KR830000255B1 - Method for preparing dibenzo [a, d] cyclooctene-5,12- (and 6,12) -imines - Google Patents

Abstract

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Description

Method for preparing dibenzo [a, d] cyclooctene-5,12- (and 6,12) -imines

The present invention provides dibenzo [a] useful for the treatment of anxiety stabilizers, sedatives, antispasmodics, muscle relaxants and mixed anxiety depression, minimal brain dysfunction and extrapyramidal diseases such as, for example, Parkinson's syndrome. , d] a method for preparing cyclooctene-5,12- (and 6,12) imine.

The invention also relates to derivatives, optical isomers and pharmaceutically acceptable salts of the compounds of the invention.

It is known in the art that structurally related compounds have similar uses in nature. For example, US Pat. No. 3,892,756 describes 10,11-dihydro-5-dibenzo [a, d] cycloheptan-5,1C-imine and derivatives thereof, and Belgian patent 829,075 describes 9,1C-. Dihydroanthracene-9-1C-imine and its derivatives are disclosed.

It is an object of the present invention to provide a new class of compounds known as dibenzo [a, d] cyclooctene-5-12- (and 6,12) imines, methods of new synthesis of such compounds, pharmaceutical compositions comprising them as active ingredients and sedatives In addition, the present invention provides a new method for treating muscle disorders such as muscle relaxants or extrapyramidal disorders.

Another object of the present invention is the central intermediate, 5,6-dichloro-5,12-dihydro-12-oxodibenzo [a, d] cyclooctene and 6-chloro-5,12-dihydro-12- Oxodibenzo [a, d] cyclooctene.

The novel compound of this invention has a structure of following General formula (1).

Food,

m is 0 or 1,

Q is -CH ₂ -when m is 1, CH ₂ CH ₂ -or -CH = CH- when m is 0,

R is (1) hydrogen,

(2) lower alkyl, in particular C _1-3 alkyl

(3) lower alkenyl, especially C _2-3 alkenyl,

(4) phenyl-loweralkyl, especially phenyl-C _1-3 alkyl, preferably benzyl, and

(5) lower cycloalkyl, in particular C _3-6 cycloalkyl,

(6) lower (cycloalkyl-alkyl), in particular C _3-6 cycloalkyl-C _1-3 alkyl, or

(7) di (lower alkyl) amino-loweralkyl, in particular dimethylaminopropyl,

R ¹ is (1) is hydrogen,

(2) lower alkyl, in particular C _1-3 alkyl,

(3) lower alkenyl, especially C _2-3 alkenyl,

(4) phenyl-loweralkyl, especially phenyl-C _1-3 alkyl, preferably benzyl, or

(5) lower cycloalkyl, in particular C _3-6 cycloalkyl,

R ² is (1) hydrogen,

(2) lower alkyl, in particular C _1-3 alkyl,

(3) lower alkenyl, especially C _2-3 alkenyl,

(4) phenyl-loweralkyl, especially phenyl-C _1-3 alkyl, preferably benzyl, or

(5) lower alkoxy, especially C _1-3 alkoxy, or

(6) di (lower alkyl) amino-loweralkyl, especially dimethylaminopropyl; and

R ² and R ⁴ are each

(1) hydrogen,

(2) halogen, in particular fluoro, chloro, or bromo, preferably bromo,

(3) lower alkoxy, especially C 1-3 alkoxy,

(4) trifluoromethylthio,

(5) cyano,

(6) carboxy, or

(7) hydroxy.

Suitable embodiments of the novel compounds of the invention are those wherein R is hydrogen, lower alkyl or benzyl, R ¹ is hydrogen or lower alkyl, R ² is hydrogen or lower alkyl, and R ³ and R ⁴ are hydrogen.

Other suitable examples of this novel compound are compounds in which R is hydrogen, lower alkyl or benzyl, R ² is lower alkyl, in particular methyl or ethyl, and R ¹ , R ³ and R ⁴ are all hydrogen.

The novel compounds of the present invention wherein m is 1 have the following structural formula.

These can be prepared by various methods depending on the substitution forms present in the final compound.

Compounds with 12-halo substituents are useful intermediates for the preparation of compounds in which R ² is hydrogen, alkoxy or alkyl.

12-Bromona or chloro-compounds are converted to 12-hydrogen compounds by hydrocracking or catalytic hydrogenation with metal hydrides such as lithium aluminum hydride or sodium borohydride. The hydride reaction is carried out in anhydrous medium in the absence of oxygen, in particular in ether solvents such as ether, tetrahydrofuran, dioxane and the like at a temperature of about -10 to 30 ° C.

Compounds wherein R ² is lower alkoxy can be prepared by refluxing the 12-bromo or 12-chloro compound with a suitable lower alkoxide of sodium or potassium for 4-10 hours in the corresponding lower alkanol as a solvent.

Compounds in which R ² is lower alkoxy can be readily prepared by refluxing 2-bromo- or 12-chloro compounds with a suitable sodium or potassium lower alkoxide in a corresponding lower alkanol as a solvent for 4-1-hours. .

Compounds in which R ² is lower alkyl can be prepared by treating a 12-bromo- or chloro compound with a suitable lower alkyl lithium. The reaction is carried out in anhydrous solvents such as benzene, ether and the like at a temperature of -10 to + 10 ° C for 1-4 hours. Many new compounds, especially those in which R ² is lower alkyl, phenyl-lower alkyl or lower alkenyl, are prepared by the formation of imine crosslinks. The reaction is treated with a 6-substituted amino-12-lower alkylene compound in a hydroxyl solvent such as ethylene glycol at a strong base such as sodium hydroxide or potassium at 150-250 ° C. for 12-36 hours. Substituents on the 6-amino group are any group included in the definition of R, or acetyl. Cyclization is carried out in an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane and the like under the influence of butyltium ganthy organic metals at 0 to 35 ° C., especially at room temperature for 30 minutes to 5 hours.

Similarly, the 6-hydroxyamino-12-alkylene compound is cyclized to form 12-alkyl-6,12-N-hydroxyimine. It is treated with generator hydrogen generated by zinc in acetic acid without temperature control and then reacted at 50 to 80 ° C. for 1-5 hours to reduce to unsubstituted 12-alkyl-6,12-imine compounds.

These N-unsubstituted imines are R, such as chromide, bromide or iodide in a solvent such as dioxane, tetrahydrofuran or ether in the presence of an inorganic base such as sodium carbonate, an organic base such as pyridine or an acidic resin such as a basic resin. It can be substituted with the R- group by treatment at reflux temperature with halide for 2-5 days.

The novel compounds of the present invention wherein m is 0 and Q is -CH ₂ -CH ₂ -or -CH ₂ -CH ₂ -have the following structural formula.

They are prepared by various processes depending on the form of substitution present in the final product.

Compounds having 12-halo substituents are useful intermediates for the preparation of compounds in which R ² is hydrogen, alkoxy or alkyl.

12-bromo- or 12-chloro or 6-chloro compounds are either 12- and 6-hydrogen compounds by hydrocracking or by catalytic hydrogenation with metal hydrides such as lithium aluminium hydride or sodium brohydride. Switch to each. The hydride reaction is carried out in an anhydrous medium in the absence of oxygen, i.e. in an ether solvent such as ether, tetrahydrofuran, dioxane, at a temperature of about -10 to 30 캜.

For 6-chloro-Δ6.7-5,12-imine, catalytic hydrogenation reduces the double bonds and hydrocracks the chloro group, while hydrides simply hydrocrack the chloro groups.

Compounds wherein R ² is alkyl may be prepared by treating the corresponding 12-bromo or chloro-compound with the appropriate alkylitrium. The reaction is carried out in anhydrous solvents such as benzene, ether and the like for 1-4 hours at a temperature of -10 ° C to + 10 ° C. Many new compounds wherein R ² is alkyl or substituted alkyl are prepared by the formation of imine crosslinks. One reaction is carried out by treating a 5-substituted-amino-12-alkylene compound in a hydroxyl solvent such as ethylene glycol with a strong base, such as potassium hydroxide or sodium, at 150-250 ° C. for 12-36 hours. Substituents on the 5-amino group may be any group included in the definition of R and may also be acetyl. Cyclization is effected by reacting for 30 minutes to 5 hours at a temperature of 0 to 35 ° C., especially at room temperature, in an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane and the like under the influence of an organometallic substance such as butyrium.

New compounds with substituents on the benzenenoid ring are generally prepared by metaposition synthesis of the appropriate bromo compounds, e.g., 50 to 150 ° C with sodium or potassium lower alkoxide in the presence of copper powder in a solvent such as dimethylformamide. Treatment of 1-1-hours at yields the corresponding lower alkoxy compounds.

These lower alkoxy compounds can be converted to the hydroxy compounds by de-etherification, in particular by pyridine hydrochloride and heating at 200 to 220 ° C. for 3-10 hours.

Similar treatment of the bromo compound and copper cyanide in a solvent such as di-methylformamide at reflux temperature for 1-10 hours yields the corresponding cyano compound.

The cyano compound is hydrolyzed at reflux with an inorganic acid such as hydrochloric acid to produce the corresponding carboxy substituted compound.

