KR830000256B1 - Method for preparing 5-substituted-10, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5, 10-imines - Google Patents

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Description

Method for preparing 5-substituted-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines

The present invention is a novel 5-substitution- useful for the treatment of extrapyramidal diseases such as anxiety stabilizers, sedatives, antispasmodics, muscle relaxants and mixed anxiety depressions, minimal sinus dysfunction and Parkinson's syndrome. A method for producing 10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines.

The present invention also includes derivatives of formula (1), optical isomers thereof, and pharmaceutically acceptable salts thereof.

It is known in the art that structurally relevant compounds have similar uses in nature.

For example, US Pat. No. 3,892,756 describes 10,11-dihydro-5H-dibenzo [a, d] cycloheptene and its derivatives unsubstituted in 5-bridged bocarbon, and Belgian Patent 829,075 discloses 9, 10-dihydro-anthracene-9,10-imine and its derivatives are described.

An object of the present invention is a novel compound, 5-substituted-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines, which is surprisingly more active than unsubstituted analogs, Novel synthetic method and an effective ingredient to provide a pharmaceutical composition containing them.

The novel compounds of the present invention are the compounds of formula (a) below, or pharmaceutically acceptable salts thereof.

Food,

R is (1) hydrogen,

(2) lower alkyl, in particular C _1-5 alkyl, preferably methyl or ethyl,

(3) lower alkenyl, especially C _2-5 alkenyl, preferably vinyl or aryl,

(4) phenyl (or substituted phenyl) -lower alkyl, especially phenyl (or substituted phenyl) -C _1-3 alkyl, preferably substituted benzyl, wherein the benzyl or substituent is halo, such as fluorine, chlorine or bromine, especially chlorine, or Lower alkyl, especially C _1-3 alkyl,

(5) lower cycloalkyl, in particular C _3-6 cycloalkyl, preferably cyclopropyl or cyclohexyl,

(6) lower (cyclo alkyl-alkyl), especially C _3-6 cyclo alkyl-C _1-3 alkyl, or

(7) di (lower alkyl) amino-loweralkyl, in particular dimethyl amino pyrophyll;

R ¹ is (1) hydrogen,

(2) lower alkyl, in particular C _1-5 alkyl, preferably methyl or ethyl,

(3) lower alkenyl, especially C _2-5 alkenyl, preferably vinyl or aryl,

(4) phenyl-lower alkyl, in particular phenyl-C _1-3 alkyl, preferably benzyl

(5) lower cycloalkyl, in particular C _3-6 cycloalkyl, preferably cyclopropyl or cyclohexyl, or

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

-CH ₂ R ² is

(1) lower alkyl, especially C _1-5 alkyl, preferably methyl or ethyl,

(2) lower alkenyl, especially C _2-5 alkenyl, preferably vinyl or aryl,

(3) phenyl-lower alkyl, in particular phenyl-C _1-3 alkyl, preferably benzyl

(4) lower (cyclo alkyl-alkyl), in particular C _3-6 cyclo alkyl-C _1-3 alkyl,

(5) di (lower alkyl) amino-lower alkyl, in particular dimethyl amino propyl, or

(6) hydroxy-lower alkyl, hydroxy-C _2-3 alkyl, preferably hydroxy ethyl, and

R ³ and R ⁴ are each

(1) hydrogen,

(2) halogen, such as chlorine, bromine, fluorine, or iodine;

(3) lower alkoxy, especially C _1-5 alkoxy, preferably methoxy,

(4) trifluoro methylio,

(5) cyano,

(6) carboxy, or

(7) hydroxy.

Preferred compounds are those wherein R ¹ is hydrogen.

Further preferred compounds are those wherein R ¹ , R ³ and R ⁴ are hydrogen.

When R ³ and / or R ⁴ are other than hydrogen, it is preferable that they occupy 2, 3, 7 or 8 positions of the tricycle ring system.

Preferred definitions for —CH ₂ R ² are lower alkyl, in particular methyl or ethyl, or hydroxy ethyl.

Preferred definitions for R are hydrogen, lower alkyl or benzyl.

Novel compounds of the invention wherein R is hydrogen are generally prepared by reduction of the N-hydroxy analogue.

Preferred reducing agents are generator hydrogens generated by reacting metals, preferably zinc, with acids such as acetic acid at 40-100 ° C. for about 1-10 hours.

The novel compounds are treated with strong bases such as organometallic reagents, such as n-butyltium, in an ethereal solvent such as tetrahydrofuran, 1,2-dimethoxy-ethane and the like at about 0-30 ° C. for about 5 minutes to about 1 hour. It is also prepared by cyclization of 10-NHR-5-(= CHR ₂ ) -10,11-dihydro-5H-dibenzo [ad] cycloheptene.

If —CH ₂ R ² is hydroxy-lower alkyl, the final step in its synthesis is the reduction of the lower alkoxy-carbonyl precursor. Preferred reducing agents are lithium aluminum hydride in ethereal solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like, the reduction being carried out at a temperature of about 15-100 ° C. and substantially within about 1-6 hours. Is completed.

This process is also used to hydrolyze the beachhead bohalo group used in the next synthesis process.

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New compounds wherein R is other than hydrogen are prepared by alkylating a compound wherein R is hydrogen with a suitable reagent of the general formula R-halo, wherein halo is chlorine, bromine or iodine. The reaction is usually carried out in an inert solvent such as benzene or toluene. However, depending on their physical properties, alkylating agents are used in excess amounts sufficient to act as solvents. It is preferable to carry out the reaction in the presence of an acid acceptor such as an inorganic carbonate such as sodium carbonate, an organic base such as pyridine or a basic resin. A temperature of about 50 ° to about 100 ° C. may be used over a reaction time of about 10 hours to about 5 days.

When R is alkyl or substituted alkyl, the present compounds may also be prepared by reducing the N-acyl compounds such that other alkanoyl groups providing methyl or other alkyl groups are obtained. Preferred reduction systems are metal hydrides such as ether, tetrahydrofuran or 1,2-dimethoxyethane and lithium aluminum hydride in a thin etheric solvent. The reaction is carried out satisfactorily at room temperature, but a temperature of about 0-50 ° C. with a reaction time of 10-13 hours is suitable.

New compounds having substituents on the benzene noid ring are generally prepared by substitution of suitable bromo or iodine compounds. For example, a lower alkoxy compound is prepared by treatment with sodium lower alkoxide in the presence of equimolar powder in an inert organic solvent such as dimethylformamide for 1-10 hours at 50-150 ° C.

2,3,7 or 8-hydroxy compounds are prepared from the corresponding alkoxy, preferably methoxy compounds, by deetherification. The most preferred method consists of heating with pyridine hydrochloride at 200-220 ° C. for 3-10 hours.

The bromo or iodine compound is treated with cyanide or the like in an inert organic solvent such as dimethyl formamide for 1-10 hours at reflux to obtain the corresponding cyano compound.

Hydrolysis of the cyano compound described above with mineral acids such as hydrochloric acid at about 50-150 ° C., especially at reflux temperature, yields the corresponding carboxy substituted compounds.

The bromo iodine compound is also treated with bis (trifluoro methylthio) water temperature and equipowder in an inert organic solvent such as dimethylformamide or quinoline at about 100-200 ° C. for 1-10 hours to obtain a prefluoro methylthio derivative. .

The bromo iodine compound is also treated with bis (trifluoro methylthio) water temperature and equipowder in an inert organic solvent such as dimethylformamide or quinoline at about 100-200 ° C. for 1-10 hours to obtain a prefluoro methylthio derivative. .

Thus, the following compounds are prepared. In other words, 3- (or 7) -R ³ -5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines;

3-R ³ -12-cyclopropylmethyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines;

2-R ³ -12- dimethylaminopropyl-5-methyl -10,11- dihydro -5H- dibenzo [a, d] cycloheptene -5,10- imine and the like; And

7-R ³ -12-diethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines.

R 3 in the compound is lower alkoxy, hydroxy, cyano, carboxy or trifluoro methyl thio.

Formation of diastereomer pairs by salting the novel compounds with optically active acids such as (-)-di-p-toluoyl-d-tartrate and / or (+)-di-p-toluoyl-1-tartrate It can be decomposed into its optical isomer by standard techniques such as fractionation and regeneration by free base.

Starting materials and processes used to prepare the intermediates used in the processes described above are described in detail in the Examples.

Also within the scope of the present invention are non-toxic pharmaceutically acceptable salts of the novel compounds.

Acid addition salts of imine compounds are prepared by mixing a solution of the imine compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, malic acid, tartaric acid, phosphoric acid, and the like.

In the case where the present novel compound has a carboxylic acid group, its sodium, calcium, carum salt and the like are also considered.

As a treatment method of the present invention, the novel immigrants of the present invention are excessive at doses of about 0.1-50 mg / kg body weight, preferably at dosages of about 0.05-10 mg / kg body weight, in 1-4 doses per day. You can relieve anxiety without causing calm or sleep.

