US3372196A - 5-(3-methyl-aminopropyl)-5h-dibenzo [a, d]-cycloheptene - Google Patents

5-(3-methyl-aminopropyl)-5h-dibenzo [a, d]-cycloheptene Download PDF

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US3372196A
US3372196A US619083A US61908366A US3372196A US 3372196 A US3372196 A US 3372196A US 619083 A US619083 A US 619083A US 61908366 A US61908366 A US 61908366A US 3372196 A US3372196 A US 3372196A
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dibenzo
cycloheptene
solution
ether
benzene
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Edward L Engelhardt
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Merck and Co Inc
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Merck and Co Inc
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Priority to BR161109/64A priority Critical patent/BR6461109D0/pt
Priority to SE09058/64A priority patent/SE331992B/xx
Priority to BE650988D priority patent/BE650988A/xx
Priority to DE19641468341 priority patent/DE1468341A1/de
Priority to NL6408512A priority patent/NL6408512A/xx
Priority to CH974964A priority patent/CH494730A/de
Priority to FR992565A priority patent/FR4407M/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • ABSTRACT OF THE DISCLOSURE 5 (3 methylaminopropyl) 5H dibenzo [a,d]-cycloheptene which is useful as an antidepressant and serves as a mood elevator or psychic energizer.
  • This invention relates to new derivatives of dibenzocycloheptenes and to processes for making them. More particularly, the invention includes 5H-dibenzo[a,d]- cycloheptenes and 10,1l-dihydro-SH-dibenzo[a,d]cycloheptenes which are substituted at their S-carbon atom with an aminopropyl or an aminopropylidene radical.
  • the amino entity may be either primary or secondary and if secondary, the substituent may be either a lower alkyl or alkenyl radical having up to 6 carbon atoms, cycloalkyl having up to 8- carbon atoms or an aralkyl radical.
  • the dibenzocycloheptene nucleus may be further substituted.
  • the invention also includes the intermediates used for obtaining these products. Also included are derivatives such as acyl derivatives which yield the active compound under physiological conditions. I
  • novel compounds of the invention may be represented by the general formulae benzyl; Y may be hydrogen or halogen, preferably bromine or chlorine; X and X are similar or dissimilar and are selected from hydrogen, an alkyl group having up "ice to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perfluoroacylamino group having up to 4 carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms, halogen (fluorine, chlorine, bro
  • the dotted line between the 10 and 11 carbon atoms indicates that the compounds may be saturated or unsaturated at this location, the saturated compound being identified by the 10,11-dihydro designation.
  • the compounds represented by the above formulae wherein R is hydrogen are useful in the treatment of mental disorders since they are anti-depressants and serve as mood elevators or psychic energizers.
  • the daily dosage is within the range of 5 mg. to 250 mg., preferably taken in divided amounts over the day.
  • the compounds are preferably administered in the form of their acid addition salts and these salts are included in the scope of this invention.
  • the compounds represented by the above formulae wherein R is a cyano radical are useful as intermediates in the preparation of the active compounds.
  • the compounds I and II differ from each other in that the side chain of compounds I is attached to the nucleus by a double bond. Because of this a process for making compounds I will not be suitable for making compounds II.
  • Method A (I) as a primary amine begins with the known ketone which may be prepared by using the process described by A. C. Cope et al., entitled, Cyclic Polyolefins, XV, l-methylene 2,3,6,7 dibenzocycloheptatriene, appearing in J.A.C.S. 73, 1673-1678 (1951). Or the starting compounds, and particularly those having substituents on the benzene rings may be made by following the teachings of T. W. Campbell et al.
  • Method A involves the attachment of an ethylidene chain to the S-carbon of the nucleus and its subsequent expansion to a propylidene chain having a terminal amino group.
  • the Grignard reagent and the reaction using it are conventional, an inert solvent such as ether is used and the reaction is completed at refluxing temperature.
  • the Grignard adduct is hydrolyzed in the usual manner but it is preferable that it be under approximately neutral conditions such as produced by the addition of ammonium chloride solution.
  • the dehydration step which next follows is carried on preferably by a chemical dehydrating agent such as acetyl chloride, acetic anhydride or trifiuoroacetic anhydride which can subsequently be removed by evaporation.
  • N-bromosuccinimide is used for the next step as it is a selective brominating agent and avoids adding bromine to the olefinic linkage. This bromination is prefebably carried on at the refluxing temperature of a low boiling inert solvent such as benzene. A substantial excess of N-bromosuccinimide is to be avoided, particularly with compounds of the 10,11-dihydro series. The resulting succinimide precipitates and is removed.
  • the substitution of the cyanide group for the bromine will occur at room temperature but to hasten it heat is preferably applied.
  • the resulting cyanoethylidene derivative in method A is then isolated by evaporation of the solvent and is then subjected to the reduction step.
