CA1129850A - 5-substituted-10,11-dihydro-5h-dibenzo ¬a,d|cyclohepten-5,10-imines - Google Patents

Abstract

Abstract of the Disclosure 5-Substituted-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imines, derivntives and pharmaceutically acceptable salts thereof are useful as antianxiety agents, as muscle relaxants and in the treatment of extrapyramidal disorders such as in Parkinson's disease.

Description

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5-SUBSTITUTED-10,11-DIHYDRO-5H-DIBENZO
[a,d]CYCLOHEPTEN-5,10-IMINES
Background of the Invention This invention is concerned with novel 5-substituted-10,11-dihydro-5H-dibenzo~,d]cyclo-hepten-5,10-imines,derivatives, optical isomers and pharmaceutically acc~ptable salts thereof which are useful as antianxiety agents, muscle relaxants, and in the treatment of extrapyramidal disorders such as in Parkinson's disease.
Structurally related compounds are known in the art to have qualitatively similar utilities. For example U.S. Patent 3,B92,756 discloses 10,11-dihydro SH-dibenzo[a,d~cyclo-hepten-5,10-imine and derivatives which are unsubstituted at the 5-bridgehead carbon; and Belgian Patent 829,075 discloses 9,10-dihydro-anthracen-9,10-imines and derivatives.
It is an object of this invention to provide the novel compounds, 5-substituted-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines, which are surprisingly more active than the unsubstituted analogs; novel processes fox their synthesis; pharmaceutical compositions comprising them as active ingredient.

29~3S~9

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Detailed Description of the Invention The novel compounds of this invention ~a~e ~tructural ~ormula:

o g ~4 ~ R3 ~2R

or a pharmaceutically acceptable alt ~hereof, wherein R is ~1) hydrogen, ~2) low~r alkyl, especially Cl_5 alkyl, preferably methyl or ethyl/

(3) lower alkenyl, especially C2 5 alkenyl, prefexably vinyl or allyl,

(4) phenyl(or substituted phenyl)-lower alkyl, especially phenyl(or substituted phenyl)-Cl_3 alkyl, pre~erably benzyl or ~ubstituted ~enzyl, wherein the ~ubstituent is halo ~uch as ~luoro, chloxo or bromo, especially chloro, or lower alkyl ~pecially Cl_3 alkyl, ~5) lower cycloalkyl, ~specially C3_6 cycloalkyl, preferably cyclopropyl or 20 . cyclohexyl, ~6) lower(cycloalkyl-alkyl), especially 3-6 c~cloalkyl-Cl_3 ~lkyl, or (7) ditlower alkyl~amino-lower alkyl, especially dime~hylaminopropyl;

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- 3 ~ 16028Y
Rl is (1) hydrogen, (2) lower alkyl, ~specially Cl 5 alkyl, preferably methyl or ethyl, (3) lower alkenyl, especially C~_5 alkenyl, preferably vinyl or allyl, (4) phenyl-lower alkyl, especially phenyl-Cl ~ alkyl, preferably benzyl, ~5) lower cycloalkyl, especially C3_6 cycloalkyl, preferably cyclopropyl or cyclohexyl, or ~6) lower(cycloalkyl~alkyl), especially 2 C3-6 cycloalkyl-Cl_3 alkyl, -CH2R is (1~ lower alkyl, especially ~1 5 al~yl, preferably methyl ox ethyl, ~2) lower alkenyl, especially C2_5 alkenyl, preferably vinyl or allyl, ~3) phenyl-lower alkyl, especially phenyl-Cl_3 alkyl, preferably benzyl, (4) lowertcycloalkyl-alkyl), especially C3 6 cycloalkyl-C1 3 alkyl,

(5) di(lower alkyl~amino-lower alkyl, especially dimethylaminopropyl; sr

(6) hydroxy-lower alkyl, especially hydroxy-C2_3 alkyl, preferably hydroxy ethyl;
and R3 and R4 are independently, (1) hydrogen, ~2) halogen, such as chloro, bromo, fluoro, or iodo, (3) lower alkoxy, especially Cl_5 alkoxy, - preferably methoxy, (4) trifluoromethylthio, (5) cyano, (6) carboxy, or ~7) hydroxy.
A preerred group of compounds is that wherein Rl is hydrogen.
Another preferred group of compounds i5 that wherein Rl, R3 and R4 are hydrogen.
Where R3 and/or R4 are other than hydrogen, it is preferred that they occupy the ~, 3, 7 or 8 positions of the tricyclic ring system.
Preferred definitions for -CH2R2 are lower alkyl, especially methyl or ethyl, or hydroxy-ethyl.
Preferred definitions for R are hydrog2n, lS lower alkyl or benzyl.
The novel compounds of this invention wherein R is hydrogen are generally prepared by reduction of the N-hydroxy analog. The preferred reducing agent is nascent hydrogen generated by the action of a metal, pre~erably zinc with an acid such as acetic acid at 40 to 100C. for l to about 10 hours.
The novel compounds are also prepared by ring closure of a lO-NHR-5-(=CHR2)-lO,ll-dihydro-5H-diben~o[a,d]cyclohep~ene by treatment with a strong base such as an oryanometallic reagent, for example, n-butyllithium in an ethereal solvent, such as tetra-hydrofuran, 1,2-dimethoxy-ethane or the like at about 0C. to about 30Co for about 5 minutes to about 1 hour.
Where -cH2R is hydroxy-lower alkyl, 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 sush as diethyl ether, ~z~so tetrahydrofuran, l,~-dimethoxyethane, or the like at a temperature o~ nbout 15C to about 100C until the redu~tion is substantially complete in abou~ 1 to &bout 6 hours. ~his proc~ure also ~erves to hydrogenolyze a bridgehead halo group ~mployed in the exemplified ~ynthetic 6ch~me.

R4 ~ 3 ~ R4 ~ 3 ;~H2C02alkyl CE~2C~20 Where R i5 other than hydrogen, the novel compounds are prepared by alkylation o~ the compounds wherein R is hydro~en with the appropriate reagent of formula R-halo wherein halo represents chloro, bromo or iodo. The reaction is normally c~nducted in an inert solvent ~uch as benzene, or toluene.
However, the alkylating reagent, depending on its physical proper~ies, may be used in ~uffi~iently excess amount to act as ~olvent. It is preferred to conduct the reaction in the presenee ~f an acid acceptor such as an inorganic carbonate such as sodium carbonate, an organic base such as pyridine, or a basic resin. Temperatures of about 50C. to ~o ab~ut lOO~C. may be empl~yed over reaction times of about 10 hours to a~out 5 days.
Where R is alkyl or ~ubstituted alkyl, the compounds also may be prepared by reduction of an N-acyl compound auch as alkoxycarbonyl to give ~ethyl or other alkanoyl groups to provide the other alkyl groups~ ~he pre~erred reducing system is a ~etal hydride ~uch zs lithium aluminum hydride in an etheraal olvent ~uch as e~her, tetra-hydrofuran or 1,2-dimethoxyethane or the like. The 2~350 reaction proceeds ~atisfactorily at room temperature but temperatures from about 0C to about 50C are appropriate with reaction times of 10-13 hours.
Novel compounds having substituents on 5 the benzenoid rings are generally prepared by m~tathesis of the appropriate bromo or iodo compound. For example treatment with a sodium lower alkoxide in the presence of copper dust in an inert organic solvent such as dimethyl formamide at 50-150C for 1-10 hours yields the 10 corresponding lower alkoxy compound.
The 2, 3, 7 or 8-hydroxy compounds are prepared from the corresponding alkoxy, preferably methoxy, com-pounds by de-etherification. The preferred process c~mprises heating with pyridine hydrochloride at 200-220C
15 for 3-10 hours.
Treatment of a bromo or iodo compound with cuprous cyanide in an inert organic solvent such as dimethyl formamide at reflux temperature for 1-10 hours yields the corresponding cyano compound.
Hydrolysis of the above cyano compounds with a mineral acid such as hydrochloric acid at about 50 to 150C and especially at reflux temperature produces the correspondiny carboxy substituted compounds.
Also treatment of the bromo or iodo compounds 25 with bis(trifluoromethylthio)mercury and copper dust in an inert organic solvent such as dimethyl formamide or quinoline at about 100-200~C for 1-10 hours yields the trifluoromethylthio derivative~.
Thus there are prepared the compounds:
3-(or 7)-R3-5-methyl-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-5,10-imines;
3-R3-12-cyclopropylmethyl-5-methyl-10,11-dihydro- -5H-dibenzo[a,d]cycl~hepten-5flO-imines;
2-R3-12-dimethylaminopropyl-5-ethyl-lO,ll~dihydro-35 5~-dibenzo[a,d]cyclohepten-5,10-imines; and

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7-R3-5,12-diethyl-10,11-dihydro SH-aibenzo [a,d]cyclohepten-5,10-imines;
wherein:
R3 is lower alkoxy, hydroxy, cyano, carboxy or trifluoromethylthio.
The novel compounds can be resolved into their optical isomers by standard techni~ues, such as the formation of diastereomeric pairs by salt formation wi~h an optically active acid, such as (-)di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
The starting materials and processes used for preparing the intermediates used in the above de-scribed processes are fully described in the Examples.
Also included within the scope of the presentinvention are the non-t~xic pharmaceutically acceptable salts of the novel 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. Where the novel compound carries a carboxylic acid group, the invention also contemplates sodium, potassium, and calcium salts thereof.
In the method of treatment aspect of the present invention, the novel imines of this invention are capable of producing anxiety relief without causing excessi~e sedation or sleep at a dosage level of from about 0~01 to about 50 mg. per kilogram of body weight preferably about 0~05 - 10 mg/kg of body weight on a regimen of 1-4 times a day. In addition, the novel compounds o~ the present invention are useful as muscle relaxants, antioonvulsants and in the treatment of extrapyramidal disorders when ~2~?85(~

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indicated at comparable dosage levels~ It is understood that the exact treatment level will depend upon the case history of the animal or human individual being treated and in the last analysis the precise treatment 5 level falling within the above guidelines is let to the discretion of the therapist.
Also included within the scope of the present invention are pharmaceutical compositions comprising the imines of this invention. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, s~erile parenteral solutions or suspensions, or suppositories for oral, parenteral or rectal administration. A unit dose contains from 0.1 to about 500 mg of active ingredient.
The following Examples representatively illustrate, but do not limit, the product, process, method of treatment, or compositional aspects of the present invention.