In addition, the novel compounds of the present invention are useful for the treatment of anxiety stabilizers, sedatives, antispasmodics, muscle relaxants and mixed anxiety depression, minimal brain dysfunction and extrapyramidal diseases such as Parkinson's syndrome when administered at significant dosage levels. The exact level of treatment differs depending on the history of each animal or human being treated, and of course the exact level of treatment within the guidelines detailed in the final analysis will depend on the judgment of the physician.

Also included within the scope of the present invention are pharmaceutical formulations containing the imines of the present invention. These compositions are preferably in unit dosage form such as tablets, pills, capsules, powders, granules, sterile injectable solutions or suspensions, or capsules for oral, parenteral or rectal administration.

The present invention will be described in detail based on the following examples.

Example 1

5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine and oxalate

Step A

Preparation of 10- (1-piperidyl) -5H-dibenzo [a, d] cyclohepten-5-one.

A mixture of 73.1 g of 10-bromo-5H-dibenzo [a, d] cyclohepten-5-one, 50 ml of piperidine, 1 L of t butanol and 33.6 g of potassium t-butoxide was added for 2 hours. After stirring under reflux, the mixture was stirred overnight at room temperature. The residue was slurried with water and then draughted. The residue was slurried with methanol and filtered to give 59.8 10- (1-piperidyl) -5H-dibenzo [a, d] cyclohepten-5-one. Melting point: 103-105 캜.

Step B

Preparation of 5-hydroxy-5-methyl-10- (1-piperidyl) -5H-dibenzo [a, d] cycloheptene.

59 g of 10- (1-piperidyl) -5H-dibenzo [a, d] cyclodissolved in a 250 mL tetrahydrofuran solution of 140 mL of 1.8 mole methylityium and 250 mL of ether in ether To the heptene-5-one solution was added dropwise at 5-10 ° C. under nitrogen. After a total of 2 hours, the mixture was poured into ice and left until the ice melted. The mixture was extracted well with ether and then the extract was dried (Na ₂ SO ₄ ), filtered and concentrated to dryness, then the residue was used directly in the next step.

Step C

Preparation of 5-methylene-10-oxo (OXO) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene.

The carbinol from step B was dissolved in 500 ml of 10N ethanol hydrogen chloride and 30 ml of concentrated hydrochloric acid and then heated under reflux overnight. The solvent was evaporated and the residue was extracted with 500 mL of benzene. The extract was dried and then concentrated to dryness and the residue was extracted with 300 ml of boiling hexane. Upon cooling the extract precipitated into 18.5 g of solid which was recrystallized from hexane to give 16.5 g of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene. Melting point: 84-86 ° C.

Step D

Preparation of 10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene.

From step C a mixture of 16.5 g of oxo compound, 6.6 g of hydroxylamine hydrochloride, 8.2 g of sodium acetate and 300 ml of methanol was heated at reflux for 5 hours. The solvent was evaporated and the residue was treated with 250 ml of water. The mixture was extracted with 3 x 150 ml of ether and the extract was dried, filtered and evaporated to 16.8 g of 10-hydroxyimino-5-methylene-10,11-dihydroxy-5H-dibenzo [a , d] cycloheptene was obtained. Melting point: 156-160 ° C.

Step E

Preparation of 10-hydroxyamino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] -cycloheptene.

A mixture of 15.3 g of oxyl, 500 ml of methanol, 12 g of sodium cyano brohydride in 450 ml of methanol from step D was added with 12 ml of 12N hydrogen chloride solution dissolved in 50 ml of methanol for at least 5 hours. Then stirred overnight at room temperature. After evaporation of the solvent, the residue was combined with 200 mL of 1N hydrochloric acid solution, made alkaline with concentrated ammonium hydroxide, and extracted with 3 × 175 mL of ether. Combine the extracts to form a precursor (Na2SO2), then filter and evaporate. The crystalline residue was washed to yield 9.6 g of 9.610-hydroxyamino-5-methylene-10,11-dihydro-5-dibenzo [a, d] cycloheptene. Melting point 145-147 ℃

Preparation of -12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine.

A solution of 8.8 g of hydroxyamino compound from E being dissolved in 20 ml of xylene was added dropwise to 80 ml of refluxed xylene. After refluxing for 1 hour the solvent was evaporated. The residue was treated with 250 ml of water and 7 ml of concentrated hydrochloric acid, then the mixture was washed with 100 ml of ether and then the wash was poured off. The aqueous phase was made basic with concentrated ammonium hydroxide and the extract was extracted with 3 × 100 mL of ether. The extract was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was recrystallized from cyclohexane to give 8.5 g of 12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine. Melting point: 141-144 ° C.

Step G

Preparation of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine and oxalate.

A mixture of 1.2 g of hydroxy-imine, 7 ml of acetic acid and 1.2 g of zinc powder from Step F was heated at 60-70 ° C. for 3.5 hours. The mixture was filtered and then the filter cake was washed with 200 ml of ether and 50 ml of water. The filtrate was basified with 5% (W / V) aqueous sodium hydroxide solution and then extracted with ether. The extract was dried (Na ₂ SO ₄ ), filtered and evaporated to dryness to afford 1.1 g of product. This material (1.1 g) was dissolved in 20 ml of acetone and then treated with 0.6 g of hydroxyl in 10 ml of acetone. After overnight cooling, 1.2 g of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine was obtained.

Melting point: 203-206 ° C. (decomposition). It had a melting point of 215-217 ° C. (decomposition) after recrystallization from methanol / acetone.

Example 2

5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Step A

Preparation of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene.

To a stirred slurry of ethyltriphenyl phosphonium bromide (21 g, 0.057 mol) in ether (400 mL) was added dropwise bectium in hexane (48 mL, 1.3 M). A solution of 1- (5-keto-5H-dibenzo [a, d] cyclohepten-10-yl) -4-methylpiperazine (13.5 g, 0.44 mol) dissolved in THF (100 mL) was added to the obtained solution. Added. The organic phase was separated and the aqueous phase was exported as ether (2 × 150 mL). The organic solutions were combined and concentrated under reduced pressure. The concentrate was stirred with a mixture of 1N aqueous hydrochloric acid solution (300 mL) and ether (300 mL). The ether phase was separated, the aqueous phase was extracted with ether, the ether solutions were combined, dried over Na ₂ SO _4, filtered and the filtrate was concentrated to 100 ml. Triphenylphosphine oxide was filtered off and the filtrate was then chromatographed on silica-gel to dissolve in chloroform. 10.1 g (98%) of 5-ethyllitene-10-oxo-10,11-dihydro-5H- Dibenzo [a, d] cycloheptene was obtained. Melting point: 93-95 ° C.

Equivalent molar amount of 5-ethylidene-10-oxo-10,11 instead of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene to be used in step D of Example 1 Following the process described in step D-step G of Example 1 using -dihydro-5H-dibenzo [a, d] cycloheptene, the following compounds were obtained in sequence: 5-Ethylidene-10-hydro Roxyimino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (yield: 86%), melting point: 128-131 ° C;

5-ethylidene-10-hydroxyamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (yield: 89%), melting point: 121-124 ° C;

5-ethylidene-12-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (yield: 21%), melting point: 112-116 ° C; And

5-ethyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine (yield: 90%) and hydrogen oxalate melting point: 240-241 ° C.

The general formula of the molar amount of ethyl triphenylphosphonium bromide in place of copper used in step _{A (C 6 H 5) 3} P + -CH 2 R 2 (Br -) [ wherein R ² is -CH ₂ -CH _3, -CH ₂ Using a wittig reagent of CH ₂ CH ₃ , or — (CH ₂ ) ₃ CH ₃ ], a compound of the following general formula was obtained following the procedure described in Example 2.

Wherein -CH ₂ R ² is -CH ₃ , -CH ₂ CH ₂ CH ₃ (melting point: CHl, 298-299.5 ° C. like ½CH ₃ COCH ₃ ) and-(CH ₂ ) ₃ CH ₃ .

Example 3

5- (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Step A

Preparation of 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one.

10 g (0.045 mol) of triethyl phosphonoacetate was added dropwise to a slurry of 1.9 g (0.04 mol) of sodium hydride (50% in mineral oil) in 20 ml of anhydrous toluene under nitrogen, followed by cooling to 30-35 ° C. The temperature was maintained.

The mixture was stirred at room temperature for 1 hour, and then a solution of 1-5-keto-5H-dibenzo [a, d] cyclohepten-10-yl) -4-methyl piperazine dissolved in 75 ml of anhydrous toluene was added dropwise. After cooling, the temperature was maintained at 25-30 ° C.

The mixture was stirred at room temperature for 3 hours and then kept at room temperature overnight. After bleeding along the solution, the precipitate was washed four times with toluene at 25 ° C. in 25 ml portions. The toluene extracts were combined and diluted with the same amount of ether and shaken with 75 ml of 0.5G hydrochloric acid. The aqueous acid layer was separated and extracted again with toluene-ether (1: 1). The combined organic phases were washed with water, dried over magnesium sulfate and filtered and concentrated. The resulting oil solids were collected on a sintered glass funnel, liberated from the bulk of the oil and triturated with cyclohexane to yield 4.5 g (47%) of 5-methoxy carbonyl methylene-10,11-dihydro-5H-dibenzo [ a, d] cycloheptene-10-one was obtained. Melting point: 56-62 ° C.