  • a chemical reducing agent such as lithium aluminum hydride in the presence of anhydrous ether. After hydrolysis as by the addition of a casutic alkali solution, the ether layer is recovered and the product obtained from it by distillation.
  • R can be alkyl, alkenyl or phenyl.
  • the conversion to the amide is readily carried out by the addition of an acyl halide or anhydride, such as acetic anhydride. This is carried on at room temperature with stir-ring or by heating.
  • The. amide is isolated by removal of the excess acylating agent and the reduction is carried out by the use of a metal hydride as explained above to avoid reduction of the olefinic double bond.
  • R may be an alkyl or an aralkyl radical.
  • Method C in general, involves the initial attachment of an alkoxy or aralkoXy propyl radical at the S-carbon of the nucleus by a Grignard reaction, the simultaneous reduction of the S-hydroxy compound and conversion of the alkoxy or aralkoxy group to an iodo radical and then the replacement of this iodo radical with an amino group.
  • the ketone used as the starting material in method C is the same as that used in Method A. It is condensed according to conventional procedures with a Gri'gnard reagent having a terminal ether group. R is preferably a lower alkyl radical having up to 6 carbons.
  • the resulting Grignard adduct is hydrolyzed preferably under neutral conditions as by using an ammonium chloride solution.
  • the resulting product is recovered from the solvent by evaporation and is treated with hydriodic acid in the presence of a solvent such as acetic acid or acetic anhydride.
  • the iodinated compound is extracted into a solvent such as benzene and recovered therefrom by evaporation of the solvent.
  • the addition to this iodo compound of the potassium phthalimide is carried on with a solvent such as dimethylforrnamide and after the complete addition, slight heat may be applied to increase the reaction rate.
  • the phthalimido compound is isolated by extraction.
  • the subsequent reaction with hydrazine hydrate is carried on in methanol or ethanol and heat may be applied up to the refluxing temperature to hasten the reaction.
  • the phthalhydrazide is separated and the primary amino compound II is recovered from the solution.
  • the phthalimide compound can be converted to the amine by hydrolysis.
  • the primary amine II is combined with a ketone or an aldehyde of the above structure wherein R is hydrogen or a lower alkyl radical and R may be hydrogen, alkyl and cycloalkyl. R and R may also be linked together through an alkylene chain to form a cyclic ketone.
  • the reaction is carried out in a solvent such as benzene or toluene and heated to refluxing temperature.
  • the resulting alkylidene or cycloalkylidene aminopropyl compound is then recovered by evaporating off the solvent and it is reduced by catalytic hydrogenation to the resulting secondary aminopropyl compound when Y is hydrogen.
  • the reduction may be accomplished with a metal hydride as described in method B.
  • the primary amine and the selected carbonyl compound can be dissolved in a suitable solvent such as a lower alcohol, and catalytic hydrogenation carried out.
  • the primary amine II may also be converted to the secondary amine II by following method B.
  • the primary amine I may be converted to the secondary amine I by following method D.
  • the 3 -dialkylaminopropylidene) -5H-dibenzol a,d] cycloheptenes and 5-(3-dialkylaminopropylidene)-10,l1- dihydro-5H-dibenzo[a,d]cycloheptenes employed as starting compounds in method B may be prepared as described in Belgian Patents 578,122 and 584,061, respectively.
  • the 5- 3-dialkylamino-propyl) -5H-dibenzo [a,d] -cycloheptenes and 5-(3-dialkylamin0pr0pyl)-10,ll-dihydro- SH-dibenzo[a,d1cycloheptenes may be prepared by condensing a S-halo derivative of the selected SH-dibenzo [a,d]cycloheptene with a dialkylaminopropyl Grignard reagent. This may be represented as follows:
  • the Grignard reagent may be prepared by employing conventional procedures.
  • the Grignard reagent may be prepared in a conventional solvent such as ether, tetrahydropyran, Z-me-thyltetrahydrofuran and tetrahydrofuran and the like, but tetrahydrofuran is preferred. These solvents may remain present during the reaction.
  • the reactants should be combined very slowly or they may be combined more rapidly if external cooling is applied to the reaction vessel so as to maintain the temperature close to that of the room.
  • heat is applied to maintain the temperature at up to refluxing temperature for from 15 to 60 minutes to obtain the maximum yield.
  • the solvent can be removed by distilling it off under reduced pressure.
  • the mixture is diluted with benzene and the excess Grignard reagent is hydrolyzed. As the desired end product is soluble in benzene, this layer is separated and the product isolated therefrom.
  • Further purification can be achieved by extraction with dilute acid which is then neutralized with alkali.
  • the product is recovered therefrom with a solvent such as benzene or hexane which is then distilled off.