5-Methyl-10~ dihydro-5H-dibenzo[a,d]cycloh~pten-5,10-imine and oxalate salt salt Step A: Preparation of 10-(1-piperidyl)-SH-dibenæo ~a,d]cyclohepten-5-one A mixture of 71.3 g o~ 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 2 hours, then at room temperature overnight. The mixture was filtered, and concentrated to dryness. The residue was slurri~d with water and decanted. The residue was slurried with methanol and filtered to give 59.8 g of 10~ piperidyl~-5H-dibenzo[a,d]
cyclohepk~A~5-one, m.p. 103-105C.

11~ 3SO

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Step B: Preparation o~ 5-hydroxy-5-methyl-10-(l-piperidyl)-5H-diben~zo[a,d]cyclohe~ene A solution of 140 ml. of 1.8 molar methyl lithium in ether and 250 ml. of ether at 5-10C 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 allowed ~o stand until the ice melted. The mixture was ex~ractad well with ether and the extract was dried ~Na2SO4), filtered, and conoentrated to dryne s, the residue being used directly in the next step.
Step C: Preparation of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene The carbinol from Step B was dissolved in 500 ml of 10N ethanolic hydrogen chloride and 30 ml 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 concentrated to dryness. The residue was extracted with 300 ml of boiling hexane. On cooling the extract deposited 18.5 g solid which after recrystallization from hexane gave 16~5 g of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene, m.p~ B4-86C.
Step D: Preparation of 10-hydroximino-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 of sodium acetate and 300 ml of methanol was heated under re1ux ~or 5 hours. The solvent was ~vaporated and the residue was treated with 250 ml of water. The mixture was ext~acted with 3 x }50 ml of ether, and the extract was dried, filtered, and - 35 evaporated to give 16.8 g of 10-hydroximino-5-methylene-10,11-dihydro-5H-dibenzola,d~cycloheptene, m.p. 156-160C.
Step E: Preparation of 10-hydroxamino-5-methylene-1O,ll-dihydro-5H-dibenzo[a~d]cycloheptene A mixture o~ 15.3 of oxime from Step D, 500 ml of methanol, 12 g of sodium cyanoborohydride in 450 ml of methanol was treated dropwise with a ~olution of 12 ml of 12N hydrochloric in 50 ml of methanol over S hours, and then stirred overnight ~t room temperature. The æolvent was evaporated, the residue was stirred with 200 ml of lN aqueous hydrochloric acid, made alkaline wi~h concentrated ammonium hydroxide and extracted with 3 x 175 ml of ether. The combined extracts were dried (Na2S04), filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 10-h~drox-amino-5-methylene-10,11-dihydro SH-dibenzo[a,d]cyclo-hepten, m.p. 145-147C.
Step F: Preparation Qf 12 hydroxy-~-methyl-10,11-dihydro-5H-dibenzo~a,d]cyclohepten-5,10-imine A solution of 8.8 g of the hydroxamino compound ~rom Step E in 200 ml of xylene w~s added dropwise to 80 ml of refluxing xylene. After 1 hour of refluxing the solvent was vaporated. The residue w s treated with 250 ml o~ water and 7 ml of concentrated hydr~chloric acid and the mixture was washed with 100 ml of ether and the wash was discarded. The aqueous phase was made basic with concentrated ammonium hydroxide and extracted with 3 x 1~0 ml of ether. The extract was dried (Na2SO4), filtered and evaporated. The residue was ~ecrystal-lized 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. 141-144~Co so ~ 1602~Y
Step G: Preparation of 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5tl0-imine and oxalate salt A mixture of 1. 2 g of the hydroxy-imine rom Step F, 7 ~1 o~ acetic acid and 1.2 g of zinc dust was heated at 60 70C for 3.5 hours. The mixtuxe was filtered and the filtPr cake was washed with 200 ml of ether and 50 ml of water. The filtrate was made ~asic with ~% (w/v) aqueous sodium hydroxide and extracted with ether. ~he extract was dried (Na2SO4), filtered and evaporated to dryness to give 1~1 g of productO 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, there was collected 1.2 g of 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclhepten-5,10-imine, m.p. 203-206C (dec.), which after recrystallization from methanol/acetone, had m.p. 215-217C (dec.).

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~cycloh2ptene To a stirred slurry of ethyltriphenyl-phosphoni~m bromide (21 g, 0.057 m~le) in ether (400 ml) was added dropwise butyllithium in hexane (48 ml, 1.3 M). To the resulting solution was added a solution o~ 1-(5-keto-5H-dibenzo[a,d~cyclohepten-10-yl~-4-methylpiperazine (13.5 g, 0.044 mole) in THF
(100 ml). The resulting mixture was stirred and h ated under reflux for 3.5 hours, cooled a~d poured into ice H20 (300 ml). The organic phase was separated and the aqueous phase extracted with ether (2 x 150 ml). The c~mbined organic so}utions were E35C~

concentrated under reduced pressure. The concentrate was stirred with a mixture of lN a~ueous hydro-chloric acid (300 ml) and ether (300 ml) . The ether phase was separated, the aqueous phase extracted with ether, and the combined ether solutions dried over Na2SO4, filtered and th~
filtrate concentrated to 100 ml. Triphenylphosphine oxide was removed by filtration and the filtrate was chromatographed on silica-gel which was eluted with chloroform to yield 10.1 g (98~) of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo[a,d3cycloheptene, m.p. 93-95CC.
Following the procedure substantially as described in Example 1, Steps D through G but sub-stituting for the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,dlcycloheptene used in Step D thereof, an equimolecular amount of 5-ethylidene-10-oxo-10,11-dihydro-SH-dibenzo~a,d~cycloheptene, there is produced in sequence:
S-ethylidene-10-hydroximino-10,11-dihydro-5H-dibenzo~a,d~cycloheptene/ ~86% yield), m.p. 128-131C;
5-ethylidene-10-hydroxamino-10,11-dihydro-5H-dibenzo~a,d]cycloheptene (89% yield), m.p. 121-124C;
5-ethyl-12-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine, (21% yield), m.p. 112-116C; and 5-ethyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine, (90% yield) and the - hydrogen oxalate salt, m.p. 240-241C.
Employing the procedure substantia~ly as described in Example 2 but substituting for the ethyltriphenylphosphonium bromide used in Step A, an equimolecular amount of ~ Wittig ~2~5~

reaqent of ~ormula (C6~5~3P -C~2R2~Br ), ~herein -C~2R is -CH3, -CH2CH2CH3~ 9r -(C~2)3CH3' there are produ~ed the compounds of formula:
~1 wherein -CH~R repre~ents -CH3, -C~2CH2CH3 (m.p.
298-299.5C as the ~Cl l/2 CH3COCH3~ and -(CH2)3CH3.

5-(2-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-S,10-imine Step A: Preparation of 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one Triethylphosphonoacet~te, 10 g (0O045 mole) was added dropwise to a slurry of 1.9 g ~0~04 mole) of ~odium hydride ~50% in miIleral oil) in 20 ml of dry toluene ~nder nitrogen and Xeepi~g the tempera-ture at 30-35 C by cooling. The mixture was ~tirred 1 hour at room temper~ture. ~ solution o~ 10 g lO.0328 mole ) of 1-(5-keto-5~-dibenzo[a,d]cyclohapten-lO~yl)-4~methylpiperazine in 75 ml of dry toluene was added dropwise, keeping the temperature at 25-30C by cooling. The mixture was ~tirred at room temperature for 3 hours and held at room temperature overn~ght.
After decantin~ ~he ~olution, the precipitate was washed with ~our 25 ml portio~s of toluene t 65C.
The ~o~bined toluene extra~ts were diluted with an equal volume ~f e~her and shaken wi~h 75 ml of 0.5N
hydr~chloric a~id. The agueous ~cid layer was ~z~

separated and re-extracted with toluene-ether (1~
The combined or~anic phases were washed with water, dried over magnesium sulfate, filtered, and con-centrated. The oily solid obtained was freed from the bulk of the oil by collec~ion on a sintered glass funnel and then triturated with cyclohexane to yield 4.~ g (47~) of 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one, m.p. 56-62C.
Ste~ Preparation of 5-ethoxycarbonylmethyl-10,12-dihydroxy-lG,ll-dihydro-5H-dibenzo-~a,d]cyclohepten-5,10~imine _ __ The keto-olefin from Step A, 23.4 g (0.08 mole), together with hydroxylamine hydrochloride (6.0 g), sodium acetate trihydrate (12.0 g) and wet ether (300 ml) was stirred at room temperature.
After 16 hours, the precipitate was collected, washed with ether, and stirred with water (300 ml) for 1 hour. The solid was cvllected and dried to obtain 21.6 g (83~) of 5-ethoxycarbonylmethyl-10,12-dihydroxy-lO,ll~dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, m.p. 193-195C dec.
Step C: Preparation of 5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo[a, a ] -cyclohepten-5 ! 10-imine The N-hydroxyimine from Step B, 21 g (0.0646 mole), was suspended in glacial acetic acid (125 ml) and zinc dust (16 g) was added in portions over 15 minutes. After the exothermic reaction had subsided, the mixture w~s stirred and heated in an oil bath at 65~C for 3 hours.
The cooled mixture was filtered and the filtrate was evaporated under reduced pressure. The residual ~yrup was dissolved in water (500 ml) and the filtered solution was made basic with 15% aquevus sodium hydroxide. The precipitate was collected, , ~