Step B

Preparation of 5-ethoxycarbonyl methyl-10,12-dihydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine.

The keto-olefin (23.4 g: 0.08 mole) from Step A was stirred with hydroxylamine hydrochloride (6.0 g), sodium acetate trihydrate (12.0 g) and wet ether (300 mL) at room temperature and then after 16 hours. The precipitates were collected, washed with ether and stirred with water (300 mL) for 1 hour. The solids were combined and dried to yield 21.6 g (83%) of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-immigration was obtained. Melting point: 193-195 ° C. (decomposition).

Step C

Preparation of 5-ethoxycarbonyl-10-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

N-hydroxyimine (21 g: 0.0646 mol) from Step B was suspended in glacial acetic acid (125 mL) and zinc powder (16 g) was added dropwise over 15 minutes. After the exothermic reaction was stopped, the mixture was stirred and heated in an oil octane at 65 ° C. for 3 hours. The cooled mixture was filtered and the filtrate was evaporated under reduced pressure. The remaining seam allowance was dissolved in water (500 mL) and the filtered solution was made basic with 15% aqueous sodium hydroxide solution. The precipitates were collected, washed with water, and then dried. 15 g of 5-ethoxycarbonyl methyl-10-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine Was obtained. Melting point: 186-189 ° C. (decomposition).

The filtered filtrate of this product dissolved in boiling acetone (350 mL) was treated with 7N ethanol hydrogen chloride (7 mL). The precipitates of hydrochloride salt were collected, washed with ether and dried to yield 14.35 g (64%). Melting point: 247-250 ° C. (decomposition).

Step D

Preparation of 10-Chloro-5-ethoxycarbonylmethyl-10,11-hydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

The hydrochloride salt (17.8 g: 0.0515 mol) of the product from step C was slurried in thionyl chloride (250 mL) and the mixture was heated to reflux. After the exothermic reaction was stopped, the mixture was heated at reflux for 20 minutes when the solid was completely dissolved. Thionylchloride was evaporated under reduced pressure and then repeatedly evaporated with toluene to remove the remaining traces. The residue was triturated with acetone and dried to give 15.35 g (81%) of 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5, Preparation of 10-imines.

Hydrochloride (15.3 g: 0.042 mol) from step D was added dropwise to a slurry of lithium aluminum hydride (5.6 g: 0.147 mol) in ether (200 mL) and tetrahydrofuran (200 mL). The mixture was stirred under reflux for 3 hours, then cooled to 0 ° C. and hydrolyzed by dropwise addition of water (4 mL) and 10% aqueous sodium hydroxide solution (4 mL). After dilution with ether, the precipitates were collected, suspended in chloroform (250 mL), and stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was combined with the ether filtrate already obtained. The solvent was evaporated under reduced pressure and the resulting solid was recrystallized from 95% ethanol to give 8.6 g of 5- (2-hydroxy ethyl) 1-, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-immigration was obtained. Melting point: 181-184 ° C. Recrystallization from 70% ethanol showed a melting point of 182-184 ° C.

A suspension of this product (4.4 g) suspended in hot anhydrous ethanol (2.5 mL) was treated with 7N ethanol hydrogen chloride (2.5 mL) and then the mixture was stirred until all solids dissolved. Dilution with ether resulted in the precipitation of the hydrochloride salt (4.8 g). Melting point: 263-265 ° C.).

As a result of recrystallization from acet natryl, the melting point was 262-264 占 폚 (decomposition).

Example 4

3- (and-7) -bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Step A

Preparation of 3,10-11-tribromo-5H-dibenzo [a, d] cyclohepten-5-one.

A solution of bromine (53 g, 0.33 mole) dissolved in glacial acetic acid (125 mL) was diluted with 3-bromo-5H-dibenzo [a, d] cyclohepten-5-one (71.25 g, 0.25 mole) in glacial acetic acid (775 mL). ) Was added dropwise to the stirred slurry. After the mixture was stirred at room temperature for several hours, solids were collected, washed with glacial acetic acid and dried to obtain 105.8 g (974%).

Melting point: 173-175 ° C.

Step B

Preparation of 3,10-dibromo-5H-dibenzo [a, d] cyclohepten-5-one and 3,11-dibromo-5H-dibenzo [a, d] cyclohepten-5-one.

The product from step A was added to a stirred solution of sodium hydroxide (28 g, 0.7 mol) dissolved in methanol (2 L). The rich mixture was stirred at reflux for 1¼ h. After cooling, the solids were collected, washed with methanol, washed with water and dried to obtain 3,10-dibromo-5H-dibenzo [a, d] cyclohepten-5-one and 3,11-dibromo-5H. The mixture of dibenzo [a, d] cyclohepten-5-one was lost. Yield: 81 ((90%), Melting point: 146-156 占 폚.

Step C

3-bromo-10- (4-methyl-piperazinyl) -5H-dibenzo [a, d] cyclohepten-5-one and 3-bromo-11- (4-methylpiperazinyl) 5H- Preparation of Dibenzo [a, d] cyclohepten-5-ones.

Potassium tert-butoxide (6.8 g, 0.06 mole) was added to 3,10-dibromo-5H-dibenzo [a, d] cyclohepten-5-one and 3,11-dibromo- at room temperature under nitrogen. It was added to a stirred copper liquid of 5H-dibenzo [a, d] cyclohepten-5-one (18.2 g, 0.05 mol), 4methyl pyreazine (10 mL), and anhydrous tert-butyl alcohol (200 mL). The dark orange mixture was heated to reflux for 2 hours and then stirred overnight at room temperature. The mixture was poured into about 800 mL ice water and then extracted with ether. The ether extract was washed with moles, dried over anhydrous sodium sulfate, filtered and evaporated to afford 3-bromo-10- (4-methylpiperazinyl) -5H-dibenzo [a, d] cyclohepten-5-one and A mixture of 3-bromo-11- (4-methyl-piperazinyl) -5H-dibenzo [a, d] cyclohepten-5-one was obtained as a residual red yellow gum. Yield 194.g (100%).

Step D

3-bromo-5-betayl-10- (4-methyl-piperazinyl) -5H-dibenzo [a, d] cyclohepten-5-ol and 3-bromo-5-methyl-11- (4 Preparation of -methylpiperazinyl) -5H-dibenzo [a, d] cyclohepten-5-ol.

Stirring of the product (18 g, 0.047 moles) from the step of dissolving a 1.6 M solution of methylityium (35 ml) dissolved in ether in ether (200 ml) and tetrahydrofuran (60 ml) cooled under ice jade and nitrogen. It was added dropwise to the solution. Stirring was continued for 3 hours at room temperature. The mixture was cooled on ice and hydrolyzed by the dropwise addition of water. After dilution with ether and water, the layers were separated and the aqueous phase was extracted again with ether. The ether extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to 3-bromo-5-methyl-10- (4-methyl piperazinyl) -5H-dibenzo [a, d] cycloheptene-5- A mixture of on and 3-bromo-5-methyl-11- (4-methyl piperazinyl) -5H-dibenzo [a, d] cyclohepten-5-one was obtained as a residual black yellow glassy phase.

Yield: 18 g (96%).

Step E

3-bromo-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-10-one and 7-bromo-5-methylene-10,11-dihydro-5H- Preparation of Dibenzo [a, d] cycloheptene-10-ones.

A mixture of the product from step D (18 g, 0.045 mol), 95% ethanol (80 ml), 7N ethanol hydrogen chloride (40 ml), and 6N aqueous hydrochloric acid solution (80 ml) was stirred at room temperature for 30 minutes and then at reflux temperature. Stirred for 1 h. The mixture consisted of a lower layer of brown oil and an upper alcoholic layer. The alcoholic top layer was drained off and the alcohol was removed in vacuo. The remaining aqueous mixture was extracted with chloroform and the brown oil obtained first was dissolved in chloroform, then the chloroform phases were combined, washed with water and dried over anhydrous sodium sulfate. The filtered extract was evaporated and the crude product remained as a dark yellow glassy residue.

This material was chromatographed on silica gel column and eluted with toluene. Evaporation of the almost collected fractions left the partially purified product as an oil solid (8.5 g). Trituration with cyclohexane gave one of the isomers of the product as a white solid. Yield: 2.5 g, Melting point: 125-158 ° C. Recrystallization twice from cyclohexane resulted in a melting point of 158-163 ° C. The cyclohexane first mother liquor was evaporated and the remaining isomer of the product remained as a dark yellow oil. Trituration three times with 10 ml of hexane successively gave a yellow solid. Yield: 3.3 g (melting point: 75-83 ° C.).

Recrystallization twice with hexane resulted in a melting point of 84-89 ° C. Isomers having a high melting point (melting point: 160-164 ° C.) have the following structural formula, and have 7-bromo-5 methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-10-one. It is called.

Another isomer, namely 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one (melting point: 84-91 ° C.), has the following structural formula.