  • the base of the product can be converted to a salt by the addition of such commonly used acids as hydrochloric acid, phosphoric acid, acetic acid, maleic acid and the like.
  • hydrochloride salt it is preferable to add a solution of hydrogen chloride to a solution of the end product in dry alcohol.
  • a variation of method C to produce compounds II as the primary amines involves starting with the S-halo (preferably chloro or bromo) derivatives of the selected SH-dibenzo[a,d]cycloheptene. This method involves the following series of steps:
  • the primary amine of the end product of method G can be converted to a secondary amine by employing method B.
  • Still another method for producing the secondary amines of compounds II involves a catalytic debenzylation' procedure. This may be represented as follows:
  • Method H C H2 HzN lower alkyl X palladium lower alkyl
  • the starting compound of method H will be recognized as the iodo derivative produced by method C and method G. It is gradually combined with the N-alkylbenzylamine to prevent a substantial temperature rise above room temperature, a solvent such as absolute alcohol being used. Heat to a refluxing temperature should be applied for from 15 to 60 minutes and the solvent distilled off.
  • the selective debenzylation action of hydrogen in the presence of palladium is utilized to remove the benzyl moiety and produce the secondary amine of compounds II.
  • the alkyl radical of the N-alkyl benzylamine is selected to produce the radical R of compounds II.
  • EXAMPLE 3 5 3-aminopropyl) -5Hdibenzo[a,d] cycl-oheptene
  • the Grignard reagent is prepared from 12.55 g. (0.075 mole) of 3-ethoxypropyl bromide and 1.82 g. (0.075 mole) of magnesium in ether.
  • the solution is cooled in an ice-bath and a solution of 5.15 g. (0.025 mole) of 5H-dibenzol[a,d]cyclohepten-S-one in dry ether is added dropwise with stirring. The mixture is stirred at room temperature for 2 hours, then at reflux for 30 minutes.
  • the Grignard adduct then is decomposed by pouring the reaction mixture into a mixture of ice and ammonium chloride solution. The ether layer is separated and the aqueous layer extracted further with ether. Evaporation of the ether gives the product as an oily crystalline solid. Two recrystallizations from alcohol gave product, M.P., 129-130 C.
  • a solution of 9.25 g. (0.0314 mole) of 5-(3-ethoxypropyl)-5-hydroxy-dibenzo[a,d]cycloheptene prepared as above in 45 ml. of acetic anhydride is heated on the steam-bath for 90 minutes then cooled to 65 C.
  • a stream of nitrogen is passed through the solution While 30 m1. of hydriodic acid (sp. gr., 1.5) is added in portions, keeping the temperature below 90 C.
  • the solution develops a dark brown iodine color during the addition.
  • the solution is heated to 80 C. for 30 minutes, then cooled and poured into ice-Water.
  • the filtered solution is evaporated by heating under reduced pressure to a volume of approximately 20 ml.
  • the hydrochloride salt of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene is precipitated in a yield of 1.35 g. (87.5%)
  • an analytical sample melted at 263- 265 C., dec.
  • the 5- (3-n-butylaminopropyl) 5H dibenzo[a,d] cycloheptene hydrogen maleate is obtained by dilution of the solution with absolute ether as white needles, M.P. 107 C., in a yield of 0.65 g. (60%). Recrystallization from mixtures of isopropyl alcoholabsolute ether and absolute alcoholabsolute ether gives product, M.P. 107.5 109 C.
  • Catalyst is filtered through a mat of diatomaceous earth and washed with absolute alcohol. The combined filtrate and washing are evaporated to dryness on the steam-bath under reduced pressure.
  • the residual oily base is dissolved in absolute alcohol and treated with a solution of dry hydrogen chloride in absolute alcohol.
  • the white crystalline 5-'(3-isopropylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride is precipitated by addition of absolute ether in a yield of 0.80 g. (92%), M.P. 234236 C.
  • the melting point was unchanged by a further recrystallization from a mixture of isopropyl alcohol and absolute ether.
  • the free base may be converted to the oxalate by dissolution in warm absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After recrystallization from a mixture of methanol and ethyl acetate,
  • the cyanamide can be hydrolyzed under alkaline conditions as follows:
  • the cyanamide, obtained as described in Step A (2.0 g., 0.007 mole) is mixed with a hot solution of 25 g. of potassium hydroxide in 38 ml. of absolute methanol. The mixture is heated to refluxing with stirring for 45 hours. The reaction mixture then is diluted with water and the yellow oil that separates is extracted into benzene. After washing with water and drying over sodium sulfate, the benzene is evaporated to give 1.75 g. of a yellow oily residue. The basic material is extracted into 1 N hydrochloric acid and after separating the neutral material by extracting with ether, the basic material is recovered by making the aqueous layer basic and extracting with ether. Evaporation of the ether lgives 1.46 g. of the base, 5-(3-methylaminopropylidene)-5H-dibenzo[a, d]cycloheptene. Conversion to the oxalate is carried out as described above.
