NO151861B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5-SUBSTITUTED-10,11-DIHYDRO-5H-DIBENZO- (A, D) -CYCLOHEPTEN-5,10-IMINER - Google Patents

Description

The present invention relates to an analog method

in the preparation of new, therapeutically active 5-substituted-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imines, derivatives, optical isomers and pharmaceutically acceptable salts thereof which are useful as anti-anxiety agents, antidepressants, anticonvulsants, muscle relaxants and in the treatment of mixed anxiety-depression, minimal brain disorder and extrapyramidal disorders such as Parkinson's disease.

Structurally related compounds are previously known to have qualitatively similar properties. For example, there are from the U.S. patent 3 892 756 known 10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and derivatives which are unsubstituted on the 5-bridgehead carbon, and from Belgian patent 829 075 known 9, 10-dihydro-anthracene-9,10-imines and derivatives thereof.

It is an aim of the present invention to provide the new 5-substituted-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imines which are surprisingly more active than the unsubstituted analogues.

The invention thus relates to an analogous method for the production of therapeutically active compounds with the general formula:

and salts thereof,

where

R is (1) hydrogen,

(2) lower alkyl,

(3) lower alkenyl,

(4) phenyl-lower alkyl, (5) chlorophenyl-lower alkyl, (6) fluorophenyl-lower alkyl, (7) lower-(cycloalkyl-alkyl) or (8) di-(lower alkyl)amino-lower alkyl;

1

R is (1) hydrogen, or

(2) lower alkyl,

-CH2R" is (1) lower alkyl,

(2) lower alkenyl, or

(3) -CH,CH_OH,

3 4 in i

R and R are, independently of each other,

(1) hydrogen, or

(2) halogen-

A closed group of compounds is that in which R 1 is hydrogen.

Another preferred group of compounds is that where

R<1>, R^ and R^ are hydrogen.

When R^ and/or R^ is different from hydrogen, it is preferred that they occupy the 2-, 3-, 7- or 8~ positions on the tricyclic ring system.

2

Preferred definitions of -CH^R are lower alkyl, especially methyl or ethyl, or hydroxyethyl.

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

The analogy method according to the invention is characterized by the fact that:

(a) a compound of the formula:

12 3 4

wherein R , R , R , and R are as above, are reduced to form the compound wherein R is hydrogen;

(b) a compound of the formula:

12 3 4

where R , R , R and R are as above,

alkylated to form the compound where R is different from hydrogen, preferably using R-halogen or acylation followed by reduction?

(c) a compound of the formula:

wherein R, R 3 and R 4 are as above, and X is hydrogen, chlorine or bromine, is reduced to form the compound wherein R 2 is -CH 2 OH and R 1 is hydrogen;

(d) a compound of the formula:

12 3 4

where R , R', R and R are as above, treated with a strong base;

(e) a compound of the formula:

where R is hydrogen, methyl, ethyl or benzyl; and R"* is hydrogen, methyl or -CH9OH, is prepared by a compound of the formula:

where R^ is as stated above,

is reduced to the compound wherein R is hydrogen, optionally followed by N-alkylation to form the compound wherein R is methyl, ethyl or benzyl;

(f) a compound of the formula:

where R 2 has the above meaning,

hydrolyzed to the compound wherein R is hydrogen, optionally followed by N-alkylation to form the compound wherein R is methyl, ethyl or benzyl, or reduced to the compound wherein R is lower alkyl;

(g) a compound of the formula:

where R<2> has the above meaning,

is reduced, optionally followed by N-alkylation to form the compound wherein R is methyl, ethyl or benzyl; and R is hydrogen,

(h) a compound of the formula:

where R has the above meaning,

is reduced, and when R is hydrogen, optionally followed by N-alkylation to form the compound where R is methyl, ethyl or benzyl;

(i) a compound of the formula:

2

where R has the above meaning,

treated with N-chlorosuccinimide followed by irradiation.

The new compounds produced according to the invention where

R is hydrogen, is prepared as indicated above in general by reduction of the N-hydroxy analogue. The preferred reducing agent is nascent hydrogen produced by the action of a metal, preferably zinc, on an acid such as acetic acid at L\ 0 - 100°C in from 1 to approx. 10 hours.

The new compounds are also prepared by cyclization of a 10-NHR-5-(=CHR<2>)-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene by treatment with a strong base as an organometallic reagent , e.g. n-butyllithium, in an ethereal solvent such as tetrahydrofuran, 1,2-dimethoxyethane or the like, at approx. 0°C to approx. 30°C in from approx. 5 minutes to approx. 1 hour.

When ~CH 2 R 2 is hydroxy-ethyl, the final step in its synthesis is reduction of the lower alkoxy-carbonyl precursor. The preferred reducing agent is lithium aluminum hydride in an ethereal solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or the like, at a temperature from approx. 15°C to approx. 100<0>C until the reduction is essentially complete during from approx. 1 to approx. 6 hours. This method also serves for hydrogenolysis of a bridgehead halogen group used in the exemplified synthetic scheme:

When R is different from hydrogen, the new compounds are prepared by alkylating the compounds where R is hydrogen with the appropriate reagent of the formula R-halogen, where halogen represents chlorine, bromine or iodine. The reaction is usually carried out in an inert solvent such as benzene or toluene. The alkylating reagent can, however, depending on its physical properties, be used in sufficient excess to act as a solvent. It is preferred 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. Temperatures of from approx. 50°C to approx. 100°C can be used in reaction times of from approx. 10 hours to approx. 5 days.

When R is alkyl or substituted alkyl, the compounds can also be prepared by reduction of an N-acyl compound such as alkoxycarbonyl to obtain methyl, or other alkanoyl groups to obtain the other alkyl groups. The preferred reduction system is a metal hydride such as lithium aluminum hydride in an ethereal solvent such as ether, tetrahydrofuran or 1,2-dimethoxyethane or the like. The reaction proceeds satisfactorily at room temperature, but temperatures from approx. 0° to approx. 50°C is suitable for reduction times of 10 - 13 thaws.

The new compounds can be resolved into their optical isomers by standard methods, such as the formation of diastereomeric pairs by salt formation with an optically active acid[ I such as v(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di- p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base.

The starting materials and methods used in the production of the intermediate products used in the processes described above,

are fully described in the examples.

The present invention also encompasses the preparation of the non-toxic pharmaceutically acceptable salts of the new compounds. Acid addition salts of the imine compounds are formed by

mixing a solution of the imine with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, phosphoric acid or the like. When the new compound has a carboxylic acid group, the invention also covers the sodium, potassium and calcium salts thereof.

The following trial report illustrates the therapeutic effect of certain compounds produced according to the invention compared to related compounds known from US Patents 3,892,756 and 4,009,273.

Trial report

116 Carworth Farm mice (CF1 strain, female) weighing 17

to 21 g, was used for the assessment of each test compound. The test compound was administered i.p. in the doses indicated

in the following table.

The number of animals that gave a response at each dose level in the individual test is indicated in the following table together with the calculated ED,-0 value. The compounds were tested by: The pentylenetetrazol convulsion test (Metrazol).: 1 1/2 hours after administration of the test compound, the mice were given pentylenetetrazol (70 mg/kg i.v.) and observed for tonic extensor spasms. The number of mice that were protected against this effect was recorded.

The electroshock convulsion test (EST): A supramaximal alternating current stimulus of 120 volts was administered for 0.3 sec. through salt water

wick corneal electrodes from a "Medcraft ECT, Model-B" unit. Precautions had to be taken to hold the wick electrodes

saturated with salt water throughout the test. An anticonvulsant of the administered compound is indicated by a modification of the maximal convulsion evoked by such a stimulus 1 hour after

administration of this. In the following table, the compounds No. 1, 6, 8, 10, 12, 14 and 16 are known from the above-mentioned US patents, while the remaining compounds are examples of compounds produced according to the invention.