Step F-I

Preparation of 3 (and 7) -bromo-5methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Example 1, using equimolar amounts of the corresponding 3- and 7-bromo-compounds instead of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene The following compounds were prepared by using the process described in step DG.

(Step F): 3 (and 7) -bromo-10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene, melting point; 171-175 ° C and 179-181 ° C, respectively;

(Step G): 3 (and 7) -bromo-10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene, melting point; 149-153 ° C. and 136-139 ° C., respectively;

(Step H): 3 (and 7) -Bromo-12-hydroxyimino-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine, melting point ; 187-189 ° C., respectively. And

(Step I): 3 (and 7) -bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine dihydro chloride, melting point; > 300 ° C., the following compounds were prepared in a similar manner.

8-bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine,

2-bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine; And

7-bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine,

Example 5

10,11-dihydro-5,12-dimethyl-5H-dibenzo [a, d] cycloheptene-5,10-imine fumarate.

Step A

Preparation of 10,11-dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo [a, d] cyclohepten-5,10-imine

1.15 g 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, 1.0 g anhydrous sodium carbonate, 1 ml ethylchloromate, and 10 ml anhydrous The mixture of benzene was stirred at reflux for 2 hours, then the mixture was filtered and the filtrate was evaporated in vacuo resulting in 1.45 g of white crystalline 10,11-dihydro-12-epoxycarbonyl-5-methyl-5H- Dibenzo [a, d] cycloheptene-5,10-imine was obtained. Melting point: 80-83 ° C.

Step B

Preparation of 10-11, -dihydro-5,12-dimethyl-5H-dibenzo [a, d] cycloheptene-5,10-imine

The urethane solution from step A dissolved in 15 ml of anhydrous ether was added to a slurry of 190 m of lithium aluminum hydride in 15 ml of anhydrous ether layer with stirring under nitrogen. After 24 hours at room temperature, the mixture was cooled in an ice bath and hydrolyzed by adding dropwise addition of a minimum amount of water containing 2-3 drops of 5% (W / V) aqueous sodium hydroxide solution. After dilution with ether, the mixture was filtered and the filtrate was evaporated in vacuo to give 1.1 g of the free base of the product as colorless oil. It was mixed with 0.9 g of analog and then dissolved in 25 ml of Emeacetate. A heating solution of 1.2 g of fumaric acid dissolved in 12 ml of methanol was added. The crystallized fumaric acid solution was collected and recrystallized from methanol-ethyl acetate, resulting in 2.1 g of 10,11-dihydro-5,12-dimethyl-5H-dibenzo [a, d] cyclohepten-5,10-imine futalic acid. A salt was obtained. Melting point: 186-188 ° C.

Example 6

12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine

2.45 g of 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, 1.9 g of benzylchloride, 3.2 g of anhydrous sodium carbonate and 50 ml of anhydrous benzene The mixture was stirred at reflux for 4 days. The mixture was filtered and the filtrate was evaporated in vacuo to yield 3.1 g of product as an oil solid. Melting point: 107-111 ° C.

This was recrystallized twice from 95% ethanol. As a result, 1.85 g of white crystals, 12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine Was obtained. Melting point: 111-114 ° C.

Example 7

12-allyl-10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine

A mixture of 2.45 g of 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, 1.8 g of allylbromide 3.0 g of anhydrous sodium carbonate and 50 mL of anhydrous benzene Was stirred at reflux for 20 h. The mixture was filtered and the filtrate was evaporated in vacuo to give 1.2 g of oily free base of the product. This was dissolved in 5 ml of acetone and then added to a heating solution of 0.75 g of fumaric acid dissolved in 75 ml of acetone. The crystallized salt was collected and recrystallized from acetone to obtain 1.45 g of white crystals, 12-allyl-10,11-polyhydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-. Imine fumarate was obtained. Melting point: 180-182 ° C.

Instead of allyl bromide and 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, the general formulas-1- and 5-R ² CH described in Table 2 ₂ -10,11- dihydro -5H- dibenzo [a, d] cycloheptene with the procedure of example 7 using -5,10- imine according to the following reaction steps described in Table 2, 5-R _² CH ² -12-R-10,11- dihydro -5H- dibenzo [a, d] cycloheptene -5,10- migration was also prepared.

Example 8

5,10,12-trimethyl 10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrochloride

Step A

Preparation of 10-amino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

10-hydroxyamino-5-methylene-10,11-dihydro-5H-dibenzo [a] in a stirring slurry of zinc powder (0.9 g, 0.138 mol) in 100 ml of glacial acetic acid stirred in an oil bath at 65 deg. , d] cycloheptene (10 g, 42 mmol) was added. The mixture was stirred in an oil bath for 2 hours, then cooled and quenched in 500 ml of water. The mixture was made ammonia basic and extracted with ether. The ether layers were combined, washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from hexane to give 7.8 g. Melting point: 84.5-36.5 ° C.

Step B

Preparation of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

Sodium hydroxide particles (4.42) in a solution of 10-amino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (8.1 g, 36.6 mmol) dissolved in chloroform (180 mL). g, 0.11 mol), benzyltriethyl ammonium chloride (0.42 g, 1.8 mmol) and mol (0.5 mL) were added. The mixture was stirred under nitrogen until the sodium hydroxide particles dissolved (4 hours), treated with anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo.

The resulting oil was dissolved in chloroform (180 mL) and then treated with 1.5 g (37.5 mmol) sodium hydroxide and 0.2 g (0.68 mmol) benzyltriethyl ammonium chloride and stirred overnight under nitrogen. The mixture was dried again over potassium carbonate and then filtered and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g silica gel and then eluted with methylene chloride. The product fractions were combined and evaporated to dryness in vacuo and the resulting solid was recrystallized from ether to give 4 g of solid. Melting point: 96-98 ° C.

Step C

Preparation of 10-isocyano-10-methyl-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

Diisopropylamine (1.1 g, 10.9 mmol) in 25 ml anhydrous tetrahydrofuran was stirred in anhydrous ice / acetone bath. The solution was treated dropwise over 10 minutes with n-butyltium / hexane (5.0 mL of 2.2 M solution) under a nitrogen blanket. After 5 minutes, 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (2.4 g, 10.4 mmol) dissolved in 25 ml anhydrous tetrahydrofuran was obtained. The solution was added dropwise (over 45 minutes) to the Lithium isopropylamine solution. The resulting deep red solution was stirred for 15 minutes in a cool place and then further stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was chromatographed on 75 g silica gel and eluted with methylene chloride. The product fractions were combined and evaporated in vacuo to yield 2.2 g (85%) of solids. Recrystallization from ether showed melting point of 146-147.5 ° C.

Step D

10-methyl-10-methylamino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene hydrogen chloride

10-isocyano-10-methyl-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (1.3 g, 7.3 mmol) was dissolved in anhydrous ether (100 mL). Then, it was added dropwise to a slurry of lithium tetrahydro aluminate (0.53 g, 14 mmol) in ether (40 mL) stirred under nitrogen. The mixture was heated to reflux for 1 hour and then cooled, and excess hydride was decomposed by careful dropwise addition of 1.5 ml of ice water. The suspension was filtered and the solid washed twice with ether. The ether fractions were combined and evaporated in vacuo to give 1.8 g of oil. The oil, dissolved in 10 ml of anhydrous ethanol, was treated with slightly fruit 8N ethanolic HCl and then cooled to give 1.7 g (81%) of powder. Melting point: 238-240 ° C. (d).

Step E

5,10,12-trimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrogen chloride

10-Methyl-10-methylamino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (1.6 g, 6.4 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). I was. To the solution stirred at room temperature under nitrogen was added dropwise n-buri (BuLi) (3.0 mL of 2.2MM solution dissolved in hexane) for at least 5 minutes. The mixture was stirred for 10 minutes and then treated with 3 ml of ice water. Tetrahydrofuran was removed in vacuo and the residue was taken as ether. The solution was washed with water, then ether dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g silica gel and eluted with 1.5%, 2%, 3% and 5% methanol in methylene chloride and methylene chloride.

The product fractions were combined, evaporated to dryness in vacuo and then dissolved in 50 ml of anhydrous ethanol and treated with a slight excess of 8N ethanol HCl. The solvent was removed in vacuo and the remaining solid was recrystallized from 20 mL of absolute ethanol to give 5,10,12-trimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10- Imine hydrogen chloride was obtained. Melting point: 295-296.5 deg.

By a similar method the following compounds were obtained. 10-allyl-: 5,12-dimethyl-5,10-diethyl-12-methyl-: 10-cyclopropyl-5,12-dimethyl-: and 10-cyclopropylmethyl-5,12-dimethyl-120, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Example 9

Optical segmentation

5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (3.93 g. 0.0178 moles) and (-) diP-toluoyl-d- of racemic acid Tartaric acid (6.88 g, 0.0178 mol) was dissolved in 21 ml of acetone. The solution was allowed to mature and left at room temperature for several hours to collect crystalline salts. This product was repeatedly recrystallized from acetone. This salt was suspended in cold water and stirred with aqueous sodium hydroxide solution, and then the base was extracted with ether. The ether extract was washed, dried and then evaporated to dryness under reduced pressure to afford (-) 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine as a solid. . Melting point: 71.5-73.5 ° C.

