US3322768A - Aralkyl piperazines and salts thereof - Google Patents

Aralkyl piperazines and salts thereof Download PDF

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US3322768A
US3322768A US471731A US47173165A US3322768A US 3322768 A US3322768 A US 3322768A US 471731 A US471731 A US 471731A US 47173165 A US47173165 A US 47173165A US 3322768 A US3322768 A US 3322768A
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propyl
bis
chlorophenyl
dichlorophenyl
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Schorr Manfred
Nesemann Georg
Bauer Fritz
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/037—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements with quaternary ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to piperazines of the Formula I to the physiologically compatible acid addition salts thereof and to their quaternary salts in which the cations are of the formulae 11a and 11b in which R is hydrogen, halophenyl or halobenzyl, R R and R are hydrogen or halophenyl, A is hydrogen or lower alkyl, R, is alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or dialkylaminoalkyl, the alkyl groups of which have 1 to 4 carbon atoms, R is hydrogen or alkyl of 1 to 4 carbon atoms, or R and R together with the nitrogen atom form a piperidino or N-methyl-piperazino ring.
  • the 4-nitrogen atom of the piperazine ring carries a chain of three carbon atoms identified herein as the ,6 and gamma carbon atoms, (b) the :x-carbon atom is always unsubstituted, (c) they contain a total of at least two halophenyl groups, i.e., at least two of R R and R are halophenyl when R is hydrogen and at least one of R R and R is halophenyl when R is halophenyl or halobenzyl, and (d) they do not contain any unsubstituted phenyl groups.
  • the products of the present invention are novel compounds exhibiting Valuable therapeutic properties, above all bacteriostatic, bactericidal, fungistatic and fungicidal properties.
  • This invention further relates to a process of preparing the new piperazines of the Formula I by reacting a primary amine of the Formula III in which R, R R R and A have the meanings given above, with alkyl-bis-(Z-halogeno-ethyl)amines of the Formula IV 3,322,768 Patented May 30, 1967 in which R, vhas the meaning given above and Hal stands for a halogen atom, or by causing amines of the Formula VI or VII (VII) to act on a bis-(Z-halogeno-ethyl)-amine of the Formula V or a salt thereof obtainable by starting from a primary amine of the Formula III and, if desired, converting the piperazine obtained into the corresponding acid addition salts by treatment with physiologically compatible inorganic acids or into monoquaternary salts by treatment with alkylating agents.
  • halophenyl and halobenzyl stand for phenyl and benzyl groups being substituted by one or two halogen atoms in the phenyl nucleus. As halogen atoms especially chlorine enters into consideration as substitucut.
  • radicals may be mentioned as examples: 2-, 3-, and 4-chlorophenyl, 2-, 3-, and 4-chlorobenzyl and the corresponding fluorine or bromine derivatives, 2,3-, 2,4-, 2,5-, 3,4 and 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dichlorobenzyl and the corresponding bromine derivatives; 4-fiuorophenyl and 4-fiuorobenzyl.
  • the substituent R may for example represent methyl, ethyl N-propyl, isopropyl, n-butyl, sec. butyl and tert. butyl groups.
  • alkyl groups R there may likewise be used the above mentioned substituents, preferably methyl or ethyl groups.
  • the compounds mentioned as starting substances may, for example, be prepared by hydrogenation of the corresponding nitriles whereas the corresponding amines substituted at the nitrogen atom by two halogenoethyl groups can be obtained from the first mentioned primary amines.
  • the primary amines mentioned above can, for example, be reacted with ethylene oxide in an inert solvent, such as benzene, at elevated temperatures preferably between 80 and 160 C., or with ethylene chlorohydrin in the presence of an acid-binding agent, for example calcium oxide, at temperatures between 80 and 160 C.
  • a primary amine of the Formula III can, for example, favorably be reacted with an alkyl-bis-(fl-halogenoethyl)- amine of the Formula IV.
  • the operation is advantageously carried out in the presence of a solvent or diluent, for example lower aliphatic alcohols, such as methanol or ethanol.
