3,576,853 United States Patent Office Patented Apr. 27, 1971 2 Both organic and inorganic acids can be employed to form 3,576,853 CYCLOPROPANECARBOXYLIC ACID DERVA such salts, illustrative acids being sulfuric, nitric, phos TIVES OF 5H-DIBENZOadICYCLOHEPTENES phoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, Carl Kaiser, Haddon Heights, N.J., and Charles L. Zirkle, ethanedisulfonic sulfamic, succinic, cyclohexylsulfamic, Berwyn, Pa., assignors to Smith Kline & French Lab fumaric, maleic, benzoic and the like. These salts are readi oratories, Philadelphia, Pa. ly prepared by methods known to the art. No Drawing. Original application June 3, 1965, Ser. No. The compounds of this invention may be present as 461,176, now Patent No. 3,449,427, dated June 10, cis-trans isomers due to the geometrical arrangement of 1969. Divided and this application Dec. 27, 1968, Ser. the dibenzocycloheptene substituent and the carboxylic No. 787,562 O acid or amide moiety with respect to the cyclopropane int, C, CO7e 63/44 ring and further as d,l optical isomers. Unless otherwise U.S. C. 260-55 5 Claims specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mix ABSTRACT OF THE DISCLOSURE tures thereof. 5 The aminocyclopropane derivatives of 5H-dibenzoad Cyclopropanecarboxylic acid and amide derivatives of cycloheptenes are prepared by several methods, the choice 5H-dibenzoadcycloheptenes wherein the tricyclic nu of which depending on the definitions of m, n, R1 and R2 cleus may be substituted by chlorine, bromine, trifluoro The starting materials for these methods are generally 5H methyl, methyl, methoxy or methylthio, as well as 10, 11 dibenzoadcycloheptenes having the formula: dihydro derivatives, and the amides are N-mono or N,N- disubstituted lower alkyl or include a cyclic amido moiety, 20 are useful as intermediates for the preparation of corre sponding aminocyclopropane derivatives. The latter have antidepressant, tranquilizing and anorectic activity. The acids and amides are generally prepared from appropriate 25 5H-dibenzo(a,d)cycloheptenes by alkylation with a bromo H. E. cyclopropanecarboxylate or a bromocyclopropane carbox FORMUL.A. amide, respectively. Also useful in the preparation of the acids are 5-vinyl-5H-dibenzo(a,d)cycloheptenes. in which Y and R are as defined in Formula I. These 3) compounds are prepared by reduction of the correspond ing 5H-dibenzoa,d)cyclohepten-5-ones with, for example, This application is a division of application Ser. No. sodium in a lower alkanol, preferably, ethanol or by the 461,176 filed June 3, 1965, now U.S. Pat. No. 3,449,427. Wolff-Kishner method. This invention relates to novel cyclopropanecarboxylic In one method of preparation of the aminocyclopro acid and amide derivatives of 5H-dibenzoa,dcyclohep 35 panes from the dibenzocycloheptenes of Formula II, the tenes useful as intermediates for the preparation of corre dibenzocycloheptene is alkylated with, for example, ethyl sponding aminocyclopropane derivatives. The latter have 2-bromo- or 2-bromoethyl- cyclopropanecarboxylate fol useful pharmacodynamic activity. More specifically, the lowed by hydrolysis to give the corresponding cyclopro aminocyclopropane products have central nervous system panecarboxylic acids of this invention having the formula: activity such as antidepressant, tranquilizing and anorectic 40 activity. The aminocyclopropane derivatives may be represented by the following general structural formula: E. (OH)-citch-coff, OOE FORMUL.A. It 50 in which Y and R are as defined in Formula I and n is 0 or 1. The useful compounds of Formula III are converted to amino compounds by several routes. Reaction of the acid with a lower alkyl haloformate gives the correspond ing cyclopropyl mixed anhydride which is then treated with sodium azide to give the cyclopropyl azide. The acid in which: azide is then thermally decompostd by heating in an inert organic solvent to give the corresponding isocyanate. Y represents CHCH or CH-CH, preferably CHCH; The resulting isocyanate is converted to aminocyclopro R represents hydrogen, chlorine, bromine, trifluoromethyl, panes of Formula I where n is 0 by: (a) hydrolysis with methyl, methoxy or methylthio, preferably in the 3-posi 60 a mineral acid such as hydrochloric acid or an alkali tion of the dibenzocycloheptene ring; metal hydroxide such as sodium or potassium hydroxide m and in each represent an integer from 0 to 1; and at elevated temperatures to give the primary aminocyclo R1 and Reach represent hydrogen, lower alkyl of from propane or (b) reaction with a lower alkyl magnesium 1 to 3 carbon atoms or when taken together with the halide or lower alkanol to give an N-lower acyl or N nitrogen atom to which they are attached, represent a 65 lower carbalkoxy aminocyclopropane, respectively, which pyrrolidine, piperidine, N'-methylpiperazine, N'-(3-hy is either reduced directly with, for example, lithium alumi droxyethyl)-piperazine or N'-(6-acetoxyethyl)-piperaz num hydride to give an N-lower aminocyclopropane or ine ring. further reacted with a lower alkyl iodide to give an N Preferred compounds are represented by the above lower alkyl-N-lower acyl or N-lower alkyl-N-lower car Formula I when m is 0 and n is 1. 70 balkoxy aminocyclopropane, respectively, which is reduced The nontoxic pharmaceutically acceptable acid addition with, for example, lithium aluminum hydride to give an salts of the compounds of Formula I are similarly useful. N,N-dialkylaminocyclopropane. 3,576,853 3 4 These reactions may be summarized as follows where Y Alternatively, the aminocyclopropanes of Formula I and R are as defined in Formula I, m is 0 or 1 and R1 and where n is 1 are prepared from the cyclopropanecarbox R2 are lower alkyl: ylic acids of Formula III by reacting the acid with a /Y\ OOC hydrolysiydrolysis R H (CH)n-CH-CHCOOH H^ N / H?cH)-CH-CHNH,N/ C. cá. CE CH NR.M.XY.