As can be seen from the above-mentioned table, the compounds prepared according to the invention exhibit a significantly better therapeutic activity than the known compounds.

When treated with the present process compounds, the new imines produced according to the invention are capable of

provide anxiety relief without causing too much sedation or sleep at a dose level of from approx. 0.01 to approx. 50 mg/kg body weight, preferably approx. 0.05 - 10 mg/kg body weight given 1-4 times daily. Additionally, the process compounds are useful as muscle relaxants, anticonvulsants and in the treatment of extrapyramidal disorders when indicated at comparable dosage levels. The exact level of treatment will of course depend on the disease history of the animal or human being treated, and the precise level of treatment within the guidelines stated above is left to the doctor's discretion.

The following examples illustrate the invention.

Example 1

5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and oxalate salt

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

A mixture of 71.3 9 10-bromo-5H-dibenzo-[a,d]-cyclohepten-5-one, 50 ml of piperidine, 1 liter of t-butanol and finally 33.6 g of potassium t-butoxide was stirred under reflux for 2 hours and then at room temperature overnight. The mixture was filtered and evaporated to dryness. The residue was slurried with water and decanted. The residue was slurried with methanol and filtered to give

59.S g 10-(1-piperidyl)-5H-dibenzo-pha,d]-cyclohepten-5-one, m.p. 103 - 105°C.

Step B: Preparation of 5-hydroxy-5-methyl-10-(l-piperidyl)-5H-dibenzo-[a,d]-cycloheptene

A solution of 140 ml of 1.8 molar methyllithium in ether and 250 ml of ether at 5 - 10°C under nitrogen was treated dropwise with a solution of 59 g of 10-(1-piperidyl)-5H-dibenzo-[a,d] -cyclohepten-5-one in 250 ml of tetrahydrofuran. After a total of 2 hours, the mixture was poured onto ice and set aside until the ice melted. The mixture was extracted well with ether, and the extract was dried over sodium sulfate, filtered and evaporated to dryness, and the residue was used directly in the next step.

Step C: Preparation of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo"[a>dl-cycloheptene

The carbinol from step B was dissolved in 500 ml of ION ethanolic hydrogen chloride and 30 ml of concentrated hydrochloric acid and heated under reflux overnight. The solvent was evaporated and the residue was extracted with 500 ml of benzene. The extract was dried and evaporated to dryness. The residue was extracted with 300 ml of boiling hexane. On cooling, the extract deposited 18.5 g of solid which after recrystallization from hexane gave 16.5 g of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo-[a,dj-cycloheptene, m.p. 84 - 86°C.

Step D: Preparation of 10-hydroxymino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene

A mixture of 16.5 g of the oxo compound from step C, 6.6 g of hydroxylamine hydrochloride, 8.2 g of sodium acetate and 300 ml of methanol was heated under 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 give 16.8 g of 10-hydroxymino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene , m.p. 156 - 160°C.

Step E: Preparation of 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene

A mixture of 15.3 g of the oxime from step D, 500 ml of methanol and 12 g of sodium cyanoborohydride in 450 ml of methanol was treated dropwise with a solution of 12 ml of 12N hydrochloric acid in 50 ml of methanol over 5 hours, and then stirred over overnight at room temperature. The solvent was evaporated, the residue was stirred with 200 ml of 1N aqueous hydrochloric acid, made alkaline with concentrated ammonium hydroxide and extracted with 3 x 175 ml of ether. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, m.p. 145 - 147°C.

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

A solution of 8.8 9 of the hydroxamino compound from

step E in 200 ml xylene was added dropwise to 80 ml under reflux boiling 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, and the mixture was washed with 100 ml of ether, and the washings were discarded. The aqueous phase was made alkaline with concentrated ammonium hydroxide and extracted with 3 x 100 ml of ether. The extract was dried over sodium sulfate, 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, m.p. l4l - l44°C.

Step G: Preparation of 5-methyl-1-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5, 10-imine and oxalate salt

A mixture of 1.2 g of the hydroxyimine from step F, 7 ni acetic acid and 1.2 g of zinc dust was heated at 60-70°C for 3.5 hours. The mixture was filtered, and the filter cake was washed with 200 ml of ether and 50 ml of water. The filtrate was made alkaline with 50 g/l aqueous sodium hydroxide and extracted with ether. The extract was dried over sodium sulfate, filtered and evaporated to dryness, whereby 1.1 g of product was obtained. This material (1.1 g) was dissolved in 20 ml of acetone and treated with 0.6 g of oxalic acid in 10 ml of acetone. After cooling overnight, 1.2 g of 5-methyl-10,11-dihydro-5H-dibenzo-i a,d]-cyclohepten-5,10-imine with m.p. 203 - 206°C (dec.), which after recrystallization from methanol/acetone had a melting point of 215 - 217°C (dec.).

Example 2

5-ethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine Step A: Preparation of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo- [a,d]-cycloheptene

To a stirred slurry of 21 g (0.057 mol) of ethyltriphenylphosphonium bromide in 400 ml of ether was added dropwise 48 ml of 1.3 M butyllithium in hexane. To the resulting solution was added a solution of 13.5 g (0.044 mol) of 1-(5-keto-5H-dibenzo-[a,d]-cyclohepten-10-yl)-4-methylpiperazine in 100 ml of THF. The resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into 300 ml of ice water. The organic phase was separated, and the aqueous phase was extracted with 2 x 150 ml of ether. The combined organic solutions were evaporated under reduced pressure. The concentrate was stirred with a mixture of 300 ml of 1N aqueous hydrochloric acid and 300 ml of ether. The ether phase was separated, the water phase was extracted with ether, and the combined ether phases were dried over sodium sulfate, filtered and the filtrate evaporated to 100 ml. Triphenylphosphine oxide was removed by filtration, and the filtrate was chromatographed on silica gel eluted with chloroform, whereby 10.1 g (98%) of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo-[a, d]-cycloheptene with m.p. 93 - 95°C.

By following the procedure essentially as described in Example 1, steps D - G, but substituting the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene used in step D with an equimolecular amount of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, the following was formed in sequence: 5-ethylidene-10-hydroxymino-10,11-dihydro -5H-dibenzo-[a,d]-cycloheptene, (86% yield), m.p. 128 - 131°C;

5-ethylidene-10-hydroxamino-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, (89% yield), m.p. 121 - 124°C;

5-ethyl-12-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, (21% yield), m.p. 112 - 116°C; and

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

Using the procedure substantially as described in Example 2, but replacing the ethyltriphenylphosphonium bromide used in step A with an equimolar amount of a

+ 2 2 Wittig reagent with the formula (C6H5)3P -CH2R (Br )' where ~CH2R

is -CH^, -CH2CH2CH2 or ~(CH2)3CH3, compounds with the formula were formed:

where -CH2R<2> is -CH3, -CH2CH2CH3 (m.p. 298 - 299.5°C as HCl-1/2 CH3COCH3) and -(CH2)3CH3. Example 3 5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-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 triethylphosphonoacetate was added dropwise to a slurry of 1.9 g (0.04 mol) of sodium hydride (50% in mineral oil) in 20 ml of dry toluene under nitrogen while the temperature was kept at 30 - 35°C during cooling. The mixture was stirred for 1 hour at room temperature. A solution of 10 g (0.0328 mol) of 1-(5-keto-5H-dibenzo-[a,d]-cyclohepten-10-yl)-4-methylpiperazine in 75 r of dry toluene was added dropwise while maintaining the temperature at 25 - 30°C on cooling. The mixture was stirred at room temperature for 3 hours and kept at room temperature overnight. After decanting the solution, the precipitate was washed with 4 x 25 ml of toluene at 65°C. The combined toluene extracts were diluted with an equal volume of ether and shaken with 75 ml of 0.5N hydrochloric acid. The aqueous acid layer was separated and again extracted with toluene-ether (1:1). The combined organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The oily solid obtained was freed from the main amount of oil by collection on a sintered glass funnel and then triturated with cyclohexane, whereby 4.5 g (47%) of 5-ethoxycarbonyl-methylene-IO;, 11-dihy dro-5H-dibenzo-[a,dJ-cyclohept en-10-one,

m.p. 56 - 62°C.