The acetone mother liquor from the initial crystals of the (-)-isomer was evaporated to dryness under reduced pressure. The remaining suspension of glass suspended in cold water was stirred with aqueous sodium hydroxide solution and then the base was extracted with ether. The washed and dried ether extract was concentrated to give an optically impure (+)-base as a solid. The product (2.27 g, 0.013 mole) and (+) di-P-toluoyl-1-tartrate (3.9 g, 0.0103 mole) were dissolved in 20 ml of acetone. After standing at room temperature for several hours, the crystalline salts were collected and recrystallized repeatedly from acetone while constantly rotating. This salt was converted back to base in the manner described above to afford (+) 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine. Melting point: 72-74 ° C.

Example 10

Tablet manufacturing

Tablet containing 10,11-dihydro-5-methyl-12-benzyl-5H-dibenzo [a, d] cycloheptene-5,10-imine each having 1.0, 2.0, 25.0, 26.0, 50.0 and 100.0 mg Was prepared as follows.

Formulation Table Containing 1-25mg of Active Compound

Formulation Table Containing 26-100mg of Active Compounds

The active compound, lactose, and corn starch were mixed and granulated at 10% corn starch face. The granules obtained were sieved, dried and mixed with the remaining corn starch and magnesium stearate. The obtained granules were compressed to prepare tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of active ingredient per tablet. Other tablets were prepared using the same amount of excipients and the same process along with other novel compounds equivalents of the present invention.

Another method for preparing the compound of the following formula (1) is as follows.

Wherein R is hydrogen, methyl, ethyl or benzyl, R ² is hydrogen, methyl or -CH ₂ OH

(a), reduction of the compound of formula (2), i.e. a solution of formula (2), for example lower alkanols such as methanol, ethanol, inopropane or butane, lower alkanoic acids or dioxanes such as acetic acid or propionic acid Or water-soluble ethers including 1,2-dimethoxyethane, water, or mixtures thereof, preferably charcoal at 1-5 atm, preferably 1 atm, 15-100 ° C., preferably 25 ° C., in an inert polar solution such as ethanol. In catalysts such as 10% palladium catalyst on platinum or Raney nickel, preferably 10% palladium on charcoal, usually about 2-24 hours, preferably 3-6 hours, until one equivalent of hydrogen is actually absorbed While shaking with hydrogen, an imine (1) corresponding to which R is hydrogen is produced.

(b), N-alkoxycarbonyl derivative of the following general formula (3) is converted to ethanol or lower alkanol such as n-butanol, water-soluble ether such as tetrahydrofuran, dioxane, or dimethoxyethane, or acetone or methyl ethyl ketone , Preferably in an inert polar solvent such as di (lower alkyl) ketone, such as n-butanol, at about 25-100 ° C., preferably at a reflux temperature of the appropriate solvent, in an inert gas atmosphere such as nitrogen, when the hydrolysis is actually complete To, usually about 2-24 hours, preferably 10-12 hours, prepared by treatment with a strong inorganic base such as potassium hydroxide or sodium hydroxide or an aqueous solution thereof (25-50% by weight), preferably potassium hydroxide.

Wherein: alkyl is methyl, ethyl, propyl or t-butyl.

(c), a compound of formula (4) is prepared from an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or di (2-ethoxyethyl) ether, preferably diethyl ether, Under about 35 ° -165 ° C., preferably at the reflux temperature of a suitable solvent, until the reaction is substantially complete, usually for about 1-24 hours, preferably for 2-24 hours, the lithium aluminum hydride ( Prepared by reduction with KiAlH ₂ ).

Food

X, Y and Z are each hydrogen, chlorine or bromine and Rα is hydrogen, hydroxy, methyl, ethyl, benzyl or benzoyl.

(d) the reduction of the compound of formula (5), i.e., the solution of formula (5) below, an inert polar solvent such as water, a lower alkanol such as ethanol, t-butanol, or ethylene glycol, or dimethyl sulfoxide Or an inert polar solvent such as a mixture thereof, preferably at about 50-165 ° C., preferably at 90-120 ° C., in ethylene glycol, usually about 0.5-16 hours until the reaction is substantially complete, preferably 1- Treatment with hydrazine for 3 hours and then at about 100-185 ° C., preferably 150-175 ° C., until the reduction is substantially complete, usually 1-24 hours, preferably 2-4 hours, potassium hydroxide, sodium hydroxide or It is prepared by treatment with a strong inorganic base, such as potassium hydroxide, preferably potassium hydroxide.

(e), di (lower alkyl) ethers of compounds of formula (6), such as ether or 1,2-dimethoxyethane, are inert solvents, chloro lower alkanes such as methylene chloride or carbon tetrachloride, or inerts such as benzene In cyclo (lower) alkanes such as aromatic solvents or cyclohexane, preferably diethyl ether or methylene chloride, at about −5 ° C. to 80 ° C., preferably at 5-25 ° C., until the N-chlorination is essentially complete Product obtained after treatment with sodium hypochloride, t-butylhypochloride or N-chlorolysineimide, preferably sodium hypochloride or N-chlorolysineimide for 0.5-12 hours, preferably 1-3 hours In 75-96 wt% sulfuric acid, preferably 85 wt% sulfuric acid, at about 15-50 ° C., preferably at 25-30 ° C., usually about 3-24 hours, preferably until photocyclization is substantially complete Roneun is produced during 6-3 hours, by irradiation with 125 watts lamp line (sunlamp).

Food

[R _β is hydrogen, methyl or ethyl]

(f) a compound in which R ² is —CH ₂ OH by reducing the compound of the following general formula (7) with lithium aluminum hydride (LiAlH ₄ ) in substantially the same manner as described in step (c). 1) was prepared.

Wherein X 'and Y' are each hydrogen, chlorine, bromine or hydroxy, and R ' _β is hydrogen, methyl, ethyl or benzyl.

(식중, R'는 수소, 메틸 또는 페닐)의 알킬화 제조 처리한 다음 리티움 알미늄 하이드라이드로 환원시켜 제조한다. 부가적인 알킬화 방법은 이민을 테트라하이드로푸란, 1,2-디메톡시에탄 또는 디(2-메톡시 에틸) 에테르, 바람직하기로는 테트라하이드로푸란에서, 약 10-50℃, 바람직하기로는 25℃에서, 반응이 사실상 완결될 때까지, 보통 약 6시간-약 3일동안, 바람직하기로는 약 2일동안 일반식 R'CHO의 알테히드 및 나트륨 시아노하이드라이드 (NaCNBH₃)로 처리하는 것을 포함한다.If the product of steps (a)-(f) is an unsubstituted imine (1) in which R is hydrogen, this is optionally N-alkylated with a suitable alkylation reagent such as R-halo as described above so that R is methyl, ethyl Or benzyl compounds or of the general formula

Wherein R 'is prepared by the alkylation preparation of hydrogen, methyl or phenyl followed by reduction with lithium aluminum hydride. An additional alkylation process comprises imine at tetrahydrofuran, 1,2-dimethoxyethane or di (2-methoxy ethyl) ether, preferably at tetrahydrofuran, at about 10-50 ° C., preferably at 25 ° C., Treatment with an aldehyde of the general formula R'CHO and sodium cyanohydride (NaCNBH ₃ ), usually for about 6 hours to about 3 days, preferably about 2 days, until the reaction is substantially complete.

The starting materials and processes used to prepare them are well described in Examples 11-21 below.

Examples 11-13 described above process (a) for preparing 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine and its hydrochloride salt, ( The modification of b) and (c) is described.

Example 11

Step A

Preparation of 6-methylene-1, 1a, 6, 10b-tetrahydro dibenzo [3.4: 6.7] cyclohept [1,2-b] aziline

Lithium aluminum hydride (0.46 g, 0.012 mol) was slurried in ether (40 mL) and then dissolved in ether (25 mL) 5-methylene-10,11-dihydro-5H-dibenzo [a, d] The solution of cyclohepten-10-one-oxime was slowly added dropwise. The mixture was stirred at room temperature for 3 hours and then hydrolyzed by successively adding water (0.4 mL), 10% aqueous sodium hydroxide solution (0.6 mL) and water (1.2 mL). The ether phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to yield 6-methylene-1, 1a, 6, 10b-tetrahydro dibenzo [3.4: 6.7] cycloheptene [1.2-b] Aziri was obtained.

Step B

Preparation of 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

Under nitrogen, 6-methylene-1, 1a, 6, 10b-tetrahydrodibenzo [3.4:] dissolved in tetrahydrofuran (5 mL) was dissolved a solution of 2M n-butylitium dissolved in hexane (0.8 mL). 6.7] It was slowly added dropwise to a stirred solution of cyclohept [1.2-b] aziline (0.44 g, 0.002 mol). After 16 hours of continuous stirring at room temperature, the mixture was quenched in ice water and extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate, filtered and the filtrate was evaporated to yield 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo [a, d] cyclone. Heptene was obtained.