-COC:H. (CEI)-CH-CHNCOOR H CH-CH-CHNOOR, N1 H CH. H.

/

R N/ H?ich) -c chNCOR, CE)-cy to HNCoor, cá, R2 Ir?ch)-c CH2CHNCHR, EI

N/ H^CE) n- c to HN Cl3 H^ CH2)n- Q M C H-NC HaRi off, R2 CB R To prepare the aminocyclopropanes of Formula I where lower alkyl haloformate to give the corresponding cyclo m is 0 and n is 1, a dibenzocycloheptene of Formula II is propyl mixed anhydride which is then treated with am advantageously alkylated with a 2-bromocyclopropanecar monia, a monoalkyl amine, a dialkylamine or a hetero boxamide to form the carboxamide derivatives of this cyclic amine to give the cyclopropanecarboxamides of this 45 invention. Reduction of the amides with, for example, invention which are reduced with, for example, lithium lithium aluminum hydride gives the corresponding aluminum hydride to give the corresponding aminometh aminomethylcyclopropanes. ylcyclopropanes as follows: The aminocyclopropanes represented by Formula I 2Y R. above where m and n are 1 are prepared by alkylation of the dibenzocycloheptenes of Formula II with an active R -- Br-c CH-C ON warm 3 ester derivative of aminocyclopropyl carbinols, for cí, R2 example, a p-toluenesulfonate derivative. These useful /N H carbinol intermediates having the formula: Y. Ri 55 R unmi Y-CH-CH-CH-CH or R? Yo?, R. FORMULA IV E. ce CH-C oN in which R1 and R2 are lower alkyl or when taken together CH2 R 60 with the nitrogen atom to which they are attached, repre /Y\ sent a pyrrolidine, piperidine or N'-methylpiperazine ring are prepared by reaction of, for example, ethyl y-bromo R Crotonate with an appropriate dialkylamine or heterocyclic amine to give the corresponding aminocrotonate which is X IR 65 then reacted with a reagent formed from trimethylsul H ce CH-CHN foxonium iodide. The latter in the presence of a strong CH2 R2 base such as sodium hydride forms a reactive substance in which Y and R are as defined in Formula I, R is called dimethylsulfoxonium methylide, hydrogen or lower alkyl, and R2 is lower alkyl or when R1 and R2 are taken together with the nitrogen atom to 70 (CEIs): =CH which they are attached, represent a pyrrollidine, piperi O dine or N'-methylpiperazine ring. The 2-bromocyclopro which produced the ethyl aminocyclopropylcarboxylate. panecarboxamides are readily prepared from the corre Similar reduction of the carboxylate with, for example, sponding carboxylic esters by hydrolysis, conversion to the lithium aluminum hydride gives the aminocyclopropyl car acid chloride, and treatment with a secondary amine. 75 binols of Formula IV where n is 1. 3,576,853 5 6 The aminocyclopropyl carbinols of Formula IV above tion mixture is added dropwise 1.6 ml. of water foll are advantageously employed in the dibenzocycloheptene lowed by 1.6 ml. of 10% aqueous sodium hydroxide alkylation as the tosylates. Thus, reaction of the amino and an additional 4.8 ml, of water. The resulting mix methylcyclopropyl carbonol tosylate with the appropriate ture is filtered and the filtrate extracted with aqueous dibenzocycloheptene gives the desired product. acetic acid. The acid extract is made alkaline with dilute The compounds of Formula I above where R1 and R2 sodium hydroxide solution and the mixture extracted together represent a heterocyclic amino moiety are pre with ether. The dried ether extract is concentrated to give pared also from the corresponding primary amines. The trans - 5 - 2-(N,N-dimethylaminomethyl)cyclopropyl)- pyrrolidinyl and piperidinyl derivatives are prepared from 10,11-dihydro-5H-dibenzo(a,dcycloheptene. the primary amine and 1,4-dibromobutane and 1,5-dibro Similarly, by employing in the above reaction se mopentane, respectively, in an organic solvent refluxing O quence 4.2 g. of 3-methyl-10,11-dihydro-5H-dibenzo at a temperature from 100-150° C. and in the presence of (a,d)cycloheptene (prepared by sodium and ethanol re potassium carbonate. Similar reaction of the primary duction of the corresponding 5-one) there is obtained amine with methyl bis-(3-chloroethyl)-amine gives the as the final product trans-3-methyl-5-2-N,N-dimethyl N'-methylpiperazinyl derivative. 