Step B: Preparation of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10)11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5>10-imine

23.4 g (0.08 mol) of the keto-olefin from step A along with

6.0 g of hydroxylamine hydrochloride, 12.0 g of sodium acetate trihydrate and 300 ml of wet ether were stirred at room temperature. After 16 hours, the precipitate was collected, washed with ether and stirred with 300 ml of water for 1 hour. The solid was collected and dried, yielding 21.6 g (83%) of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10 -imine, m.p. 193 - 195 C (dec.).

Step C: Preparation of 5-ethoxycarbonylmethyl-10-hydroxy-10,11 -

dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

21 g (0.0646 mol) of the N-hydroxyimine from step B was suspended in 125 ml of glacial acetic acid, and 16 g of zinc dust was added in portions over 15 minutes. After the exothermic reaction had subsided, the mixture was stirred and heated in an oil bath

65°C for 3 hours. The cooled mixture was filtered, and the filtrate

was evaporated under reduced pressure. The remaining syrup was dissolved in 500 ml of water, and the filtered solution was made alkaline with 15% aqueous sodium hydroxide. The precipitate was collected,

washed with water and dried, thereby obtaining 15 g of 5-ethoxycarbonyl-methyl-10-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine with m.p. 186 - 189°C during decomposition. A filtered solution of this product in 350 ml boiling acetone was treated with 7N 7 ml 7N ethanolic hydrogen chloride. The precipitate of the hydrochloride salt was collected, washed with ether and dried, whereby 14.35 g (64%) with m.p. 247 - 250°C during decomposition.

Step D: Preparation of 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

17.8 g (0.0515 mol) of the hydrochloride salt of the product from step C was slurried in 250 ml of thionyl chloride and the mixture was heated under reflux. After the exothermic reaction had subsided, the mixture was heated under reflux for 20 minutes, and the solid was then completely dissolved. The thionyl chloride was evaporated under reduced pressure, and the last traces were removed by repeated evaporation with toluene. The residue was triturated with acetone and dried to give 15.35 g (81%), m.p. 223 - 227°c (dec.),

of 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine hydrochloride.

Step E: Preparation of 5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept en-5,10-imine

15.3 g (0.042 mol) of the hydrochloride from step D was added portionwise to a slurry of 5.6 g (0.147 mol) lithium aluminum hydride in 200 ml ether and 200 ml tetrahydrofuran. The mixture was stirred under reflux for 3 hours, then cooled to 0°C and hydrolysed by the dropwise addition of 4 ml of water and 4 ml of 10% aqueous sodium hydroxide. After dilution with ether, the precipitate was collected, suspended in 250 ml of chloroform and stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was combined with the previously obtained ethereal filtrate. The solvents were evaporated under reduced pressure, and the resulting solid was recrystallized from 95% ethanol, whereby 8.6 g of 5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a ,d]-cyclohepten-5,10-imine with m.p. 181 - 184°C. Recrystallization from 70% ethanol gave m.p. 182 - 184°C.

A suspension of 4.4 g of this product in 20 ml of warm absolute ethanol was treated with 2.5 ml of 7N ethanolic hydrogen chloride, and the mixture was stirred until all the solid was dissolved. Dilution with ether field 4.8 9 of the hydrochloride salt with m.p. 263-265°C. Recrystallization from acetonitrile gave m.p. 262 - 264°C (dec.).

Example 4

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

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

A solution of 53 g (0.33 mol) bromine in 125 ml glacial acetic acid was added dropwise to a stirred slurry of 71.25 g (0.25 mol) 3-bromo-5H-dibenzo-a,dj-cyclohepten-5- on in 775 ml glacial acetic acid. After the mixture was stirred at room temperature for several hours, the solid was collected, washed with glacial acetic acid and dried to give 105.8 g (95%) m.p. 173 - 175°C.

Step B: Preparation of 3,10-dibromo-5h-dibenzo-[a,d]-cyclohepten-5-one and 3,11-dibromo-5H-dibenzora,d]-cyclohepten-5-one The product from step A was added to a stirred solution of 28 g (0.7 mol) sodium hydroxide in 2 liters of methanol. The thick mixture was stirred under reflux for 1.25 hours. After cooling, the solid was collected, washed with methanol and then with water, and dried, whereby 81 g (90%) of the mixture of 3,10-dibromo-5H-dibenzo-[a,d]-cycloheptene was obtained -5-one and 3,H-dibromo-5H-dibenzo-f a , d J-cyclohept en-5-one, m.p. 146 - 156°C.

Step C : Preparation of 3-bromo-10-(4-methylpiperazinyl)-5H-dibenzo-[α,dJ-cyclohepten-5-one and 3-bromo-11-(4-methyl-piperazinyl)-5H-dibenzo- f a, d]-cyclohepten-5-one

6.8 g (0.06 mol) of potassium t-butoxide was added to a stirred slurry of 18.2 g (0.05 mol) of 3,10-dibromo-5H-dibenzo-[a,d]-cycloheptene- 5-one and 3,11-dibromo-5H-dibenzo-[a,d]-cyclohepten-5-one, 10 ml of 4-methylpiperazine and 200 ml of dry t-butyl alcohol at room temperature and under nitrogen. The dark orange colored mixture was heated under reflux for 2 hours and then stirred at room temperature overnight. The mixture was left for approx. 800 ml of ice and water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The mixture of 3-bromo-10-(4-methylpiperazinyl)-5H-dibenzo-[a,d]-cyclohepten-5-one and 3-bromo-11-(4-methylpiperazinyl)-5H-dibenzo-[a,d ]-cyclohepten-5-one was obtained as a residual red-yellow gum in a yield of 19.4 g (100%).

Step D: Preparation of 3-bromo-5-methyl-10-(4-methylpiperazinyl)-5H-dibenzo-[α,dj-cyclohepten-5-ol and 3-bromo-5-methyl-11-(4-methylpiperazinyl) )- 5H-dibenzo-[a,d]-cyclohepten-5-ol 35 ml of a 1.6 M solution of methyllithium in ether was added dropwise to a stirred solution of 18 g (0.047 mol) of the product from step C in 200 ml of ether and 60 ml of tetrahydrofuran cooled in an ice bath and under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolysed by dropwise addition of water. After dilution with ether and water, the layers were separated, and the water phase was again extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. A mixture of 3-bromo-5-methyl-10-(4-methylpiperazinyl)-5H-dibenzo-[a,d]-cyclohepten-5-ol and 3-bromo-5-methyl-11-(4- methylpiperaziny1)-5H-dibenzo-[a,d]-cyclohepten-5-ol as a residual dark yellow glass in a yield of 18 g (96%).