  • a solvent or diluent for example lower aliphatic alcohols, such as methanol or ethanol.
  • an acid-binding agent for binding the hydrogen halide set free during the reaction there is suitably added an acid-binding agent.
  • alkali metal carbonates, alkali metal bicarbonates or tertiary amines such as pyridine or triethyl amine.
  • the alkyl-bis- (fi-halogenoethyD-amine serving as the reaction component of the primary amine may be used in the form of the free base as well as in the form of a corresponding salt, for instance the hydrochloride. In the latter case the basic compound has to be added in a bimolar excess.
  • the temperatures required for the reaction vary according to the nature of the starting substances and the solvents used. In order to accelerate the reaction it is of advantage to operate at raised temperatures, for example, between 80 and 160 C.
  • the reaction can be carried out in an open vessel as well as in an autoclave.
  • the reaction mixture is made alkaline by adding bases, such as sodium hydroxide solution, and the piperazines formed during the reaction are extracted by means of suitable organic solvent. Since, as a rule, the free piperazines cannot be distilled without decomposition, it is of advantage to purify them by conversion into a corresponding acid addition salt, preferably into the corresponding hydrochlorides.
  • an amine of the above-mentioned Formula III may first be converted into a corresponding bis-(fi-halogenoethyD- amine.
  • Amines of the Formula VI may then be reacted with the reaction product obtained, which if necessary, may be used in the form of a corresponding salt. This reaction and processing can be carried out in the abovedescribed manner.
  • the piperazines obtained are generally very viscous, yellow oils only distillable with decomposition. They can be transformed into the corresponding salts by means of inorganic or organic acids. It has already been mentioned that the transformation of the free bases into the corresponding salts can advantageously be used for purification and isolation of the products from the reaction mixture.
  • the salt formation can take place at one or at both basic nitrogen atoms. Generally, the salts obtained by reaction with 2 equivalents of an acid crystallize well and, according to the nature of the anions and of the radicals R they dissolve more or less easily in water.
  • inorganic acids for instance, hydrohalic acids such as hydrochloric acid or hydrobromic acid, or sulfuric acid, phosphoric acid, amidosulfonie acid.
  • organic acids there are suitable, for example: acetic acid, propionic acid, butyric acid, stearic acid, oxalic acid, tartaric acid, malic acid, succinic acid, fumaric acid, maleic acid, citric acid, aspartic acid, aceturic acid, salicylic acid, para-amino-benzoic acid or ethylene-diamine-tetraacctic acid.
  • the piperazines thus formed can be transformed into the corresponding monoquaternization products by treatment with equimolar quantities of a suitable alkylating agent.
  • a solvent or diluent is not absolutely necessary for this reaction but is of advantage in most cases.
  • diluents there enter, for example, into consideration: hydrocarbons such as benzene, carboxylic acid esters such as ethyl acetate, ketones such as acetone, acyclic or cyclic ethers such as dioxane or tetrahydrofurane or aliphatic alcohols such as methanol or ethanol.
  • the reaction is advantageously carried out at elevated temperatures, preferably Within the range of the boiling point of the solvent used.
  • al-kylating agents there may be used lower alkyl esters of hydrohalic acids, such as methyl iodide or ethylene chlorohydrin, of sulfonic acids such as para-toluene-sulfonic acid ethyl ester, or of sulfuric acid, for example dimethylor diethyl sulfate.
  • the quaternary compounds crystallize from the reaction solution on cooling or can be obtained in solid form by treatment with suitable solvents, if necessary after previous evaporation of the reaction mixture.
  • nitrogen atom is quaternized is not quite certain but the nitrogen atom carrying the radical R is, for steric reasons, more suitable, so that the quaternized products obtained probably consist mainly of salts in whose molecule the radical R is bound to this nitrogen atom.
  • the monoquaternary piperazinimum salts prepared according to the process of the present invention constitute in most cases crystalline substances which often contain water of crystallization. Most of them are soluble in water, even in the weakly alkaline range.
  • the piperazinium hydroxides on which the salts are based are strong bases.