5 aminomethyl)-cyclopropyl - 10,11-dihydro-5H-dibenzo In the above described preparation methods, when the (a,d)cycloheptene. first step of the reaction sequence consists of alkylation of a dibenzocycloheptene with an ethyl 2-bromomethyl EXAMPLE 2. cyclopropanecarboxylate or a carbinol intermediate of To a stirred mixture of 115 g. of 3-chloro-10,11-di Formula IV, both the cis and trans products are ob 20 hydro-5H-dibenzoa,d] cycloheptene (prepared by sodium tained depending on the stereochemistry of the alkylat and ethanol reduction of the corresponding 5-one) in ing agent. However, when an ethyl 2-bromocyclopropane 500 ml. of dry toluene is added, under nitrogen, 21.5 carboxylate or a 2-bromocyclopropanecarboxamide is em g. of sodium amide. The mixture is stirred and refluxed ployed, the more stable trans products are obtained. for two hours, the heat is removed and a solution of To prepare the cis as well as trans aminocyclopropane 25 dimethylaminoethyl chloride in toluene is added drop derivatives of dibenzocycloheptene of Formula I in which wise. The latter is prepared by dissolving 144 g. of di m is 0 and n is 0 or 1, and Y-CH2CH2, an appropri methylaminoethyl chloride hydrochloride in a minimum ate 5-vinyldibenzocyclopheptene is reacted with ethyl di volume of water, adding with cooling excess 40% so azoacetate to give a mixture of cis- and trans-dibenzocy dium hydroxide solution, saturating the mixture with cloheptenyl cyclopropanecarboxylates. This mixture is 30 sodium carbonate and extracting with toluene. selectively hydrolyzed with alkali to give the trans-acid The reaction mixture is stirred and refluxed for two and unhydrolyzed cis-ester. Subsequent hydrolysis of the hours, cooled and then treated with 25 ml. of ethanol cis-ester with excess alkali affords the cis-acid. Both iso followed by 250 ml. of water, the latter added slowly. meric acids are thus available for further reaction as The separated organic layer is dried and concentrated in described hereinabove. The 5-vinyldibenzocycloheptenes 35 vacuo. The residue is distilled to give 3-chloro-5-(2-di are conveniently prepared via Hofmann degradation of methylaminoethyl)-10,11-dihydro - 5H - dibenzoadcy corresponding 5-dimethylaminoethyl-5H-dibenzo(a,dlcy cloheptene. cloheptene methiodides. To a stirred solution of 125 g. of the above dibenzo The aminocyclopropane products may be administered cycloheptene in 1.2 . of acetone is added dropwise a orally or parenterally in conventional dosage forms such 40 solution of 71 g, of methyl iodide in 200 ml of ace as tablets, capsules, injectables or the like, by incorporat tone. The reaction mixture is stirred at room tempera ing the appropriate dose of a compound of Formula I ture for one hour and then filtered to give the correspond with carriers according to accepted pharmaceutical prac ing methiodide. tices. A suspension of anion exchange resin (hydroxide form) The foregoing is a general description of the main 45 is washed several times with methanol, then suspended synthetic routes for the preparation of the compounds in 500 ml. of methanol and 73.5 g. of the above dibenzo of this invention and their use in the preparation of the cycloheptene methiodide suspended in 150 ml. of meth aminocyclopropane products. It will be readily appar anol is added. The mixture is stirred at room temperature ent to one skilled in the art that variations of these pro for one hour, filtered and the resin cake is washed with cedures are possible. The following examples illustrate 50 methanol. The filtrates are concentrated in vacuo and the these procedures but should not be construed as lim residue (the corresponding dibenzocycloheptene methyl iting the invention to the specific compounds prepared hydroxide) is heated on a steam bath in vacuo until gas thereby. Where the examples specify reaction of a trans evolution is complete. The residue is taken up into ether compound, the corresponding cis isomer can of course and the solvent removed in vacuo to give 3-chloro-5-vinyl be similarly employed. 10,11-dihydro-5H-dibenzoa,d)cycloheptene. To a refluxing mixture of 2 g. of anhydrous cupric EXAMPLE 1. sulfate powder and 100 ml. of dry benzene is added, To a stirred solution of 4.0 g. of 10,11-dihydro-5H dropwise with stirring, a solution of 47.0 g. of the above dibenzo(a,d)cycloheptene (prepared by sodium and eth 5-vinyl dibenzocycloheptene and 27.4 g. of ethyl diazo anol reduction of the corresponding 5-one (in 50 ml. of 60 acetate in 150 ml. of dry benzene. After addition is com dimethylsulfoxide is added, in portions, 0.95 g. of 52% plete, the mixture is refluxed for 30 minutes, filtered and dispersion of sodium hydride in mineral oil. The mixture the filtrate concentrated in vacuo to give the residual 3 is heated at 60-70° C. for 20 minutes, then cooled to chloro - 5-(2-carbethoxycyclopropyl)-10, 11 - dihydro-5H 20° C. and a solution of 4.0 g. of 2-bromo-N,N-dimeth dibenzoa,d)cycloheptene. ylcyclopropanecarboxamide in 20 ml. of dimethylsulfox 65 To a stirred solution of the above carbethoxycyclo ide is added dropwise. The resulting mixture is heated propyl derivative (34.1 g., 0.1 mole) in 200 ml. of at 100° C. for one hour, cooled, diluted with 500 ml. of ethanol at 0 is added a solution of 