~2~351~) washed with water, and dried to yield 15 g of 5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, m.p. 186-189C dec. A filtered solution o~ this produot in boiling acetone (350 ml) was treated with 7N ethanolic hydrogen chloride (7 ml~. The precipitate of the hydrochloride salt was collected, washed wi~h ether, and dried to obtain 14.35 g (64%), m.p. 247-250C dec. 0 Step D: Preparation of 10-chloro-5-ethoxycarbonyl-methyl-lO,ll~dihydro-5H-dibenzo[a,d]cyclo-hepten-5!10-imine The hydrochloride salt of the product from Step C, 17.8 g (0.051~ mole) was slurried in thion~l chloride (250 ml) and the mixture was heated to refluxing. After the ensuing exothermic reaction subsided the mixture was heated at reflux for 20 minutes when the solid had dissolved completely. The thionyl chloride was evaporated under redured pressure and the last traces were removed by repeated co-evaporation with $oluene.
The residue was triturated with Acetone and dried to give 15.35 y ~81~, m.p. 223-227C dec., sf 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrochloride.
Step E: Preparation of 5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine .
The hydrochloride from Step D, 15.3 g (0.042 mole)l was added in portions to a slurry of lithium aluminum hydride (5.6 g, 0.147 mole) in ether (200 ml) and tetrahydrsfuran ~200 ml).
The mixture was stirred at reflux ~or 3 hours, then cooled to O~C, and hydrolyzed by the dropwise addition of water (4 ml) and 10% ~queous sodi~m ~L2~5(~

hydroxide (4 ml.). A~ter dilution with ether, the precipitate was collected, suspended in chloro-form (250 ml) and stirred at room temperature for 1 hour. The mixture was ~iltered and the filtrate was combined with the previously obtained ethereal filtrate. Solvents were evaporated under reduced pressure and the ~olid obtained was recrystalli~ed from 95% ethanol to yield 8.6 g of 5-(2-hydroxy-ethyl)-10,11-dihydro-5H-dibenzola~d~cyclohepten~
5,10-imine, m.p. 181-184C. Recrystallization from 70~ ethanol gave m.p. 182 184C.
A suspension of this product ~4.4 g) in warm absolute ethanol (20 ml) was treated with 7N ethanolic hydrogen chloride (2.5 ml) and the mixture was stirred until all of ~he solid dissolved.
Dilution with ether precipitated the hydrochloride salt; 4.8 g, m.p. 263-265~C. Recrystallization from acetonitrile gave m.p. 262-264C dec.

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,dlcyclohepten-5-one A solution of bromine (53 g., 0.33 mole) in glacial acetic acid (125 ml.) was added dropwise to a stirred slurry of 3-bromo~5H dibenzo[a,d]cyclo-hepten-5-one (71.25 g., 0.25 mole) in glacial acetic acid (775 ml.). After the mixture had been stirred at room temperature for several hours, the ~olid was collected, washed with glacial acetic acid and dried; yield, 105.8 gO ~95%J, m~p. 173-175~C.
Step B- Preparation of 3,10-dibromo-5H dibenzo[a,d]
cyclohepten-5-one and 3,11-dibromo~5H-dibenzo la,d~cyclohepten~5~one The product from Step A was added to a stirred solution of sodium hydroxide (28 g., 0~7 mole) in methanol (2 liter). The thick mixture was stirred at reflux for 1 1/4 hours. After cooling, the solid was collected, washed with methanol and then with water, and dried to obtain 81 g. (90%) of the mi~ture of 3,10-dibromo-5H-dibenzo[a,d]cyclohepten-5-one and 3,11-dibromo-5H-dibenzo[a,d]cyclohepten-S-one, m.p. 146-156C.
Step C: Preparation of 3-bromo-10-(4-methyl-piperazinyl)-5H-dibenzo~a,d]cyclohepten-5-one and 3-bromo~ (4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one Potassium tert-butoxide (6.8 g., 0.06 mole) was added to a stirred slurry of 3,10 dibromo-5H-dibenzo [a,dJcyclohepten-5-one and 3,11-dibromo-5H-dibenzo[a,d]
cyclohepten-5-one (18.2 g., 0.05 mole~, 4-methyl-piperazine tlO ml.), and dry tert-butyl alcohol (200 ml.) at room temperature and under nitrogen.
The dark orange mixture was heated to refluxing for 2 hours and then stirred at room temperature over-night. The mixture was poured into approximately800 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-methylpipera2inyl)-5H-dibenzo[a,d]cyclohepten-5-one and 3-bromo-11-(4-methyl-piperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one was obtained as a residual red-yellow gum; yield, 19.4 g. 100%.
5tep D: Preparation of 3-bromo-5-methyl10-(4-methyl-piperazinyl)-5H-dibenzo[a~d]cyclohepten-5-ol and 3-bromo-5-methyl~ 4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-ol Methyllithium, 35 ml. of a 1.6 M ~olution in ether, was added dropwise to a s~irred solution of the product from Step C ~18 g., 0.047 mole) in ether ~IlZ~I~S~

(200 ml~ and tetrahydrofuran ~60 ml) cooled in an ice bath and under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolyzed by the dropwise addition of water. After dilution with ether and water, the layers were separated and the agueous phase was re-extracted with ether. The combined ether extracts were washed with water, dried over ~nhydrous sodium sulfate and evaporated. The mix~ure of 3-bromo-5-methyl-10-(4-methylpiperazinyl)-5H-dibenzo-[a,d]cyclohepten-5-ol and 3-bromo-5-methyl~ 4-methylpipera~inyl)-5H-dibenzo[a,d~cyclohepten-5-ol was obtained as a residual dark yellow glass; yield, 1~ g. 196%)~
Step E: Preparation of 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo[ald]cyclohepten-lO one and 7-bromo-5-methylene-10,11-dihydro-5H-dibenzola,d]cyclohepten-10-one -A mixture of the product from Step D ~18 g., 0.045 mole), 95% ethanol (80 ml.), 7N ethanolic hydrogen chloride (40 ml.), and 6N aquPous hydrochloric acid ~80 ml.) was stirred at room tempera~ure for 30 minutes and at reflux temperature for 1 hour. The mixture consisted of a brown oily lower phase and an aqueous alcoholi~ upper phase. The latter was decanted and the alcohol was stripped in vacuo. The residual 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 30 dried over anhydrous magnesium sulfate. Evaporation of the filtered extract left the crude product as a residual dark yellow glass. This material was chromato-graphed on a silica gel column, eluting wi~h tolue~e.
Evaporation o~ the appropriately combined fractions left the partially purfied product as an oily solid (8.~ g.). Trituration with cyclohexane afforded one of the isomers of the product as a white solid;

. .

31 ~L29~3sat yield, 206 g., m.p. 125-158C. . Two recrystalliz~tions from cycl~hexane gave m.p. 158-163C. Evaporation of the first cyclohexane mother liguor left the remaining i60mer of the product as a dark yellow oil.
Trituration with three succes~ive 10 ml. portions of hexane afforded a yellow 601id yield, 3,3 y., m.p. 75-83C. Two recry~tallizations from hexane gave m.p. 84-89C.
~ he higher melting isomer (m.p. 160-10 164 C) has 6tructurai formula:
.

~r and is named 7-bro~o-5-methylene-lQ,ll-dihydro-5H-dibenzo[a,d]cyclohepten-10-one.
The other isomer, 3-bromo-5-methylene-10,11-dihydro-5H-dib~nzola,d]cyclohepten-lO-one (m.p. 84-91C) has ~tructural formula:

E~rJ~) Step F through I: ~reparation o~ 3 ~and 7)-bromo~5-methyl-10,11-dihydro-5H-di~e~zola,d~-cyclohepten-5,1~-imine ~Z~8S~