  • the hydrochloride s'alt may be formed directly from the crude free base or through the oxalate as follows: An aqueous solution of the oxalate salt is basified with lithium hydroxide and the free base extracted into benzene. Evaporation of the benzene leaves the base in substantially pure form. Treatment of the base with ethanolic hydrogen chloride and precipitation by the addition of ether gives the hydrochloride salt which, after recrystallization from a mixture of ethanol and ether, melts at l-182 C.
  • EXAMPLE 8 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene Upon following the procedure given in Example 6A, but employing an equivalent quantity of 5-(3-dimethylaminopropyl) 5H dibenzo[a,d]cycloheptene in place of 5-(3-dimethylaminopropylidene) 5H dibenzo[a,d]- cycloheptene, the corresponding cyanamide is obtained.
  • Example 6B Upon hydrolysis, according to the procedure of Example 6B, there is obtained 5-(3-methylaminopropyl) 5H-dibenzo[a,d]cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride s'alt melts at 166.5-167.5 C. (uncorrected) Analysis.Calcd. for C H N-HCl: C, 76.11; H, 7.40;
  • ethyl bromide can be employed in a quantity of 0.05 mole per mole of magnesium.
  • the syrupy mixture is dissolved in 75 ml. of benzene and water, 15 ml., is added dropwise with stirring.
  • the benzene layer is decanted from the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling benzene.
  • the combined benzene extracts are Washed with water and extracted with three 15 ml. portions of 3 N hydrochloric acid.
  • the acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the combined extracts with water, the hexane is evaporated and the product obtained as a yellow oil in a yield of 4.61 g.
  • the base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether.
  • the yield of 5 (3 dimethylaminopropyl)-5H-dibenzo[a,d]cyclohep tene hydrochloride, M.P. 186190 C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, M.P. 191-193" C.
  • the starting 10,11-dihydro-5-(3-dimethylaminopropyl)- 5H-dibenzo[a,d]cycloheptene used in this example may be prepared by following Steps A and B in Example 9, but employing 5-chloro-l0,1l-dihydro-SH-dibenzo [a,d] cycloheptene as the starting compound.
  • This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride salt melts at 192.5l93.5 C., dec.
  • the starting 3 chloro 10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene used in this example may be prepared by following Steps A and B of the above Example 9, employing 3,5-dichloro-10,11-dihydro-SH-dibenzo[a,d]cycloheptene as the starting compound.
  • EXAMPLE 12 5 3-aminopropyl -5H-dibenzo [a,d] cycloheptene
  • A 5 -(3-ethoxypr0pyl -5H-dibenz0 [a,d cycloheptene
  • the Grignard reagent is prepared from 6.44 g. (0.0386 mole) of 3-ethoxypropyl bromide and 940 mg. (0.0386 g. atom) of magnesium in ether.
  • a solution of 5.67 g. (0.025 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in a mixture of dry ether and tetrahydrofuran is added dropwise with stirring.
  • the mixture is stirred at room temperature for 1 hour.
  • the Grignard adduct then is decomposed -by pouring the reaction mixture into a mixture of ice and ammonium chloride solution.
  • the ether layer is separated, the aqueous layer extracted further with ether. Evaporation of the ether and distillation of the residue under reduced pressure gives the product as a yellow oil, B.P. 148 C. (0.1 mm.).
  • cycloheptene 3 chloro 5 (aminopropyl) 5H-dibenzo[a,d] cycloheptene is dissolved in acetic anhydride and the solution heated to refluxing for 20 minutes. The solution then is cooled and poured into a large volume of water. The mixture is stirred until the excess reagent is hydrolyzed. The product then is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.
  • EXAMPLE 16 5-( 3-ethylaminopropyl) -5H-dibenzo [a,d] cycloheptene
  • A 5- (3-acetamid0pr0pyl) -5H-dibenz0 [a,d] cycloheptene
  • a solution of 5 (3 aminopropyl)-5H-dibenzo[a,d] cycloheptene (0.75 g., 0.003 mole) in 5 ml. of dry pyridine is treated with 1 ml. of acetic anhydride and then heated to refluxing for 30 minutes. The cooled solution is poured into ml. of water and the oil extracted into benzene.
  • the benzene extract is washed with water, 3 -N hydrochloric acid, water, and evaporated to dryness under reduced pressure.
  • the 5-(3-acetamidopropyl)-5H- dibenzo[a,d]cycloheptene is obtained as a yellow oily residue weighing 087 g.
  • the mixture is cooled in ice and stirred while water, 0.25 ml., 20% sodium hydroxide, 0.25 ml., and water, 0.75 ml., are added cautiously dropwise in succession.