Step E: Preparation of 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-10-one and 7-bromo-5-methylene-10,11-dihydro-5H- dibenzo-[a,d]-cyclohepten-10-one

A mixture of 18 g (0.045 mol) of the product from step D,

80 ml 95% ethanol, 40 ml 7n ethanolic hydrogen chloride and

80 ml of 6N aqueous hydrochloric acid was stirred at room temperature i

30 minutes and boiled under reflux for 1 hour. The mixture consisted of a brown oily lower phase and an aqueous ethanolic upper phase. The latter was decanted off, and the alcohol driven off in a vacuum. The remaining aqueous mixture was extracted with chloroform. The previously obtained brown oil was dissolved in chloroform, and the combined chloroform phases were washed with water and dried over anhydrous magnesium sulfate. Evaporation of the filtered extract gave the crude product as a residual dark yellow glass. This material was chromatographed on a silica gel column eluting with toluene. Evaporation of the appropriately combined fractions gave the partially purified product as 8.5 g of an oily solid. Trituration with cyclohexane gave one of the isomers of the product as a white solid in a yield of 2.6 g and mp 125-158°C. Two recrystallizations from cyclohexane gave m.p. 158~163°C. Evaporation of the first cyclohexane mother liquor gave the remaining isomer of the product as a dark yellow oil. Trituration with 3 x 10 ml of hexane gave a yellow solid in a yield of 3.3 9°9 with m.p. 75 - 83°C. Two recrystallizations from hexane gave m.p. 84 - 89°C.

The higher-melting isomer (m.p. l60 - l64°C) has the structural formula:

and is designated as 7-bromo-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept en-10-one.

The other isomer, 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-10-one (m.p. 84 - 91°C) has the structural formula:

Steps F - I: Preparation of 3(and 7)-bromo-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

Using the procedure essentially as described in Example 1, steps D - G, but replacing the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene used therein with an equimolecular amount of the corresponding 3~ and 7-bromo compounds, the following were obtained in order: (Step F): 3(and 7)-bromo-10-hydroxymino-5-methylene-10,11-dihydro- 5H-dibenzo-[a,d]-cycloheptene, m.p. 171-175°C or 179-181°C;

(Step G): 3(°97)-bromo-10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, m.p. 149-153°C or 136-139°C;

(Step H): 3(pg 7)-bromo-12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, m.p. 175-180°C or 187-189°C; and

(Step I): 3(°97)-bromo-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrochloride, m.p. >300°C.

Example 5

10,11-dihydro-5,12-dimethyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine-fumaric acid salt

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

A mixture of 1.15 g of 10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, 1.0 g of anhydrous sodium carbonate, 1 ml of ethyl chloroformate and 10 ml of dry benzene was stirred at reflux temperature for 2 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to give 1.45 g of white crystals of 10,11-dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo-[a,d]-cyclo-hept en- 5,10-imine, m.p. 80-83°C.

Step B: Preparation of 10,11-dihydro-5,12-dimethyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

A solution of the urethane from step A in 15 µl of absolute ether was added dropwise to a slurry of 190 mg of lithium aluminum hydride in 15 mL of absolute ether with stirring and under nitrogen. After 24 hours at room temperature, the mixture was cooled in an ice bath and hydrolyzed at dropwise addition of the minimal volume of water containing a few drops of 50 g/l aqueous sodium hydroxide. After dilution with ether, the mixture was filtered. The filtrate was evaporated in vacuo to give 1.1 g of the free base of the product as a colorless oil. This was combined with 0.9 g of similar material and dissolved in 25 ml of ethyl acetate. A hot solution of 1.2 g of fumaric acid in 12 ml of methanol was added. The fumaric acid salt that crystallized was collected and recrystallized from methanol-ethyl acetate, thereby obtaining 2.1 g of 10,11-dihydro-5,12-dimethyl-5H-dibenzo-[a,d]-cycloheptene-5,10-imine-fumaric acid salt, mp 186-188°C.

Example 6

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

A mixture of 2.45 g of 10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, 1.9 g of benzyl chloride, 3.2 g of anhydrous sodium carbonate and 50 ml dry benzene was stirred under reflux for 4 days. The mixture was filtered, and the filtrate was evaporated in vacuo to give 3.1 g of the product as an oily solid with m.p. 107-H1°C. This was recrystallized twice from 95% ethanol, yielding 1.85 g of white, crystalline 12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cycloheptene -5,10-imine, m.p. III-II4°C.

Example 7

12-ally1-10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

A mixture of 2.15 g of ]0,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, 1.8 g of allyl bromide, 3j0 g of anhydrous sodium carbonate and 50 ml of dry benzene was stirred under reflux for 20 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to give 1.2 g of the oily free base of the product. This was dissolved in 5 ml of acetone and added to a hot solution of 0.75 g of fumaric acid in 75 ml of acetone. The salt that crystallized was collected and recrystallized from acetone to give 1.45 g of white, crystalline 12-allyl-10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cycloheptene-5,10 -imine-funric acid salt, m.p. 180-182°C.

Using the procedure in Example 7, but by replacing the allyl bromide and the 10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine used there with a compound of the formula R-I and 5-R<2>CH2-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, as indicated in Table II, gave 5-R2CH2-12-R-10 The ,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imines also listed in Table II, according to the following reaction:

Example 8

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

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

10 g (42 mmol) of 10-hydroxamino-5-methylene-10,11-dihydro-5H- dibenzo-[a,d]-cycloheptene. The mixture was stirred in the oil bath for 2 hours, cooled and poured into 500 ml of water. The mixture was made alkaline with concentrated ammonia and then extracted with ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from hexane, whereby 7.8 g of product with m.p. 84.5-86.5°C

Step B: Preparation of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo-)a,d]-cycloheptene

4.42 g ( 0.11 mol) sodium hydroxide pellets, 0.42 g (1.8 mmol) benzyltriethylammonium chloride and 0.5 ml water. The mixture was stirred under nitrogen until the sodium hydroxide pellets were dissolved (about 4 hours), treated with aqueous potassium carbonate, filtered and evaporated to dryness in vacuo. The remaining oil was dissolved in 180 mL of chloroform, treated with an additional 1.5 g (37.5 mmol) of sodium hydroxide and 0.2 g (0.86 mmol) of benzyltriethylammonium chloride, and stirred overnight under nitrogen. The mixture was again dried over potassium carbonate, filtered and evaporated to dryness in vacuo. The oil obtained was chromatographed on 120 g of silica gel and eluted with methylene chloride. The combined product fractions were evaporated to dryness in vacuo, and the resulting solid was recrystallized from ether, yielding 4 g of m.p. <Q>6-98°C.

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

1.1 g (10.9 mmol) of diisopropylamine in 25 ml of dry tetrahydrofuran was stirred in a dry ice/acetone bath. Under a nitrogen blanket, this solution was treated with 5.0 ml of 2.2 M n-butyllithium/hexane added dropwise over 10 minutes. After 5 minutes, a solution of 2.4 g (10.4 mmol) of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene in 25 ml of dry tetrahydrofuran added dropwise over 45 minutes to the lithium diisopropylamide solution. The resulting deep red colored solution was stirred cold for 15 minutes and then treated with 4.56 g (32 mmol) of methyl iodide added in one go. The mixture was stirred for 2 hours in the cold and a further 1 hour at room temperature. The solvent was removed in vacuo, and the residue was chromatographed on 75 g of silica gel, eluted with methylene chloride. The combined product fractions were evaporated in vacuo to give 2.2 g (86%) of solid. Recrystallization from ether gave m.p. 156-147.5°C.

Step D: Preparation of 10-methyl-10-methylamino-5-methylene-10,11-dihydro-5H-dibenzo-|"a,d]-cycloheptene- hydrogen chloride 1.8 g (7.3 mmol) 10-isocyano -10-methyl-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, dissolved in 100 ml of dry ether, was added dropwise to a slurry of 0.53 g (14 mmol) lithium -tetrahydridoaluminate in 40 mL of ether stirred under nitrogen. The mixture was heated under reflux for 1 hour, cooled, and excess hydride cleaved by careful dropwise addition of 1.5 mL of ice water. The suspension was filtered, and the solids were washed twice with ether. The combined ether fractions were evaporated in vacuo to 1.8 g of oil. This oil, dissolved in 10 ml of absolute ethanol, was treated with a small excess of 8N ethanolic hydrogen chloride and cooled to give 1.7 g (81%) powder with m.p. 238-240°C (dec.).