Employing the procedure substantially as described in Example 1, Steps D through G, but 8Ub-~tituting for the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene employed therein, an equimolecular amount of the corresponding 3- and 7-bromo- compounds there is produced in sequence, the fsllowing:
(Step F): 3(and 7)-bromo-10-hydroximino-S-methylene-10,11-dihydro-5H-dibenzo~a,d~cycloheptene, m.p.'s 171-175C and 179-181C respectively;
(Step G): 3(and 7)-bromo-10-hydroxamino-S-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, m.p.'~ 149-153C and 136~139C respectiv~ly;
(Step H): 3(and 7)-bromo-12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, m.p.'s 175-180C and 187-189C
respectively; and (Step I): 3(and 7)-bromo-5-methyl-10,11-dihydro-SH-dibenzo[a,d~cyclohepten-5,10-imine hydro-chloride, m.p.'s ~300C.
Similarly prepared are:
8-bromo-5-methyl-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-5,10-imine;
2-bromo-5-ethyl-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-5,10-imine; and 7-bromo-5-ethyl-10,11-dihydro-5H-dibenzo[ald]
cyclohepten-5,10-imine.
ExAMæLE-5 10,11-Dihydro-5 r 12-dimethyl-5H-dibenzo[a~d]cyclohepten-3Q 5,10-imine_fumaric acid salt - Step A: Preparation of 10~ dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo[a,dlcyclohepten-5,10-imine_ A mixture of 1.15 g. of 10,11-dihydro-5-methyl-5H~dibenzo[a,d]oyclohepten-5,10-imine, 1.0 g 35 of anhydrous sodium carbonate, 1 ml of ethyl chloro-~ 21 - 160~8Y
formate 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 crystalline 10,11-dihydro-12-e~hoxy-carbonyl-5-methyl-5~-dibenzo[a,d]cyclohepten-5,10-imine, m.p. 80-83C.
B: Preparation of 10,11-dihydro-5,12-dimethyl-5H-dibenzo[a,d]cyclohepten-5,10-imine A solution of the urethan from Step A in 15 ml of absolute ether was added dropwise to a slurry of 190 mg of li~hium aluminum hydride in 15 ml of absolute ethPr with stirring and under nitrogen. After 24 hours at room temperature, the mixture was cooled in an ice bath and hydrolyzed by the dropwise addition o the minimum volume of water containing a few drops of 5%
(w/v) aqueous sodium hydroxide. After dilution with ether, the mixture was filtered. The fil~rate 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 warm solution of 1.2 g of fumaric acid in 12 ml of methanol was a~ded. The fumaric acid salt which crystallized was collected and was recrystal-lized from methanol-ethyl acetate to give 2.1 g of 10,11-dihydro-5,12-dimethyl-5H-dibenzo~ald~cyclohepten-5,10-imine fumaric acid salt, m.p. 186-188C.

12-Benzyl-10,11-dihydro-5-methyl-5H-diben20[a,d]cyclo he ten-5 10-imine p A mixture of 2.45 g of 10,11-dihydro-5-methyl-5H~dibenzola,d]cyclohepten-5,10-imine, 1.9 g of benzyl chloride, 3.2 g of anhydrous sodium carbonate and 50 ml of dry benzene was stirred at reflux temperature ~or 4 days~ The mix~-ure was filtered and the filtrate was evaporated in ~acuo to give 3.1 g of the product as an oily olid, ~2~SO

- 2~ - 16028Y
m.p. 107-111C. This was recry~tallized twice from 95~ ethanol to give 1.85 g of white crystalline 12-benzyl-10,11-dihydrs-5-methyl-5H-dibenzo[a,d]cyclo-hepten-5,10-imine, m.p. 111~ C.

12-Allyl-10,11-dihydro-5-methyl-5H-dibenzo[a,d~cyclo-hepten-5,10-imine A mixture of 2~45 g of 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine, 1.8 g of al~yl bromide, 3.0 g of anhydrous ~odi~m carbonate and 50 ml of dry benzene was stirred at reflux temperature for 20 hours. The ~ixture was filtered and the filtrate was evaporated in vacuo to give 1.~ g of the oily free base of the product. This was dissolved in 5 ml of acetone and added to a warm solu~ion of 0.75 g of fumaric acid in 75 ~1 of acetone. The salt which crystallized was collected and recrystallized ~rom acetone to give 1.45 g of white crystalline 12-allyl-10,11-dihydro-5-methyl-5H-dibenzo~a,d]cyclohepten-5,10-imine fumaric acid sal~, ~.p~ lB0-182C.
Employing the procedure of Example 7, but substituting for the allyl bromide and the 10,11-dihydro-5-methyl-5H-dibenzo~a,d~cyclohepten-5,10-imine 2~ used therein a compound of formula R-I and 5-R2CH2-10,11-dihydro-5H-dibenzo ra,d~cyclohepten-5,10-imine, described in Table II, there are produced the 5-R2CH2-12-R-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines also described in Table II, in accordance with the following reaction:
~ ~X
c~2~ ~2~
, ~z~o - 23 - 16028Y .
TABLE II
R2 ~, X
-H -CH2 ~ H (m.p. 132.5-135.5C) -H -C~2- ~ Cl H (m.p. 111-113C
hydro~en o~alate) -H CH2CH2 ~ H (m.p. 115.5-117C) -CH3 -CH2 ~ H ~m.p. 163-164C) 2 3 -CH2 ~ H (m.p. 132.5-135.5C) H -C~2 ~ H (m.p. 112-114.5C~

H -CH2 ~ H (m.p. 111-113C, base) H -CH2 ~ 3-Br -CH3-(CH2)3N(CH2)3 2-Br -CH32 5 7-Br ExAMæLE 8 5llo~l2-Trimethyl-lo~ll-dihydrQ-5H-dibenzo[aJd]
heptene-5,1~-imine hydrochloride Step A: Pr~paration of 10-amino-5-methylene-10,11-dihydro-5H-di~en~o[a,d]cycloheptene To a stirred slurry of zinc dust (.9 g, 0.138 mole) in 1~0 ml of glacial acetic acid stirred in an oil bath at 65 wa~ added 10-hydroxamino-5-methylene-lD,ll-dihydro-SH-dibenzo~a,d]cycloheptene tlO g, 4~ mmole~. The mixture was stirr~d in the oil bath for 2 hours, cooled, and quenched in 500 25 ml of water. The mixture was made basic with c~n-centrated ammonia, then extracted with etherl The combined ether layers were wa~hed with water, dried over ~odium sulfate, filtered, and evaporated L2~S~

- 24 - 16~28Y
to dryness ln vacuo. The residue was recrystallized from h~xane to give 7.8 g, m.p. 84.5-86.5.
Step B: Preparation of 10-isocyano-5-methylene 10,11-dihydro-5H-dibenzo[a,dJcycloh~ptene To a solution of 10-amino-5-methylene~
10,11-dihydro-SH-dibenzo[a,d]cyclsheptene (8.1 g, 36.6 mmole) in chloroform (180 ml~ was added sodium hydroxide pellets (4.42 g, 0.11 mole) benzyltriethylammonium chloride (0.42 g, 1.8 mmole) and water (0.5 ml). The mixture was stirred under nitrogen until the sodium hydroxide pellets dissolved ~ca 4 hours), treated with anhydrous potassium carbonate, filtered, and evaporated to dryness _ vacuo. The resulting oil was dissolved in chloroform (180 ml), treated with another 1.5 g (37.5 mmole) of sodium hydroxide and 0.2 g (.86 mmole) of benzyltriethylammonium chloride, and stirred overnight under nitrogen. The mixture was again dried over potassium carbonate, filtered, and evaporated to dryness in vacuo. The resulting oil 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 to give 4 g of solid, m.p. 96-98.
Step C; Preparation of 10-isocyano~10-methyl-5-methylene-10,11-dihydro-5H-dibenzola,d~-cycloheptene Diisopropylamine (1.1 g, 10.9 mmole) in 25 ml of dry tetrahydrofuran was stirred in a dry ice/acetone bath. Under a nitrogen blanket, ~his ~olution was treated with n-butyllithium~hexane (5.0 ml o 2.2M solution) added drvpwise over 10 minutes. After 5 minutes, a solution of 10-isocyano-5 methylene-10,11-dihydro-5H-dibenzo[a,d]-~z9~s~

cycloheptene (2.4 g, 10.4 mmole) in 25 ml of dry tetrahydrofuran was added dropwise (over 45 minutes) to the lithium diisopropylamide solution. The resulting deep red solution was stirred in the cold for 15 minutes then treated with methyl-iodide (4.56 g, 32 mmole) added all at once.
The mixture was stirred 2 hours in the cold and an additional 1 hour at room temperature. The solvent was removed in vacuo a~d the residue chromatographed on 75 g of silica gel, eluted with methylene chlorideO The combined product fractio~s were evaporated in vacuo to give 2.2 g (86%) solid. Recrystallization from ether gave, m.p. 146-147.5C. 5 Step D: Preparation of 10-methyl-lO~methylamino-5-methylene-10,11-dihydro-5H-dibenzo[a,d~
cycloheptene hydrogen chloride 10-isocyano-10-methyl-5-methylene-10,11-dihydro-SH-dibenzo[a,d~cycloheptene (1.8 g, 7.3 mmole), dissolved in dry ether (100 ml) was added dropwise to a slurry of lithium tetrahydridoaluminate (0~53 g, 14 mmole) in ether (40 ml) stirred under nitrogen. The mixture was heated a* reflux for 1 hour, cooled, and the excess hydride decomposed by careful dropwise addition of 1.5 ml of ice water. The suspension was filtered and the solids 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 slight excess of 8N
ethanolic HCl and cooled to yive 1.7 g (81%) of powder, m.p. 238-240(d).

