled for 2 hours in a flask under reflux. A solution of 19.5 g of allyl bromide in 50 ml of benzene is then added and the boil is continued for another 3 hours. A white precipitate falls out. After keeping overnight at room temperature, the reaction mixture is successively washed with water, dilute hydrochloric acid, 2% sodium bicarbonate and again with water, dried over calcined sodium sulphate and evaporated. A total of 29 g of phenyl-allyloxy- (1-formyl-piperidyl-2) -methane is obtained in the form of an orange oil, which is deformed by boiling over a day with a 700 lm solution of hydrogen chloride in absolute methanol with a strength of about 7%. The methanol is evaporated, the residue is dissolved in water, washed with ether and the aqueous phase is alkalinized. The separated bases were extracted with 400 ml of ether (4 times 100 ml each, dissolved over potassium carbonate and evaporated. An oily phenyl-allyloxy- (piperidyl-2) -methane was obtained in an amount of 16.3 g. To obtain the hydrochloride, this oil was dissolved in 200 ml of ethyl acetate and poured thereto with 20 ml of a solution of hydrogen chloride in absolute ether with a concentration of 15%. 17.3 g of phenyl-allyloxy- (piperidyl-2) methane hydrochloride drops out, form B, mp 180-181 °.

Example 9. A mixture of 14.5 g of a levorotatory form of phenyl- (1-benzoylpiperidyl-2) -carbinol and 2.03 g of sodium amide in 500 ml of absolute toluene was boiled for 1.5 hours in a flask under reflux. Then, a solution of 10.4 g of ethyl iodide in 30 ml of absolute toluene is poured and heating is continued for 2 hours.

The mixture was left overnight and then the toluene solution was washed successively with 200 ml of water, 250 ml of two-normal hydrochloric acid and again with water. The washed solution is dried over potassium carbonate and the toluene is distilled off in vacuum at a temperature not higher than 50 °. A 12 g residue is dissolved in 20 ml of benzene and 180 ml of petroleum ether are added. Drops 8.7 g of phenyl-ethoxy- (1-benzoylpiperidyl-2) -methane in the levorotatory form B, so pl. 120-122 °, specific rotation {о.о 99.4 ° (1% in chloroform). After repeated recrystallization from 50 ml of cyclohexane, 7.53 g of product with a melting point of 122 ° and with a specific rotation of Ldb of 106 ° (1% in chloroform) are obtained. Another 1.08 g of product can be isolated from the mother liquor with the same KOI stantam. Phenyl-ethoxy- (1-benzoylpiperidyl-2) -methan to left-handed.

In general, Form B, a total weight of 8.6 g, is de-benzylated by boiling for 3 hours in the presence of lithium aluminum hydride (0.67 g) in 260 ml of tetragndrofuran freshly distilled over metallic sodium. Cool down to 0 ° and successively pour with stirring 0.67 ml of distilled water, 0.67 ml of a four-normal solution of sodium hydroxide and 2.01 / og of water. Continue mixing for 20 minutes at 0 °. The inorganic precipitate is filtered off and dissolved in 50 ml of tetrahydrofuran, boiled for 15 minutes. Filter again, the combined tetrahydrofuran solutions are evaporated at a temperature not exceeding 40 ° and a residual pressure of 20 mm. The resulting oily residue, in an amount of 9 g, is dissolved in ether and the free bases are extracted with two-normal hydrochloric acid. The aqueous c) base is basified and the free bases are extracted again with ether. The ether solution is washed with water, dissolved over potassium carbonate and evaporated. The residual oil (4.7 g) is dissolved in ethyl acetate with a content of 10% ethanol (60 ml) and converted into hydrochloride by the action of 4.8 ml of a 15% solution of hydrogen chloride in absolute ether.

Just get 2.55 g of phenyl-ethoxy- (piperidyl-2) -methanum hydrochloride in the levorotatory form B, t. Pl. 260-265 °, specific rotation a) (1% in chloroform).

The starting 1-benzoylpiperidyl-2-phenylcarbinol in the levorotatory form B is prepared by the action of an equal weight of benzoyl chloride on phenyl (piperidyl-2) -methanol of the same configuration in a mixture of semi-normal caustic potassium and ether. This compound melts at 170 ° and has a specific rotation of W about 109 °, (1% in chloroform),

Example 10. Hydrochloride phenyl-ethoxy- (piperidyl-2) -methanum in the ortho-rotary form B with m. Pl. 260-265 ° (according to Makenna) and specific rotation a (1% in chloroform) can be prepared in the same way as its optical antipode, by debenzoylating phenyl-ethoxy- (1-benzoylpiperidyl-2) -methane in the right rotational form B with mp. . 122 and specific rotation (1% in chloroform). In turn, the benzoyl derivative is obtained from phenyl- (1-benzoylpiperidyl-2) methane with the same configuration, so pl. 170 °, and about 108 ° (1% in chloroform).

Example 11. A solution of para-methoxyphenyl- (piperidyl-2) -chloromethane hydrochloride in form B with m. Pl. 206-208 ° in 150 L1L of alcohol boiled for 2 hours in a flask with reflux condenser; the alcohol is evaporated, the residue is triturated with ether and 3 g of p-parathoxyphenyl-ethoxy- (piperidyl-2) -methanum hydrochloride in form B are obtained, which after recrystallization from methyl ethyl ketone or acetone melts at 237 °.

In this and subsequent examples, the required chloro derivatives are obtained by reacting the corresponding alcohols with thionyl chloride.

Example 12. A solution of 8.8 g of hydrochloride 3,4-methylenedioxyphenyl (piperidyl 2) -chloromethane in the form of B with so pl. 160.5-161.5 ° in 50 liters of ethanol is refluxed for 2 hours. A white solid falls out. Filtration gives 7 g of 3,4 methylenedioxyphenyl-ethoxy- (piperidyl-2) -methane hydrochloride, Form B, t. Pl. 260 ° (after recrystallization from isopropyl alcohol).

Example 13. The procedure is the same as in Example 12, it comes from 2 g of hydrochloride 3,4-1 methylenedioxyphenyl- (piperidyl-2) chloromethane, form 1, t. Pl. 160.5-161.5 ° after recrystallization from isopropyl alcohol. In this way, 1.8 g of 3,4-methylenedioxyphenyl-isopropoxy- (piperidyl-2) -methane hydrochloride, Form B, t.p. 303-305 ° after recrystallization from ethanol.

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Example 14. A solution of 6.5 g of hydrochloride para-ethoxy-phenyl- (piperidyl-2) -chloromethane, form B, t, pl. 168-169 °, 50 g of methanol is boiled for 2 hours in a flask with reflux condenser. After concentration and addition of ether, 6 g of para-ethoxyphenyl-ethoxy- (nineridyl-2) -methane hydrochloride are obtained; form B, so pl. 232 ° after recrystallization from a mixture of isopropyl alcohol and isonpropyl ether.

Subject invention

The method of preparing ethers of aryl-2-piperidyl-carbinal, characterized in that, in order to synthesize an agent against fatigue and depression, the racemate or optically accurate isomer of the threo form of aryl-2-piperidylcarbiiol or its chlorine derivatives is subjected to esterification by known methods - actions compounds containing a lower alkyl or alkenyl radical.