SU356847A1 - - Google Patents

Description

WAY OF OBTAINING DERIVATIVES 6,7-BENZOMORFAN

The invention relates to the field of the preparation of new compounds derived from benzomorphane, may be applied in the pharmaceutical industry and is based on the cyclization reaction of certain substituted 2-benzyl-4-niceridinols, known from 9-monosubstituted or 9-monosubstituted benzomorphans. As a result of the use of 2-benzyl4-piperidinols with other substituents, besides those used in the known cyclization reaction, new benzomorphans are synthesized, which have a greater physiological activity.

A method of obtaining derivatives of 6,7-benzomorphan of the general formula

Kg

nilia, alkynyl, aralcnyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl;

R2 is an alkyl, aryl, heteroaryl, aralkyl group; -Ra is hydrogen or hydroxy-, alkoxy-, alkoxyalkoxy-, acyloxy.

The described method differs from the known one in that the substituted 2-benzyl-4-niperidinols of the general formula

BUT R-i

20

where RJ is an alkyl or aralkyl group; Rg is hydrogen, hydroxy, alkoxy, is cyclized at elevated temperatures with a strong inorganic acid, mainly hydrobromic or phosphoric acid. In this case, it is possible to introduce new or replace existing substituents, as well as to isolate the target product in the form of optical enantiomers or to convert it into salts.

ilpHMep 1. 2-Hydroxy-2,5,9,9-tetramethyl6, 7-benzomorfap

A mixture of 7 g (2- (p-methoxybenznl) -1,3,3,4-tetramethyl-4-piperidiaol and 70 ml of phosphoric acid (89% j is heated to 180-185 ° C for 16 hours. After cooling, the reaction mixture is added liquid ammonium is then extracted with chloroform and the mixture becomes alkaline. The extract is dried over magnesium sulfate and evaporated leaving a solid residue. The latter, after recrystallization from methyl ethyl ketone, melts at 157-16PC with agglomeration at 153 ° C. The yield is 48%. Hydrochloride nlavnts at 180-183 ° C with decomposition.

Similarly, 5-ethyl-2-hydroxy2, 9,9-trimethyl-6,7-bepsomorphan, 2-hydroxy-5propyl-2, 9,9-trimethyl-6,7-benzomorphane hydrochloride, 2-hydroxy-5-phenyl are obtained -2,9,9-trimethyl6, 7-benzomorphan, 2,5,9,9-tetramethyl-6,7-bepsomorphan hydrochloride, 5-ethyl-2,9,9-trimethyl 6, 7-benzomorphan, 2-methyl- 9,9-peptamethylep6, 7-benzomorfan hydrochloride and other compounds.

Example 2. 9,9-Dimethyl-5-ethyl-2-hydroxy-6, 7-benzomorfan

A mixture of 13.5 g of 5-ethyl-2-hydroxy-2,9,9-trimethyl-6, 7-benzomorfana and 52 ml of acetic aphydride is heated to 100 ° C with 45 lshn. After cooling, the solution is poured onto ice, and after conversion to base with 50% liquid potassium hydroxide, the 0-acetyl derivative is obtained by extraction with ether. The product is dissolved in 75 ml of dry chloroform. A solution of 8 g of cyanide bromide in 50 ml of dry chloroform is stirred and added dropwise at room temperature. Stirring is continued for 3 hours at a reflux temperature. The solvent is then removed by evaporation in vacuo, and the residue is heated at reflux for 18 h with a mixture of 160 ml of 4N hydrochloric acid, 160 ml of water and 80 ml of acetic acid. The resulting clear solution is basified with a liquid ammonium solution and the oil, which is separated, is placed in chloroform containing some butanol. The organic solution is dried over magnesium sulfate and concentrated. Stirring the residue with the metapoly causes the product to crystallize. Exit 59%, so pl. 170-174 ° C.

Example 3. 9,9-Dimethyl-5-ethyl-2-hydroxy-2- (3-methyl-2-butenyl) -6,7-benzomorphap bromohydrate.

A mixture of 400 mg of 9,9-dimethyl-5-ethyl-2-hydroxy-6, 7-benzomorphane, 300 mg of 3-methyl-2-butenyl bromide, 250 mg of sodium bicarbonate and 10 ml of dimethylformamide is stirred and heated at 120 ° C. 3, 5 hours The mixture is then concentrated in vacuo, ether is added, the insoluble material is removed by filtration, the filtrate is evaporated in vacuo. The main residue is converted to the hydrobromide, which

after recrystallization from ethanol mixture

and ether melt at 213-215 ° C. Yield 50%.

Similarly, 2-allyl-5-ethyl-2-hydroxy-9, 9-dimethyl-6,7-benzomorphan, 2-allyl-2-hydroxy-5, 9.9 - trimethyl-6,7 - beisomorphane hydrohydrate, 2-cyclopropylmethyl are obtained. -5,9,9-trimethyl-6, 7-benzomorfap hydrochloride, 2-cyclopropylmethyl-2-hydroxy-5, 9,9-trimethyl-6,7 - benzomorphane hydrobromide.