~2~3~3SO

Ste~ Preparation of 5,10,12-trimethyl-10,11-dihydro 5H-dibenzo[a,d]cyclohept~n-5,10-imine hydro~en chloride 10-Methyl-10-methylamino-5-methylene-10,11 dihydro-5H-dibenzo~a,d]cycloheptene (1.6 g, 6.4 mmole) was dissolv~d in dry te~rahydrofuran ~40 ml).
To this solution, stirred at room temperature under nitrogen, was added n-BuLi (3. 0 ml of a 2.2M solution in hexane) dropwise over 5 minutes.
The mixture was stirred 10 minute~, then treated with 3 ml of ice water. The tetrahydrofuran was removed under vacuum and the residue taken up in ether.
The ether solution wa~ washed with water, dried over sodium sulfate, filtexed, and evaporated to dryne~s in Yacuo. The resulting oil was chromato-graphed on 120 g of silica gel, eluted 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 slight excess of 8N ethanolic HCl. The solvent was removed in vacuo and the re--idual solid recrystallized ~rom 20 ml of absolute ethanol to give 5,10,12-trimethyl-10,11-dihydro-5H-dibenzo [a,dJcyclohepten-5,10-imine hydrogen chloride, m.p.295-296.5C.
Similarly prepared are:
lO~allyl-5,12-dimethyl-; 5,10-diethyl-12-methyl-;
10-cyclopropyl-5,12-dimethyl-; and 10-cyclopropylmethyl-5,12-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

385C~

. _ Optical Resolution Racemic 5-methyl-10,11-dihydro-5H~dibenzo [a,d]cyclohepten-5,10-imine (3.93 g, 0.0178 mole) and (-)di-p-toluoyl-d-tartaric acid ~6.88 g, 0.0178 mole) are dissolved in 21 ml of acetone. The solution is seeded and after seYeral hours of standing at room temperature, the cxystalline salt is collected. This product is recrystallized repeatedly from acetone to constant rotation.
The salt is suspended in cold water, s~irred with aqueous sodium hydroxide and the base is extracted into ether. The washed and dried ether extract is evaporated to dryness ~nder reduced pressure lS ~eaving (-) 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine as the residual solid, m.p. 71.5-73.5C.
The acetone mother liquor from the initial crystallization of ~he (-~-isomer is 20 evaporated to dryness under reduced pressure.
A suspension of the residual glass in cold water is stirred with aqueous sodium hydroxide and the base is extracted into ether. The washed and dried ether extract is concentrated to obtain 25 the optically impure (~) base as the residual solid. This product (2.27 g, 0.0103 mole) and (+)di-p-toluoyl-l-tartaric acid (3.9 g, 0.0103 mole) are dissolved in 20 ml o~ acetone. After several hours of standing at room temperature, 30 the crystalline salt is collected and recrystallized xepeatedly from acetone to constant rotation.
The salt is reconverted to the base in the manner previously described to ~btain (~) 5-methyl-10,11-dihydro-5~-dibenzota,d]cyclohepten-5,10-imine, 35 m-p. 72-74Oc~

Z91~5(~

Tablet Preparation Tablets containing 1.0l 2.0, ~5.0, Z6.~
S0.0, and 100.0 mg, r~spectively, of 10011-dihydro-5-methyl-12-benzyl-5H-dib~nzo~a,d]cyclohepten-5,10-imine are prepared as illustrated below.
TABLE E~R DOSES CONTAINING FROM
1-~5 MG OF THE ACTIVE COMPOUN~
~mount - mg 10,11-dihydro-5-methyl-12-benzyl 5~-dibenzo[a,d]cyclohepten-5,10-imine 1.0 2.0 25.0 Microcrystalline cellulose49.25 48.7537.25 Mbdified food corn starch49.25 48~75 37.25 Magnesium stearate 0.50 0.50 0.50 TABLE FOR DOSES CONTAINING FROM

Amount - mg 10,11-dihydro-5-methyl-12-benzyl 5H-dibenzo[a,d]cyclohepten-5,10-imine 26.0 5~.~ 100.0 Microcrystalline cellulose25.0 100.0 200.0 Modified food corn s~arch2.21 4.25 8.5 Magnesium stearate u39 0.75 1l5 All of the active compound, lactose, and a portion of the corn starch are mixed and granulated to a 10~ corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting gxanulation is then compressed into ~2~85~

- 29 - 1~028Y
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 are prepared using the same procedures and the equivalent amounts of excipients along with equivalent amounts of any of the novel compounds of the present invention.

5q) ~ 30 - 16028Y
Additional processes for preparing a compound of structural formula:

(I) wherein R is hydrogen, methyl, ethyl or benzyl; and R2 is hydroqen, methyl or -CH2OH, are:
(a) the reduction of a compound of structural ormula:
~1 to the corresponding imine (I) wherein R is hydrogen by shaking a solution of compound (II) in an inert polar solvent such as a lower alkanol, for example, methanol, ethanol, isopropanol or butanol, a lower alkanoic acid, for example, acetic acid or propionic acid, a water soluble ether including dioxane or 1,2-dimethoxyethane;
water. or mixtures thereof, preferably ethanol, with hydrogen at 1-5 atm., preferably at 1 atm., at about 15-100C, preferably at 25C, over a catalytic amount of a catalyst such as 10% palladium on carbon, platinum or Raney nickel, preferably 10% palladium on carbon, until one equivalent of hydrogen is substantially absorbed, ~sually about 2-24 hours, pre~erably 3 6 hours;

~L~Z~850 (b) the treatment of a N-alkoxycarbonyl derivative of formula:

AlkylOOC
~, CH2~ (III) wherein alkyl represents Cl 4 alkyl such as methyl, ethyl, propyl or t-butyl, with a strong inorganic base such as potassium hydroxide ox sodium hydroxide or the aqueous solutions thereof (25-50% by weight), preferably potassium hydroxide, in an inert polar solvent such as a lower alkanol including ethanol or n-butanol, a water-soluble ether, for example, tetrahydrofuran, dioxane, or dimethoxye~hane, or a di(lower alkyl)ketone such as acetone or methylethyl ketone, preferably n-butanol, at about 25-100C, preferably at the refluxing tempera-ture of an appropriate solvent, in an inert gas atmosphere such as nitrogen, until the hydrolysis is substantially complete, usually for about 2-24 hour~, preferably 10-12 hours;
(c) ~he reduction of a compound of structural formula:
X Y

~-CH-R2 ~IY) wherein X, Y and ~ are independently hydrogen f chlorine or bromine; Ra is h~rogen, hydroxy, methyl, ethyl9 benzyl or benzoyl, with lithium aluminum hydride ~LiA1~4) in an ether such as diethylether, tetrahydrofuran~ 1,2-1~2~85C~

dimethoxyethane or di(2-methoxyethyl)ether, preferably diethylether, under nitrogen, at about 35-165C, pre-ferably at the refluxing temperature of an appropriate solvent, until the reaction is substantially complete, usually about 1-24hours, preferably 2-4 hours.
(d) the reduction of a compound of structural formula:
o CH2R2 ( V) via treating a solution of compound (V) in an inert, polar solvent such as water, a lower alkanol such as ethanol, t-butanol, or ethylene glycol, or an inert polar solvent such as dimethylsulfoxide or mixtures thereof, prefexably ethylene glycol, with hydrazine at about 50-165C, preferably 90-120C, until the reaction is substantially complete, usually for about 0.5-16 hours, preferably 1-3 hours, followed by treatment with a strong inorganic base such as potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably potassium hydroxide, at about 100-185C, preferably 150-175C, until the reduction is substantially complete, usually for 1-24 hours, preferably 2-4 hours.
(e) the treatment of a compound of structural formula:
NHR~
~, CH2R (V:[) ~LZ985C~

_ 33 _ 160~8Y
wherein R~ is hydrogen, methyl or ethyl with a chlorinating agent such as sodium hypochlorite, t-butyl-hypochlorite or N-chlorosuccinimide, preferably sodium hypochlorite or N-chlorosuccinimide, in an inert solvent such as a di~lower alkyl) ether, ~or example, diethylether or 1,2-dimethoxyethane, a chloro lower alkane such as methylene chloride or carbon tetra-chloride, or an inert aromatic solvent such as benzene or a cyclo(lower)alkane such as cyclohe.xane, preferably diethylether or methylene chloride, at about -5-80C, preferably 5-25C, until the N-chlorination is e~sentially complete! usually for 0.5~12 hours, preferably 1-3 hours, followed by irradiating the resulting product in 75-95% by weight sulfuric acid~ preferably 85~, at about 15-50QC, preferably at 25-30~C, with a 125 watt G ~
sunlamp until the photocyclization is substantially com-plete, usually or about 3-24 hours, preferably 6-8 hours;
and (f) the reduction of a compound of structural formula:
X' Y' CH2COOalkyl (VII) wherein X' and Y' are independently hydrogen, chlorine, bromine or hydroxy; and R~ is hydrogen~ methyl, ethyl, or benzyl with lithium aluminum hydride (LiAlH4) in sub-stantially the same manner as described in process (c) to produce the compound (I) wherein R2 is -CX2OH.

. . .

~L%~35~

~ 34 ~ 16028~
When a product of the processes ~a)-(f) is an unsubstituted lmine (I) wherein R is hydrogen, it is N-alkylated, if desired, to the compound wherein R is methyl, ethyl or benzyl by an appropriate alkylating reagent such as R-halo as previously described, or by treatment with an acylating reagent of formula:
R'-~-Cl wherein R' is hydroyen, methyl or phenyl, followed by reduction with lithium aluminum hydride. An additional alkylation method involves the treatment of an imine with an aldehyde of formula:
R'CHO

and sodium cyanoborohydride (NaCNBH3) in an ether such as tetrahydrofuran, 1,2-dimethoxyethane or di(2-methoxyethyl)ether, preferably tetrahydrofuran, at about 10-50C, preferably 25C, until the reaction is substantially compl~te, usually for about 6 hours to about 3 days, preferably 2 days.
The starting materials and processes used for preparing them are fully described below in Examples 11-21.