Step C

Preparation of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

The product from step B dissolved in anhydrous ethanol (5 mL) (0.001 mol) with hydrogen at 25 ° C., at high pressure, on 10% palladium supported on carbon (50 mg) until 1 equivalent of hydrogen was absorbed Shaken. The catalyst was filtered off and the aqueous solution was evaporated to afford 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine.

Using the same process described in Example 11, except that the equivalent of 5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one-oxime is substituted for the starting material Methyl ethylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one oxime using 5-ethyl-10,11-dihydro-5H-dibenzo [a, d] cyclo Heptene-5, 10-imine was prepared.

Example 12

12-methoxycarbonyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (2.93 g, dissolved in n-butyl alcohol (100 mL) 0.01 mol) and sodium hydroxide (20 g) were heated and refluxed under nitrogen atmosphere for 12 hours. The solvent was evaporated and the residue was partitioned between toluene and water. The toluene phase was separated, washed with water and extracted with 1N aqueous hydrochloric acid solution. The acid extract was made basic with 10% sodium hydroxide and the mixture was extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to yield 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine. Obtained.

Example 13

Step A

Preparation of 5-azido-5-iodinemethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-10-one

5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one (8.2 g) in acetonitrile (30 mL) was stirred in a solution of iodine azide (methanol / ice bath) To a suspension of 5.6 g of sodium azide suspended in 37 ml of acetonitrile, 6.8 g of iodine monochloride was added dropwise. The mixture was heated at room temperature and then stirred overnight. It was then poured into 250 mL of ice water and extracted with ether (3 x 50 mL). The ether extracts were combined, washed with 5% sodium thiosulfate solution (1 × 50 mL), washed with water (3 × 50 mL), dried over sodium sulfate, filtered and evaporated to dryness under vacuum. Iodinemethyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one was obtained.

Step B

Preparation of 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

5-azido-5-iodinemethyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one (4.3 g) and 10% palladium / charcoal (0.3 g) were added to ethanol ( 80 ml) and then shaken under hydrogen atmosphere (50 p.sig) in a paar shaper. The mixture was filtered and evaporated to dryness in vacuo to afford 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Step C

Preparation of 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

20 minutes in thionylchloride (30 mL) refluxing 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (3.5 g) Heated during. The mixture was cooled and then evaporated to dryness in vacuo.

Toluene (60 mL) was added twice and then removed in vacuo. The residue was slurried in ether (50 mL) and then treated with excess 1N NaOH aqueous solution (25 mL). The ether layer was separated and the aqueous layer was extracted with ether (2 x 50 mL). The combined layers of ether were washed with water (3 × 100 mL), dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo [a, d Cycloheptene-5,10-imine was obtained.

Step D

Preparation of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrochloride

10-chloro-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-imine (5 g) was dissolved in eteph (100 mL) and then stirred under nitrogen (80 mL). ) Was added dropwise to a slurry of lithium aluminum hydride (0.76 g). The mixture was heated at reflux for 2 hours, then cooled and treated dropwise with ice water (2 mL). The suspension is filtered and the solid is washed with ether. The filtrate and ether washes were combined, washed with water (2 × 100 mL), dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was treated with excess 8N ethanol HCl in ethanol (10 mL) and the solution was evaporated to dryness in vacuo. The residue was recrystallized from ethanol to give 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrochloride.

Using the same method described in Example 13, the equivalent of 5-methylmethylene- instead of the starting material 5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one 5-ethyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5, using 10,11-dihydro-5H-dibenzo [a, d] cycloheptene-10-one 10-imine was prepared.

Examples 14-16 describe methods (d) and (e) of preparing 5,12-dimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine It is.

Example 14

Step A

Preparation of 5-formylamino-5H-dibenzo [a, d] cycloheptene

A solution of 5H-dibenzo [a, d] cyclohepten-5-amine (20.7 g, 0.1 mol) dissolved in ethyl formate (200 mL) was heated at reflux for 10 hours. The solvent was evaporated and the residue was partitioned between 1N aqueous hydrochloric acid solution and ether. The ether solution was separated, washed with water, dried over sodium sulfate, filtered and the filtrate was evaporated to afford 5-formylamino-5H-dibenzo [a, d] cycloheptene.

Step B

Preparation of 5-isocyano-5H-dibenzo [a, d] cycloheptene

6-formylamino-5H-dibenzo [a, d] cycloheptene (18.8h, 0.08 mol), triphenylphosphine (25 g, 0.095 mol), carbon tetrachloride (12.3 g, 0.08 mol) and triethylamine (8.1 g, 0.08 mole) was dissolved in chloroform (80 mL) and heated at 60 ° C. for 2.5 h. After evaporation of the solvent the residue was extracted five times with hexane. The hexane extracts were combined, concentrated and chromatographed on silica gel eluting with toluene. Evaporation of the toluene solution gave 5-isocyano-5H-dibenzo [a, d] cycloheptene.

Step C

Preparation of 5-isocyano-5-methyl-5H-dibenzo [a, d] cycloheptene

Under nitrogen, 2MN-butyltium and tetra hydrofuran (30 mL) in hexane (28 mL) were stirred and then cooled to -70 ° C. 5-isocyano-5H-dibenzo [a, d] cycloheptene (10.85 g, 0.05) added dropwise with diisopropylamine (5.65 g, 0.056 mole) and then dissolved in tetrahydrofuran (100 mL) 5 minutes later Mole) was added. After another 10 minutes, methyl iodine (21.3 g, 0.15 mol) was added in one portion. The mixture was stirred at −70 ° C. for 15 minutes and then at room temperature for 2 hours. The mixture was washed with water then dried over sodium sulfate, filtered and the filtrate was evaporated to afford 5-isocyano-5-methyl-5H-dibenzo [a, d] cycloheptene.

Step D

Preparation of 5, N-dimethyl-5H-dibenzo [a, d] cyclohepten-5-amine

Lithium aluminum hydride (1.0 g, 0.026 mol) was slurried in ether (25 mL) and then dissolved in ether (60 mL) 5-isocyano-5-methyl-5H-dibenzo [a, d A solution of cycloheptene (6.0 g, 0.026 mol) was added dropwise. The mixture was stirred at room temperature for 16 hours and then hydrolyzed by successively dropwise addition of water (1 mL), 10% aqueous sodium hydroxide solution (1.5 mL) and water (3 mL). The ether solution floated on the surface was separated by filtration and the filtrate was evaporated to give 5, N-dimethyl-5H-dibenzo [a, d] cyclohepten-5-amine.

Step E

Preparation of 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

A solution of 5, N-dimethyl-5H-dibenzo [a, d] cyclohepten-5-amine (4.7 g, 0.02 mol) dissolved in 1N aqueous hydrochloric acid solution (20 mL) and water (50 mL) was stirred at room temperature. Bromine (3.2 g, 0.02 mol) was then added dropwise. After 10 minutes, potassium carbonate (5.5 g, 0.04 mole) was added in one portion and then tetrahydrofuran (50 mL) was added. The mixture was stirred at ambient temperature for 16 hours and then the aqueous phase was separated and extracted several times with chloroform. The chloroform and tetrahydrofuran phases were combined and extracted with 1N aqueous hydrochloric acid solution. The cooled acid extract was made basic with 20% sodium hydroxide and then the mixture was extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate and then filtered to concentrate the filtrate. The residue was chromatographed on silica gel eluting with methanol-toluene (5:95). Evaporation of the eluent gave 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Step F

Preparation of 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10 with triethylamine (10 mL) and dimethyl sulfoxide (10 mL) Imine was stirred at room temperature dropwise with sulfitrioxide trimethylamine complex (2.1 g). The mixture was stirred for 48 hours at room temperature and then quenched in ice water. The mixture was extracted with ether, the ether extract was washed with water, dried over sodium sulfate, filtered and the filtrate was evaporated to yield 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo [a, d Cycloheptene-5,10-imine was obtained.

Step G

Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,12-imine

5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (2.0 g) was added 64% hydrazine (0.8 mL) and ethylene glycol ( 20 ml). The mixture was heated at 100 ° C. for 2 hours, potassium hydroxide (1.5 g) was added and then heating continued at 165 ° C. for 3 hours. The mixture was poured into water (200 mL) and then extracted with ether. The ether extract was washed with water, dried over sodium sulfate and filtered to concentrate the filtrate. The residue was chromatographed on silica gel followed by methanol-toluene (10:90). Evaporation of the eluent gave 5,12-dimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Using the same process described in step AG of Example 14, except that an equivalent amount of ethyl bromide or benzenechloride was used in place of the methyliodine used in the step, each of 5-ethyl-12-methyl-10,11-dihydro Prepares -5H-dibenzo [a, d] cycloheptene-5,10-imine and 5-benzene-12-methyl-10,11-5H-dibenzo [a, d] cycloheptene-5,10-imine It was.