Step E: Preparation of 5,10,12-trimet hy1-10,11-dihydro-5H-dibenzo -|~ a, d]- cyclohept en- 5, 10- imine- hydrogen chloride

1.6 g (6.4 mmol) of 10-methyl-10-methylamino-5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene was dissolved in 40 ml of dry tetrahydrofuran. To this solution, stirred at room temperature under nitrogen, was added 3.0 ml of a 2.2M solution in hexane of n-butyllithium added dropwise over the course of 5 minutes. The mixture was stirred for 10 minutes and then treated with 3 ml of ice water. The tetrahydrofuran was removed under vacuum, and the residue was taken up in ether. The ether solution was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The oil obtained was chromatographed on 120 g of silica gel eluting with methylene chloride and 1%, 1.5%, 2%, 3% and 5% methanol in methylene chloride.

The combined product fractions were evaporated to dryness in vacuo, dissolved in 50 ml of absolute ethanol and treated with a small excess of 8N ethanolic hydrogen chloride. 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 j-cycloheptene-5,10-imine hydrogen chloride,

m.p. 295-296.5°C.

Example 9

Optical splitting

3.93 9 (0.0178 mol) racemic 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and 6.88 9 (0.0178 mol) ( -)-di-p-toluoyl-d-tartaric acid was dissolved in 21 ml of acetone. The solution was inoculated, and after standing for several hours at room temperature, the crystalline salt was collected. The product was repeatedly recrystallized from acetone to constant rotation. The salt was suspended in cold water, stirred with aqueous sodium hydroxide, and the base was extracted into ether. The washed and dried ether extract was evaporated to dryness under reduced pressure to give (-)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine as the remaining solid substance with m.p. 71.5-73»5°C.

The acetone mother liquor from the first crystallization of the (-) isomer was evaporated to dryness under reduced pressure. A suspension of the remaining glass in cold water was stirred with aqueous sodium hydroxide, and the base was extracted with ether. The washed and dried ether extract was evaporated to give the optically impure (+) base as the remaining solid. This product 2.27 g (0.0103 mol) and 3.9 g (0.0103 mol) of (+)-di-p-toluoyl-1-tartaric acid were dissolved in 20 ml of acetone. After standing for several hours at room temperature, the crystalline salt was collected and recrystallized repeatedly from acetone to constant rotation. The salt was transferred to the base in the same manner as described above, whereby (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine was obtained with mp 72-74°C.

Example 10

Step A: Preparation of 6-methylene-1,1a,6,10b-tetrahydrodibenzo-[3,4:6,7]-cyclohept-|~1,2-b]-azirine

0.46 g (0.012 mol) lithium aluminum hydride is suspended in 40 ml ether and a solution of 0.94 9 (0.004 mol) 5-methylene-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-10-one -oxime in 25 ml of ether is slowly added dropwise. The mixture is stirred at room temperature for 3 hours and then hydrolysed by successive dropwise addition of

ning of 0.4 ml of water, 0.6 ml of 10% aqueous sodium hydroxide and 1.2 ml of water. The ether phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated, whereby 6-methylene-1,1a,6,10b-tetrahydrodibenzo-[3,4=6,7J-cyclohept-[1,2 -b]-azirine.

Step B: Preparation of 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept one

Under nitrogen, a solution of 0.8 ml of 2M n-butyllithium in hexane is slowly added dropwise to a stirred solution of 0.44 g (0.002 mol) 6-methylene-1,1a,6,10b-tetrahydrodibenzo-[3,4: 6,7]-cyclohept-[1,2-b]-azirine in 5 ml of tetrahydrofuran. Stirring is continued at room temperature for 16 hours. The mixture is poured into ice water and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, filtered, and the filtrate is evaporated, whereby 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene is obtained .

Step C: Preparation of 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

A solution of 0.001 mol of the product from step B in 5 ml of absolute ethanol is shaken with hydrogen at atmospheric pressure at 25°C over 50 mg of 10% palladium-on-carbon until 1 equivalent of hydrogen is absorbed. The catalyst is removed by filtration, and the filtrate is evaporated, whereby 5-methyl-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5,10-imine is obtained.

Example 11

A solution of 2.93 g (0.01 mol) of 12-ethoxycarbonyl-5~ methyl-10,11-dihydro-5H-dibenzo-<[>a,d J-cyclohepten-5,10-imine and 2o g of potassium hydroxide in 100 ml of n-butyl alcohol is stirred and heated under reflux in a nitrogen atmosphere for 12 hours. The solvent is evaporated, and the residue is distributed between toluene and water. The toluene phase is separated, washed with water and extracted with IN aqueous hydrochloric acid. The acid extract is made alkaline with 10% aqueous sodium hydroxide, and the mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated, whereby 5-methyl-10,11-dihydro-5H-dibenzo-La,d]-cyclohepten-5,10-imine is obtained.

Example 12

Step A: Preparation of 5-azido-5-iodomethy1-10,11-dihydro-5H-dibenzo-[a,dj-cyclohepten-10-one

8.2 g of 5-methylene-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-10-one in 30 ml of acetonitrile are added dropwise to a solution of iodoazide (prepared by the dropwise addition of 6.8 g of iodine monochloride to a suspension of 5.6 g of sodium azide in 37 ml of acetonitrile stirred in a methanol/ice bath). The mixture is allowed to warm to room temperature and stirred overnight. It is then poured into 250 ml of ice water and extracted with 3 x 50 ml of ether. The combined ether extracts are washed with 50 ml of 5% sodium thiosulphate solution and with 3 x 50 ml of water, dried over sodium sulphate, filtered and evaporated to dryness in vacuo, whereby 5-azido-5-iodomethyl-10,11-dihydro- 5H-dibenzo-[a,d]-cyclohepten-10-one.

Step B: Preparation of 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

4.3 g of 5-azido-5-iodomethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-10-one and 0.3 g of 10% palladium/charcoal are combined in 80 ml of ethanol and shaken under a hydrogen atmosphere (3.5 kg/cm gauge pressure) in a Paar shaker. The mixture is filtered and evaporated to dryness in vacuo to give 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine.

Step C: Preparation of 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo-[a,c]-cyclohepten-5,10-imine

3.5 g of 10-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine are heated in refluxing 30 ml of thionyl chloride for 20 minutes. The mixture is cooled and evaporated to dryness in vacuo. 60 ml of toluene is added twice and removed in vacuo. The residue is suspended in 50 ml of ether and treated with an excess of IN aqueous sodium hydroxide (25 ml). The ether layer is separated, and the aqueous layer is extracted with 2 x 50 ml of ether.

The combined ether layers are washed with 3 x 100 ml of water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo, which gives 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene -5,10-imine.

Step D: Preparation of 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine-hydrochloride 5 g 10-chloro-5-methyl-10,11-dihydro- 5H-dibenzo-[a,d]-cyclohepten-5,10-imine is dissolved in 100 ml of ether and added dropwise to a slurry of 0.76 g of lithium aluminum hydride in 80 ml of ether, stirred under nitrogen. The mixture is heated under reflux for 2 hours, cooled and treated with 2 ml of ice water added dropwise. The suspension is filtered, and the solids are washed with ether. The filtrate and the ether washings are combined, washed with 2 x 100 ml of water, dried over sodium sulphate, filtered and evaporated to dryness in vacuo. The residue in 10 ml of ethanol is treated with an excess of 8N ethanolic hydrogen chloride, and the solution is evaporated to dryness in vacuo. The residue is recrystallized from ethanol, which gives 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrochloride.