:

29~SC~

~ 35 - 16028Y
Example~ 13 illustrate the alternative processes (a), (b), and tc) described above for the pxeparation of 5-methyl~10,11-dihydro-5H-dibenzo[a,d~
cyclohepten-5,10-imine or its hydrochloride salt.
E~AMPLE 11 Step A: Preparation of 6-methylene-l,la,6,10b-tetra-hydrodibenzo[3,4:6,7]cyclohept[1,2-~]azirine Lithium aluminum hydride (0.46 g., 0.012 mole) is slurried in ether (40 ml) and a solution of 5-methylene-10,11-dihydro-5H-dibenzo~a,d]cyclohepten-10-one oxime (0.94 g, 0.004 mole) in ether (25 ml) is added slowly dropwise. The mixture is stirred at room temperature for 3 hours and then hydrolyzed by the successive drop-wise addition of water (0.4 ml), 10% a~ueous sodium hydroxide (0.6 ml) and water (1.2 ml). The ether phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to yield 6-methylene-l,la,6,10b-tetrahydrodibenzo[3,4:
6,7]cyclohept[1,2-b]azirine.
Step B: Preparation of 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo~a,dJcycloheptene -Under nitrogen, a solution of 2M n-butyllithium in hexane (0.8 ml) is added slowly dropwise to a stirred solution of 6-methylene-l,la,6,10b-tetrahydrodibenzo [3,4:6,7]cycloheptEl,2-b]azirine (0.44 g, 0~002 mole) in tetrahydrofuran (5 ml). Stirring is continued at room temperature for 16 hours. The mixture is quenched in ice water and extracted with chloroform. The chloro-form extract is washed with water, dried over sodium sulfate! filtered and the filtrate evaporated to yield 5-methyl-5,10,11-nitrilo-10,11-dihydro-5H-dibenzo~a,d]cyclo-heptene.
Step C: Preparation of 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im-ine A solution of the product from Step B (0.001 mole) in absolute ethanol (5 ml) is shaken with hydrogen s~

at atmospheric pressure at 25C over 10~ palladium on carbon (50 mg) until one equivalent of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is evaporated to yield 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Employing substantially the same procedures described in Example 11, but substituting for the starting material 5-methylene-10,11-dihydro-5H-dibenzo[a,dJcyclo-hepten-10-one oxime used therein an equimolar amount of 5-methylmethylene-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-10-one oxime, there is prepared 5-ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

A solution of 12-ethoxycarbonyl-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (2.93 g, 0.01 mole) and potassium hydroxide (20 g) in n-butyl alcohol (100 ml) is stirred and heated under reflux in a nitrogen atmosphere for 12 hours. The solvent is evaporated and the residue is partitioned between toluene and water. The toluene phase is separated, washed with water, and extracted with lN aqueous hydrochloric acid. The acid extract is made basic 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 evaporated to yield 5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine.
EXAMæLE 13 Step A: Preparation of 5-azido-5-iodomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one -5-Methylene-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-10-one ~8.2 g) in acetonitrile (30 ml) i~ added dropwise to a solution of iodine azîde (preparea by dropwise addition of 6.8 g of iodine monochloride to suspension of 5.6 g of sodium azide in 37 ml of aceto ~:~L%98~i~

nitrile stirred in a methanol/ice bath). The mixture is allowed to warm up ~o room temperature and stirred over~
night. It is then poured into 250 ml of ice water and extracted with ether (3 x 50 ml). The combined ether extracts are washed with 5% sodium thiosulfate solution (1 x 50 ml) and with water (3 x 50 ml), dried over sodium sulfate, fil~ered, and evaporated to dryness in vacuo to give 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 5-Azido-S-iodomethyl-10,11-dihydro-SH-dibenzo [a,d]cyclohepten-10-one (4.3 g) and 10% palladium/char-coal (0.3 g) are combined in ethanol (80 ml) and shaken under an atmosphere of hydrogen ~50 p.s.i.g~ in a Paax 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,d]cyclohepten-5,10-imine 10-Hydroxy-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine (3.5 g) is heated in refluxing thionyl chloride (30 ml) for 20 minu~es. The mixture is cooled and evaporated to dryness in vacuo. Toluene (60 ml) is twice added and removed in vacuo. The residue is slurried in ether (50 ml) and treated with excess lN aqueous NaOH (25 ml). The ether layer is separated and the aqueous layer extracted with ether (2 x 50 ml~.
The combined ether layers are washed with water (3 x 30 100 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10 imine.

o Step D: Preparation of 5-methyl 10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10~imine ~drochloride 10-Chloro-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine (5 g) is dissolved in ether (100 ml) and added dropwise to a slurry of lithium aluminum hydride (0.76 g) in ether (80 ml) stirred under nitxogen. The mixture is heated at re~lux for 2 hours, cooled, and treated with ice water (2 ml) added dropwise. The suspension is filtered and the solids washed with ether~ The filtrate and ether washings are combined, washed with water (2 x 100 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue, in e~hanol (10 ml), is treated with excess 8N ethanolic HCl and the solution is evaporated to dryness in vacuo. The residue is re-crystallized from ethanol to give 5-methyl~10,11-dihydro-5H~dibenzo[a,d]cyclohepten-5,10-imine hydrochloride.
Employing substantially the same procedure described in Example 13 r but substituting for the starting material 5-methylene-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-10-one used therein an equimolar amount of 5-methylmethylene-10,11-dihydro-5~-dibenzo[a~dJcyclo-hepten-10-one, there is produced 5-ethyl-10,11-dihydro-5H-dibenzoEa,d]cyclohepten-5,10-imine.
Examples 14-16 illustrate the alternative processes (d) and (e) for the preparation of 5,12-di-methyl-10,11-dihydro-5H-di~enzo[a,d]cyclohepten-5,10-imine.

Step A: Preparation of S-form~lamino-5H-dibenzoEa~dJ
uy~loheptene _ ~ . .. ~ _ ~- -- --- --A solution of 5H-dibenzo[a,d]cyclohepten-5-amine (~0.7 g, 0.1 mole) in ethyl formate ~200 ml) is heated under reflux for 10 hoursu The solvent is evaporzted.
The residue is distributed between lN aqueous hydro-chloric acid and ether. The ether solution is ~eparated, ~Jz~

washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated to yield S-formylamino-5H-dibenzo~a,d]cycloheptene.
Step B: Preparation of 5-isocyano-SH-dibenæo[a,d]
cycloheptene 5~Formylamino-5H-dibenzo[a,d]cycloheptene (18.8 g, 0.08 mole), triphenylphosphine (25 g, 0.095 mole), carbon tetrachloride (12.3 g, 0.08 mole), and triethylamine (8.1 g, 0.08 mole) are dissolved in chloro-form (80 ml) and heated at 60C for 2.5 hours The solvent is evaporated and the residue is extracted with five portions of hexane. The combined hexane extracts are concentrated and chromatographed on silica gel, eluting with toluene. The toluene eluate is evaporated to yield 5-isocyano-5H-dibenzo[a,d~cycloheptene.
Step C: Preparation of 5-isocyano-5-methyl-5H-dibenzo [a,d]cycloheptene Under nitrogen, 2M n-butyllithium in hexane (28 ml) and tetrahydrofuran (30 ml) are stirred and cooled to -70C. Diisopropylamine t5.65 g, 0.056 mole) is added dropwise followed, after 5 minutes, by a solution of 5-isocyano-5H-dibenzo[a~d]cycloheptene (10.85 g, 0.05 mole) in tetrahydrofuran ~100 ml~. After another 10 minutes, methyliodide (21.3 g, 0.15 mole) is added all at once. The mixture is stirred for 15 minutes at -7QC and then for 2 hours at room temperature. The mixture is quenched in ice water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated to yield 5-isocyano-5-methyl-5H-diben~o~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 mole) is slurried in ether (25 ml) and a solution of 5-isocyans-5-methyl-SH-dibenzo[a,d]cyclohepte~e (6.0 g, 0.026 ~L~2~850 - 40 - 1~028Y
mole) in ether (60 ml) is added dxopwise. The mixture is stirred at room temperature for 16 hours and then hydrolyzed by the successive dropwise addition o water (1 ml), 10% aqueous sodium hydroxide (1.5 ml) and water (3 ml). The supernatant ether solu~ion is separated by filtration and the filtrate is evaporated to yield 5,N-dime~hyl-5H-dibenzo[a,d]cyclohepten-5-amine.
Step E: Preparation of 5,12-dimethyl~ hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine .
A solution of 5,N-dimethyl-5H-dibenzo[a,d]
cyclohepten-5-amine (4.7 g, 0.02 mole) in lN aqueous hydrochloric acid (20 ml) and water (50 ml) is stirred at room temperature and bromine (3.2 g, 0.02 mole) is added dropwise. After 10 minutes, potassium carbona~e (5.5 ~, 0.04 mole) is added all at once followed by tetrahydrofuran (50 ml). The mixture is stirred at room temperature for 16 hours. The aqueous phase is separated and extracted with several portions of chloroform. The combined chloroform and tetrahydrofuxan 20 phases are extracted with lN aqueous hydrochloric acid.
The cooled acid extract is made basic with 20~ aqueous sodium hydroxide and the mixture is extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, filtered, and the 25 filtrate concentrated. The residue is chromatographed on silica gel, eluting with methanol-toluene (5:95).
The eluate is evaporated to yield 5,12-dimethyl-11-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine. 0 Step F: Preparation of 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzoEa,d~cyclohepten-5,10-imine 5,12-Dimethyl~ hydroxy-10,11 dihydro-5H-dibenzoEa,d]cyclohepten-5,10-imine (2.5 g), together with triethylamine (10 ml) and dimathylsulfoxide 35 (10 ml) is stirred at room temperature while sulfur 35~

trioxide trimethylamine complex (2.1 g) is added in por-tions. The mixture is stirred at room temperature for 48 hours and then quenched in ice water. The mi~ture is extracted with ether. The ether extract i5 washed with water, dried over sodium sulfate, filtered and the filtrate evaporated to yield 5,12-dimethyl-11-keto-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine.
Step G: Preparation of 5,12-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine 5,12-Dimethyl-ll-keto-10,11-dihydro-5H-dibenzo-[a,d~cyclohepten-5,10-imine (2.0 g) is slurried with 64~ hydrazine (0.8 ml) and ethylene glycol (20 ml).
The mixture is heated at 100C for 2 hours. Potassium hydroxide (1.5 g) is added and heating is continued at 165C for 3 hours. The mixture is poured into water (200 ml) and extracted with ether. The ether extract is washed with water, dried over sodium ~ulfate, filtered, and the filtrate concentrated. The residue is chromatographed on silica gel and eluted with methanol-toluene (10:90). The eluate is evaporated to yield5,12-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Employing substantially the same procedures described in Example 14, Steps A-G, but substituting for the methyliodide used in Step C, an equimolar amount of ethyl bromide or benzylchloride, there are produced respectively 5-ethyl-12-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine and 5-benzyl-12-me~hyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine.