  • the granular precipitate is collected and washed thoroughly with ether.
  • the combined ethereal filtrate and washings are washed with water and dried over anhydrous sodium sulfate.
  • Ether is evaporated under reduced pressure to obtain the oily base.
  • the hydrochloride is prepared by treating a solution of the base in absolute alcohol-absolute ether with a solution of dry hydrogen chloride in absolute alcohol.
  • the white crystalline 5-(3-ethylaminopropyl)-5H- dibenzo-[a,d]cycloheptene hydrochloride is obtained by dilution of the solution with absolute ether in a yield of 0.50 g. (53%), M.P. 224.5226.5 C., dec. Repeated recrystallizations from absolute alcohol-absolute ether and isopropyl alcoholabsolute ether mixtures raised the M.P. to 227.5-228.5 C., dec.
  • EXAMPLE 17 3 chloro 5-(3-methylaminopropyl)-5H-dibenzo[a,d] v cycloheptene
  • 3-dimethylaminopropylmagnesium chloride is prepared from magnesium turnings (1.22 g., 0.051 g. atom) and 3-dimethylaminopropyl chloride (6.2 g., 0.051 mole) in 25 ml. of tetrahydrofuran following the method of Example 9, Step A.
  • EXAMPLE 18 3-dimethylsulfamoyl-5-(3-methylaminopropyl)-5H- dibenzo[a,d]cycloheptene Fluorosulfonic acid, 100 ml., is placed in a 300 ml. 3-necked round bottom flask equipped with polyethylene inlet tube and polyethylene exit tube with drying tube half-filled With anhydrous sodium fluoride. A nitrogen atmosphere is maintained throughout the reaction. With stirring, 17.0 g. (0.059 mole) of 3-bromo-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-S-one is added in portions over 20 minutes.
  • the reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in water.
  • the aqueous solution is made alkaline with sodium hydroxide and the oily base that separates is extracted into ether.
  • the washed and dried ether extract is evaporated under reduced pressure, leaving 3 dimethylsulfamoyl-S-(3-methylaminopropyl)- SH-dibenzo[a,d]cycloheptene as an oil weighing 170 mg.
  • the base may be converted to the hydrogen oxalate salt by dissolution in absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After repeated recrystallizations from absolute ethanol and from isopropyl alcohol, the hydrogen oxalate melts at 133.5-
  • the 3-chloro-5-(3-methylaminopropylidene -5H-dibenzo a,d] cycloheptene hydrochloride is separated into the aand fl-forms by fractional precipitation from the ethanolic solution with absolute ether.
  • the a-form melts at 263-265 C., dec. after repeated recrystallizations from a mixture of absolute ethanol and absolute ether.
  • the aqueous layer is rendered alkaline with sodium hydroxide and the product is extracted into benzene. After washing with water, the benzene is distilled, leaving the mixed eometric isomers of 10-brcmo-5-(3-methylaminopropylidene)-5H-dibenzo[a,d]cycloheptene as a yellow oily resi due in a yield of 1.86 g.
  • the mother liquors from another experiment such as E. are concentrated and amorphous hydrogen maleate of the fl-isomer is converted to the base.
  • the base 10.8 g., is disolved in 20 ml. of benzene and 10 ml. of the solution applied to each of two chromatography columns constructed of polyethylene tubing, 2 cm. in diameter and packed with 60 g. of alumina activated in situ by means of acetone. Each column is developed by passing 100 ml. of chloroform through it. The columns then are slit longitudinally. A zone is visible approximately /3 of the distance from the top of the adsorbent. The section of the column below this zone is removed and eluted with boiling methanol.
  • EXAMPLE 22 5-(3-cyclopropylaminopropyl-SH-dibenzo[a,d] cycloheptene 5-(3iodopropyl)-5H-dibenzo[a,d]cycloheptene, 3.6 g. (0.01 mole), is dissolved in 15 ml. of absolute ethanol. Cyclopropylamine, 3 ml., is added and the mixture allowed to stand overnight at room temperature. Ethanol is evaporated under reduced pressure and the residual solid treated with aqueous sodium hydroxide and extracted into benzene. After washing with water, the benzene layer is shaken thoroughly with several portions of 3 N hydrochloric acid and again washed with water.
  • EXAMPLE 23 5 -(3-dimethylaminopropylidene) -3-methylsulfonyl-5H- dibenzo[a,d]cycloheptene
  • A Preparation of cuprous methylmercaptide Concentrated ammonium hydroxide solution, 300 ml., is placed in a 1 liter, 3-necked flask fitted with a stirrer and gas inlet tube. The apparatus is cooled in an ice-bath and flushed with dry nitrogen while 40.0 g. (0.40 mole) of cuprous chloride is added portion-wise with stirring.