  • the compounds of this invention are well tolerated and possess valuable therapeutic properties, above all bacteriostatic, bactericidal, fungistatic or fungicidal activity. In view of these properties the compounds are, for example, suitable as disinfectants in the most varied fields of applieation.
  • the pharmaceutical preparations may be prepared by the usual methods.
  • the following examples illustrate the invention; but they are not intended to limit it thereto:
  • Toxicity in mice in mg./2O g. of the compounds a-g a b c d c f g Orally. 25 100 100 25 25 12. 15. 6 subcutaneously 100 4 2 2 5 0.8 12. 5
  • the lowest concentration causing a bactericidal action is between about 8-l5' /rnl.
  • the lowest concentration causing a fungistatic action is of about the same order.
  • the tolerability of the products of the invention is likewise excellent as results from the indicated toxicity data.
  • the compounds may be used as such or in the form of galenic preparations, for example, gelees, powders, ointments, pastes, mixtures that require shaking, tinctures, solutions or suspensions in admixture or conjunction with a pharmaceutical organic or inorganic carrier that does not react with the active ingredient.
  • carrier substances there may be mentioned, for example, water, gelatine, bolus, lactose, starch, magnesium stearate, talcum, vegetable oils, benzyl alcohol, gums, polyethylene-glycol, cholesterol, white petroleum jelly, zinc oxide, titanium dioxide or other carriers known for medicaments.
  • the prodbilizers, buffers, wetting agents, emulsifiers or salts for 50 grams of N-['y,'y,'y-tri-(4-chlorophenyl)-propyl]-N, N-bis-(ii-chloroethyD-aminc hydrochloride, 250 cc. of a1- cohol and 20 grams of n-butylamine are heated in a shaking autoclave for 5 hours at 120130 C. Most of the solvent is distilled otf, water and sodium hydroxide solution are added to the residue and the base is extracted by means of ether. After drying over potassium carbonate 22 cc.
  • the free l-butyl 4 -tri-(4'-chlorophenyl)-propyl]-piperazine is obtained from the salt by treating it with sodium hydroxide solution and ether, drying and evaporating the ether layer, as a viscous, light-yellow oil.
  • N-[y,v,'y-tri-(4-chlorophenyl)-propyl]-N,N-bis-(B- chloroethyl)-amine hydrochloride can, for example, be prepared as follows:
  • EXAMPLE 2 1-(01' 4-) methyl-1-butyl-4-[ -lri-(4-chl0r0phenyl)- propyl]-piperazinium methyl sulfate To a solution of 25 grams of 1-butyl-4-[ -tri-(4- chlorophenyl)-propyl]-piperazine in 100 cc. of benzene there is added dro wise a solution of 6 grams of dimethyl sulfate in 25 cc. of benzene. The reaction mixture is heated for one hour under reflux. After cooling 50 cc. of petroleum ether are added. The quaternary salt crystallizesvery slowly but more rapidly upon inoculation.
  • EXAMPLE 4 1(0r 4-) methyl-1-(;8-hydroxyethyl) 4- -tri-(4- chlorophenyl) -prpyl] -piperazinium methyl sulfate To a solution of 29 grams of l-(p-hydroxyethyl)-4- -tri-(4-chlorophenyl)-propyl]-piperazine in 150 c-c. of benzene there is added dropwise a solution of 7.3 grams of dimethyl sulfate in 25 cc. of benzene. The reaction mixture is then heated for one hour under reflux. The solvent is distilled off and the residue is dissolved in 40 cc. of ethyl acetate.
  • the solution obtained is extracted three times with ethyl acetate, the latter is dried over solid potassium hydroxide and, after filtering, carbon dioxide gas is introduced. The slight precipitate formed is filtered off. The ethyl acetate in the filtrate is distilled off for the most part and ether is added to the residue. After prolonged standing, more rapidly upon inoculation, the 1,1- diethyl 4 tri (4 chlorophenyl) propyl]- piperaziniurn bicarbonate crystallizes out. The yield amounts to 37 grams.
  • the product can be recrystallized from ethyl acetate or acetonitrile. It melts at 148-150 C. with weak decomposition.