Example 13

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

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

Step B: Preparation of 5-isocyano-5H-Idibenzo-[a,d]-cycloheptene

18.8 g (0.08 mol) 5-formylamino-5H-dibenzo-[a,d]-cycloheptene, 25 g (0.095 mol) triphenylphosphine, 12.3 9 (0.08 mol) carbon tetrachloride and 8, 1 9 (0.08 mol) of triethylamine was dissolved in 80 ml of chloroform and heated at 6o°C for 2.5 hours. The solvent was evaporated and the residue was extracted with 5 portions of hexane. The combined hexiextracts were evaporated and chromatographed on silica gel eluting with toluene. The toluene eluate was evaporated, whereby 5-isocyano-5H-dibenzo-[a,d]-cycloheptene was obtained.

Step C: Preparation of 5-isocyano-5-methyl-5H-dibenzo-[a,d]-

cy cloheptene

28 ml of 2M n-butyllithium in hexane and 30 ml of tetrahydrofuran under nitrogen were stirred and cooled to -70°C. 5.65 g (0.056 mol) of diisopropylamine was added dropwise followed, after 5 minutes, by a solution of 10.85 g (0.05 mol) of 5-isocyano-5H-dibenzo-[a,d]-cycloheptene in lOO ml of tetrahydrofuran. After a further 10 minutes, 21.3 g (0.15 mol) of methyl iodide was added at once. The mixture was stirred for 15 minutes at -70°C and then for 2 hours at room temperature. The mixture was poured into ice water and extracted with ether. The ether extract was washed with water, dried over sodium sulfate, filtered, and the filtrate was evaporated to give 5-isocyano-5-methyl-5H-dibenzo-[a,d]-cycloheptene.

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

1.0 g (0.026 mol) of lithium aluminum hydride was slurried in

25 ml of ether, and a solution of 6.0 g (0.026 mol) of 5-isocyano-5-methyl-5H-dibenzo-[a,d]-cycloheptene in 60 ml of ether was added dropwise. The mixture was stirred at room temperature for 16 hours and then hydrolysed by the successive dropwise addition of 1 ml of water, 1.5 ml of 10% aqueous sodium hydroxide and 3 ml of water. The above ether solution was separated by filtration, and the filtrate was evaporated, whereby 5,N-dimethyl-5H-dibenzo-[a,d]-cycloheptene- was obtained. 5-amine.

Step E: Preparation of 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

A solution of 4.7 g (0.02 mol) of 5,N-dimethyl-5H-dibenzo-[a,d]-cyclohepten-5-amine in 20 ml of 1N aqueous hydrochloric acid and 50 ml of water was stirred at room temperature, and 3.2 g (0.02 mol) of bromine was added dropwise. After 10 minutes, 5.5 g (0.04 mol) of potassium carbonate was added all at once followed by 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 16 hours. The aqueous phase was separated and extracted with several portions of chloroform. The combined chloroform and tetrahydrofuran phases were extracted with 1N aqueous hydrochloric acid. The cooled acid extract was made alkaline with 20% aqueous sodium hydroxide, and the mixture was extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with methanol-toluene (5:95) - The eluate was evaporated, whereby 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo-[a,d] -cyclohept en-5,10-imine.

Step F: Preparation of 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept en-5,10-imine

2.5 g of 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine together with 10 ml of triethylamine and 10 ml of dimethylsulfoxide were stirred at room temperature while 2.1 g of sulfur trioxide-trimethylamine complex was added portionwise. The mixture was stirred at room temperature for 48 hours and then poured into 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 give 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10 -in my.

Step G: Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept en-5,10-imine

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

Example 14

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

3.5 g of 5-formylamino-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene, 5.3 ml of triethylamine and 15 ml of methylene chloride were stirred in an ice bath. 1.5 g of phosgene was introduced into the solution. 50 ml of water was added and the layers were separated. The organic layer was washed with 2 x 50 ml of water, dried over sodium sulfate, filtered and evaporated in vacuo, whereby 5-isocyano-10,11-dihydro-5H-dibenzo-f a,d]-cycloheptene was obtained.

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

To 15 ml of 2.2M n-butyllithium in hexane in 91 ml of dry tetrahydrofuran cooled in a dry ice/acetone bath and stirred under nitrogen, a solution of 3.3 g of diisopropylamine in 15 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 5 minutes and treated with a solution of 6.8 g of 5-isocyano-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene in 15 ml of tetrahydrofuran added dropwise. The mixture was stirred in a cold bath for 10 minutes before 8.7 g of iodomethane in 15 ml of tetrahydrofuran was rapidly added. The mixture was stirred in the cold bath for a further 15 minutes and then allowed to warm to room temperature. After a further 2 hours, the solution was treated with 2 ml of water, and the bulk of the tetrahydrofuran was removed under vacuum. 100 ml of ether and 50 ml of water were added, and the layers were separated, and the water layer was extracted with 2 x 50 ml of ether. The combined ether layers were washed with 2 x 50 mL water, dried over sodium sulfate and evaporated to dryness in vacuo to give 5-isocyano-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene.

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

3.3 g of 5-isocyano-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene in 120 ml of ether was added dropwise to 0.6 g of lithium aluminum hydride stirred in 60 ml of ether under nitrogen. The mixture was heated under reflux for 4 hours and then cooled in ice.

2 ml of ice water was added dropwise, and the mixture was stirred in

15 minutes. The mixture was filtered, and the solids were washed with 2 x 50 ml of ether, and the ether washings were combined with the filtrate.

The ether layer was washed with 3 x 50 ml of water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give 5-methyl-5-methylamino-10,11-dihydro-5H-dibenzo-[a,d] -cycloheptene.

Step D: Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo-I" a , d]-cyclohepten- 5 , 10-imine-hydrochlor id 6 g 5-methyl-5-methylamino- 10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene was stirred in 30 mL of ether and cooled in ice. The mixture was treated with 30 mL of a 1N aqueous solution of sodium hypochlorite added dropwise over 3- 5 minutes. The mixture was stirred cold for 1/2 hour and separated. The aqueous layer was extracted with 2 x 30 mL ether, and the combined ether layers were washed with 2 x 30 mL water, dried over sodium sulfate, filtered, and evaporated in vacuo to a residue containing the crude chloramine product.

The residue was treated with 50 ml of cold 85% sulfuric acid. The mixture was stirred under nitrogen in a quart flask and irradiated with a 125 W "GE" solar lamp until the chloramine was consumed. The mixture was added to 600 ml of stirred ice water, made alkaline with 3N aqueous sodium hydroxide and extracted with 3 x 100 ml of ether. The ether layers were combined, washed with 2 x 50 ml of water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue in ethanol was treated with an excess of 8N ethanolic hydrogen chloride, and the solvent was removed in vacuo. The residue was recrystallized from ethanol, whereby 5,12-dimethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrochloride was obtained.