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 35 methylene chloride (15 ml) are s~irred in an ice bath.

~2~8~i~

Phosgene ~1.5 g) is led into the solution. Water (50 ml) is added and the layers separated. The organic layer is washed with water (2 x 50 ml), dxied over sodium sulfate, filtered, and evaporated in ~acuo to give 5-isocyano-10,11-dihydro-5H-dibenzo[a,d~cyclo-heptene.
Step B: Preparation of 5-isocyano-5-methyl-10,11-dihydro~
5H-dibenzo[a,d]cycloheptene _ To n-butyllithium (15 ml o 2.2M in hexane) in dry tetrahydrofuran (91 ml) cooled in a dry ice/acetone bath and stirred under nitrogen is added dropwise a solution of diisopropylamine ~3~3 g) in tetrahydrofuran (15 ml). The mixture is stirred for 5 minutPs and treated with a solution of 5-isocyano-10,11-dihydro-5H-dibenzo[a,d3cycloheptene (6.8 g) in tetrahydro-furan (15 ml~ dropwise. The mixture is stirred in the cold bath for 10 minutes before iodomethane (8.7 g) in tetrahydrofuran (15 ml) is added rapidly.
The mixture is stirred in the cold bath for another 15 minutes, then allowed to warm up to room temperature.
After an additional 2 hours, the solution is treated with water (2 ml) and the bulk of the tetrahydrofuran removed in vacuo. Ether (100 ml) and water (50 ml) _ are added and the layer~ separated, the aqueous layer is extracted with ether (2 x 50 ml). The combined ether layers are washed with water (2 x 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. 0 Step C: Preparation of 5-methyl-5-methylamino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene , ~2~

_ 43 - ~6028Y
5-Isocyano-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cycloheptene ~3.3 g) in ether (120 ml) is added dropwise to lithium aluminum hydride (0.6 g) ~irred in ether (60 ml) under nitrogen. The mixture i~ heated at reflux for 4 hours, then cooled in ice. Ice water ~2 ml) is added dropwise and the mixture ~tirred for 15 minutes. The mi~ture is filtered and the ~olids washed with ether (2 x 50 ml), and the ether washings combined with the filtrate. The ether layer is washed with water (3 x 50 ml), dried over sodium sulfate, filtered, and evaporated ~o 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[a,d]cyclohepten-5,10-imine hydrochloride 5-Methyl-5-methylamino 10,11~dihydro-5H-dibenzo ~a,d]cycloheptene (6 g) is stirred in 30 ml of ether and cooled in ice. The mixture is treated with 30 ml of a lN aqueous solution of sodium hypochlorite added dropwise over 3-5 minutes. The mixture is stirred in the cold for 1/2 hour and separated. The aqueous layer is extracted with ether (2 x 30 ml) and the combined ether layers are washed with water ~2 x 30 ml), dried over sodium sulfate, filtered, and evaporated in vacuo to a residue containing the crude chloramine product.
The residue is treatad with cold 85% sulfuric acid (50 ml). The mixture is stirred under nitrogen ln a quartz flask and irradiated with a 125 watt G
sunlamp until the chloramine has been consumed. The mixture is added to 600 ml of stirred ice water, basified with 3N aqueous NaOH, and extracted with ether (3 x 100 ml)~ The ether layers are combined, washed with water (2 x 50 ml), dried over sodium sulfate, filtered, and evapora~ed in acuo. The residue in ethanol is treated with excess 8N ethanolic HCl .
~: .

:

35(~9 - 44 ~ 16028Y
and the solvent removed in vacuo. The residu~ is recrystallized from ethanol ~o give 5~12-dimethyl-10,11-dihydro-5H~dibenzo[a,d]cyclohepten-5,10~imine hydrochloride.
Employing substantially the same pr~cedures described in Example 15, Steps A-D, but substituting for the iodomethane used in Step B,an equimolar amount of ethyliodide,there is produced 5-ethyl-12-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

Step A: Preparation of 10-amino-5-methyl-10,11-dihydro-5Hodibenzo[a,d]cycloheptene 10-Hydroximino-5-methylene-10,11-dihydro-5H-dibenzo~a,d]cycloheptene ~10 g) and 10~ palladium/charcoal (O.2 g) are combined in absolute ethanol (100 ml) and shaken under an atmosphere of hydrogen (50 p.s.i.g).
After uptake of calcd. 0.12 mol, hydrogen absorption ceases. The solution is filtered and the filtra~e 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 10-Amino-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (5 g) is dissolved in a mixture of pyridine ~50 ml) and benzene (100 ml). Ethyl chloro-formate (32.4 g) is added dropwise to the stirred solu-tion, and the resulting mixture is warmed to 50 for 30 minutes. The mixture is cooled, quenched in ice water (500 ml), and separated. The aqueous phase - is extracted with benzene (2 x 100 ml), and the organic phase combined with the benzene extracts and washed with water (4 x 100 ml). The solution is dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue is dissolved in tetrahydrofuran 98S(~

~ 45 ~ 16028Y
(100 ml) and added dropwise to lithium aluminum hydride ~1.1 g) stirred in tetrahydrofuran (50 ml) under nitrogen.
The mixture is heated at reflux for 20 minute~, cooled, and the excess hydride decomposed by dropwise addition of ice water. The mixture is filtered and the ~olids extracted with tetrahydrofuran (2 x 20 ml). The combined organic layers are evaporated in vacuo and the residue dissolved in ether. The ether solution is washed witn water (2 x 50 ml), dried over Yodium sulfate, filtered, and evaporated to dryness in vacuo to give 15-methylamino-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Step C: Preparation of 5,12-dimethyl-lO,ll~dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine hydrochloride _ 10-Methylamino-5-methyl-10,11-dihydro-SH-dibenzo [a,d]cycloheptene (4.7 g) in methylene chloride (30 ml) is cooled to 5~ and treated with N-chlorosuccinimide (55 ml of a 0.4M solution in methylene chloride). After 30 minutes at 5C, the mixture is stirred at room temperature for an additional 1 hour and the solvent removed in vacuo. The residue i~ extracted with hexane (3 x 50 ml), and the combined extracts are filtered and evaporated to dryness in vacuo. The re~idue is dissolved in cold 85~ sulfuric acid (40 ml) in a quartz flask and the solution irradiated with a 125 watt G ~ sunlamp until the chloramine has been consumed.
The mixture is added carefully to stirred ice water (500 ml), made basic by careful addition of 3N sodium hydroxide and extracted with ether (3 x 100 ml). The combined ether layers are washed with water (2 x 100 ml), dried over sodium sulfate, filtered, and evaporated in vacuo. The residue is dissolved in absolute ethanol and treated with a slight exce~s o~

8N HCl in ethanol. ~he solvent is removed in vacuo and the residue recrystallized from ethanol to give 5,12-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepken-S,10-imine hydrochloride.
Examples 17-19 illustrate the previously de-scribed process (f~ to produce the compound (I) wherein R is -CH2OH.

12-Ethyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine Step A: Preparation of 5-ethoxycarbonylmethylene-5H-dibenzo~a,d]cycloheptene Triethylphosphonoacetate ~0.045 mole) is added dropwise to a slurry of sodium hydride (0.04 mole) in dry toluene (20 ml) at 30-35C under nitrogen. After stirring for 1 hour at room temperature, a solution of 5H-dibenzo[a,d]cyclohepten-5-one (0.033 mole) in dry toluene (75 ml) is added dropwise and stirring is con-tinued for 16 hours. The solution is decanted and the residue washed with toluene. The combined organic solutions are extracted with 0.5N aqueous hydrochloric acid, washed with water, and then dried over magnesium sulfa~e. It is filtered and the filtrate evaporated to yield 5-ethoxycarbonylmethylene-5H-dibenzo[a,d]cyclo~
heptene.
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 mole) in THF (~00 ml) was treated with ethylamine (0.012 mole) and stirred - for 24 hours. Evaporation of this solution gave 5-ethoxy-carbonylmethyl-5-ethylam~no-SH-dibenzo[a,d~cy~oheptene.
Step C: Preparation of 5-ethoxycarbonylmethyl-12-ethyl-.
ll-hydroxy-lQ,ll-dihydro 5H-dibenzo[a,d]cyclo-hepten-5,10-imine _ _ _ ~L~29850 - 47 ~ 16028Y
A solution of 5-ethoxycarbon~lmethyl S-ethyl-amino-5H-dibenzo[a,d]cycloheptene (0.02 mole) in lN
aqueous hydrochloric acid (20 ml) and water (50 ml) is stirred at room temperature and bxomine (0.02 mole) is added dropwise. ~fter 10 minutes, potassium carbonate (0.04 mole) is added all at once followed by tetrahydro-furan (50 ml). The mixture is stirred at room tempera-ture for 16 hours. The aqueous phase is separated and extracted with several portions of chloroform. The combined chlorofoxm and tetrahydrofuran phases are extracted with lN aqueous hydrochloric acid. The cooled acid extract is made basic with 20~ aqueous sodi~m hydroxide and the mixture is axtracted with chloroform. The chloroform extract is washed with water, 15 dried over sodium sulfate, filtered, and the filtrate concentrated. The residue is chromatographed on silica gel, eluting with methanol toluene (5:95). The eluate is evaporated to yield 5-ethoxycarbonylmethyl-12-ethyl-ll-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-20 5,10-imine.
Step D: Preparation of ll-bromo-5-methoxycarbonylmethyl-12-ethyl-10,11-dihydro-5H-dibenzo Ea, d]cyclo-hepten-5,10-imine _ _ A mixture of 5-ethoxycarbonylmethyl-12-ethyl-25 11-hydroxy-10,11-dihydro~5~I-dibenzo[a,d]cyclohepten-5,10-imine (0.01 mole) and phosphorous tribromide (1.0 ml~
in toluene (50 ml) is heated under reflux for 6 hours.
The solvent is evaporated, the residue stirred with 2% aqueous sodium hydroxide solution (~00 ml), and 30 extracted with ether. The ether extract is dried over sodium sulfate, filtered and the filtrate evaporated.
The residue is eluted from a silica-gel gel column with chloxoform to obtain ll-bromo-5-ethoxycarbonylmethyl-12-ethyl-10,11-dih~dro-5H-dibenzo[a,d~cyclohepten-5,10-35 imine.