  • EXAMPLE 6 3 4ri- (4 -chl0r0phenyl -pr0py1 -3 ,6-diazaspiro- [5,5] -undecanium bicarbonate 55.2 grams of N-[ -tri-(4'-chlorophenyl)-propyl]- N,N-bis-(,8-choloethyl)-amine hydrochloride (obtained according to the directions given in Example 1), 300 cc. of alcohol and 26 grams of piperidine are heated in a shaking autoclave for 5 hours at l20-l30 C.
  • the alcohol is distilled off, the residue is dissolved in a little water, the solution is made strongly alkaline by means of concentrated sodium hydroxide solution and extracted several times with ethyl acetate.
  • the organic layer is dried over potassium hydroxide. A'fter separation of the drying agent, carbon dioxide gas is introduced into the solution obtained, the solution is concentrated to a small volume and about 1.5 liters of ether are added.
  • the 3-[ -tri- (4' chlorophenyl) proply] 3,6 diaza spiro [5,5]- undecanium bicarbonate crystallizes rapidly and, after standing for several hours, it can be filtered off with suction.
  • the slightly brownish product melts at 138-141 C. By recrystallization from dioxane ether and from acetonitrile it can be obtained in a colorless form, the melting point remaining constant.
  • the free base can be obtained from the salt in usual manner; it constitutes a yellow, very viscous oil.
  • EXAMPLE 9 52.5 grams of N-[B(3,4-dichlorobenzyl)'y-(3,4-dichlorophenyl)-propyl]-N,N-bis-(,8-chloroethyl) amine hydrochloride, 70 cc. of alcoholic ethylamine solution of 21.6% strength and 80 cc. of alcohol are heated in a shaking autoclave for 5 hours at 120-140 C. The alcohol is distilled off to a great extent, the residue is shaken with dilute sodium hydroxide solution and ether, the ether layer is separated, dried over magnesium sulfate and evaporated. The oily residue (41 grams) is dissolved in 250 cc.
  • the free base can be obtained in usual manner. It constitutes a light yellow, very viscous oil.
  • the N-[fl-(3,4-dichlorobenzyl)-'y-(3,4-dichlorophenyl)-propyl] -N,N-bis-(fl-ch1oroethyl) -arnine hydrochloride serving as starting substance can, for example,
  • the hydrochloride crystallizes from isopropanol/diisopropyl ether and melts at 116-118 C.
  • the alcohol is distilled off for the most part, the residue is poured into Water, the reaction mixture is made distinctly alkaline by means of sodium hydroxide solution and extracted several times with chloroform. The combined extracts are dried over magnesium sulfate and the solvent is distilled off. The oil remaining behind is treated on the steam bath with 100 cc. of ethyl acetate, whereupon it crystallizes. 100 cc. of diisopropyl ether are added, the whole is cooled and filtered with suction.
  • EXAMPLE 1 1 3 8 (3,4' dichlorobenzyl)-'y-(3,4-dichl0rophenyl) propyl] 9 methyl 3,6,9 triaza-spiro [5,5] undecanium chloride
  • the alcohol is distilled off for the most part, the residue is dissolved in water and rendered distinctly alkaline by means of sodium hydroxide solution.
  • the reaction solution is extracted several times with chloroform, the combined extracts are dried over magnesium sulfate and concentrated again.
  • the residue obtained in the form of crystals is dissolved in cc. of isopropauol, clarified by means of animal charcoal and precipitated again by addition of 500 cc. of diisopropyl ether.
  • N,N bis (fi-chloroethyD-amine hydrochloride serving as starting substance may, for example, be prepared as follows: 200 grams of B-(4-chlorophenyl)-' -(2, 4-dichloropheriyl)-propylamine are dissolved in 400 cc. of benzene and, after addition of 85 cc. of ethylene oxide, heated in an autoclave for 5 hours at 120 C. The solvent is then completely distilled off under reduced pressure.
  • N- [B- 4-chlorop-henyl) -'y- 2,4-dichlorophenyl propyl]-N,N-di-(fl-chloroethyl)-amine hydrochloride can be recrystallized from isopropanol/diisoproylether and melts than at 132133 C.