The bromo compound is treated in a solvent such as bis (trifluoromethylthio) mercury in a solvent such as dimethylformamide for 1 to 10 hours at reflux temperature to obtain a trifluoromethylthio derivative.

This process can be used to prepare the following compounds.

2- (or 3) -R ³ -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

2- (or 3) -R ³ -12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

R ³ in the above is lower alkoxy, hydroxy, cyano, carboxy or trifluoromethylthio.

Starting materials and methods for preparing the intermediates used in the process are described in detail in the Examples.

Non-toxic pharmaceutically acceptable salts of the novel compounds are also within the scope of the present invention. Imine Compounds Acid addition salts are formed by mixing an imine solution with a solution of pharmaceutically acceptable nontoxic acids such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaphic acid, carbonic acid, phosphoric acid, and the like. When the novel compounds have carboxylic acid groups, their sodium, potassium and calcium salts also belong to the present invention.

5,12-imine of the present invention and 6,12-imine having a substituent on the benzenenoid ring form a diastereomer pair with optically active acids, which are then divided into optical isomers by fractional crystallization and regeneration of optically active free bases. Can be.

In the treatment method of the present invention, the dibenzocyclooctene-6,12-imine of the present invention is about 0.01-50 mg / kg (body weight), particularly, 0.05-10 mg / kg at a dosage level of 1-4 times a day for excessive sedation or sleep. It can relieve anxiety without causing it. It is useful for the treatment of muscle relaxants and mixed anxiety depression, minimal brain dysfunction and extrapyramidal diseases such as Parkinson's syndrome. The exact amount of treatment depends on the individual case of the animal or human being treated and in the final analysis the exact amount of treatment is left to the differences of therapists.

Pharmaceutical compositions comprising the imine of the invention are also within the scope of the invention. These compositions are in the form of single doses containing 0.1-100 mg of active ingredient such as tablets, pills, capsules, powders, granules, parenteral income solutions or suspensions, suppositories for oral, parenteral or anal administration.

The following examples illustrate, but are not limited to, the products, methods of preparation, methods of treatment or compositions of the present invention.

Example 1

12-bromo-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Step A

Preparation of 8,8-dichloro-2,3,5,6-dibenzobicyclo [5,1,0] octan-4-one

5H-dibenzo [a, d] cyclohepten-5-one (20.52 g, in a 500 ml round flask, dried with a flame, equipped with a dropping funnel, agitator and a condenser with a calcium chloride drying tube and cleaned with nitrogen. 0.1 mol) sodium methoxide (50 g, 0.925 mol) and 150 ml of dry benzene are added and the mixture is cooled in an ice bath with stirring. Ethyl trichloroacetate (165 g, 0.25 mol) was added dropwise over 3-4 hours with vigorous stirring and the mixture was stirred again at 0 ° C. for 5 hours and at room temperature overnight. Water (150 mL) is added to hydrolyze the mixture and the benzene phase and the aqueous phase benzene extracts are combined to evaporate the solvent under reduced pressure on a steam bath. Grinding of the brown residue results in rapid crystallization, recovery of the solid product, washing with cold methanol and recrystallization from methanol yields 17.65 g (61%) of product having a melting point of 132-133 ° C.

Step B

Preparation of 5,6-dichloro-5,12-dihydro-12-oxodibenzo [a, d] cyclooctene

37 g of 8,8-dichloro-2,3,5,6-dibenzodicyclo 5,1,0 octane-4-one and 200 ml of nitrobenzene were refluxed for 4 hours, then the solvent was distilled off by steam and the residue Crystallization twice from acetonitrile gave 28 g of 5,6-dichloro-5,12-dihydro-12-oxo-dibenzo [a, d] cyclooctene with a melting point of 123-125 ° C.

Step C

Preparation of 6-chloro-5,12-dihydro-12-oxo-dibenzo [a, d] cycloocte

A drop of 14.4 g of dichloro-ketone obtained from 75 mL of tetrahydrofuran and 125 mL of ether in 125 mL of ether was added dropwise with stirring over 1 hour to 3.8 g of lithium aluminum hydride slurry in 400 mL of ether. do. The resulting mixture was refluxed for 10 minutes and removed by addition of 13 ml of water with stirring of excess lithium aluminum hydride and the mixture was filtered to wash the inorganic residue with ether. The combined filtrate and washings are dried (magnesium sulfate), filtered and evaporated to dryness to yield 13.8 g of oil. The oil is dissolved in 500 ml of acetone and drops over 40 minutes at 5 ° C. with stirring of 1.4 M chromium trioxide (mixing 70 g of C ₂ O ₃ and 61 ml of sulfuric acid with water to 500 ml) in 40 ml of aqueous sulfuric acid. The solution is added dropwise and stirred for 1 hour at room temperature, and then isopropane is added dropwise until the orange color develops. Pour the acetone and wash the residue (A) with acetone to evaporate the combined acetone solution to dry. (B) The residue (A) is dissolved in 200 ml of water and extracted with 300 ml of ether to add an ether extract to the residue (B) and the solution is extracted with water. The water extract was extracted twice again with 200 mL of ether, and the combined ether extracts were washed with 200 mL of water and water was extracted again with 150 mL of ether. The combined ether phases were dried (magnesium sulphate), filtered and evaporated to give 12.7 g of impure product which was recrystallized from methanol and 10.6 g (83%) of 6-chloro-5, having a melting point of 109-110 ° C., 12-dihydro-12-oxo-dibenzo [a, d] cyclooctene is obtained.

Step D

Preparation of 6,12-dioxo-5,6,7,12-tetrahydro-dibenzo [a, d] cycloocte

A mixture of 40 g of monochloroketone and 240 ml of n-butylamine from step c is stirred and refluxed for 23 hours under anhydrous conditions and then the mixture is evaporated to dry under vacuum. The residue is dissolved in 800 ml 0.5N hydrochloric acid and filtered to heat the filtrate in a steam bath for 2 hours. After cooling, the precipitate was recovered, washed with water and dried to obtain 36 g of 6,12-dioxo-5,6,7,12-tetrahydro dibenzo [a, d] cyclooctene having a melting point of 158-160 ° C. .

5H-dibenzo [a, d] cyclopenten-5-one used in the step but using the same process as described in step AD of Example 1 is equivalent to 3-bromo-5H-dibenzo [a, d Cyclohepten-5- is converted to 3-chloro-5H-dibenzo [a, d] cyclohepten-5-one or 3-fluoro-5H-dibenzo [a, d] cyclohepten-5-one And substituted with 5-chlorobromobenzene as a solvent in step B, so that 2-bromo-6,12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene, 2-chloro-5,12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene and 2-fluoro-6, having a melting point of 148-149 ° C .; Prepare 12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene.

Step E

Preparation of 12-hydroxy-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

A mixture of 4.72 g (0.02 mole) of diketone from step D and 3.93 g of methylamine in 270 g of tetrahydrofuran was stirred for 5 hours at room temperature under anhydrous conditions and cooled to 10 ° C., followed by 3.6 g (0.06 mole) of 3.77 g (0.06 mol) of sodium cyanoborohydrate are added with vinegar and the mixture is stirred at room temperature for 30 minutes. The supernatant is decanted and the precipitate is washed with benzene and ether, the combined supernatant and wash are evaporated in vacuo and the residue is partitioned between benzene and 200 mL of 1N hydrochloric acid. The aqueous layer is separated and made basic with an aqueous sodium hydroxide solution, and then the product is filtered and washed with water. Recrystallization from benzene results in 3.9 g of 12-hydroxy-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine having a melting point of 237-239 ° C. To obtain.

Using the process as described in step E of Example 1, 6,12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene is equivalent to 2-bromo- and 2-bromo- and 2-chloro-12-hydroxy-13, each substituted with 2-chloro-6,12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene -Methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine is prepared.

Step F

Preparation of 12-bromo-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

2.5 g of carbinol obtained from 50 mL of toloe in step E were refluxed with 1.0 mL of phosphorus tribromide for 6 hours, and the mixture was concentrated to dryness and the residue was concentrated to 250 mL of water, 300 mL of Benzene; Dissolve at ice bath temperature in a mixture of ether (1: 1 v / v) and 25 mL of 5% (w / v) aqueous sodium hydroxide solution. The organic layer was separated, washed with cold water, dried (sodium sulfate), filtered and concentrated to yield 2.7 g of impure product having a melting point of 135-139 ° C. This material was chromatographed on 150 g silica gel using chromoform saturated with ammonium hydroxide as eluent and recrystallized from cyclohexene. Then, 2.0 g of 12-bromo-13-methyl having a melting point of 147-149 ° C was obtained. Obtain -5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine.