3.9 g (0.07 mole) ice-water and extracted with ether. The extract is dried of potassium hydroxide in 20 ml. of water. The mixture and concentrated to give trans-5-[2-(N,N-dimethylcar is stirred at room temperature for 1 hr. then it is re boxamido) - cyclopropyl)-10,11-dihydro-5H-dibenzo(a,d) 70 fluxed for two hours and concentrated in vacuo. The cycloheptene. residue is diluted with water and extracted with ether. A solution of this amide in 50 ml. of dry ether is added This ether solution contains the cis-ester. The aqueous dropwise to a stirred suspension of 1.6 g. of lithium layer is acidified with acetic acid (pH 6) and extracted aluminum hydride in 150 ml. of ether. The mixture is with ether. The ether extract is dried and concentrated in stirred and refluxed for four hours. To the cooled reac 75 vacuo to give, after crystallization from ethyl acetate 3,576,853 7 8 hexane, trans - 3-chloro-5-(2-carboxycyclopropyl)-10, 11 ethyl acetate-petroleum ether to give trans-3-trifluoro dihydro-5H-dibenzo(a,d) cycloheptene. methyl - 5-(2-carboxycyclopropyl)-10,11-dihydro-5H-di The above ether solution of cis-ester is dried and con benzoadcycloheptene. centrated. The residual oily ester is hydrolyzed with ex To a mixture of 3.9 g, of the above trans carboxycyclo cess aqueous-ethanolic potassium hydroxide in an analo propyl derivative and 3 ml. of triethylamine, cooled to gous manner to give cis - 3 - chloro-5-(2-carboxycyclo 0° C., is added 2 ml. of ethyl chloroformate in acetone. propyl)-10,11-dihydro-5H-dibenzoadcycloheptene. The mixture is stirred for 15 minutes and then 4.4 g. of To a solution of 6.2 g. of the above trans carboxy N-(6-hydroxyethyl)piperazine in acetone is added with cyclopropyl derivative in 60 ml. of acetone, cooled to 0 cooling. After stirring for three hours at room tempera C. is added 4.7 ml. of triethylamine in acetone and 3.2 O ture, the reaction mixture is poured into cold water and ml. of ethyl chloroformate. The mixture is stirred for 15 extracted with ether. The dried extract is evaporated to minutes and then a solution of 2.6 g. of sodium azide in give trans - 3 - trifluoromethyl-5-(2-N-((3-hydroxyethyl)- water is added. After stirring for 30 minutes, the reaction N'-piperazinoyl-cyclopropyl - 10, 11 - dihydro-5H-di mixture is poured into ice-water and extracted with benzoa,dcycloheptene. toluene. The dried extract is heated on the steam bath 5 To a suspension of 1.0 g. of lithium aluminum hydride to decompose the acid azide. Removal of the solvent in ether is added a suspension of 3.9 g, of the above gives the residual trans-cyclopropyl isocyanate derivative. piperazinyl derivative in ether and the mixture stirred and To a stirred mixture of 50 ml. of 3 M methyl magnesium refluxed for eight hours. After standing overnight at room bromide in ether is added 7.1 g. of the above isocyanate temperature, the reaction mixture is decomposed, filtered in ether. The mixture is refluxed for two hours, cooled 20 and the filtrate acidified with ethanol-ethereal hydrogen and 200 ml. of 10% hydrochloric acid solution is added chloride. Addition of excess ether precipitates the solid slowly. The separated aqueous layer is extracted with trans - 3 - trifluoromethyl-5-2-N-(3-hydroxyethyl)-N'- ether. Concentration of the organic solutions gives the piperazinylmethyl) - cyclopropyl) - 10,11-dihydro-5H-di trans-3-chloro-5-[2-(N-acetylamino) - cyclopropyl)-10, benzo(a,d)cycloheptene hydrochloride. Acetylation with 11-dihydro-5H-dibenzo(a,d)cycloheptene. 25 acetyl chloride yields the corresponding 6-acetoxyethyl To a solution of 7.4 g. of the above N-acetyl-amino derivative. cyclopropyl derivative in 70 ml. of tetrahydrofuran is EXAMPLE 4 added 1.0 g. of 53.5% sodium hydride and the mixture is A solution of 9.8 g. of trans-3-trifluoromethyl-5-(2-car stirred and refluxed for one hour. A solution of 8 ml. of boxycyclopropyl) - 10,11-dihydro-5H-dibenzo(a,d) cyclo ethyl iodide in 25 ml. of tetrahydrofuran is added to the 30 heptene (prepared as in Example 3) in acetone is treated cooled reaction mixture which is then refluxed for four with 7 ml. of triethylamine in acetone. The resulting mix hours. An additional 8 ml. of ethyl iodide in 10 ml. of ture is cooled to 0 C. and 5 ml. of ethyl chloroformate tetrahydrofuran is added and refluxing continued for 12 in acetone is added. After stirring for 20 minutes, a solu hours. The reaction mixture is filtered and the filtrate tion of 7.1 g of dimethylamine in acetone is added and concentrated in vacuo. The residue is taken up in water 35 stirring continued for 30 minutes with cooling and then and ether, extracted with ether and the dried solvent re for two hours at room