  • EXAMPLE 13 1 (0r 4-) methyl 1 ethyl 4 [/3-4'-chl0r0phenyl)-'y- To a solution of 21.4 grams of 1-ethyl-4-[l3-(4chlorophneyl) 'y (2',4'-dichlorophenyl)-propyl]-piperazine in 150 cc. of benzene there is added dropwise a solution of 6.6 grams of dimethyl "sulfate in 50 cc. of benzene and the reaction mixture is then stirred for 15 minutes at room temperature and for one hour at the boiling temperature. Two layers are formed. After distilling off the benzene the residue is dissolved in 75 cc.
  • dichlorophenyl propyl] -piperazine A mixture of 119 grams of N-[B-(4-chlorophenyD-y- (2,4 dichlorophenyl) propyl]-N,N-bis-(,8-chloroethyl) amine hydrochloride, 500 cc. of alcohol and 55 grams of n-butylarnine are heated in a shaking autoclave for 5 hours at 110120 C. After most of the alcohol has been distilled ofi, the residue is poured into water, the reaction mixture is rendered alkaline by means of sodium hydroxide solution and the oil that has separated is taken up in ether.
  • the free base is obtained from the dihydrochloride in usual manner as a light-yellow, viscous oil.
  • EXAMPLE 16 95.2 grams of N-[fl (4-chlorophenyl)--, -(2,4-dichlorophenyl)-propyl] N,N-bis (li-chloroethyD-amine hydrochloride, 400 cc. of alcohol and 46.4 grams of diethylaminoethylamine are heated in an autoclave for 5 hours at l20-130 C. After distilling off the alcohol, water and dilute sodium hydroxide solution are added, the separated oil is taken up in ether and the ethereal solution is dried over potassium carbonate. After separation of the drying agent there are added to the solution cc. of alcoholic hydrochloric acid of 27.8% strength.
  • the l-diethylaminoethyl-4-[p-(4'-chlorophenyl) y-(2,4'-dichlorophenyl)- propyl]-piperazine trihydrochloride precipitates at first in a smeary form which solidifies slowly and can then be filtered off with suction. The yield amounts to 98 grams.
  • the salt can further be purified by recrystallization from alcohol/diisopropyl ether. It crystallizes with one molecular proportion of water of crystallization and melts at 225-227 C. with slight decomposition.
  • the free amine can be obtained from the trihydrochloride in usual manner as light yellow, viscous oil.
  • the alcohol is distilled off, the residue is dissolved in water, made alkaline by means of sodium carbonate solution and the excess of methyl-piperazine is extracted by means of ether.
  • the aqueous phase is rendered strongly alkaline by addition of concentrated sodium hydroxide solution and extracted by shaking several times with chloroform.
  • the combined extracts are dried over magnesium sulfate and 24 cc. of alcoholic hydrochloric acid of 31% strength are added thereto.
  • the 3-[ 3-(4-chlorophenyl-3-(2'-4-dichlorophenyl) propyl]- 9-methyl-3,6,9-triaza-spiro-[5,5]-undecanium chloride hydrochloride separates at once in a solid form. After recrystallization from cc. of alcohol there are obtained 30 grams of the salt crystallizing with 2 molecular proportions of water. It melts at 274276C.
  • EXAMPLE 18 A mixture of 63 grams of B-(4-chlorophenyl)-'y-(2,4- dichlorophenyl)-propylamine, 38.5 grams of methyl-bis- (B-chloroethyD-amine hydrochloride, 44.4 grams of triethlamine and 200 cc. of ethanol is heated in an autoclave for 5 hours at -130" C. The reaction mixture is poured into water, rendered alkaline by means of sodium hydroxide solution, the oil that has separated is taken up in ethyl acetate and the solution is dried over potassium carbonate. The solution is completely evaporated under reduced pressure, the residue is dissolved in 500 cc. of
  • N-[@fi-bis-(4'-chlorobenzyl)-propyl] N,N bis- (fi-chloroethyD-amine hydrochloride can, for example, be prepared as follows:
  • EXAMPLE 2O 39.3 grams of N-[B-(ZA dichlorobenzyl)-'y-(2,4-dichlorophenyl)-propyl] N,N-bis (fi-chloroethyD-amine hydrochloride, 16.5 grams of diethylamine and 100 cc. of ethanol are heated in a closed vessel for 5 hours at 110-120 C. The alcohol is distilled oif, the residue is dissolved in water and, after addition of a little 2 N-sodium hydroxide solution, the solution is extracted by shaking with ether.