2-Bromo- and 2-chloro-12-bromo-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene- using the process of Step F of Example 1 6,12--can produce imine

Example 2

12-methyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrochloride

A solution of 3.1 g of 12-bromo compound obtained from step F of Example 2 in 270 ml of anhydrous ether and 30 ml of benzene was stirred while cooling by an internal ice bath under nitrogen atmosphere (about 0.95 M Dropwise to 30 ml of ethyltium over 70 minutes. After stirring for another hour while cooling, excess ethyltium is decomposed by adding a drop of water. The ether solution is washed with water until neutral and concentrated to dryness (sodium sulfate), filtered and dried. The residue is triturated with 50 ml of hexane, the supernatant is decanted and concentrated to dryness to yield 1.95 g of viscous yellow oil. 10 ml of 95% ethanol and 90 volumes of toluene mixed with this oil are used as eluents and chromatographed on 200 g silica gel, and the combined fractions of 4 ml are collected according to the tin layer chromatographic comparison. The eluted material fraction 43-70 contains 650 mg of oily solid. 650 mg of this material is dissolved in 5 ml of warm methanol and treated with ethanol 0.3 ml 9NHCl. Dilution with 15 ml of anhydrous ether results in crystallization of 550 mg of hydrochloride salt having a melting point of 267-269 ° C. (decomposition). It was recrystallized from methanol-acetone to give 12-ethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrochloride having a melting point of 273-274 ° C. To obtain.

2-Bromo and 2-chloro-12-ethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrochloride are prepared in a similar manner do.

Example 3

12-methoxy-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

1.6 g 12-bromo-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (Example 1), 0.3 g sodium methoxide And 30 ml of a mixture of methanol were refluxed for 6 hours, then concentrated to dryness and the residue was stirred for 30 minutes with 100 ml of ether. The mixture was filtered and concentrated to dryness, 0.78 g of 12-methoxy-13-methyl-5,6,7,12-tetrahydro having a melting point of 70-90 ° C. and recrystallization from methanol-water of 91-93 ° C. Obtain dibenzo [a, d] cyclooctene-6,12-imine.

Example 4

13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine oxalate

Step A

12-chloro-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-12-imine

The mixture of 0.7 g of 12-hydroxy compound obtained from the step of Example 1 in 10 ml of thionyl chloride was refluxed for 1 hour and then concentrated in vacuo and the residue was co-distilled with dry benzene. Trituration of the residue with ether twice gives a white solid that can be used directly in the next step.

Step B

Preparation of 13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-dioxalate

The product from step A is suspended in a mixture of 10 ml dry ether and 20 ml dry tetrahydrofuran and treated with 0.8 g of lithium aluminum hydride (51.6% by weight) of mineral oil suspension under nitrogen atmosphere with stirring. The mixture is refluxed for 1 hour and then stirred overnight at 20-25 ° C. The mixture is treated with 1.5 ml of water, the supernatant is decanted and the residue is extracted well with ether, the combined extracts are dried and concentrated. The oily residue is partitioned between benzene and 1N aqueous hydrochloric acid solution, benzene is extracted again with 1N hydrochloric acid solution, the combined acid extracts are basified with 10N sodium hydroxide solution and then extracted again with benzene. Benzene is washed with water, dried and concentrated and the residue (0.63 g) is dissolved in 7 ml of acetone and 7 drops of ethanol and treated with 0.27 g of oxalic acid solution in 1 ml of acetone. 0.72 g of product having a melting point of 176-178 ° C. was recovered and recrystallized twice from methanol, followed by 13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cycle having a melting point of 178-180 ° C. Obtain octene-6,12-imine oxalate.

In a similar manner, 2-bromo- and 2-chloro-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imines are prepared.

Example 5

12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrochloride

Step A

Preparation of 6,6-spiro (ethylenedioxy) -12-oxo- (OXO) -5,6,7,12-tetrahydroxydibenzo [a, d] cyclooctene.

A mixture of 40 g of 6,12-dioxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene, 35 ml of ethylene glycol, 250 mg of p-toluene sulfonic acid and 600 ml of benzene It is refluxed for 22 hours in the Dean-Stark apparatus. The cooled mixture is filtered to give a solid (A) after washing the solid with water. The organic filtrate is dried (sodium sulfate), concentrated after filtration and the remaining residue is washed with a small amount of cooled benzene and with hexane to give residue B.

When A and B are combined, 44.3 g of 6,6-spiro (ethylenedioxy) -12-oxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclone has a melting point of 195-198 ° C. Obtain octene.

Step B

Preparation of 12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one

A solution of 2.0 M of methylitrium (125 mL) in tet is added dropwise to a slurry of 44.3 g of the eltirendioxy compound obtained from the step in 1 L of ether with stirring and after overnight stirring, the mixture is lump-water Spills on

The ether was separated, washed twice with 200 ml of water (Na ₂ SO ₄ ), filtered and evaporated. The residue was treated with 400 ml chloroform and 200 ml 4N hydrochloric acid to reflux for 18 hours. The oil phase is washed twice with 150 mL of water and water is extracted again with 150 mL of croro product to dry the combined organic phases (magnesium sulphate), filter and concentrate. The crystalline residue was washed with hexane and 34.5 g (94% from ditetone) of 12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6 having a melting point of 68-70 ° C. -Get on.

Step C

Preparation of 6-methylamino-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene and hydrochloride

The product from step B (2.0 g) is added to a solution of 6.5 g of methylamine in 200 ml of tetrahydrofuran, a slight molecular sieve is added as a desiccant and the mixture is stirred for 1 hour. After cooling to 5 ° C., 3 g of vinegar acid is added and after 5 minutes 3 g of sodium cyanoborohydride are added and the mixture is stirred for one week (about 72 hours).

The mixture is filtered to evaporate the filtrate and the residue is added with 150 ml of water and concentrated hydrochloric acid until pH 1-2. After 1 hour the mixture is washed with 100 ml of ether and the ether is discarded.

Ammonia aqueous solution was made into a mixture of base and extracted three times with 100 ml of ether, and the combined extracts were dried (sodium sulfate), filtered and concentrated. Washing the residue with hexane yields 1.9 g of freebase product. It was dissolved in 20 ml of 4N hydrogen chloride methanol solution, concentrated, and the residue was triturated with ether and recrystallized from acetonitrile. 1.9 g of 6-methylamino-12-methylene-5 having a melting point of 238-242 DEG C (decomposition), 6,7,12-tetrahydrodibenzo [a, d] cyclooctene hydrochloride is obtained.

Step D:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrochloride.

A mixture of 7.1 g secondary amine, 4.6 g potassium hydroxide solid and 150 ml ethylene glycol obtained from step C is refluxed under nitrogen atmosphere for 18 hours. From the mixture, distilled the ethylene glycol (100 mL) at 62 ° C / 0.3 mmHg, the reaction mixture was poured into 600 mL of water, extracted three times with 250 mL of ether, the extracts were combined and slurried with 350 mL of water, and then 100 mL. After washing with ether, the mixture was basified with concentrated aqueous ammonia solution and extracted three times with 150 ml each. The combined ether extracts were dried (sodium sulfate), filtered and evaporated to yield 5.8 g of impure product. The impure material is dissolved in 75 ml of acetone, treated with 2.0 g of oxalic acid in 25 ml of hot acetone and cooled to recrystallize the precipitate from methanol to give 5.2 g of oxalate salt. It is dissolved in 200 ml of aqueous ammonia and 250 ml of ether, the ethers are separated, washed with water, dried (sodium sulfate) and filtered and evaporated. The residue is dissolved in 50 ml of methanol and treated with 3.5 ml of 11N hydrogen chloride ethanol solution. The mixture is concentrated and the residue is slurried with 200 mL of ether and filtered to recover solid (4.6 g). This solid was refluxed with 100 ml of acetone, cooled in a freezer and filtered to yield 3.7 g of product having a melting point of 249-254 ° C. 350 ml of acetone was concentrated to 150 ml and recrystallized to give 3.1 g of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6, having a melting point of 252-254 占 폚. Obtain 12-imine hydrochloride.

Step D (Transformation Method):

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrogen oxalate

2.1 g (7.3 mmol) of 6-methylamino-12-methylene-5,6,7,12-tetrahydrodibenzo [ad] cyclooctene hydro stirred in THF (75 mL) dried at room temperature and under nitrogen atmosphere To chloride, butyriumium (6.5 mL, 1.6 M) in hexane is added and the mixture is stirred for 24 hours, treated with ice water (2 mL) and concentrated under reduced pressure. The residue was treated with water (50 mL) and extracted with ether (3 × 25 mL). The combined ether solutions were washed with water, dried over potassium carbonate and filtered and evaporated under reduced pressure to yield 12,13-dimethyl-5,6 as yellow oil. , 7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine is obtained.

The oil dissolved in acetone (2 ml) was treated with oxalic acid (0.96 g, 0.01 mol) in acetone and cooled to obtain 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d as white powder. Cyclooctene-6,12-imine hydrogenoxalate is obtained (2.4 g, 96%). Recrystallization from methanol yields 1.2 g (48%) of product having a melting point of 181.5-3.5 ° C. (decomposition).

Example 6

12-ethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrochloride

Step A:

Preparation of 6,6-spiro (ethylenedioxy) -12-ethylidene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene.

To a stirred slurry of ethyl triphenylphenylphosphonium bromide (4.9 g, 0.11 mole) in ether (400 mL) was added m-butyltium (50.3 mL, 2.17 M) in hexane and the resulting solution was dried THF (300 mL). Solution of 6,6-spiro- (ethylenedioxy) -12-oxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (29 g, 0.10 mol) in Time to reflux. The solvent is evaporated and the residue is partitioned between water (300 mL) and chloroform (500 mL) and the chloroform solution is dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica-gel using chloroform as eluent to give 20.3 g of 6,6-spiro (ethylenedioxy) -12-ethylenedene-5,6,7,12- having a melting point of 84-86 ° C. Tetrahydrodibenzo [a, d] -cyclooctene is obtained.