11 p and me 4. 4. 2-cyclopropylmethyl-9,9-dimethyl-5-ethyl-2-hydroxy-6, 7-bepsomorfap bromgadrate

The compound described in the previous example can be obtained through the corresponding compound cyclopronanecarbopyl by reduction with lithium aluminum hydride. This process eliminates the formation of an isomeric derivative of n-cyclobutyl, a by-product that can be molten using the method described in section 13.

To a solution of 1 е 9,9-dimethyl-5-ethyl-2-hydroxy-6, 7-bepsomorphap in 15 g of dry pyridine is added dropwise with stirring

and cooling with ice 1.4 ml of cyclopropanecarbyl chloride. The solution is stirred at ambient temperature for 16 hours and then at 60 ° C for 1 hour and concentrated by evaporation in vacuo, leaving a residue

dissolved in ether.

The ethereal solution is washed with 2n hydrochloric acid, hydrated with a liquid solution of sodium bicarbonate and, after drying, concentrated in vacuo. The residue consists of O, L-di (cyclopropylcarboyl) derivative. A solution of the latter in 10 liters of dry tetrahydrofuran is added dropwise to 1.5 g of lithium aluminum hydride suspended in 20 ml of dry tetrahydrofuran. The mixture is stirred and cooled with ice. Stirring is continued at the temperature of the return cooler. After cooling, 50 ml of wet ether are added to the mixture, and then carefully 10 ml of water. Received

The suspension is filtered and the filtrate, after drying over sodium sulfate, is evaporated in vacuo. Hydrogen bromide dissolved in acetic acid is added to a solution of this precipitate in Q ml of isopropanol until

until the mixture becomes weakly acidic (rPZ).

After the addition of 20 ml of ether, the above product is separated in crystalline form. The yield is 77%, m.p. 280 ° C

with decomposition.

Example 5. 9,9-Dimethyl-5-ethyl-2-hydroxy2-phenethyl-6, 7-benzomorfan bromohydrate

To transfer a mixture of 490 mg of 9.9-dimethyl-5-ethyl-2-hydroxy-6, 7-bepsomorpha, 8 m, 1 l of dimethylformamide and 830 mg of potassium carbonate, 780 mg of phenacetyl chloride are added at room temperature over 20 minutes. The mixture was heated for 3 hours at 120 ° C, then cooled, diluted with water and shifted with the mixture.

the extract is washed with dilute hydrochloric acid and subsequently with a liquid solution of sodium bicarbonate, dried and evaporated.

The residue, consisting of a 1H, O, N-di- (fe1P1 acetyl) derivative of the final material, is dissolved in 10 ml of dry tetrahydrofuran, after which a suspension of 0.5 g of lithium aluminum in 10 ml of dry ether is added to the stirred mixture at room temperature temperature 45 min. Stirring is continued at the temperature of the back of the nostalle refrigerator for 2 hours, after which the mixture is cooled with ice, the organometallic complexes are decomposed by adding 5 ml of water with 5 ml of 48% hydrobromic acid. The organic solvents are removed by vacuum evaporation, leaving a liquid solution from which the semi-solid material is separated as crystals containing one mole of ethanol. The substance is collected by filtration and dissolved in a small volume of ethiol, which can be removed by heating at a pressure of 15 mm and at a temperature of 120 ° C. The yield is 29%. The substance melts partially at 140-150 ° C, then solidifies and finally melts at 222-225 ° C with decomposition.

Example 6. 2-Benzyl-9,9-dimethyl-5-ept2-hydroxy-6, 7-benzomorfap bromohydrate

A mixture of 1.8 g of 9,9-dimethyl-5-ethyl-2-hydroxn6, 7-benzomorfan bromohydrate, 1.7 ml of benzyl chloride, 3 g of potassium carbonate, 2.5 g of potassium iodide is transferred 3 ml of dimethylformamide and heated to 90 ° C 16 hours The reaction of the Eiyjo mixture is processed as usual, a product is obtained which can be contaminated with O, S-dibenzylated material. For cleaning, the product is heated with 48% hydrobromic acid to 90 ° C for 30 minutes. After cooling, the hardened cosiness is then collected and treated with benzene and liquid ammonium. Beisol is evaporated and the rest is dissolved in a small volume of methanol.

The solution is acidified with hydrobromic acid, pacTBopeHiioii in acetic acid, after which metalcutting was added, and the crystalline compound crystallized. The yield is 51%, m.p. 234-236 C (with decomposition) after recrystallization from methyl ethyl ketope (methanol).

Example 7. (+ and) - / 2-hydroxn-5,9,9trimethyl-6, 7-benzomorfan

13.9 g of the racemic compound obtained in accordance with Example 2 are dissolved in 1 liter of a hot liquid solution of 20 g ammopi d (|) -3-bromine. For-8-sulfopate and 15 g of 4ii hydrochloric acid. From the solution, after incubation for 16 hours in the refrigerator, the salt is centrified, which, after being removed from the water, has + 0.20 ° (2% in ethanol). The yield is 4 g.