temperature. The reaction mix moved to give trans - 3 - chloro-5-2-(N-acetyl-N-ethyl ture is poured into ice-water, extracted with methylene amino)-cyclopropyl) - 10, 11 - dihydro-5H-dibenzo(a,d) chloride and the dried extract evaporated. The residue is cycloheptene. taken up in ether, extracted with 10% sodium hydroxide A solution of the above N-acetyl-N-ethylaminocyclo 40 solution and the dried ether solution evaporated to give propyl derivative (7.9 g.) in ether is added to a suspen the solid trans-3-trifluoromethyl-5-[2-(N,N-dimethylcar sion of 5.0 g. of lithium aluminum hydride in ether and boxamido) - cyclopropyl) - 10, 11 - dihydro-5H- dibenzo the mixture stirred and refluxed for six hours. Decom (a,d)cycloheptene. position of the metal complex yields an oil which is To 2.5 g. of lithium aluminum hydride in ether is added treated in acetone solution with ethereal hydrogen chlo 45 a Solution of 9.8 g. of the above carboxamido derivative ride to give trans - 3 - chloro-5-2-(N,N-diethylamino)- in ether and the mixture is stirred and refluxed for eight cyclopropyl) - 10, 11 - dihydro - 5H-dibenzoadcyclo hours. After standing at room temperature overnight, the heptene hydrochloride. reaction mixture is decomposed, filtered and the filtrate Direct hydrolysis of the above trans-cyclopropyl iso evaporated. The residue is taken up in ethanol and treated cyanate derivative in concentrated hydrochloric acid at 50 with ethereal hydrogen chloride. Addition of excess ether reflux for 12 hours yields upon workup trans-3-chloro-5- precipitates the solid trans-3-trifluoromethyl-5-2-(N,N- (2-aminocyclopropyl)-10,11-dihydro - 5H - dibenzo(a,d) dimethylaminomethyl) - cyclopropyl-10,11-dihydro-5H cycloheptene. dibenzo(a,d] cycloheptene hydrochloride. EXAMPLE 3 Similarly, by employing 11 g. of pyrrolidine instead of To a solution of 6.6 g. of 3-trifluoromethyl-10,11-dihy dimethylamine in the above reaction sequence with sub dro-5H - dibenzoa,d] cycloheptene (prepared by sodium sequent reduction by 2.5 g. of lithium aluminum hydride and ethanol reduction of the corresponding 5-one) in 20 there is obtained trans-3-trifluoromethyl-5-[2-(N-pyrro ml. of dimethylsulfoxide is added in portions 1.2 g of lidinylmethyl) - cyclopropyl) - 10,11-dihydro-5H-dibenzo a 53.5% suspension of sodium hydride in mineral oil, Ia,d) cycloheptene. maintaining the temperature below 40° C. A solution of 60 4.8 g. of ethyl 2-bromocyclopropanecarboxylate in 10 ml. EXAMPLE 5 of dimethylsulfoxide is added dropwise and the mixture is To a stirred solution of 49.6 g. of piperidine in 170 heated on the steam bath for one hour. The reaction mix ml. of dry benzene is added dropwise during ten minutes, ture is poured onto ice/water mixture and extracted with 56.1 g. of ethyl 4-bromocrotonate. The mixture is stirred ether. The dried extract is concentrated to give 3-trifluoro 65 and refluxed for one hour, cooled and filtered. After wash methyl-5-(2-carbethoxycyclopropyl)-10, 11 - dihydro - 5H ing the filter cake with ether, the combined organic fil dibenzoa,d] cycloheptene. trates are washed with water, dried and concentrated to A mixture of 8.6 g. of the above carbethoxycyclopropyl give ethyl 4-(N-piperidinyl)-crotonate, B.P. 95-99 C./ derivative in 100 ml. of ethanol and 2.6 g. of potassium 0.4 mm. hydroxide in water is stirred and refluxed for two hours. 70 To a stirred suspension of 102.5 g. of trimethylsul The alcohol is replaced by water using a trap and the foxonium iodide in 500 ml. of dimethylsulfoxide is added filtered aqueous solution is extracted with ether. Acidifica in portions, maintaining the temperature below 35° C., tion with concentrated hydrochloric acid gives a solid 13.0 g. of sodium hydride (53.5% suspension in mineral which is taken up in ethyl acetate. This solution is dried oil). After hydrogen evolution is completed, 31.6 g. ethyl and evaporated to give an oil which is crystallized from 4-(N-piperidinyl)-crotonate is added dropwise at 25 C. 3,576,853 10 The mixture is stirred at 25 C. for one hour, at 60° C. adcycloheptene in 250 ml. of dry toluene is added 4.6 for two hours, then poured into 2 I. of ice-water, and g. of sodium hydride (53.5% dispersion in mineral oil). extracted with ether. The ether solution is extracted with The mixture is stirred and refluxed for one hour, then it 5% hydrochloric acid solution and the acid extract made is cooled to 25 and a solution of 20.7 g. of ethyl trans alkaline with sodium hydroxide solution. This mixture is 2-bromomethylcyclopropane-carboxylate in 50 ml. of extracted with ether, the extract dried and concentrated toluene is added dropwise. The mixture is stirred and in vacuo to give ethyl trans-2-(N-piperidinylmethyl)-cy refluxed for 8 hours, cooled and diluted with water. Con clopropanecarboxylate, B.P. 112-114.5 C./3.5 mm. centration of the dried toluene solution affords trans-5- A solution of 21.1 g. of the above carboxylate in 100 (2-carbethoxycyclopropylmethyl) - 10, 11 - dihydro - 5H mi. of ether is added dropwise to a stirred suspension of O dibenzoa,dicycloheptene. 