  • the reaction mixture is poured into 6 N hydrochloric acid, 120 ml., and ice and extracted with five 150 ml. portions of boiling benzene.
  • the combined extracts are washed with three 200 ml. portions of 3 N hydrochloric acid.
  • the solvent is evaporated under reduced pressure leaving a brown oil, weight 7.41 g., as residue.
  • the oil is dissolved in absolute methanol, 125 ml., and boiled with 370 mg. decolorizing carbon for thirty minutes.
  • the filtrate is concentrated to 60 ml. and a yellow solid separates, along with a brown oil.
  • the solid is mechanically separated from the oil and dried in a vacuum dessicator over concentrated sulfuric acid.
  • the product weighs 2.77 g.
  • the brown oil is evaporatively distilled at 146 C./0.1 mm. and the sublimate is crystallized from 25 ml. of absolute methanol to give 2.65 g. of material melting at 66.5-67.5" C. (77% yield).
  • the benzene solution is separated and the gelatinous residue is extracted three times with 50 ml. portions of boiling benzene.
  • the combined benzene extracts are extracted with three 45-ml. portions of 0.5 M. citric acid solution and washed once with 50 ml. H O.
  • the combined aqueous solutions are made basic with sodium hydroxide solution and extracted with ether.
  • the combined extracts are washed with water and evaporated under reduced pressure.
  • the yellow solid residue, M.P. 1 27129 C. weighs 6.88 g. Recrystallization from ethanolwater yields 6.50 g. of product melting at 128-129 C.
  • the solution is cooled in an ice-bath while 30% hydrogen peroxide, 25.-8 ml., is added dropwise with stirring. After standing at room temperature for twenty-two hours, the solution is saturated with sulfur dioxide for one hour with periodic cooling in an ice-bath.
  • the solution is made basic with 10 N. sodium hydroxide solution, 625 ml., and extracted with three 300 ml. portions of benzene. After Washing the combined extracts with water, solvent is distilled under reduced pressure leaving a yellow oily residue, weight 23.20 g. The oil solidifies on standing at room temperature. Four recrystallizations from methanol-water gives 13.22 g. (57%) of product melting at 170.5l71.5 C.
  • the benzene layer is separated, washed with water and the benzene distilled under reduced pressure.
  • the base of the fi-isomer is covered with hexane and allowed to stand until partially crystalline. The base then is recrystallized to constant melting point from cyclohexane.
  • the product obtained in a typical experiment sintered at 141 C., melted at 142.5-143" C., clearing at 144 C.
  • EXAMPLE 25 5 3-methylaminopropylidene) -3-methylsulfonyl-5H- dibenzo [a,d] cycloheptene (B-isomer) By substituting 5-(3-dimethylaminopropylidene)-3- methylsulfonyl-5H-dibenzo a,d] cycloheptene B-isomer (product of Example 23, Step G), for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A and B, 5-(3-methylaminopropylidene) -3-methylsulfonyl-SH-dibenzo [a,d] cycloheptene (13- isomer) is obtained in the form of a yellow oil. The product is converted to the hydrogen maleate that melts at 175-176 C.
  • EXAMPLE 26 10,1 l-dihydro-S- 3 -methylarninopropylidene -3 -methylsulfonyl-S H-dibenzo a,d] cycloheptene (tl-lSOIIlCI') .
  • 10,11 dihydro-543-methylaminopropylidene)-3-methylsulfonyl-SH-dibenzo[a,dlcycloheptene (ct-isomer) is obtained as a yellow oil.
  • the product is converted to the hydrochloride that melts at 275.5276.5 C. (sintered, 274.5 C.) after recrystallization from methanol-ether mixtures.
  • (C) 5 (3-dz'methylamin0pro pyl -3-m-ethylm ercapto- 5H-dibenzo [a,d] cycloheptene
  • the Grignard reagent is prepared from dimethylaminopropyl chloride (0.2 mole) and magnesium (0.2 g. atom) in 75 ml. of dry tetrahydrofuran following the method described in U.S. Patent No. 2,996,503. A 15 ml. portion of this solution is cooled in an ice-bath and stirred while a solution of 4.7 g.
  • the combined benzene solutions are extracted with 50 ml. of 0.5 M. citric acid.
  • the acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene.
  • Evaporation of the washed benzene extract under reduced pressure leaves 5 3-dimethylaminopropyl) -3-methy1mercapto-SH-dibenzo [a,d] cycloheptene as the oily residue Weighing, typically, 4.2 g. (75%).
  • the solution is cooled in an ice bath and stirred while sulfur dioxide is introduced for 1 hour. After dilution with an equal volume of water and with stirring and cooling, the mixture is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. Solvent is evaporated from the Washed benzene extract under reduced pressure, leaving the product as a viscous oily residue in a yield of 1.75 g. (93%).