Step B:

Preparation of 12-ethylriten-5,6,7,12-tetrahydrodibenzo [a.d] cyclooctene-6-one.

Of 6,6-spiro (ethylenedioxy) -12-ethylidene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (15.4 g, 0.053 mol) in HCCl ₃ (400 mL) The solution is slurried and refluxed with 4N hydrochloric acid (200 mL) for 3 hours. The HCCl ₃ solution is separated, washed with water, dried over sodium sulfate, separated by filtration and the filtrate is evaporated. Recrystallization of the residue from acetonitrile yields 11.8 g of 12-ethylidene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one having a melting point of 145-147 ° C.

12-methylene-5,6,7,12-12-tetrahydrodibenzo [a, d] cyclooctene-6- used in the process as described in steps C and D of Example 5 but in step C Substituting on produces the following compounds.

Step C:

12-ethylidene-6-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene and hydrochloride thereof.

Step D:

12-ethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrochloride or hydrogenoxalate.

Example 7

12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Step A:

Preparation of 6-hydroxyamino-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene.

5.8 g of 12-methylene-6-oxo-5,6,7,12-tetrahydrodibenzo [a, d] cyclomotene, 2.4 g of hydroxyamine hydrochloride, 4.8 g of sodium acetate trihydrate and 130 The mixture of ml of ether was stirred at room temperature for 24 hours, the supernatant was decanted from the solid, and the residue was washed well with ether. The combined ether solutions were washed three times with 75 ml of water, dried (natrasulphate) and concentrated. 6.2 g of 6-hydroxyimino-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene were obtained as white crystals of 119-123 ° C.

Step B:

Preparation of 6-hydroxylamino-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene.

A solution of oxyl, 6.2 g of hydrogen chloride in 4.5 mL of 7N ethanol and 200 mL of methanol from step 6.2 g was stirred at room temperature and 2.1 g of sodium cyanoborohydride were added in small portions over 20 minutes and again after 2 minutes Hydrogen chloride in ml 7N ethanol was added and stirred for 1.5 kH. The solvent was evaporated and the residue was partitioned between chloroform and 5% (W / V) aqueous sodium hydroxide solution. The chloroform extract was washed with water, dried (sodium sulfate) and concentrated to give 6.3 g of 6-hydroxyamino as a colorless glass. -12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene is obtained.

Step C:

Preparation of 12-hydroxy-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine.

The solution of the hydroxyl amino compound obtained from the 5 g step in 200 ml of dry xylene was added dropwise to the 200 ml reflux xylene over 80 minutes with stirring, and then refluxed for another 1.5 hours and the solvent was evaporated in vacuo. Crystallization of the residue from 50 ml of 95% ethanol yielded 2.6 g of 13-hydroxy-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12- having a melting point of 186-192 ° C. Obtain imine.

Step D:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine.

To a stirred solution of 17.95 g of imine from 70 ° C. in glacial acetic acid was added zinc powder (20.0 g) in small portions over 25 minutes and the exothermic reaction mixture was cooled to about 60 ° C. and then 2.5 at 60-65 ° C. Stir for time. The mixture is cooled to room temperature, filtered and the precipitate is washed with vinegar acid. The filtrate and washings were concentrated in vacuo and the residue was partitioned between ether and 10% (W / V) aqueous sodium hydroxide solution. The separated ether layer was washed with water, dried (sodium sulfate) and concentrated to give a melting point of 102-104 ° C. 16.4 g of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cychlorooctene-6,12-imine is obtained.

Example 8

13-benzyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine, hydrochloride

2.6 g 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine, 1.55 g benzyl chloride, 3.2 g sodium carbonate anhydrous and 50 ml dioxane The mixture of was stirred at reflux for 5 days, the mixture was filtered and the filtrate was evaporated to dryness in vacuo to give 4 g of oil. The oil was dissolved in 15 ml of anhydrous ethanol, treated with hydrogen chloride in 1.6 ml of 7N ethanol, diluted with 70 ml of anhydrous ether, and recrystallized from 2.5 g of anhydrous ethanol having a melting point of 265-270 ° C. 2.2 g of phosphorus was obtained, which was mixed with 300 mg of similar material and recrystallized from a mixture of 8 ml of methanol and 20 ml of ether to give 2.15 g of 13-benzyl-12-methyl- having a melting point of 245 ° C. (decomposition). 5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrochloride is obtained.

Example 9

6,13,13-trimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Step A:

Preparation of 6-hydroxy-3-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

Magnesium ribbon 9 (3.03 g, 0.125 mol) is placed in 18 ml ether. A solution of 7.8 ml (17.9 g, 0.126 mole) in 37 ml ether is added and about 3.5 ml of solution is added to the magnesium slurry. When the mixture is slowly heated, the Grinaad reaction begins and the remaining iodine solution is added at a rate that maintains a stable reflux. The reaction mixture is kept under nitrogen atmosphere. After the addition was completed, the mixture was refluxed for 1 hour, cooled to room temperature, and then stirred in Grinaad solution in 15.1 g (0.065 mol) of 12-methylene-6-oxo-5,6,7,12 in 100 ml of ether. A solution of tetrahydrodibenzo [a, d] cyclooctene is added over 5 minutes and the resulting mixture is stirred at room temperature for 1 hour and then quenched in 1 liter of ice water containing 5 g of ammonium chloride. The resulting suspension was extracted three times with ether (200 mL) and the combined extracts were washed once with dilute sodium sulfite, once with dilute sodium bicarbonate and twice with water. The washed ether solution was dried over potassium carbonate, filtered and vacuum evaporated to give 17.7 g of 6-hydroxy 6-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] as colorless oil. Obtain cyclooctene.

Step B:

Preparation of 6,12-dimethyl-6-hydroxy-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

The impure methylene compound (17.7 g) from step A in 100 mL of anhydrous ethanol was treated with 1 g of decolorized oxygen, filtered and additionally 80 mL of ethanol was added followed by 0.5 g of 10% pd / activated catalyst. Add and hydrogenate the mixture at 50 p.sig.

After taking 1 molar equivalent, hydrogenation was continued until hydrogen absorption was stopped, and then the mixture was filtered and distilled under vacuum. The mixture of two isomers was 15.8 g of impure 6,12-dimethyl-3- having a melting point of 100-135 ° C. Obtain hydroxy-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene.

Step C:

Preparation of 6-acetylamino-6,12-dimethyl-5,6,7,12-detrahydrodibenzo [a, d] cyclooctene

Dimethylcarbinol (11.5 g. 0.046 mol) from step B is dissolved in 120 ml of acetonitrile and 50 ml of 95% sulfuric acid is added with stirring in ice. The rate of addition is controlled to maintain the temperature of the mixture at 15 ° C. After the addition is complete the mixture is stirred for 3 hours at room temperature and then quenched in 700 ml of ice water. The obtained slurry was stirred for 15 minutes, filtered and the filtrate was extracted twice with chloroform, and the filtered solid was dissolved in the same solvent (total volume 400 ml). The combined chloroform fractions were triturated twice with water, once with sodium bicarbonate and once with water, dried over potassium carbonate, filtered and evaporated. The solid obtained was dried overnight at 40 ° C under vacuum for 13.2 g of 6-acetylamino-6,12-dimethyl-5,6,7,12-tetradibenzo [a, d] having a melting point of 185-224 ° C. Obtain cyclooctene (mixture of isomers). Recrystallization from ethanol yields a material with a melting point of 232-233.5 ° C.

Step D:

Preparation of 6- (N-acetyl-N-methylamino) -6,12-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

Methylrium (42 mL 1.8 M solution, 42 mL) in diethylpropylamine (7.6 g, 0.973 moles) in 75 mL of tetrahydrofuran (THF) previously dried on molecular sieves was stirred in an ice bath and kept under nitrogen atmosphere. 0.076 mol) is added dropwise. The mixture is stirred for 30 minutes in an ice bath and then transferred to an addition funnel attached to a separate reaction vessel via a shiring.

Lithium diisopropylamide was added to the reaction vessel by adding 12.7 g (0.043 mol) of the amide compound from Step C and 50 mg of triphenylmethanol dissolved in 150 ml of THE while stirring the amide solution in ice under nitrogen atmosphere. The solution is added dropwise at a rate sufficient to maintain a reaction temperature below 10 ° C. The addition was continued until the orange color of triphenylmethane was developed, and the mixture was stirred for 15 minutes, and then 17 ml of methyl iodide in 20 ml of THF was added at a rate such that an internal temperature of 10 ° C. or lower was maintained, and the mixture was iced. Stir for 1 hour in a bath and again for 1 hour at room temperature.