3.8 g. of lithium aluminum hydride in 300 ml. of dry To a solution of the above ester (16.9 g.) in 200 ml. ether and the mixture is refluxed for 30 minutes. Then is of ethanol is added a solution of 5.6 g. of potassium added successively, 4 ml. of water, 4 ml. of 10% aqueous hydroxide in 10 ml. of water. The solution is heated under sodium hydroxide and 12 ml. of water. The mixture is reflux for two hours, concentrated and diluted with Water. filtered and the filter cake is washed thoroughly with 15 After extraction of the mixture with ether the aqueous methylene chloride. The combined organic filtrates are solution is acidified to give trans-5-(2-carboxycyclopropyl dried and concentrated to give 2-hydroxymethyl-1-(N- methyl) - 10, 11 - dihydro - 5H-dibenzoadcycloheptene. piperidinylmethyl)-cyclopropane. To a solution of 5.9 g, of the above carboxycyclopropyl To a suspension of 4.5 g. of sodium hydride (53.5% derivative in 60 ml. of acetone at 0° C. is added 4.7 mi. suspension in mineral oil) in 100 ml. of dry tetrahydro 20 of triethylamine in acetone and then 3.2 ml. of ethyl furan is added dropwise 16.9 g, of the above cyclopropane chloroformate. The mixture is stirred for 15 minutes and in 30 ml. of tetrahydrofuran. The mixture is stirred at then a solution of 2.6 g. of sodium azide in water is added. 25° C. The reaction mixture is filtered to give a solution After stirring for 30 minutes, the reaction mixture is of 2 - hydroxymethyl-1-(N-piperidinylmethyl)-cyclopro poured into ice-water and extracted with toluene. The pane, p-toluenesulfonate in tetrahydrofuran which may 25 dried extract is cautiously heated on the steam bath. After be used directly in the following alkylation step or iso nitrogen evolution is completed the Solution is concen lated as a p-toluenesulfonate salt by treatment of the trated in vacuo to give the trans-cyclopropyl isocyanate tetrahydrofuran solution with p-toluene sulfonic acid, con derivative. centration and recrystallization of the residue. The above isocyanate is diluted with 50 ml. of ethanol, A solution of 19.2 g of 5H-dibenzoadcycloheptene 30 the solution is refluxed for two hours and concentrated in in 100 ml. of dimethylsulfoxide is added slowly to a sus vacuo to afford an oily carbamate. This carbamate (3.4 pension of 4.5 g. of sodium hydride (53.5% dispersion in g.) is dissolved in 50 ml. of dimethylsulfoxide and 0.46 mineral oil) in 100 ml. of dimethylsulfoxide at 20-25 C. g. of sodium hydride (53.5% dispersion in mineral oil) After hydrogen evolution is completed, a solution of is added. The mixture is stirred at 40 C. until hydrogen 32.3 g of 2-hydroxymethyl-1-(N-piperidinylmethyl)-cy 35 evolution is completed, then 5 ml. of methyl iodide is clopropane, 6-toluenesulfonate in 160 ml. of tetrahydro added and the mixture is stirred at 50 C. for two hours. furan is added dropwise. The mixture is stirred and re The mixture is diluted with ice-water and extracted with fluxed for one hour, poured into 1 . of ice-water and ether. The ether extracts are dried and concentrated to extracted with ether. The extract is washed with water, give the N-methylcarbamate derivative. dried and concentrated to give trans-5-[2-(N-piperidinyl 40 A solution of the above N-methylcarbamate (3.5 g.) methyl) - cyclopropylmethyl)-5H-dibenzo(a,d)cyclohep in ether is added to a suspension of 2.0 g. of lithium tene. aluminum hydride in ether and the mixture is stirred and EXAMPLE 6 refluxed for two hours. Decomposition of the metalcom plex gives an oil which is treated in ethanol solution with To a suspension of 4 g. of lithium aluminum hydride in 45 ethereal hydrogen chloride to give trans-5-2-(N,N-di ether is added a solution of 10 g. of trans-3-chloro-5-2- methylamino)cyclopropylmethyl - 10, 11 - dihydro - 5H (N-acetylamino) - cyclopropyl)-10,11-dihydro-5H-diben dibenzoadcycloheptene hydrochloride. zoadcycloheptene (prepared as described in Example Similarly, 3 - methylthio - 10, 11 - dihydro - 5H - di 2) in ether and the mixture stirred and Tefluxed for eight benzoa,d)cycloheptene (prepared by sodium and ethanol hours. The reaction mixture is decomposed, filtered and 50 the filtrate evaporated to give trans-3-chloro-5-[2-(N- reduction of the corresponding 5-one) yields trans-3- monoethylamino) - cyclopropyll - 