so - 48 - 160~8Y
Step E: Preparation of 12-ethyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5 ! 10-imine A mix~ure of ll-bromo-5-ethoxycarbonylmethyl-12-ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten~5,10-imine (0.01 mole) and lithium aluminum hydride (0.011 mole) in ether (300 ml) is stirred and heated under reflux for 6 hours. Water (3.5 ml) is added dropwise with stirring and the slurry is filtered. Evaporation of the filtrate gives 12-ethyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

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~cyclo-hepten-5,10-imine _ Following substantially the same procedure of Example 17, Step B, 5-ethoxycarbonylmethylene-10,11-dihydro-5H-dibenzo~a,d]cyclohepten-10-one is treated with anhydrous benzylamine l0.012 mol) to yield 12-benzyl-5-ethoxycarbonyl-methyl-10-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine.
Step B: Preparation of 12-benzyl-10-bromo-5-ethoxycarbonyl-methyl-10,11-dihydro-5H-diben~o[a,d}cyclohepten-5,10-imine _ _ A mixture of 12-benzyl-5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (0.01 mole) and phosphorous tribromide (1~0 ml) in toluene (50 ml) is heated under reflux for 6 hours. The solvent is evaporated, the residue ~tirred - with 2~ aqueous sodium hydroxide solution (200 ml), and extracted with ether. The ether extract is dried over sodium sulfate, filtered and the filtrate evaporated. The residue i5 eluted from a silica-gel column with chloroform to obtain 12-benzyl 10-bromo-5 ethoxycarbonylmethyl-10,11-~2~S~

dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Step C: Preparation of 12-benæyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo Ea, d]cyclohepten-5,1Q-imine In substantially the same mannar as described in Example 17, Step E, 12-benzyl-10-bromo-5-ethoxycarbonyl-methyl-10,11-dihydro-5H-dibenzola,d]cycloheptPn-5,10-imine (0.01 mole) is reduced to give 12-henzyl-5-(2-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

5-(2-Hydroxyethyl)-12-methyl-10,11-dihyaro-5H-dibenzo [a,dlcyclohepten-5,10-imine Step A: ~reparation of 5-ethoxycarbonylmethylene-10,11-lS dihydro-5H-dibenzo[a,d]cycloheptene Employing substantially the same proc~dure described in Example 17, Step A, but substituting for the starting material used therein an equimolar amount of 10,11-dihydro-5H-dibenzo[a,d~cyclohepten-5-one, there is produced 5-ethoxycarbonylmethylene-10,11-dihydro~5H-dibenzo[a,d]cycloheptene.
Step B: Preparation of S-ethoxycarbonylmethyl-5-methyl-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene Following substantially the same procedure of Example 17, Step B, S-ethoxycarbonylmethylene-10,11-dihydro-SH-dibenzo[a,d]cycloheptene is treated with anhydrous methylamine to afford 5-ethoxycarbonylmethyl-5-methyl-amino-10,11-dihydro-5H-dibenzo[a,d]~ycloheptene.
tep C: Preparation of 5-ethoxycarbonylmethyl-12-methyl 10,11-d hydro-5H-dibenzo[a,d]cyclohepten~5,10-imine 5-Ethoxycarbonylmethyl-5-methylamino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is converted to S-ethoxycarbonylmethyl-12-methyl-10,11-dihydro-5H-dibenzo . ~a,d]cyclohepten-5,1Q-imine in essentially the same manner as described in ~xample 16, Step C.

~2g~5~

Step D: Preparation of 5-(2-hydroxyethyl)-12~methyl-10,11-dihydro-5H-dibenzo~a,d]cyclohepten-5,10-imine Employing substantially the same procedure as described in Example 17, Step E, 5-ethoxycar~onylmethyl-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.

Examples 20-21 illustrate N-alkylation to pro- 0 duce the compound (I) wherein R is other than hydrogen.
ExAMæLE 20 12-Ben7yl-5-methyl-10,11-dihydro-5H-diben2O[a,d]cyclo-hepten-5,10-imine To a solution of 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (2.35 g) and benz-aldehyde (1.1 g) in THF (100 ml) is added acetic acid (1 ml) and sodium cyanoborohydride (1.0 g). The mixture is stirred for two days, filtered and the filtrate evaporated. The residue is slurried with lN aqueous NH40H and extracted with HCC13. The chloroform extract is dried over sodium sulfate, filtered and evaporated.
The residue is recrystallized from ethanol to yield 12-benzyl-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine.

12-Ethyl-5~methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine An ice cold solution of 5-methyl 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (2035 g) and tri-ethylamine (2.D g) in ether (100 ml) is treated dropwise with acetyl chloride (1.5 g). Af~er 10 hours, the solu-tion is washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated to dryness~ The residue is redissolved in ether ~200 ml) and 400 mg of LiAlH4added. ~he resulting slurry is stirred for 24 hour~.

985~

Water is added slowly and the resul~ing slurry filtered.
The filtrate is dried over sodium sulfate, filtered and the filtrate evaporated to yield 12-ethyl-5~methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

Claims (13)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the structural formula:

and the isomers thereof wherein R is hydrogen, lower alkyl or phenyl-lower alkyl;
R1 is hydrogen or lower alkyl;
-CH2R2 is lower alkyl;
R3 and R4 are hydrogen, which comprises (a) reducing a compound of the formula:

to produce the compound where R is hydrogen;
(b) treating a compound of the formula:

with a strong base;
(c) reducing a compound of the formula:

to provide a compound where R is hydrogen;
(d) hydrolyzing a compound of the formula:

to provide a compound where R is hydrogen;
(e) reducing a compound of the formula wherein X and Y are independently hydrogen or chlorine, R is hydrogen, lower alkyl or phenyl-lower alkyl, and when R is hydrogen submitting same to N-alkylation when compounds where R is other than hydrogen are desired;
(f) reducing a compound of the formula:

and when R is hydrogen submitting same to N-alkyl-ation when compounds where R is other than hydrogen are desired;
(g) photocyclizing a compound of the formula:

wherein R.beta. is hydrogen or lower alkyl and R is to be phenyl-lower alkyl submitting the compound obtained where R is hydrogen to N-alkylation;

(h) and when R is to be other than hydrogen: sub-mitting the compound obtained in steps (a), (b), (c), (d) to N-alkylation; and finally when the respective isomers are desired sub-mitting the racemic compound obtained to reaction with an optically active acid followed by fractional re-crystallization and regeneration of the free base.

2. Process for the preparation of the 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine which comprises reducing 12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine and recovering the desired product.

3. Process for the preparation of 10,11-dihydro-5,12-dimethyl-5H-dibenzo[a,d]cyclohepten-5,10-imine which comprises hydrolyzing the 10,11-dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine and recovering the desired product.

4. The process of Claim 2, wherein the compound obtained is reacted with a benzyl halide to form the 12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo-[a,d]cyclohepten-5,10-imine and recovering the desired product.

5. The process for preparing 5,10,12-tri-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine which comprises treating the 10-methyl-10-methyl-amino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten with a strong base and recovering the desixed product.

6. The process for preparing 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine which comprises reducing the 10-chloro-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine and recovering the desired product.

7. The process for preparing the 5,12-dimethyl-10,11-dihydro-5H-aibenzo[a,d]cyclohepten-5,10-imine which comprises reducing the 5,12-dimethyl-11-keto-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

8. Compound of the structural formula:

and the isomers thereof wherein R is hydrogen, lower alkyl or phenyl-lower alkyl, R1 is hydrogen or lower alkyl;
-CH2R2 is lower alkyl; and R3 and R4 are hydrogen, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

9. The 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine, when prepared by the process defined in Claims 2 and 6 or by an obvious chemical equivalent.

10. The 10,11-dihydro-5,12-dimethyl-5H-dibenzo-[a,d]cyclohepten-5,10-imine, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

11. The 12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

12. The 5,10,12-trimethyl-10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, when prepared by the process deflned in Claim 5 or by an obvious chemical equivalent.

13. The 5,12-dimethyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.