Division of (±) -5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

Enzymatic isomer: 163 in 66.1 g (0.299 mol) of racemic 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine in 107 ml of warm acetone 115.4 g (0.200 mol) of di-p-toluoyl-d-tartaric acid dissolved in mL acetone was added. The solution was stirred until homogeneous, left at 25 ° C. for 18 hours and then cooled to 0 ° C. in a freezer for 4 hours. The formed salt was filtered off, washed once with cold acetone, collected and dried (vacuum oven) at 50 ° C. to obtain A as 82.97 g of a white solid.

[α] ^D ₅₈₉ = -125.9 ° (separated EtOH), melting point 141-146 ° C. (bubble) The filtrate of solid A was concentrated to dryness in vacuo and solid residue B was used for the preparation of the preferred isomers (see below).

Salt A was dissolved in 3450 ml of boiling acetone, filtered, concentrated to 1500 ml, left at 25 ° C. for 18 hours, and then concentrated in a freezer to 0 ° C. for 4 hours. The precipitate was filtered off, washed once with cold acetone and collected and dried (vacuum oven) at 60 ° C. to give C as 45.5 g of a white solid. *** =-131.9 ° (extract EtOH) Melting Point 142-144 ° C (Foam)

The partitioned solid C (44.8 °, 0.0737 moles) was treated with 300 mL 10% sodium hydroxide and 300 mL diethyl ether to stir the mixture until the solids dissolved. The ether layer was separated, dried over MgSO ₄ , filtered and evaporated to dryness in vacuo to give 16.0 g of tlc (silica GK eluted with 1: 9 methanol: chloroform) homogeneous colorless oil. Recrystallization from 400 ml of cyclohexane gave 14.16 g (-)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine as a white solid. [α] 589 = -160.8 °, (C = 0.032 g / 2 mL ethanol) Melting Point 68.5-69.5 ° C

Priority isomers

The residue B in the preparation of the left isomer was stirred with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether until the solid was dissolved and converted to the free base form. The ether layer was dried over MgSO ₄ and filtered to remove the solvent under reduced pressure to give 37.9 g of orange oil dissolved in 67 mL of warm acetone, which was 69.3 g (0.171 mol) of di-p- in 98 cc acetone. The solution was treated with a solution of toloyl-1-tartaric acid monohydrate. The solution was stirred until homogeneous, left at 25 ° C. for 18 hours and then cooled in a freezer at 0 ° C. for 4 hours. The formed salt was removed by filtration, washed once with cold acetone, collected and dried (vacuum oven) at 60 ° C. to obtain D as 68.8 g of a white solid. [α] 589- + 127.1 ° (extraction EtOH), melting point 136-144 ° C. (foam)

The D salt was dissolved in 2900 ml of boiling acetone, filtered, concentrated to 900 ml, left at 25 ° C. for 18 hours and then cooled in a freezer to 0 ° C. for 4 hours. The precipitate was filtered off, washed once with cold acetone, collected and dried (vacuum oven) at 60 ° C. to give E as 36.5 g of a white solid. [α] 589 = -132.0 ° (separated EtOH), melting point 142-144 ° C (foam)

The partitioned salt E (36.5 g, 0.0601 mol) was treated with 300 mL of 10% sodium hydroxide and 300 mL diethyl ether to stir the mixture until the solids dissolved. The ether was separated, dried over MgSO _4, filtered and evaporated to dryness in vacuo to give 12.6 g of tlc (silica GF eluted from 1: 9 methanol: chloroform) homogeneous colorless oil. Recrystallization from 25 ml of cyclohexane gave 11.26 g of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine as a white solid.

[α] ²⁰ 589 = + 161.4 ° (C = 0.038 ㅎ / 2 mL ethanol), Melting point 68.5-69.0 ° C

Example 15

(+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-imine hydrogen maleate

A solution of 10.05 g (0.0454 mol) of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine in 25 ml anhydrous ethanol Filter in the scrubber and filter was washed with anhydrous ethanol until the final filtrate was 40 ml. A solution of 5.27 g (0.0454 mol) maleic acid in 20 mL of anhydrous ethanol was filtered in the same flask. The mixed filtrates were mixed and kept at room temperature for a short time before cooling overnight. The crystalline material was collected and dried to give (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrogen maleic acid salt. Melting Point: 208.5-210 ℃

[α] * = + 114 ° (C = 0.0128 g / 2 mL ethanol)

Example 16

Step A

Preparation of 5-isocyano-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

5-formylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (3.5 g), triethylamine (5.3 mL) and methylene chloride (15 mL) were stirred in an ice bath. Phosphine (1.5 g) was injected into the solution, water (50 mL) was added and the layers separated. The organic layer was washed with water (2 × 50 mL), dried over sodium sulfate, filtered and dried in vacuo to afford 5-isocyano-10,11-dihydro-5H-dibenzo [a, d] cycloheptene. .

Step B

Preparation of 5-isocyano-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

5- dissolved in tetrahydrofuran (15 mL) in n-butylitrium (15 mL in 2.2 M hexane) in anhydrous tetrahydrofuran (91 mL), cooled in an anhydrous ice / acetone bath and stirred under nitrogen. Treatment was performed dropwise with a solution of isocyano-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (6.8 g). The mixture was stirred in a cold bath for 10 minutes before rapidly adding iodine methane (8.7 g) in tetrahydrofuran (1.5 mL). The mixture was stirred for 15 minutes in a cooling bath and then left to warm to room temperature. After 2 hours, the urine solution was treated with water (2 mL) and the bulk of tetrahydrofuran was removed in vacuo. Ether (100 mL) and water (50 mL) were added and the layers were separated. The aqueous layer was extracted with ether (2 × 50 mL), then the ether layers were combined, washed with water (2 × 50 mL), dried over sodium sulfate and evaporated to dryness in vacuo to give 5-isocyano-5-methyl-10, 11-dihydro-5H-dibenzo [a, d] cycloheptene was obtained.

Step C

Preparation of 5-methyl-5-methylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

Reity stirred 5-isocyano-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (3.3 g) in ether (120 mL) under ether (60 mL) under nitrogen Was added dropwise to Um aluminum hydride (0.6 g). The mixture was heated at reflux for 4 h and then cooled on ice. Ice water (2 mL) was added dropwise and the mixture was stirred for 15 minutes. The mixture was filtered and then the solid was washed with ether (2 × 50 mL) and then ether washings were combined with the filtrate. The ether layer was washed with water (3 × 50 mL), dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 5-methyl-5-methylamino-10,11-dihydro-5H-dibenzo [a , d] cycloheptene was obtained.

Step D

Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrochloride

5-Methyl-5-methylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (6 g) was stirred in 30 mL of ether and then cooled on ice. The mixture was treated dropwise with 30 ml of 1N nitrile hypochlorite aqueous solution over 3-5 minutes. The mixture was stirred for 1/2 hour in a cold place and then separated. The aqueous layer was extracted with ether (2 × 30 mL), the ether layers were combined, washed with water (2 × 30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to give a residue containing the prepared chloramine product.

The residue was treated with cooled 85% sulfuric acid and then the mixture was stirred under nitrogen in a flask and irradiated with a 125 watt GE * sunlamp until chloramine was consumed. The mixture was added to stirred ice water (600 mL), treated with an aqueous 3N NaOH solution to make basic, and then extracted with ether (3 x 100 mL). The ether layers were combined, washed with water (2 x 50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue in ethanol was treated with excess 8N ethanol HCl and then the solvent was removed in vacuo. The residue was recrystallized from ethanol to give 5,12-dimethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine hydrochloride.

Using the same process described in step AD of Example 15, except that 5-ethyl-12-methyl-10,11-dihydro-5H-di was substituted using an equivalent amount of ethyl iodine instead of the iodine methane used in the step Benzo [ad] cycloheptene-5,10-imine was prepared.

Example 17

Step A

10-amino-5-methyl-10,11-dihydro-5H-dibenzo [a.d]

10-hydroxy imino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (10 g) and 10% palladium / charcoal (02.g) were anhydrous ethanol (100 mL) Combined at and then shaken under nitrogen atmosphere (50 p.sig). The solution was filtered and the filtrate was dried in vacuo to afford 10-amino-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene.

Step B

Preparation of 10-methyl amino-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

10-Amino-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclo heptene (5 g) was dissolved in a mixture of pyridine (50 mL) and benzene (100 mL). Ethylformate (32.4 g) was added dropwise to the stirred solution and the resulting mixture was allowed to warm to 50 ° for 30 minutes. The mixture was cooled and quenched in ice water (500 mL) and then separated. The aqueous phase was extracted with benzene (2 x 100 mL) and then the organic phase was combined with the benzene extract and washed with water (4 x 100 mL). The solution was dried over sodium sulfate and then filtered and evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran (100 mL) and then added dropwise to lithium aluminum hydride (1.1 g) stirred in tetrahydrofuran (50 mL) under nitrogen. The mixture was heated at reflux for 20 minutes, then cooled and the excess hydride was decomposed by the dropwise addition of ice water. The mixture was filtered and the solid was washed with tetrahydrofuran (2 × 50 mL), dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 10-methylamino-5-methyl-10,11-dihydro-5 -Dibenzo [a, d] cycloheptene was obtained.