Example 15

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

10 g of 10-hydroxymino-5-methylene-10,11-dihydro-5H-dibenzo-[a,dJ-cycloheptene and 0.2 g of 10% palladium/charcoal were combined in 100 ml of absolute ethanol and shaken under an atmosphere of hydrogen (3.5 kg/cm 2 manometer pressure). After absorption of the calculated 0.12 mol, hydrogen absorption ceased. The solution was filtered, and

the filtrate was evaporated to dryness in vacuo to give 10-amino-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene. Step B: Preparation of 10-methylamino-5-methyl-10,11-dihydro- 5H-dibenzo-[a,d]-cycloheptene 5 g of 10-amino-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene was dissolved in a mixture of 50 ml of pyridine and 100 ml benzene. 32.4 g of ethyl chloroformate was added dropwise to the stirred solution, and the resulting mixture was heated to 50°C for 30 minutes. The mixture was cooled, poured into 500 ml of ice water and separated. The aqueous phase was extracted with 2 x 100 ml of benzene, and the organic phase was combined with the benzene extracts and washed with 4 x 100 ml of water. The solution was dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was dissolved in 100 ml of tetrahydrofuran and added dropwise to 1.1 g of lithium aluminum hydride stirred in 50 ml of tetrahydrofuran under nitrogen. The mixture was heated under reflux for 20 minutes, cooled, and excess hydride was cleaved by dropwise addition of ice water. The mixture was filtered and the solids were extracted with 2 x 20 ml of tetrahydrofuran. The combined organic layers were evaporated in vacuo, and the residue was dissolved in ether. The ether solution was washed with 2 x 50 ml of water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give 10-methyl-amino-5-methyl-10,11-dihydro-5H-dibenzo-[a,d ]-cycloheptene.

Step C: Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrochloride

4.7 g of 10-methylamino-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene in 30 ml of methylene chloride was cooled to 5°C and treated with 55 ml of a 0.4m N -chlorosuccinimide solution in methylene chloride. After 30 minutes at 5°C, the mixture was stirred at room temperature for a further 1 hour, and the solvent was removed in vacuo. The residue was extracted with 3 x 50 mL hexane, and the combined extracts were filtered and evaporated to dryness in vacuo. The residue was dissolved in 40 ml of cold 85% sulfuric acid in a quartz flask, and the solution was irradiated with a 125 W "GE" solar lamp until the chloramine was consumed.

The mixture was carefully added to 500 ml of ice water with stirring, made alkaline by the careful addition of 3N sodium hydroxide and extracted with 3 x 100 ml of ether. The combined ether layers were washed with 2 x 100 ml of water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in absolute ethanol and treated with a small excess of 8N hydrogen chloride in ethanol. The solvent was removed in vacuo and the residue was recrystallized from ethanol to give 5,12-dimethyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine hydrochloride.

Example 16

12-ethy1-5-(2-hydroxyethy1)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

Step A: Preparation of 5-ethoxycarbonylmethylene-5H-dibenzo-[a,d]-cycloheptene

0.045 mol of triethylphosphonoacetate was added dropwise to a slurry of 0.04 mol of sodium hydride in 20 ml of dry toluene at 30-35°C under nitrogen. After stirring for 1 hour at room temperature, a solution of 0.033 mol of 5H-dibenzo-[a, d]-cyclohepten-5~one in 75 mL of dry toluene was added dropwise, and stirring was continued for 16 hours. The solution was decanted, and the residue was washed with toluene. The combined organic solutions were extracted with 0.5N aqueous hydrochloric acid, washed with water and then dried over magnesium sulfate, filtered, and the filtrate was evaporated to give 5-ethoxycarbonylmethylene-5H-dibenzo-[a,d]-cycloheptene.

Step B: Preparation of 5-ethoxycarbonylmethyl-5-ethylamino-5H-dibenzo-| a , d]-cycloheptene

A solution of 0.01 mol of 5-ethoxycarbonylmethylene-5H-dibenzo-1α,d]-cycloheptene in 200 ml of THF was treated with 0.012 mol of ethylamine and stirred for 24 hours. Evaporation of this solution gave 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]-cyclohepten-5,10-imine A solution of 0.02 mol of 5-ethoxycarbonylImet Hy1-5-ethylamino-5H-dibenzo-ia,d]-cycloheptene in 20 ml of 1N aqueous hydrochloric acid and 50 ml of water was stirred at room temperature, and 0.02 mol of bromine was added dropwise. After 10 minutes, 0.04 mol of potassium carbonate was added in one go followed by 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 16 hours. The aqueous phase was separated and extracted with several portions of chloroform. The combined chloroform and tetrahydrofuran phases were extracted with 1N aqueous hydrochloric acid. The cooled acid extract was made alkaline with 20% aqueous sodium hydroxide, and the mixture was extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with methanol-toluene (5=95). The eluate was evaporated, and 5-ethoxycarbonylmethyl-12-ethy1-11-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine was obtained.

Step D: Preparation of 11-bromo-5-methoxycarbonyImethy1-12-ethyl -

10, ll- dihydro- 5H- dibenzo-[ a, d]- cyclohepten- 5, 10- imine

A mixture of 0.01 mol of 5-ethoxycarbonylmethyl-12-ethyl-11-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and 1.0 ml of phosphorus tribromide in 50 ml of toluene was heated under reflux for 6 hours. The solvent was evaporated, the residue was stirred with 200 ml of 2% aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried over sodium sulphate, filtered and the filtrate evaporated. The residue was eluted from a silica gel column with chloroform, whereby 11-bromo-5-ethoxy-carbonylmethyl-12-ethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine was obtained.

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

A mixture of 0.01 mol of 11-bromo-5-ethoxycarbonylmethyl-12-ethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and

0.011 mol of lithium aluminum hydride in 300 ml of ether was stirred and heated under reflux for 6 hours. 3.5 ml of water was added dropwise with stirring, and the slurry was filtered. Evaporation of the filtrate gave 12-ethyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine.

Example 17

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

Step A: Preparation of 12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine

Following essentially the same procedure as in Example 16, step B, 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-10-one was treated with 0.012 mol of anhydrous benzylamine, whereby 12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine was obtained.

Step B: Preparation of 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine A mixture of 0.01 mol of 12-benzyl -5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and 1.0 ml phosphorus tribromide in 50 ml toluene were heated under reflux for 6 hours. The solvent was evaporated, the residue stirred with 200 ml of 2% aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried over sodium sulfate, filtered, and the filtrate evaporated. The residue was eluted from a silica gel column with chloroform, whereby 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-1-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine was obtained.

Step C: Preparation of 12-benzyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohept en-5,10-imine

in substantially the same manner as described in Example 16, step E, 0.01 mol of 12-benzyl-10-bromo-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene- 5,10-imine reduced, whereby 12-benzyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine was obtained.

Example 18

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

Step A: Preparation of 5-ethoxycarbonylimethylene-10,11-dihydro-5H-dibenzo-| a , d ]-cyclohept one

Using essentially the same procedure as described in Example 16, step A, but by replacing the starting material used there with an equimolar amount of 10,11-dihydro-5H-dibenzo-1 a,d]-cyclohepten-5- on, 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene was obtained.

Step B: Preparation of 5-ethoxycarbonylmet hy1-5-methylamino-10, 11- dihydro- 5H- dibenzo- i a, d]- cycloheptene

Following essentially the same procedure as in Example 16, step B, 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo-fa,d]-cycloheptene was treated with anhydrous methylamine to give 5-ethoxycarbonylmethyl-5- methylamino-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene.

Step C: Preparation of 5~ethoxycarbonylmethy1-12-methy1-10,11 -

dihydrQ- 5H-dibenzo-[" a , d] - cyclohepten- 5, 10-imine 5-ethoxycarbonylImethy1-5-methylamino-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene is transferred to 5-ethoxycarbonylmethyl -12-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine in substantially the same manner as described in Example 16, step C.

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

Using essentially the same procedure as described in Example 16, step E, 5-ethoxycarbonylmethyl-12-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine is reduced to 5-(2-Hydroxyethyl)-12-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine.

Example 19

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

To a solution of 2.35 g of 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and 1.1 g of benzaldehyde in 100 ml of THF was added 1 ml of acetic acid and 1.0 g of sodium cyanoborohydride. The mixture was stirred for 2 days, filtered, and the filtrate was evaporated. The residue was slurried with 1N aqueous ammonium hydroxide and extracted with chloroform. The chloroform extract was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from ethanol to give 12-benzyl-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine.