The solution was quenched in 1.5 ml ice-water and extracted three times with chloroform and the combined chloroform fractions were washed twice with water, twice with 1N hydrochloric acid, twice with dilute sodium sulfite solution and twice with water and dried over sodium carbonate. After filtration and vacuum evaporation, 11.2 g (0.036 mol) of 6- (N-acetyl-N-methylamino) -6,12-dimethyl-5,6,7,12-tetrahydro having a melting point of 118-187 ° C Dibenzo [a, d] cyclooctene (mixture of isomers) is obtained. Chromatography on silica gel elutes with chloroform and recrystallizes from acetone hexane to give a material having a melting point of 150-151.5 ° C.

Step E:

Preparation of 6- (N-acetyl-N-methylamino) -6-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

N-methylamide compound from step E (11.9 g, 0.039), 11 g (0.048 M) of 2,3-dichloro-5,6, -dicyano-1,4-benzoquinone (DDQ) and 1.1 L of benzene The mixture was refluxed under nitrogen for 40 minutes, and the mixture was cooled, washed three times with 1N sodium hydroxide solution and twice with water, dried over potassium carbonate, filtered and evaporated in vacuo to give 11.4 g of 6- (N-acetyl-N as brown oil). -Methylamino) -6-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene is obtained.

Step F:

Preparation of 6,12,13-trimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

8.6 g (0.033 M) of N-methylamide obtained from Step E in 86 ml of ethylene glycol are treated with 2.9 g (0.052 mol) of potassium hydroxide and the mixture is refluxed under nitrogen atmosphere for 24 hours. The solution is cooled, quenched in 1 L of ice water and the resulting slurry is extracted three times with chloroform.

The combined chloroform extracts are washed with water, dried over potassium carbonate, filtered and evaporated in vacuo to give 6.5 g of a tan oil. The oil is treated with hydrogen chloride (excess) in ethanol, vacuum evaporated and the residue is triturated twice with ether and re-evaporated to give 10.4 g of an impure gray solid. Recrystallized from ethanol, 6,1,2,13-trimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imihydrochloride having a melting point of 287-288 ° C. Get

Example 10

2-methoxy-12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

0.00905 moles of 2-bromo-12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] zocyclooctene-6,12-imine, 0.181 moles of sodium methoxide, 5.56 A mixture of g powder and 87 ml of DMF is heated and stirred in a steam bath for 2.5 hours and then cooled to add 150 ml of water and 150 ml of ether to the mixture, stirred and the mixture is filtered through a celite pad. . The ether phase is separated, washed with water, dried over magnesium sulfate, filtered and the ether is removed on a rotary evaporator. The residue is dissolved in warm acetonitrile and left to crystallize. The supernatant containing the desired product was decanted from the crystals and the solvent evaporated to 2-methoxy-12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12 -Get immigration.

Example 11

13-ethyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Step A:

Preparation of 13-acetyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Dissolved stirring of 3.5 g of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine with 2.0 g of triethylamine in 60 mL of anhydrous ether And acetyl chloride (1.45 g) was added dropwise to the ice cooled solution, and after 20 minutes at room temperature, the mixture was diluted with ether and filtered.

The filtrate was evaporated and the residual solid was recrystallized from ethanol-water to yield 2.25 g of a white crystalline solid with a melting point of 143-144 ° C. The precipitate is suspended in water, ether is extracted, and the washed and dried ether extract is evaporated in vacuo to yield 1.6 g of white crystalline solid with a melting point of 142-144 ° C. The two portions combined with 0.35 g of analogue and recrystallized from 50% ethanol yielded 4.1 g of 13-acetyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine is obtained.

Step B:

Preparation of 13-ethyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

A solution of 0.98 moles of diborane (10 ml) in tetrahydrofuran (10 ml) was added to 2.8 g of an amide solution obtained from 30 ml of dry tetrahydrofuran stage with stirring under a nitrogen atmosphere with stirring and stirred overnight. Treat with water and vacuum distillate tetrahydrofuran.

The residue is partitioned between ether and dilute sodium hydride, the ether layer is separated, washed with water and extracted with 1N hydrochloric acid. The acid extract is basified with 5% (W / V) aqueous sodium hydroxide solution and extracted with ether-benzene (1: 1). Vacuum evaporation of the washed and dried organic extract yields a product of 1.75 G having a melting point of 152-158 ° C. Recrystallization twice from 95% ethanol gave 1.35 G of 13-ethyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12 having a melting point of 159-161 ° C. Obtain white crystals of imine.

Example 12

13-benzyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

To a solution of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (2.35 g) and benzaldehyde (1.1 g) in THF (100 mL) 1 ml) and NaCHBH ₃ (1.0 g) are added and the mixture is stirred for 2 days and then filtered to evaporate the filtrate. The residue is slurried with 1N aqueous ammonium hydroxide solution and extracted with chromoform. The chloroform extract was dried over sodium sulfate, filtered and evaporated and the residue was recrystallized from ethanol to give 13-benzyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12 -Get immigration.

Example 13

13-allyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

Of 2.6 g 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine, 1.8 g aryl bromide, 3 g anhydrous sodium carbonate and 50 ml dry benzene The mixture is stirred at reflux for 20 hours, the mixture is filtered and the filtrate is evaporated to dryness in vacuo to yield 1.6 g of solid with a melting point of 90-107 ° C. This product was mixed with 0.274 g of analogue and recrystallized twice from 95% ethanol to give 1.6 g of 13-allyl-12-methyl-5,6,7,12-tetrahydro as a white crystal with a melting point of 112-114 ° C. Obtain dibenzo [a, d] cyclooctene-6,12-imine.

Example 14

18-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrogen chloride

Step A:

Preparation of cis- and trans 2,3: 5,6-dibenzo-8,8-dichloro-6- (N-methylamino) bicyclo [5,1,0] octane hydrogen chloride

Methylamine is passed through 150 mL of benzene stirred at room temperature until 3.1 g (0.1 mole) of methylamine is absorbed. To the obtained solution was added [5,1,0] octane-4- (7.5 g, 0.26 mole) with 2,3: 5,6-dibenzo-8,8-dichlorocycle while stirring and then in 20 ml of benzene. Dissolved 0.013 mole (2.47 g, 1.43 mL) of tinanium tetrachloride is added. The red slurry is stirred overnight and the mixture is treated. The slurry is stirred overnight at room temperature.

The mixture was treated with 100 ml of 1N sodium hydroxide and 150 ml of water, extracted three times with ether (100 ml), the ether extract was washed three times with water, dried over sodium sulfate, filtered and evaporated in vacuo to give 8.9 g of pale orange color. Gets oil. The oil is dissolved in 50 ml of methanol, treated with excess hydrogen chloride in ethanol and left to stand. The obtained white crystalline solid was separated by filtration and recrystallized from a mixture of 250 ml of methanol and 150 ml of ethanol to give a trans crystalline solid having a melting point of 280-285 ° C. as a white crystalline solid, 2,3: 5,6-dibenzo-. Obtain 8,8-dichloro-4- (N-methylamino) bicyclo [5,1,0] octanehydrogen chloride.

The mother liquor was concentrated to 150 ml and left as a white crystalline solid having a melting point of 340 ° C. as cis 2,3: 5,6-dibenzo-8,8-dichloro-4- (N-methylamino) bicyclo [5, 1,0] octane hydrogen chloride is obtained.

Step B:

Preparation of 6-chloro-13-methyl-6,12-dihydrodibenzo [a, d] cyclooctene-6,12-imine hydrogen chloride

2,3: When 5,6-dibenzo-8,8-dichloro-4- (N-methylamino) bicyclo [5,1,0] octane hydrogen chloride (mixed isomers, mainly trans) becomes homogeneous The ether and excess potassium hydroxide aqueous solution and agitated are separated and the aqueous layer is extracted twice with ether. The combined extracts were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to give 2,3: 5,6-dibenzo-8,8-dichloro-4- (N-methylamino) bicyclo [5,1, 0] octane (mixed isomers) is obtained.

20 g (0.066 mol) of the amine and 100 mL of tetramethylurea are combined and heated at 200 ° C. for 2 hours under reflux condenser and drying. The mixture was cooled, treated with 400 ml of water and 65 ml of 1N sodium hydroxide, extracted three times with ether, and the combined ether fractions were washed with water, dried over sodium sulfate, filtered and evaporated under vacuum to afford 19.4 g of impure brown solid. do. The solid was dissolved in 300 µl of warm methanol, treated with hydrogen chloride in 35 ml of 8.3 N ecanol, and cooled for 2 hours. Cis-2,3: 5,6-dibenzo-8 was unreacted as a pale yellow crystalline solid. Obtain 8, dichloro-4- (N-methylamino) bicyclo [5,1,0] octane hydrogen chloride (5.56 g, 0.016 mol, 25%).

The mother liquor is concentrated in vacuo and the oil obtained is treated with 600 ml acetone and left at room temperature for 2 hours. The white solid (1.4 g) was filtered and the filtrate was evaporated. The brown solid obtained was treated with 250 ml of acetone, cooled and scraped to give crystallization. 6-chloro-13-5 having a melting point of 224-229 ° C. (decomposition). , 12-dihydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride (10.8 g, 0.035 mol, 53%) is obtained.