10,11-dihydroadlcy methylthio - 5 - 2-(N,N-dimethylamino)cyclopropyl cloheptene. methyl-10,11-dihydro-5H-dibenzoadcycloheptene. EXAMPLE 7 EXAMPLE 9 To a solution of 6.2 g of cis-3-chloro-5-(2-carboxycy To a solution of 60 g. of 3-chloro-10,11-dihydro-5H clopropyl) - 10,11-dihydro-5H-dibenzoadcycloheptene dibenzo(a,d)cycloheptene in 200 m. of dimethylsulfoxide (prepared as in Example 2) in 60 ml of acetone, cooled is added 13 g. of 55.6% sodium hydride in portions, with to 0 C. is added 4.7 ml. of triethylamine in acetone and cooling, and the mixture is stirred for 15 minutes. A 3.2 mi. of ethyl chloroformate. The mixture is stirred for 60 solution of 57 g. of ethyl 2-bromocyclopropanecarboxylate 15 minutes and then a solution of 2.6 g. of Sodium azide in 190 ml. of dimethylsulfoxide is added and the mixture in water is added. After stirring for 30 minutes, the reac is stirred at room temperature for 45 minutes. After sub tion mixture is poured into ice-water and extracted with sequent heating on the steam bath for 30 minutes, the toluene. The dried extract is heated on the steam bath to reaction mixture is poured into 2 liters of ice-water, ex decompose the acid azide. Removal of the solvent gives 65 tracted with ether and the dried extract evaporated to the corresponding cyclopropyl isocyanate derivative. give 3 - chloro - 5 - (2 - carbethoxycyclopropyl) - 10,11 The above isocyanate is suspended in a large volume dihydro-5H-dibenzo(a,d) cycloheptene. of 20% aqueous hydrochloric acid and the mixture is A mixture of 83 g. of the above carbethoxycyclopropyl refluxed and stirred for four hours. The resulting solu derivative in 800 ml. of ethanol and 27 g. of potassium tion is made basic and extracted with ether. Evaporation O hydroxide in water is stirred and refluxed for one hour. of the ether extract gives cis-3-chloro-5-(2-aminocyclo After standing at room temperature overnight, the reac propyl)-10,11-dihydro-5H-dibenzo(a,d)cycloheptene. tion mixture is concentrated in vacuo, diluted with 1 1. of water and extracted with ether. Acidification with con EXAMPLE 8 centrated hydrochloric acid solution gives a solid which To a solution of 19.4 g of 10,11-dihydro-5H-dibenzo 75 is trans - 3 - chloro - 5 - (2 - carboxycyclopropyl) - 10, 11 3,576,853 11. 12 dihydro-5H-dibenzoa,d)cycloheptene, identical with that EXAMPLE 11 prepared by the method of Example 2. To a suspension of 2.4 g. of 53.5% sodium hydride in Similarly, by employing ethyl 2 - bromomethylcyclo 300 ml. of dimethylsulfoxide is added a solution of 13.7 g. propanecarboxylate in the above reaction sequence fol of 3 - bromo-5H-dibenzo(a,d)cycloheptene (prepared by lowed by hydrolysis yields trans - 3 - chloro - 5 - (2- sodium and ethanol reduction of the corresponding 5-one) carboxycyclopropylmethyl) - 10, 11 - dihydro - 5H - di in 50 ml. of dimethylsulfoxide. The mixture is stirred for benzoadcycloheptene. 30 minutes at 90° C., cooled and 9.7 g of ethyl 2-bromo To a suspension of 25.1 g of the above trans-3-chloro cyclopropane-carboxylate in 10 ml. of dimethylsulfoxide 5 - (2 - carboxycyclopropyl) - 10, 11 - dihydro - 5H-di is added. After stirring for one hour at 90-95 C., the benzo(a,d)cycloheptene in 200 ml. of acetone is added O reaction mixture is poured into ice-water, extracted with 19 ml. of triethylamine in acetone. The mixture is cooled ether and the dried ether extract evaporated to give 3 to -5° C., 14 ml. of ethyl chloroformate in acetone is bromo-5-(2-carbethoxy-cyclopropyl) - 5H - dibenzo(a,d) added and stirred for 30 minutes. A solution of 16 g. of cycloheptene. dimethylamine in 80 ml. of acetone is added over 45 A mixture of 12 g. of the above carbethoxycyclopropyl minutes, maintaining the temperature below 0° C. After 15 derivative in 100 ml. of ethanol and a solution of 5.6 g. 30 minutes the reaction mixture is stirred at room tem of potassium hydroxide in water is stirred and refluxed perature for one hour, then 15 minutes at 40° C. and for two hours. The solvent is removed in vacuo and the poured into ice-water. The mixture is extracted with residue is taken up in 175 ml. of water, extracted with methylene chloride and the dried extract evaporated to ether and the aqueous solution is acidified to give the give trans - 3-chloro-5-2-(N,N-dimethylcarboxamido)- 20 solid trans-3-bromo-5 - (2 - carboxycyclopropyl) - 5H cyclopropyl) - 10, 11 - dihydro - 5H - dibenzoadcyclo dibenzoadcycloheptene. heptene. To a suspension of 30 g. of the above carboxycyclo A solution of 30.8 g. of the above carboxamido deriva propyl derivative in 200 ml. of acetone is added 19 mi. tive in 225 ml. of ether is added to a suspension of 8 g. of triethylamine in acetone. The