  • the base may be converted to the hydrogen oxalate salt by treating a solution in ethanol with an equimolar quantity of oxalic acid dissolved in ethanol.
  • the base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a 10% excess of oxalic acid in ethanol.
  • Dilution With absolute ether precipitates 5 (3 methylaminopropyl)-3-methylsulfonyl-SH-dibenzo[a,d]cycloheptene hydrogen oxalate as a white crystalline solid, M.P. 1l4l19 C. dec. -An analytical sample melts at 114-115 C. dec. after two recrystallizations from mixtures of absolute ethanol and absolute ether.

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US619083A 1963-07-25 1966-11-25 5-(3-methyl-aminopropyl)-5h-dibenzo [a, d]-cycloheptene Expired - Lifetime US3372196A (en)

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SE09058/64A SE331992B (enrdf_load_stackoverflow) 1963-07-25 1964-07-24
BE650988D BE650988A (enrdf_load_stackoverflow) 1963-07-25 1964-07-24
DE19641468341 DE1468341A1 (de) 1963-07-25 1964-07-24 Dibenzocycloheptan- und -hepten-Verbindungen und Verfahren zu ihrer Herstellung
NL6408512A NL6408512A (enrdf_load_stackoverflow) 1963-07-25 1964-07-24
CH974964A CH494730A (de) 1963-07-25 1964-07-24 Verfahren zur Herstellung von Dibenzocyclopentenen
BR161109/64A BR6461109D0 (pt) 1963-07-25 1964-07-24 Processos de preparacao de derivados de dibenzo ciclo heptenos
FR992565A FR4407M (enrdf_load_stackoverflow) 1963-07-25 1964-10-23
US619083A US3372196A (en) 1963-07-25 1966-11-25 5-(3-methyl-aminopropyl)-5h-dibenzo [a, d]-cycloheptene
US05/567,157 US3981917A (en) 1963-07-25 1975-04-11 Chemical compounds
US05/567,165 US3978121A (en) 1963-07-25 1975-04-11 5H Dibenzo[a,d]cycloheptene derivatives

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435073A (en) * 1966-04-19 1969-03-25 Colgate Palmolive Co 5-(n-benzyl-n-lower alkylaminoalkylene)-5h-dibenzo(a,d)cycloheptenes
US3468951A (en) * 1965-06-14 1969-09-23 American Hospital Supply Corp Bis-(alkoxyaryl)alkyl-n-alkenyl-and-alkynyl-amines
US3520930A (en) * 1964-12-31 1970-07-21 Merck & Co Inc Lower alkoxy-amino-benzylamines
US3522301A (en) * 1962-09-24 1970-07-28 Merck & Co Inc 10,11-dihydro-7-halo-3-halosulfonyl-5h-dibenzo(a,d)cyclohepten-5-one
US3527806A (en) * 1966-03-17 1970-09-08 Hoffmann La Roche 10-alkyl-alkenyl- or benzyl-5-(3-aminopropylidene)-dibenzo(a,d)cycloheptenes
US3718694A (en) * 1968-10-09 1973-02-27 Leo Ab N-ARYLACYLAMINO-ALKYL-{11 AND-ALKYLIDENE-DIBENZO {8 a,d{9 CYCLOHEPTENES AND-ANTHRACENES AND THE SALTS THEREOF
US3919321A (en) * 1966-11-08 1975-11-11 Hoffmann La Roche Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones
US3927128A (en) * 1971-01-18 1975-12-16 Hoffmann La Roche Tricyclic amines and processes for the preparation thereof
US3991103A (en) * 1973-10-22 1976-11-09 Research Institute For Medicine And Chemistry Inc. 5H Dibenzo (a,d) cycloheptene, 10,11 dihydro, 5(1-halo-3-dimethylaminoprop-1-ylidene) derivatives
US4020096A (en) * 1974-02-01 1977-04-26 Merck & Co., Inc. 10,11,Dihydro-N-alkoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamines
US4051260A (en) * 1975-04-28 1977-09-27 Syntex (U.S.A.) Inc. 2-Substituted-5-oxo-5H-dibenzo[a,d]cycloheptenes, and derivatives thereof, and methods and compositions for the use thereof
US4307245A (en) * 1978-12-29 1981-12-22 Syva Company Amitriptyline conjugates to antigenic proteins and enzymes
US4569944A (en) * 1984-06-21 1986-02-11 Warner-Lambert Company Dibenzosuberone as a non-steroidal anti-inflammatory compound and compositions thereof
US4795822A (en) * 1984-05-23 1989-01-03 Syntex (U.S.A.) Inc. Nortriptyline conjugates to antigenic proteins and enzymes
US4874793A (en) * 1988-07-29 1989-10-17 Darrell Franks Use of protriptyline for the treatment of mental health problems in children