In 1 hour, the oil that was separated became crystalline. The salt is recrystallized from 200 ml of hot water, obtaining 7.2 substances with + 2.00 ° (2% in ethanol).

Additional amounts of both salts can be obtained from stock solutions. Each of the diastereomeric salts is decomposed by mixing with chlorofor and mn and 20% liquid ammopi. Extras smiling

113 chloroform, enantiomers can be obtained by evaporation of the solvent.

The bases are non-recrystallized from c -,;.; Si methanol n acetone (1: 3). From 3.75 g of salt with «JD + 0.20 - 0.75 g (-) of base is obtained, having - 2.05 ° (2% in ethiol). From another salt (8.5 g), 1.7 g (+) precipitation is obtained with -} - 2.10 °.

Example 8. (+) p (-) 9,9-Dimethyl-5 ethnl-2-hydroxy-6, 7-benzomorfan.

A hot aqueous solution (1 L) of 17.5 g of ammonium (4 -) - 3-bromo-camphor-8-sulfonate, 13 ml of 4N chloric acid and 13 e of the racemic compound obtained in accordance with Example 2 are cooled to room temperature. After 3 hours, the crystals, which were nauchepy, collected. The yield is 16.3 g 1.50 ° (2% in ethanol). This cheese {+ - | -) salt is non-recrystallized from 1 liter of water. The solution is cooled in the refrigerator.

16 hours, giving coarse crystals of pure () salt. The outputs are 7.2 g aJD + 1.80 °. After concentration of the mother liquor to 350 ml, a second batch of less pure product is obtained from 1.65 °.

Note that the diastereomeric salt can be isolated from the mother liquor. As a result, they are combined and ammonium solution is added, and their

the mixture becomes alkaline. The oil is separated, which slowly crystallizes. From this oslovapi (8.5 g), 7 g is converted into I (-) - 3-bromo-camphor-8-sulfonate in the same way as it was written, that is, using 9.5 g

ammonium 1 - (-) - 3-bromocamphor-8-sulfonate 7.1 ml of 4N hydrochloric acid and 500 ml of hot water. At room temperature, the salt is separated and purified by subsequent recrystallization from water.

and isopropanol, get 6 g of pure (-) salt, 83 °. Both ethantiomers are obtained from their salts according to the method described in Example 7. The output is 2.1 g with + 1.50 ° (2% in ethanol) from 6.5 g (+ +) salt, and 1.4 g

s, 50 ° (2% in ethanol) of 5 g ()

salt. Both eiantiomers appear in two modes that are irreversible, namely: one crystallizes from methanol to bulky needles, and others

in raw crystals (also from methanol). Melting point: 190-195 ° C. Melt melt is purified at 215 ° C. A solution of 490 mg of (+) 9,9-dimethyl-5-ethyl-2 hydroxy-6, 7-benzomorfan in 7 ml of dry pyridine is added They were mixed with 700 mg of cyclobutanecarboyl chloride at room temperature. Stirring was continued for 3 hours at room temperature and then at 40 ° C for 10 minutes. The pure tannic reaction mixture is evaporated in vacuo, after which the residue is mixed with ether and water. The ether solution is washed with dilute hydrochloric acid and water, dried and evaporated. A solution of this residue in 25 ml of dry tetrahydrofuran is mixed with a stirred and cooled suspension of 750 mg of lithium aluminum hydride in 15 ml of the same solvent. The mixture is heated with a refrigerator for 3 hours and then the process is carried out as usual .. The product is obtained in the form of hydrochloride, which, after recrystallization from a mixture of ethanol and ether, melts at 285 ° C with decomposition. The yield is 60%, and about + 131 ° (1.2% in dimethylformamide). Example 10. (-) 2-Cyclobutylmethyl-9,9 dimethyl-5-ethyl-2-hydroxy-6, 7-benzomorphane hydrobromide This compound was prepared in a similar manner to method 9. Melting point 288 ° C with decomposition, yield 60%, and ° - 126 ° (1.2% in dimethylformamide). The subject of the invention is a method for producing 6,7-benzomorphan derivatives of the general formula where both R are lower alkyl groups or in combination with d are cycloaliphatic rings; RI is a hydrogen or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, aralkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylidene alkyl, alkyl group; Cs is an alkyl, aryl, heteroaryl, aralkyl group; Ra is hydrogen or a hydroxy, alkoxy, alkoxyalkoxy, acyloxy group, characterized in that the substituted 2-benzyl-4-piperidinols of the general formula where RJ is an alkyl or aralkyl group, Rg is hydrogen, a hydroxy group, an alkoxy group is cyclized at an elevated temperature using a strong inorganic acid, such as hydrobromic acid, phosphoric acid, followed by isolation of the product, possibly after the introduction of new substituents or the replacement of the existing substituents as a base or by transferring it to salt, or by decomposition into optics RP G enantiomers.