mixture is cooled to of lithium aluminum hydride in ether and the mixture 25 -5 C, 14 ml. of ethyl chloroformate in acetone is refluxed for five and one-half hours. The reaction mixture added and stirred for 30 minutes. A solution of 16 g. of is decomposed, filtered and the filtrate evaporated to give dimethylamine in 80 ml. of acetone is added over 45 a solid which is dissolved in acetone. Ethereal hydrogen minutes, maintaining the temperature below 0° C. After chloride is added to the acetone solution to yield trans-3- 30 minutes the reaction mixture is stirred at room ten chloro-5 - 2-(N,N-dimethylaminomethyl)-cyclopropyl)- 30 perature for one hour, then 15 minutes at 40 C. and 10, 11 - dihydro - 5H - dibenzo(a,d)cycloheptene hydro poured into ice-water. The mixture is extracted with chloride. methylene chloride and the dried extract evaporated to Similarly, by employing 33 g. of N-methylpiperazine give trans-3-bromo-5-2 - (N,N-dimethylcarboxamido)- instead of dimethylamine in the above reaction sequence, cyclopropyl-5H-dibenzo(a,d)cycloheptene. the corresponding trans - 3 - chloro - 5 - 2-(N-methyl 35 A solution of 36.8 g. of the above carboxamido deriva N' - piperazinoyl)cyclopropyl - 10, 11 - dihydro - 5H tive in 225 ml. of ether is added to a suspension of 8 g. dibenzo(a,d)cycloheptene is obtained which is reduced of lithium aluminum hydride in ether and the mixture with 8 g. of lithium aluminum hydride to yield trans - 3 refluxed for six hours. The reaction mixture is decom chloro - 5 - 2-(N-methyl-N'-piperazinylmethyl)cyclo posed, filtered and the filtrate evaporated to give trans propyl - 10,11-dihydro-5H - dibenzo(a,d] cycloheptene. 40 3-bromo-5-2 - (N,N-dimethylaminomethyl) - cyclo propyl-5H-dibenzoadcycloheptene. EXAMPLE 10 Similarly, by employing in the above reaction sequence 11.2 g of 3-methoxy-5H-dibenzo[a,d)cycloheptene (pre To a suspension of 10.6 g. of trans - 3-chloro-5-(2- pared by sodium and ethanol reduction of the correspond carboxycyclopropyl) - 10, 11 - dihydro - 5H - dibenzo 45 ing 5-one) or 9.6 g. of 5H-dibenzo(a,d)cycloheptene a,d] cycloheptene in 60 ml. of acetone is added 8 ml. of there is obtained as final products trans-3-methoxy-5-2- triethylamine in acetone, cooled to -5° C., 6 ml. of ethyl (N,N-dimethylaminomethyl)-cyclopropyl-5H dibenzo chloroformate in acetone is added and the mixture is adjcycloheptene or trans-5-[2-(N,N - dimethylamino stirred for 15 minutes in the cold. A solution of 4.4 g. methyl)-cyclopropyl)-5H-dibenzo(a,dlcycloheptene. of sodium azide in water is added, stirred for 30 minutes, 50 poured into ice-water and extracted with toluene. The What is claimed is: fried extract is heated until gas evolution ceases and then 1. A chemical compound of the formula: the solvent is removed to give the corresponding trans isocyanate derivative. The latter (12.2 g.) is dissolved in 60 ml. of ethanol and stirred and refluxed for two hours. Removal of the solvent in vacuo gives the ethyl carbamate derivative. A solution of 11.6 g. of the above carbamate in 50 ml. of dimethylsulfoxide is added to a suspension of 1.4 g. of 55.6% sodium hydride (mineral oil) in 35 ml. of di 60 methylsulfoxide. The mixture is heated briefly, cooled to 20 C. and 7 ml. of methyl iodide is added, maintaining the temperature between 15-20 C. This mixture is heated at 55-60° C. for 30 minutes, poured into 250 ml. of ice-water, extracted with ether and the dried extract 65 evaporated to give trans-3-chloro-5-2 - (N - methyl-N- carbethoxyamino)-cyclopropyl) - 10, 11 - dihydro - 5H in which: dibenzoadcycloheptene. Y is CHCH or CH=CH; To a suspension of 2.5 g. of lithium aluminum hydride R is hydrogen, chlorine, bromine, trifluoromethyl, methyl, in ether is added a solution of 11.8 g. of the above N 70 methoxy or methylthio; and methyl carbamate derivative in ether and the mixture is m is 0 or 1. refluxed for four hours. The reaction mixture is decom 2. A chemical compound according to claim 1 in which posed, filtered, and the ether removed to give trans-3- m is 0 and Y is CH2CH2. chloro-5-2-(N,N-dimethylamino) - cyclopropyl) - 10, 11 3. A chemical compound according to claim 2 in dihydro-5H-dibenzo(a,d) cycloheptene. which R is in the 3-position. 3,576,853 3 4. 4. A chemical compound according to claim 3 in which JAMES A PATTEN, Primary Examiner R is chlorine 5. A chemical compound according to claim 3 in which V. GARNER, Assistant Examiner Ristrifluoromethyl. U.S. C. X.R. References Cited 5 260-268, 293, 293.4, 294, 294.7, 326.3, 326.5, 326.81, 453, 456, 469, 471, 501.1, 516, 520, 558, 559, 562, UNITED STATES PATENTS 570.5, 573, 609, 612, 649, 668, 699 3,423,461 1/1969 Kaiser et al. ------260-570.5