  • the aqueous phase is then extracted several times by means of methylene chloride, the combined methylene chloride extracts are dried over magnesium sulfate and the solvent is evaporated.
  • the viscous oil remaining behind is dissolved in 100cc. of acetonitrile.
  • the product can further be purified by recyrstallization from the same solvents.
  • the salt contains 1 molecular proportion of water of crystallization. It melts at 130-131 C.
  • N-[fl-(2.,4-dichlorobenzyl) -'y-(2,4-dichlorophenyl) propyl]-N,N-bis (fl-chloroethyl) amine hydrochloride used as starting substance can, for example, be prepared as follows:
  • the alcohol is distilled off for the most part, the residue is dissolved in water, a small amount of 2 N- sodium hydroxide solution is added, the whole is extracted with ether and the aqueous phase is then extracted several times with methylene chloride.
  • the combined methylene chloride extracts are dried over magnesium sulfate and evaporated.
  • the oily residue crystallizes after some time on mixing with cc. of ethyl acetate. The crystallization can be accelerated by inoculation.
  • N-[B-(3,4-dichlorophenyl)-y-(4 chlorophenyl)- propyl] N,N-bis-(fi-chloroethyl) amine hydrochloride can, for example, be prepared as follows:
  • N-[yq-bis-(4-chlorophenyl) propyl] N,N-bis- (B-chloroethyD-amine hydrochloride used as starting substance can, for example, be prepared as follows:
  • R is hydrogen, halophenyl or halobenzyl
  • R R and R are hydrogen or halophenyl, at least two of R R and R being halophenyl when R is hydrogen and at least one of R R and R being halophenyl when R is halophenyl or halobenzyl
  • A is hydrogen or lower alkyl
  • R is hydrogen, alkyl of l-4 carbon atoms, hydroxyalkyl of l-4 carbon atoms or dialkylaminoalkyl, the alkyl groups of which have l-4 carbon atoms
  • R is hydrogen or alkyl of 1-4 carbon atoms; or R and R together with the nitrogen atom form a piperidino or N-methylpiperazino ring.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
US471731A 1959-12-28 1965-07-13 Aralkyl piperazines and salts thereof Expired - Lifetime US3322768A (en)

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DEF30184A DE1126880B (de) 1959-12-28 1959-12-28 Verfahren zur Herstellung von Piperazinderivaten

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BE (1) BE598602A (de)
CH (3) CH398615A (de)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599335A (en) * 1983-05-06 1986-07-08 Basf Aktiengesellschaft Diamine derivatives, compositions and use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3218394A1 (de) * 1982-05-15 1983-11-17 Basf Ag, 6700 Ludwigshafen Diaminderivate, verfahren zu ihrer herstellung und ihre verwendung als fungizide
CN108003158B (zh) * 2017-12-06 2020-05-19 石家庄学院 一种胡椒碱季铵盐衍生物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2767186A (en) * 1956-10-16 Quaternary ammonium salts of substi-

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB467970A (en) * 1934-12-04 1937-06-21 Carbide & Carbon Chem Corp Improvement in production of morphaline alkanols

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2767186A (en) * 1956-10-16 Quaternary ammonium salts of substi-

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599335A (en) * 1983-05-06 1986-07-08 Basf Aktiengesellschaft Diamine derivatives, compositions and use

Also Published As

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CH401067A (de) 1965-10-31
CH398613A (de) 1966-03-15
CH398615A (de) 1966-03-15
DE1126880B (de) 1962-04-05
NL6503308A (de) 1965-11-25
BE598602A (fr) 1961-06-28

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