Step C:

Preparation of 13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride

6-chloro-13-methyl-5,12-dihydrobenzo [a, d] cyclooctene-5,12-imine hydrogen chloride (9.0 g, 29.6 mA), 10 g (102 mA) potassium vinegar and 1.0 g Palladium on 10% active carbon in is combined in 200 ml of 95% ethanol and shaken under 50 psig of hydrogen until absorption of hydrogen is stopped. The mixture is filtered, evaporated under vacuum and the residue is treated with excess 1M sodium hydroxide and extracted three times with ether. The ether extract is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to yield 6.6 g of a colorless oil. The oil is dissolved in 100 ml of acetone, treated with hydrogen chloride in 3.5 ml of 8.4 M ethanol and evaporated in vacuo. Acetone is added twice to remove under vacuum and the residue is scraped under acetone to become a white solid. Recrystallization from acetonitrile gives 13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride with a melting point of 24.5-248.5 ° C.

Example 15

13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride

Step A:

Preparation of 13-methyl-5,12-imino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-ol

100 ml of 5 g (22.5 mmol) 5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-one, 3.8 g (23.8 mmol) bromine and 10 mg dibenzoylperoxide The mixture is mixed in carbon tetrachloride and refluxed for 24 hours, illuminating the 275 watt General Electric Sunalmp. The mixture was cooled, washed with dilute sodium sulfite solution and with water, dried over sodium sulfate, filtered and evaporated in vacuo to yield 8.5 g of brown oil. The oil is combined with 8 g (0.258 moles) of liquid methylamine condensed in a stainless steel barrel and heated at 50 ° C. for 1.5 hours. Cool down the container, carefully pour it, rinse with chloroform, wash the crorofoam twice with water and extract three times with 0.5M citric acid. The combined acid fractions are washed with crorofoam, basified with 1M sodium hydroxide and washed three times with ethylene. The ether fractions are washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to give 1.4 g of solid. Recrystallization from 95% ethanol yields 0.6 g of 13-methyl-5,12-imino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12- with a melting point of 170-171.8 ° C. Obtain ol.

Step B:

Preparation of 13-methyl-5,12-imino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-imine hydrogen oxalate

15 ml of refluxed thionyl chloride with 13-methyl-5,12-imino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-ol (1.2 g, 4.8 mmol) Heat for 20 minutes. The mixture is cooled, evaporated in vacuo, treated with 30 ml of toluene and evaporated again in vacuo.

12-Chloro-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-imine is washed with a residue with petroleum ether and dried under steam of nitrogen. The residue is dissolved in 20 ml of tetrahydrofuran and added dropwise to a stirred slurry of 1 g (0.026 moles) of relysed aluminum hydrolide in 20 ml of tetrahydrofuran under nitrogen atmosphere. The mixture is refluxed for 40 minutes, cooled and hydrolyzed by careful addition of water drops. The resulting mass is filtered and the solid is washed with dilute sodium hydroxide and ether.

The filtrate is diluted with 200 ml of water and the acid extract is extracted three times with sodium hydroxide ether with sodium hydroxide solution. The combined ether fractions were washed with water, extracted three times with 1N hydrochloric acid, and the combined acid extracts were basified with sodium hydroxide solution to extract ether twice. The combined ether layers are washed with water, dried over sodium sulfate, filtered and distilled under vacuum.

The residue (800 mg) is chromatographed on 65 g of silica gel and eluted with 2%, 4%, 6% and 10% methanol in chromoform and chromoform. Evaporation of the product fraction yields 450 mg (1.92 mmol) of oil, which is dissolved in 3 ml of acetone and treated with 1.92 mmol (173 mg) of oxalic acid in 1 ml of acetone. The solution was evaporated in vacuo and treated twice with ether to redevaporate and the residue crystallized from 30 ml of acetone to give 270 mg of solid with a melting point of 186.5-188 ° C.

Example 16

12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-iminehydrogen chloride

Step A:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cycloocten-6-one

31.4 g (0.134 mole) of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one and 270 mg of 10% palladium on hard carbon 225 ml of 95% ethanol Mix in and shake under 50 p.sig of hydrogen. The mixture was filtered and evaporated under vacuum when the hydrogen uptake was cut at about 1 molar equivalent to give 31.1 g of a white solid with a melting point of 152-155 ° C.

Step B:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-ol

12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one (3.6G, 15.3 mmol) in 250 ml of methanol was followed by several drops of 1 m sodium hydroxide. Treated with 0.58 g (13.5 mmol) sodium borohydride in 5 ml of water. The mixture is refluxed for 20 minutes, cooled and concentrated in vacuo. The residue was slurried in water and extracted three times with crorofoam, the croro product fraction was washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to yield 3.7 g of a white solid having a melting point of 142-145 ° C.

Step C:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-ol (2.7 g, 0.011 mole) in 50 ml of pyrimidine with 15 ml of phosphorus oxychloride The mixture is refluxed for 45 minutes, cooled, carefully poured into 600 ml of stirred ice water, and the resulting mixture is extracted three times with ether, and the combined exports are washed once with water, once with 1N hydrochloric acid and twice with water. The washed ether solution is dried over potassium carbonate, filtered and evaporated in vacuo to give 1.9 g of a colorless oil.

Step D:

5- (N-acetylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

12-methyl-7,12-dihydroxy dibenzo [a, d] cyclooctene (5 g, 22.7 mmol) in 70 m of acetonitrile was treated with 2.5 ml of water and 18 ml at a rate such that the reaction temperature was kept below 30 ° C. A cooled mixture of concentrated sulfuric acid is added dropwise followed by stirring the mixture overnight at room temperature. TLC (Silica gel plate, chromoform eluate) indicated that the starting olepin was still present.

Another 300 ml of concentrated sulfuric acid is added and the mixture is stirred for 3 hours at room temperature, then the solution is poured into 1 L of ice water and extracted three times with chloroform. The combined chloroform extracts were washed twice with dilute sodium bicarbonate solution and twice with water, dried over potassium carbonate, filtered and evaporated in vacuo to yield 8.7 g of orange oil, which was triturated with petroleum ether and 6.0 g of pale yellow. To get a solid. Samples from chromoform / hexanes have a melting point of 164.5-166 ° C.

Step E:

Preparation of 5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

1.6 M methylitium in ether (61 mL, 97.6 mmol) to 10 g (99 mmol) diisopropylamine in 100 mL dry tetrahydrofuran in 100 mL dry tetrahydrofuran stirred in an ice bath under nitrogen atmosphere. After the addition of the solution, the solution was stirred for 15 minutes and transferred to the addition funnel through a shiring.

18.1 g (64.9 mmol) of 5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclo in 200 ml of dry tetrahydrofuran The octene is treated with 0.3 g triphenylmethane and stirred in an ice bath under nitrogen. The amide solution is added dropwise until the color of triphenylmethane anion is colored from the addition funnel at a rate that the reaction temperature can be maintained below 15 ° C. The mixture is stirred for 15 minutes in an ice bath and 20 ml (45.6 g, 314 mmol) methyl iodide is added rapidly (<5 minutes). The obtained solution is cooled with ice if necessary, stirred for 2 hours while maintaining the temperature below 30 ° C, and then treated with 30 ml of water. The mixture is passed through a drop of nitrogen overnight and the residual liquid is evaporated in vacuo.

The residue was treated with 300 ml of water and extracted three times with chloroform, and the chloroform extract was washed once with dilute sodium sulfite solution and twice with water, dried over potassium carbonate, filtered and evaporated under vacuum to give 33 g of red. Get oil. The oil was washed four times with petroleum ether and evaporated in vacuo to give 16.0 g of foam, which was dissolved in 10 ml of warm toluene, diluted with 250 ml of diethyl ether, and frozen overnight to precipitate an unreacted starting amide. do. The solution was filtered and evaporated in vacuo to the filtrate to give 5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] as an orange brown oil. Obtain cyclooctene (10.5 g).

Step F:

Preparation of 5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (10.5 g, 34 mmol), dichlorodicyanobenzoquinone ( 9.5 g, 98% 41 mmol) and 750 ml of benzene were mixed and refluxed under a nitrogen atmosphere for 3.5 hours, and then the mixture was cooled, washed four times with 1 M sodium hydroxide solution and twice with water, and dried over potassium carbonate to obtain 0.5 g of Treatment with bleaching carbon, filtration and vacuum evaporation yields 10.5 g of brown oil.

Step G:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride

9.5 g (32.6 mmol) of 5- (N-acetyl-N-methylamino) -12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene in 166 ml of ethylene glycol Potassium hydroxide (7.6 g, 0.136 mol) is added and the solution is refluxed under nitrogen for 22 hours, then cooled and quenched in 2 liters of ice water. The resulting suspension is extracted three times with chloroform, the chloroform extract is washed with water and the chloroform solution is extracted four times with 0.5M citric acid. The combined citrate fractions are basified with 1M sodium hydroxide and extracted three times with chloroform. The chloroform extract is washed twice with water, dried over potassium carbonate, filtered and evaporated under vacuum to yield 3.5 g of stork oil.

The oil is treated with 8 ml of dry vinegar and extracted three times at room temperature. The combined extracts were washed with water and extracted three times with 0.5 M citric acid, and the combined acid fractions were washed with chloroform, basified with 1 M sodium hydroxide and then extracted three times with chloroform. The combined extracts are washed once with water, dried over sodium carbonate, filtered and evaporated in vacuo to yield 2.6 g of yellow oil.