Step C

Preparation of 5,12-dimethyl-10,11-dihydro-5-dibenzo [a, d] cycloheptene-5,10-imine hydrochloride

10-methylamino-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (4.7 g) in methylene chloride (30 mL) was cooled to 5 ° and N-chlorosuccinate Treated with mid (55 mL of 0.4 M solution in methylene chloride). After 30 minutes at 5 ° C., the mixture was stirred for an additional hour at room temperature and then the solvent was provided in vacuo. The residue was extracted with hexane (3 x 50 mL), and the combined extracts were filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 85% sulfuric acid (40 mL) in a sediment flask and the solution was irradiated with a 125 Watt GE * sunlamp until chloramine was consumed.

The mixture was carefully added to stirred ice water (500 mL), and then made basic by dropwise addition of 3N sodium hydroxide, followed by extraction with ether (3 x 100 mL). The ether layers were combined, washed with water (2 × 100 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in anhydrous ethanol and treated with a slight excess of 8N HCl in ethanol. The solvent was removed in vacuo and the residue was recrystallized from ethanol to give 5,12-dihydro-5H-dibenzo [a, s] cyclohepten-5,10-iminehydrochloride.

Examples 17-19 illustrate the method (5) already described for the preparation of compound (1), wherein R ² is -CH ₂ OH.

Example 18

12-methyl-5- (2-hydroxyethyl) 1-, 11-dihydro-5H-dibenzo [a, s] cycloheptene-5,10-imine

Step A

Preparation of 5-ethoxycarbonyl methylene-5H-dibenzo [a, d] cycloheptene

Triethylphosphonoacetate (0.045 mol) was added dropwise at 30-35 ° C. to a slurry of sodium hydride (0.045 mol) in anhydrous toluene (20 mL) under nitrogen. After stirring for 1 hour at room temperature, a solution of 5H-dibenzo [a, d] cyclohepten-5-one (0.033 mol) dissolved in anhydrous toluene (75 mL) was added dropwise and stirring continued for 16 hours. The solution was decanted and the residue washed with toluene. The organic solution was collected, extracted with 0.5N aqueous hydrochloric acid solution, washed with water, and dried over sodium sulfate. Filtration followed by evaporation gave 5-ethoxycarbonylmethylene-5H-dibenzo [a, d] cycloheptene.

Step B

Preparation of 5-ethoxycarbonylmethyl-5-ethylamino-5H-dibenzo [a, d] cycloheptene

A solution of 5-ethoxycarbonylmethylene-5H-dibenzo [a, d] cycloheptene (0.01 mol) dissolved in THF (200 mL) was treated with ethylamine (0.012 mol) and stirred for 24 hours. This solution was evaporated to give 5-ethoxycarbonylmethyl-5-ethylamino-5H-dibenzo [a, d] cycloheptene.

Step C

Preparation of 5-ethoxycarbonylmethyl-12-ethyl-11-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

A solution of 5-ethoxycarbonylmethyl-5-ethylamino-5H-dibenzo [a, d] cycloheptene (0.02 mol) dissolved in aqueous hydrochloric acid solution (200 ml) and mol (50 ml) was stirred at room temperature. Then bromine (0.02 mol) was added dropwise. After 10 minutes potassium carbonate (0.04 mol) was added at a time and then tetrahydrofuran (50 L) was added. The mixture was stirred at room temperature for 16 hours. The aqueous phase was separated and then extracted several times with chloroform. The chloroform and tetrahydrofuran phases were combined and then extracted with 1N aqueous hydrochloric acid solution. The chloroform extract was washed with water, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was chromatographed on silica gel and then eluted with methane-toluene (5:95).

Preparation of 5-ethoxycarbonyl-12-ethyl-11-hydrocy-10-11-dibenzo [a, d] cycloheptene-5,10-imine by evaporation of the eluent

5-ethoxycarbonylmethyl-12-ethyl-11-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (0.1 mol) in toluene (50 mL) ) And phosphorose tribromide (1.0 mL) were heated under reflux for 6 h. The solvent was evaporated and the residue was stirred with 2% aqueous sodium hydroxide solution (200 mL) and then extracted with ether. The ether extract was dried over sodium sulfate, then filtered and the filtrate was evaporated. The residue was eluted from a silica gel column using chloroform to yield 11-bromo-5-ethoxycarbonylmethyl 12-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10- Immigration was obtained.

Step E

Preparation of 12-ethyl-5 (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [[a, d] cyclohepten-5,10-imine

11-Bromo-5-ethoxycarbonylmethyl-12-ethyl-10,11-polyhydro-5H-dibenzo [[a, d] cycloheptene-5,10-imine (0.01) in ether (300 mL) Mole) and lithium aluminum hydride (0.011 moles) were stirred and heated under reflux for 6 hours. Water (3.5 mL) was added dropwise with stirring, followed by filtration of the slurry. The filtrate was evaporated to give 12-ethyl-5- (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [[a, d] cycloheptene 5,10-imine.

Example 19

12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [[a, d] cycloheptene 5,10-imine

Step A

Preparation of 12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy1-10,11-dihydro-5H-dibenzo [[a, d] cycloheptene 5,10-imine

5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo [[a, d] cyclohepten-10-one was dried with anhydrous benzylamine (0.012 mol) according to the same process as in Step B of Example 17. ) Gave 12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [[a, d] cycloheptene 5,10-imine.

Step B

Preparation of 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo [[a, d] cycloheptene 5,10-imine

12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-polyhydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (0.01 mol) in toluene (500 mL) ) And phosphorus tribromide were heated under reflux for 6 hours. After evaporation of the solvent, it was stirred with 2% aqueous sodium hydroxide solution (200 mL) and extracted with ether. The ether extract was dried over sodium sulfate, filtered and the filtrate was evaporated. The residue was eluted from a silica gel column using chloroform to yield 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5 , 10-immigration was obtained.

Step C

Preparation of 12-benzyl-5- (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Using the same method as described in Step E of Example 17, 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo [a, d] Reduction of cycloheptene-5,10-imine (0.01 mol) resulted in 12-benzyl-5 (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-immigration was obtained.

Example 20

5- (2-hydroxyethyl) -12-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Step A

5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

Using the same method as described in Step B of Example 17, except that the molar amount of 10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5 is used instead of the starting material used in Step A above. 5-Ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene was prepared using -one.

Step B

Preparation of 5-ethoxycarbonylmethyl-5-methylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene was treated with anhydrous ethylamine according to the same method as described in step B of Example 17. 5-Ethoxycarbonylmethyl-5-methylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene was obtained.

Step C

Preparation of 5-ethoxycarbonyl-12-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

5-Ethoxycarbonylmethyl-5-methylamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene was prepared in the same manner as described in step C of Example 16 in 5-ethoxycarbonyl Methyl-12-methyl-10,11-dihydro-5H-dibenzo [a, d] was converted to cycloheptene-5,10-imine.

Step D

Preparation of 5- (2-hydroxyethyl) -12-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

5-Ethoxycarbonylmethyl-12-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10- using the same method described in step E of Example 17 Imine was reduced to prepare 5- (2-hydroxyethyl) -12-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene.

Examples 20-21 describe N-alkylation for preparing compound (1) in which R is not hydrogen.

Example 21

12-benzyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Acetic acid solution of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine (2.35 g) and benzaldehyde (1.1 g) dissolved in THF (100 mL) (1 mL) and sodium cyanobrohydride (1.0 g) were added. The mixture was stirred for 2 days, then filtered and the filtrate was evaporated. The residue was slurried with 1N aqueous ammonium hydroxide solution and then extracted with HCCl ₃ . The chloroform extract was dried over sodium sulfate, then filtered and evaporated. The residue was recrystallized from ethanol to give 12-benzyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine.

Example 22

12-ethyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine

Ice of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine (2.35 g) and triethylamine (2.0 g) dissolved in ether (100 mL) The cooled solution was treated dropwise with acetyl chloride (1.5 g). After 10 hours the solution was washed with water then dried over sodium sulfate, filtered and the filtrate was evaporated to dryness. The residue was dissolved again in ether (200 mL) and then 400 mg LiAlH 4 was added. The resulting slurry was stirred for 24 hours. Water was added slowly, then the resulting slurry was filtered. The filtrate was dried over sodium sulfate and then filtered and the filtrate was evaporated to give 12-ethyl-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine. .

Claims (1)

A method for preparing the compound of formula (A) by reducing the compound of formula (B) or further alkylating the obtained compound

[Meal, R is hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, lower cycloalkyl, lower (cycloalkyl-alkyl) or di (lower alkyl) amino-lower alkyl R 'is hydrogen lower alkyl, lower alkenyl, phenyl-lower alkyl, lower cycloalkyl, lower (cycloalkyl-alkyl) -CH ₂ R ² is lower alkyl, lower alkenyl, phenyl lower alkyl, lower (cycloalkyl-alkyl Or di (lower alkyl) amino-lower alkyl, R ³ and R ⁴ each represent hydrogen, halogen, lower alkoxy, trifluoromethylthio, cyano or carboxy]