US5010104A (en) * 1987-10-14 1991-04-23 Kyowa Hakko Kogyo Co., Ltd. Tricyclic compounds
US5464840A (en) * 1993-12-06 1995-11-07 Schering Corporation Tricyclic derivatives, compositions and methods of use
US5574173A (en) * 1993-12-06 1996-11-12 Schering Corporation Tricyclic derivatives, compositions and methods of use
EP2102146A4 (en) * 2006-12-11 2010-10-27 Apicore Llc PROCESS FOR THE PREPARATION OF 5H-DIBENZOÝA DERIVATIVES, DECYCLOHEPTENE

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3258488A (en) * 1963-08-12 1966-06-28 Colgate Palmolive Co Dibenzo[a, d]cycloheptene derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3258488A (en) * 1963-08-12 1966-06-28 Colgate Palmolive Co Dibenzo[a, d]cycloheptene derivatives

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3522301A (en) * 1962-09-24 1970-07-28 Merck & Co Inc 10,11-dihydro-7-halo-3-halosulfonyl-5h-dibenzo(a,d)cyclohepten-5-one
US3520930A (en) * 1964-12-31 1970-07-21 Merck & Co Inc Lower alkoxy-amino-benzylamines
US3468951A (en) * 1965-06-14 1969-09-23 American Hospital Supply Corp Bis-(alkoxyaryl)alkyl-n-alkenyl-and-alkynyl-amines
US3527806A (en) * 1966-03-17 1970-09-08 Hoffmann La Roche 10-alkyl-alkenyl- or benzyl-5-(3-aminopropylidene)-dibenzo(a,d)cycloheptenes
US3435073A (en) * 1966-04-19 1969-03-25 Colgate Palmolive Co 5-(n-benzyl-n-lower alkylaminoalkylene)-5h-dibenzo(a,d)cycloheptenes
US3919321A (en) * 1966-11-08 1975-11-11 Hoffmann La Roche Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones
US3718694A (en) * 1968-10-09 1973-02-27 Leo Ab N-ARYLACYLAMINO-ALKYL-{11 AND-ALKYLIDENE-DIBENZO {8 a,d{9 CYCLOHEPTENES AND-ANTHRACENES AND THE SALTS THEREOF
US3927128A (en) * 1971-01-18 1975-12-16 Hoffmann La Roche Tricyclic amines and processes for the preparation thereof
US3991103A (en) * 1973-10-22 1976-11-09 Research Institute For Medicine And Chemistry Inc. 5H Dibenzo (a,d) cycloheptene, 10,11 dihydro, 5(1-halo-3-dimethylaminoprop-1-ylidene) derivatives
US4020096A (en) * 1974-02-01 1977-04-26 Merck & Co., Inc. 10,11,Dihydro-N-alkoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamines
US4051260A (en) * 1975-04-28 1977-09-27 Syntex (U.S.A.) Inc. 2-Substituted-5-oxo-5H-dibenzo[a,d]cycloheptenes, and derivatives thereof, and methods and compositions for the use thereof
US4307245A (en) * 1978-12-29 1981-12-22 Syva Company Amitriptyline conjugates to antigenic proteins and enzymes
US4795822A (en) * 1984-05-23 1989-01-03 Syntex (U.S.A.) Inc. Nortriptyline conjugates to antigenic proteins and enzymes
US4569944A (en) * 1984-06-21 1986-02-11 Warner-Lambert Company Dibenzosuberone as a non-steroidal anti-inflammatory compound and compositions thereof
US5010104A (en) * 1987-10-14 1991-04-23 Kyowa Hakko Kogyo Co., Ltd. Tricyclic compounds
US4874793A (en) * 1988-07-29 1989-10-17 Darrell Franks Use of protriptyline for the treatment of mental health problems in children
US5464840A (en) * 1993-12-06 1995-11-07 Schering Corporation Tricyclic derivatives, compositions and methods of use
US5574173A (en) * 1993-12-06 1996-11-12 Schering Corporation Tricyclic derivatives, compositions and methods of use
US5688805A (en) * 1993-12-06 1997-11-18 Schering Corporation Tricyclic derivatives, compositions and methods of use
EP2102146A4 (en) * 2006-12-11 2010-10-27 Apicore Llc PROCESS FOR THE PREPARATION OF 5H-DIBENZOÝA DERIVATIVES, DECYCLOHEPTENE

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BR6461109D0 (pt) 1973-07-19
DE1468341A1 (de) 1969-05-22
NL6408512A (enrdf_load_stackoverflow) 1965-01-26
BE650988A (enrdf_load_stackoverflow) 1965-01-25
SE331992B (enrdf_load_stackoverflow) 1971-01-25
CH494730A (de) 1970-08-15
FR4407M (enrdf_load_stackoverflow) 1966-09-12

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