The oil is dissolved in 95% ethanol, treated with excess hydrogen chloride in ethanol, the solution is evaporated in vacuo and then re-evaporated by two treatments with ethanol. The residue is treated with ether, evaporated again and crystallized from acetone to give a white solid having a melting point of 243-244.5 ° C.

Example 17

13-methyl-5,12-dihydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride

58.6% of lithium aluminum hydride mineral oil suspension (1.28 g, 19.7 mmol) is washed twice with petroleum ether, the supernatant is decanted and the solvent is removed. The residue is added with 30 ml of tetrahydrofuran followed by dropwise addition of 0.8 ml (1.38 g, 7.3 mmol) of titanium tetrachloride in 20 ml of tetrahydrofuran with stirring. The resulting mixture was stirred for 15 minutes and then 2.0 g (6.6 mmol) of 6-chloro-13-methyl-5,12-dihydrodibenzo [a, d] cyclooctene-5,12-iminehydrogen chloride (Obtained from the step of Example 15) in small portions as a solid and the mixture was refluxed under nitrogen for 4 hours and cooled to cautiously add 0.75 ml of water, 0.75 ml of 15% aqueous sodium hydroxide solution and 2.25 ml of water. By hydrolysis. The mixture was stirred for 15 minutes, filtered, the solid was washed with warm chloroform, the filtrate was vacuum distilled and the residue was stirred with 50 ml of 1 M sodium hydroxide for 2 hours. The mixture is extracted three times with chloroform and all the chromoform fractions are combined, washed with water, dried over magnesium sulfate, filtered and vacuum distilled. The oil is treated with excess 9N ethanol with hydrogen chloride and evaporated in vacuo followed by removal of acetone twice under vacuum. Recrystallization of the residue from acetone gives 13-methyl-5,12-dihydrodibenzo [a, d] cyclooctene-5,12-imine hydrogen chloride having a melting point of 244-254 ° C. (decomposition).

Example 18

Tablet manufacturing

Tablets containing 1.0, 2.0, 25.0, 50.0 and 100.0 mg of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrochloride, respectively, are shown below. Prepare as described.

Table of dosages containing 1-25 mg of active ingredient

Table of dosages containing 26-100 mg of active compound

All of the active compound, whole and a portion of lactose and corn starch are mixed and ground to 10% corn all paste. The obtained milled product is sieved and dried, and then mixed with the remaining corn starch and magnesium stearate. The resulting mill is compressed into tablets containing 1.0 mg, 25.0 mg, 50.0 mg and 100.0 mg of active ingredient per tablet. Other tablets can also be prepared using the same process and equivalent amounts of novel compounds of the invention.

Additional processes for preparing the compound of formula (1) are as follows.

In the stomach,

R is hydrogen, methyl, ethyl or benzyl,

R ² is hydrogen, methyl or ethyl.

(a) ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxy ethane or di (2-methoxyethyl) ether or inert aromatic solvents such as toloene, benzene or xylene, in particular in diethyl ether usually a compound of 1-24 hours, especially 2-4 hours following structural formula (2) until the completion of the reaction at a temperature, particularly the reflux temperature of a suitable solvent for 35-165 ℃ under a nitrogen atmosphere lithium aluminum hydride (LiAlH ₄₎ Or n-butyl tin hydride (nBu ₄ SnH).

In the above formula,

(b) inert polar solvents such as lower alkanols including ethanol or n-butanol, or water-soluble ethers such as tetrahydrofuran, dioxane or dimethoxyethane, or di (lower alkyl) ketones such as acetone or methyl ret ketones, both Especially in N-butanol under an inert atmosphere such as nitrogen at 25-100 ° C., especially at the reflux temperature of the solvent used, usually for 2-24 hours, especially 10-12 hours, until the hydrolysis is completed. The -alkoxycarbonyl derivative of is treated with a strong inorganic base such as potassium hydroxide or sodium hydroxide or an aqueous solution thereof (25-50% by weight), in particular potassium hydroxide.

In the above formula,

썬램프로 조사한다.(c) di (lower alkyl) ethers such as diethyl ether and 1,2-dimethoxyethane; N-chlorination is complete at -5 ° C to 80 ° C, especially at 5-25 ° C, in an inert solvent such as diethylether or methylenechloride, especially in chloro lower alkanes such as methylene chloride or carbon tetrachloride and in aromatic solvents such as benzene and cyclohexane Treatment of compounds of structural formulas with sodium hypochloride, t-butylhypochloride or N-chlorolysineimide, especially from sodium hypochloride or N-chlorolysineimide, since 0.5-12 hours, especially 1-3 hours The resulting product was then weighed in 75-95%, in particular 85% sulfuric acid, usually 3-24 hours, especially 6-8 hours, 125 watts until optical cyclization was connected at 15-50 ° C., especially 25-30 ° C.

Investigate with sunlamps.

In the above formula. [Rβ is hydrogen, methyl or ethyl.]

Examples 19-20 are modification processes described for the preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine or its hydrochloride salt (a) And (b).

Example 19

Step A:

Preparation of 12-azido-12-iodinemethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one

12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-one (40 mmol) in acetonitrile (35 mL) was stirred in 40 mL of ethanol ice bath. A drop of 90 mmol of sodium azide in acetonitrile is added dropwise under nitrogen atmosphere to an iodide azide solution prepared by adding dropwise 45 mmol of iodine monochromide. The mixture is left to stir overnight to cool to room temperature, then the mixture is poured onto 300 ml of ice water and extracted with ether (3 x 50 ml).

The combined ether extracts were washed with 5% sodium thiosulfate solution (1 × 50 mL), dried over sodium sulfate, filtered and evaporated to give 12-azido-12-iodinemethyl-5,6,7,12-tetrahydrodi. Obtain benzo [a, d] cyclooctene-6-one.

Step B:

Preparation of 6-hydroxy-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

12-azido-12-iodinemethyl-5,6,7,12-tetrahydrodibenzo [a, d] cycloocten-6-one (10 mmol) and 10% palladium / activated carbon (0.25 g) were added to ethanol ( 70 ml) and shake in a Parr stirrer under a hydrogen atmosphere (50 p.sig). The mixture was filtered and evaporated in vacuo to give 6-hydroxy-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imines.

Step C:

Preparation of 6-chloro-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

6-hydroxy-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (15 mmol) and thionyl chloride (30 mL) were mixed to obtain nitrogen. Under reflux for 30 minutes. The cooled mixture was evaporated in vacuo and the residue was washed with ether (2 × 50 mL), the ether layers combined and washed with water (3 × 50 mL), dried over sodium sulfate and filtered and evaporated in vacuo to give 6-chloro-12-methyl-5. Obtain 6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine.

Step D:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrogen chloride

6-Chloro-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (20 mmol) is dissolved in ether (100 mL) and the ether is evaporated under nitrogen atmosphere. Droplets are added to a stirred slurry of (100 mL) lithium lithium hydride (22 mmol). The mixture was refluxed for 3 hours, cooled, washed with ice water (2.5 ml, dried over sodium sulfate and evaporated. The residue was dissolved in ethanol (10 ml), treated with excess hydrogen chloride in 8N ethanol and evaporated in vacuo and the residue from ethanol. Recrystallization gives 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrochloride.

Example 20

13-ethoxycarbonyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (0.005 mol) in n-butyl alcohol (50 mL) and Potassium hydroxide (1.0 g) is stirred and refluxed under nitrogen atmosphere for 12 hours. The solvent is evaporated and the residue is partitioned between toluene and water, the toluene phase is separated, washed with water and extracted with 0.5N hydrochloric acid. The acid extract is basified with 5% aqueous sodium hydroxide solution and the mixture is extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine. do.

Examples 21-24 are additional processes described above for the preparation of 12, 13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine or hydrochloride thereof. (a) and (b) are described.

Example 21

Step A:

Preparation of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-amine

Zinc powder was added to a stirred solution of 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-hydroxylamine) (0.35 mol) in glacial acetic acid (35 ml). 7.0 g) is added in small portions and when the exotherm is stopped, the mixture is heated at 60-65 ° C. for 2 hours with stirring. The precipitate was filtered to concentrate the filtrate, and the residue was partitioned between ether and 10% aqueous sodium hydroxide solution, the ether phase was separated, washed with water, dried over anhydrous sodium sulfate and filtered to evaporate the filtrate. 12-methylene-5,6 , 7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-amine is obtained.

Step B:

Preparation of N-ethoxycarbonyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-imine

12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-amine (0.02 mol) was dissolved in anhydrous sodium carbonate (3 g), ethyl chloroformate (3 mL) and toluene (30 Ml), heated at reflux for 2 hours, filtered and the filtrate was concentrated to 12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N- Oxycarbonylamine).