Example 2Q

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

An ice-cold solution of 2.35 g of 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine and 2.0 g of triethylamine in lOO ml of ether was treated dropwise with 1 .5 g of acetyl chloride. After 10 hours, the solution was washed with water, dried over sodium sulfate, filtered and the filtrate evaporated to dryness. The residue was dissolved in 200 ml of ether, and 400 mg of lithium aluminum hydride was added. The resulting slurry was stirred for 24 hours. Water was slowly added and the resulting slurry was filtered. The filtrate was dried over sodium sulfate, filtered, and the filtrate was evaporated to give 12-ethyl-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine.

Example 21

Cleavage of (t)-5-methyl-10, 11-dihydro-5H-dibenzo-ja,d]-cyclo-heptene-5, 10-imine

Left rotating in summer: To a resolution of 66.1 g

(0.299 mol) of raceinic 5-methyl-10,1l-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine in 107 ml of hot acetone is added to 115.4 9 (0.299 mol) of di-p- toluoyl-d-tartaric acid dissolved in 163 ml of acetone. The solution is stirred until it is homogeneous, left for 18 hours at 25°C, and then cooled in a freezer to 0°C for 4 hours. The salt that forms is removed by filtration, washed once with cold acetone, collected and dried at 50°C (vacuum oven), whereby 82.97 9 of A is obtained as a white solid [a-J°gg = -125.9 ° (abs. EtOH),

m.p. l4l-l46°C (foam). The filtrate from the solid A is evaporated to dryness in a vacuum, and the solid residue B is used in the preparation of a<y> the dextrorotatory isomer (see below).

The salt A is dissolved in 3450 ml of boiling acetone, filtered, evaporated to 1500 ml, left for 18 hours at 25°C, and then cooled in the freezer at 0°C for 4 hours. The precipitate is removed by filtration, washed once with cold acetone, collected and dried at 6o°C (vacuum oven), thereby obtaining 45.5 g of C as a white solid [aj-g9 = -13L.9° (abs .EtOH), m.p. l42-l44°C (foam).

The cleaved salt C (44.8 g, 0.0737 mol) is treated with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether, and the mixture is stirred until the solid is dissolved. The ether layer is separated, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo, whereby 16.0 g of a thin-layer chromatographic (silicon oxide GF eluted with .1:9 methanol:chloroform) homogeneous, colorless oil is obtained. Crystallization from 40 ml of cyclohexane gives 14.16 g

(-)-5-methyl-10,11-dihydro-5H-dibenzo-"a,d]-cyclohepten-5,10-

imine as a white solid, LaJ589<=> -160.8°, (C = 0.032 g/2 ml ethanol), mp 68.5-69.5°C.

Right-handed isomer: The residue B from the preparation of the left-handed isomer is transferred to the free base form by stirring with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether until the solid is dissolved. The ether layer is dried over Raagnesium sulfate, filtered, and the solvent is removed under reduced pressure, whereby 37.9 g of an orange-coloured oil is obtained, which is dissolved in 6l ml of hot acetone and treated with a solution of 69.3 g (0.171 mol) of di- p-toluoyl-l-tartaric acid monohydrate in 98 ml of acetone. The solution is stirred until it is homogeneous, left for 18 hours at 25°C and then cooled in a freezer to 0°C for 4 hours. The salt that forms is removed by filtration, washed once with cold acetone, collected and dried at 6o°C (vacuum oven), whereby 68.8 9 of D is obtained as a white solid, [a]^gg = +127 ,1° (abs. EtOH),

m.p. 136-144°C (foam).

The salt D is dissolved in 2900 ml of boiling acetone, filtered, evaporated to 900 ml, left for 18 hours at 25°C, and then cooled

in a freezer at 0°C for 4 hours. The precipitate is removed by filtration, washed once with cold acetone, collected and dried at 60°C (vacuum oven), thereby obtaining 36.5 g of E as a white solid, [a]58q = +132.0° ( abs. EtOH), m.p. l42-l44°C (foam).

The cleaved salt E (36.5 g, 0.0601 mol) is treated with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether, and the mixture is stirred until the solid is dissolved. The ether is separated, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo, whereby 12.6 g of a thin-layer chromatographic (silicon oxide GF eluted with 1:9 methanol:chloroform) homogeneous, colorless oil is obtained. Crystallization from 25 ml of cyclohexane gives 11.26 g of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine as a white solid [a] |gg = +161.4°, (C = 0.038 g/2 ml ethanol), m.p. 68.5-69.0°C.

Example 22

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

A solution of 10.05 9 (0.0454 mol) (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a ,d ]-cyclohepten-5,10-imine in 25 ml of absolute ethanol is filtered into a flask, and the filter is washed with absolute ethanol to a final filtrate volume of 40 ml. A solution of 5.27 g (0.0454 mol) of maleic acid in 20 ml of absolute ethanol is filtered in the same flask. The combined filtrates are mixed, inoculated, kept at room temperature for a short time, and then refrigerated overnight.

The crystalline material is collected and dried, whereby (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine hydrogen maleate is obtained, m.p. 208.5-210°C} [α]^<0> +114°, (C = 0.0128 g/2 ml ethanol) .

Claims (1)

Analogous procedure in the preparation of therapeutically active compounds with the general formula: and salts thereof, wherein R is (1) hydrogen, (2) lower alkyl, (3) lower alkenyl, (4) phenyl-lower alkyl, (5) chlorophenyl-lower alkyl, . (6) fluorophenyl-lower alkyl, (7) lower-(cycloalkyl-alkyl) or (8) di-(lower alkyl)-amino-lower alkyl; R"*" is (1) hydrogen, or (2) lower alkyl, -CH 2 R" is (1) lower alkyl, (2) lower alkenyl, or (3) -CHpCH 2 OH, 3 4 R and R are, independently of each other, (1) hydrogen, or (2) halogen, characterized in that: (a) a compound with the formula: 12 3 4 where R , R , R and R are as indicated above, is reduced for forming the compound wherein R is hydrogen; (b) a compound with the formula: 12 3 4 where R , R , R and R are as above, alkylated to form the compound wherein R is different from hydrogen, preferably using R-halogen or acylation followed by reduction; (c) a compound of the formula: 3 4 wherein R, R and R are as above, and X is hydrogen, chlorine or bromine, is reduced to form the compound wherein R 2 is -CI^OH and R"*" is hydrogen; (d) a compound with the formula: 12 3 4 where R , R , R , and R are as above, treated with a strong base; (e) a compound of the formula: wherein R is hydrogen, methyl, ethyl or benzyl; and R<5> is hydrogen, methyl or -CH9OH, is prepared by reducing a compound of the formula: 5 where R is as indicated above to the compound where R is hydrogen, optionally followed by N-alkylation to form the compound where R is methyl, ethyl or benzyl; (f) a compound of the formula: 2 where R has the above meaning, hydrolyzed to the compound where R is hydrogen, optionally followed by N-alkylation to form the compound where R is methyl, ethyl or benzyl, or reduced to the compound where R lower alkyl (g) is a compound with the formula: where R 2 has the above meaning, is reduced, optionally followed by N-alkylation to form compounds wherein R is methyl, ethyl or benzyl; and R<1> is hydrogen, (h) a compound of the formula: where R 2 has the above meaning, is reduced, and when R is hydrogen, optionally followed by N-alkylation to form the compound where R is methyl, ethyl or benzyl; (i) a compound of the formula: where R has the above meaning, treated with N-chlorosuccinimide followed by irradiation.