Step C:

Preparation of 13-ethoxycarbonyl-12-phenylselenylmethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-ethoxycarbonylamine) (0.01 mol) was dissolved in dry methylene chloride (30 mL) The resulting solution was stirred and cooled to −10 ° C. to add dropwise a solution of phenylserenyl chloride (0.011 mol) in methylene chloride (20 mL) and after 30 min at −10 ° C. and 2 h at room temperature the mixture was iced. Quench with radish. The aqueous phase was separated, extracted with methylene chloride, and the combined methylene chloride phases were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to afford 13-ethoxycarbonyl-12-phenylcerenylmethyl-5,6,7. Preparation of, 12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

13-ethoxycarbonyl-12-phenylcerenetylmethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (0.01 mol), triphenylhydr under nitrogen The mixture of lide (0.02 mole) and dry toluene (75 mL) is stirred and refluxed for 21 hours and the mixture is quenched in ice water. The toluene phase is separated, washed with water, separated over anhydrous sodium sulfate, filtered and the filtrate is concentrated. The residue was chromatographed on silica gel and eluted with a croro product, and the eluate was evaporated. Side 13-ethoxycarbonyl-12-phenylseretylmethyl-5,6,7,12-tetrahydrodibenzo [a, d ] Cyclooctene-6,12-imine is obtained.

Step E:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

A solution of 13-ethoxycarbonyl-12-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (0.005 mol) in anhydrous ether (15 mL) was prepared. Droplets are added to a stirred slurry of lithium aluminum hydride (0.005 mol) in anhydrous ether (15 mL) at room temperature and then stirred for 6 hours at room temperature. The mixture was hydrolyzed by successively adding drops of water (0.2 mL), 10% aqueous sodium hydroxide solution (0.3 mL) and water (0.5 mL), filtered and the filtrate was evaporated to give 12,13-dimethyl-5,6. , 7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine is obtained.

Example 22

Preparation of 12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-chloro-N-methylamine)

Cooled (5 ° C.) of 12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-methylamine) (0.03 mol) in methylene chloride (100 mL) N-chlorosuccinimide (0.03 mol) was added to the solution, and after 30 minutes at 5 ° C. and 1 hour at room temperature, the solution was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to give 12-methylene-5,6. , 7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-chloro-N-methylamine) is obtained.

Step B:

Preparation of 12-chloromethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

12-Methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6- (N-chloro-N-methylamine) (0.01 mole) in 70% vinegar acid (50 mL) After dissolving and cooling the solution to 0 ° C. and stirring under nitrogen vapor, 15% aqueous titanium trichloride solution (10 ml) was slowly added dropwise. The mixture was further stirred at 6 ° C. for 30 minutes, diluted with water, stirred for 10 minutes in air, filtered and the filtrate was extracted repeatedly with ether. The combined ether extracts are washed with water, dried over anhydrous sodium sulfate and filtered to concentrate the filtrate. The residue was chromatographed on silica gel, eluted with ethanol-toluene (5:95) and the eluate evaporated to 12-chloromethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene Obtain -6,12-imine.

Step C:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine

A solution of 12-chloromethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine (0.005 mol) in anhydrous diethyl ether was purged with nitrogen under 0-. Treated with tri-n-butyltinhydride (0.006 mol) at 10 ° C. The mixture was refluxed for 3 hours, quenched in ice water, the ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to give 12,13-dimethyl-5,6,7,12-tetrahydrodi. Obtain benzo [a, d] cyclooctene-6,12-imine.

Example 13

Step A:

Preparation of 12-bromoethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene 6,12-imine

A solution of N-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene 6,12-amine (0.02 mol) in water (75 mL) was stirred at room temperature and bromine (3.02 G, 0.02 mol) is added dropwise. After 10 minutes potassium carbonate (5.5 g, 0.04 mol) is added in one portion and tetrahydrofuran (50 ml) is added. The mixture was stirred at room temperature for 12 hours, and then the aqueous phase was extracted with a few portions of chloroform, and the combined extract and tetrahydrofuran phase were extracted with 1N hydrochloric acid. The cooled acid extract is basified and extracted again with chromoform.

The chloroform extract is washed with water, dried over anhydrous sodium sulfate and filtered to concentrate the filtrate. The residue was chromatographed on silica gel, eluted with ethanol-toluene (5:95), and the eluate was evaporated to 12-bromomethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d]. Obtain cyclooctene 6,12-imine.

Step B:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene 6,12-imine

In the same manner as described in step C of Example 22, 12-bromomethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine ( 0.01 mole) to give 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine.

Example 24

Step A:

Preparation of 12-methyl-6-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

6-methylamino-12-methylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (10 mmol) and palladium on 10% carbon (200 mg) are mixed in ethanol (50 mL) Shake under hydrogen psig until the equivalent is absorbed, and then the mixture is filtered and the filtrate is evaporated in vacuo to give 12-methyl-6-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene is obtained.

Step B:

Preparation of 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6-12-imine hydrogen chloride

12-methyl-6-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (20 mmol) was stirred in 25 mL of ether cooled in ice weight and sodium hypo Chloride (25 mL of 1 M aqueous solution) is added dropwise over 3-5 minutes. After stirring for 30 minutes under cooling, the mixture was separated, the aqueous phase was extracted with ether (2 × 25 mL), the combined extracts were washed with water (2 × 25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. .

The residue is treated with cooled 85% sulfuric acid (40 mL) and irradiated with 125 Watt GE * sunlamp under nitrogen in a quartz flask until chloroamine is consumed. The mixture is poured into 600 ml of stirred ice water, made up of a base with concentrated aqueous sodium hydroxide solution and extracted with ether (3 x 80 ml). The combined ether layers were washed with water (3 x 80 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue in ethanol was treated with excess hydrogen chloride in 8Nethanol and evaporated in vacuo and the residue recrystallized from ethanol to give 12,13-dimethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene Obtain -6,12-imine hydrogen chloride.

Example 25

Step A:

Preparation of 12-methylmethylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-12-one (30 mmol) in ether (100 mL) was treated with triphenylphosphine (40 mol), ethyl bromide (40 mol) and Droplets were added to a stirred solution of sodium hydride (40 moles) in ether and the solution was refluxed for 4 hours to reflux and the residue was washed twice with 30 ml of ether. The combined ether layers were washed with 0.5N aqueous hydrochloric acid solution and water, dried over magnesium sulfate, filtered and evaporated in vacuo to give 12-methylmethylenete-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene. Get

Step B:

Preparation of 12-isocyanate-12-ethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

Silver cyanate (60 mmol) was added to a solution of ether (50 mL) 12-methylmethylene-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (20 mmol) and the slurry was added. Stir and cool then treat with iodine (60 mmol). The mixture was stirred overnight at room temperature, then poured into ice water (20 mL) and the layers separated. The aqueous layer was washed with ether (2 × 50 mL) and water (3 × 50 mL), dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo.

The residue in ethanol (200 mL) was treated with 10% (palladium / activated charcoal) and shaken under a vacuum of hydrogen (50 p.sig) in a paler stirrer and the mixture was filtered and concentrated in vacuo to 12-isocyanato-12-. Ethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene is obtained.

Step C:

Preparation of 12-ethyl-12-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene

12-isocyanato-12-ethyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene (20 mmol) in tetrahydrofuran (100 mL) was dissolved in ether at room temperature under nitrogen atmosphere. Droplets of Lithium aluminum hydride (20 mmol) stirred at 20 ° C. were added, the mixture was refluxed for 3 hours, and cooled, followed by drop of ice water (2 mL). The suspension was filtered to wash the solid with ether (3 × 50 mL), the combined filtrate and ether washes were washed with water (2 × 75 mL), dried over sodium sulfate, filtered and evaporated in vacuo to 12-ethyl-12-methyl. Amino-5, 6,7, 12-tetrahydrodibenzo [a, d] cyclooctene is obtained.

Step D:

12-ethyl-13-methyl-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-5,12-iminehydrogen chloride and 12-ethyl-13-methyl-5,6,7 Preparation of 12-tetrahydrodibenzo [a, d] cyclooctene-6,12-imine hydrogen chloride

12-ethyl-12-methylamino-5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene was converted to 12-ethyl-13-methyl according to the same process as described in Step B of Example 24. -5,6,7,12-tetrahydrodibenzo [a, d] cyclooctene-6,12-iminehydrogen chloride and 12-ethyl-13methyl-5,6,7,12-tetrahydrodibenzo [ a, d] A mixture of cyclooctene-5,12-imine hydrogen chloride was converted.

Claims (1)

The compound of formula (2) is reacted with a strong base at 150-250 ° C. or with lithium alkyl in an ether solvent or the compound of R is hydrogen in the obtained product to alkylate the compound of formula (1) by alkyl halide. How to manufacture.

[m is 0 or 1, Q is CH ₂ when m is 1, and when m is 0, -CH ₂ -CH ₂ -or -CH = CH-, R is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkenyl, lower (cycloalkyl-alkyl) or di (lower alkyl) amino-loweralkyl; R ¹ is hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl or lower cycloalkyl, R ² is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkenyl, lower alkoxy or di (lower alkyl) amino-lower alkyl, R ³ and R ⁴ are hydrogen, halogen, lower alkoxy, trifluoro methylthio, cyano, carboxy or hydroxy, Y is hydrogen or acetyl, = (R ² α-H) is lower alkylene, phenyl-lower Or alkylene, lower alkenyl or di (lower alkyl) amino-lower alkylene.]