SE435507B - PROCEDURE FOR THE PREPARATION OF TRIMETOXIFENOXY-PROPYL-PIPEREZINE DERIVATIVES - Google Patents

Description

p 1ao3742 + 1 cnßo 01130 o-cxiz-fx-cnz-N N-RZ I- - en o _ OR 3 1 wherein R1 represents hydrogen, alkanoyl having 2 to 6 carbon atoms, alkenoyl having 3 to 6 carbon atoms, benzoyl, alkoxybenzoyl with 1-4 carbon atoms, nicotinoyl or thienylcarbonyl and R 2 represents a phenyl, naphthyl or pyridyl group optionally substituted by the groups R 3 and R 4, wherein R 3 and R 4 are the same or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine , nitro, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms. alkanoyl having 2 to 6 carbon atoms, amino, acylamino or acyloxy, wherein in the latter two groups acyl may be an acyl group indicated for R1, and their salts.

The alkanoyl and alkenoyl groups may be straight or branched.

The alkanoyl groups preferably have 2, 3 or 4 carbon atoms, the alkenoyl group preferably 3, 4 or 5 carbon atoms. The thienyl group may consist of the corresponding thienyl (2) - or thienyl (3) -carbonyl group.

The alkyl groups in the alkyl, alkoxy and alkylthio groups may be straight or branched. Examples are methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, methylthio, ethylthio, propylthio and butylthio. Examples of the acylamino group are acetamino and benzoylamino. If R 2 represents a naphthyl group, this may be the naphthyl (1) or naphthyl (2) group, this naphthyl group in both rings being substituted by the groups R 3 and R 4. Preferably, however, the naphthyl ring is substituted in the 6-ring, which is not linked to the piperazine ring. If R2 represents a pyridyl ring, this can be connected to the piperazine ring in the 2-, 3- or 4-position.

R 1 represents, for example, hydrogen or alkanoyl having 2, 3 or 4 carbon atoms.

If R 2 represents one phenyl or pyridyl group, the substituents R 3 and / or R 4 are preferably in the position adjacent to the site where R 2 is attached to the piperazine ring.

Preferably R 1 hydrogen or 1 R 2 represents an alkoxyphenyl group having 1 to 4 carbon atoms (for example methoxyphenyl, ethoxyphenyl) hydroxyphenyl, aminophenyl, alkanoylamino-ayl having 2 to 4 carbon atoms (for example acetylaminophenyl, propionylaminophenyl) or an alkanoyloxy-2-oxyloxyphenyl propionyloxyphenyl) wherein these substituents are in the o- or p-position, preferably in the o-position.

The new compounds are pharmacodynamically active and possess, for example, a pronounced anti-aggressive effect as well as neurolemic properties, whereby anticonvulsant and hypnotic effects are only present to a small degree or are absent. In addition, they possess antipyretic and anti-edema effects. According to the invention there are provided compounds with favorable pharmacodynamic properties which can be used as medicaments.

In contrast to the compounds of the invention, the few (5,6, 7,8-tetrahydro-naphthyl- (1) -oxypropyl] -piperazine derivatives described in German Offenlegungsschrift 2,235,597 possess antihypertensive and thus antihypertensive properties. the compounds according to the invention show no or only a low blood pressure lowering effect.

The compounds of the invention are prepared by reacting a compound of the formula cHo 3 o oï _ II _ __ 3 - _ o _H? 5He with a compound of the formula F '\ z-N mig y * 111'. . wherein Y and Z are always different and either represent hydrogen or the group -CH 2 -CH (OR 1) -CH 2 -V and V represents chlorine, bromine or iodine or if R represents hydrogen together with this hydroxy group 1 may also form an ethylene oxide ring and that optionally one or two nitro groups are reduced to amino groups and / or that the obtained compounds are acylated with an acid resp. an acid derivative corresponding to the group R1. 780-3742-1 4 The process for the preparation of compounds according to the invention can be carried out with or without solvent at temperatures between 20 to 200 ° C, preferably 50 to ISOOC. As a reading resp. dispersants include, for example: aromatic hydrocarbons such as benzene, tohien or xylene; aliphatic ketones such as acetone or methyl ethyl ketone; halogenated hydrocarbons such as, for example, chloroform, tetrachlorohydrocarbon, chlorobenzene or methylene chloride; aliphatic ethers such as butyl ether; cyclic ethers such as, for example, tetrahydrofuran or dioxane; sulfoxides such as, for example, dimethyl sulfoxide; tertiary acid amides such as, for example, dimethylformamide, N-methylpyrrolidone; aliphatic alcohols such as methanol, ethanol, isopropanol, amyl alcohol or tert-butanol; cycloaliphatic hydrocarbons such as cyclohexane and the like. Aqueous mixtures of the mentioned solvents can also be used. Often you work with the used solution resp. the reflux temperature of the dispersant.

In general, the reactants are reacted in molar amounts.

However, it may be appropriate to use the compound of formula III if Z represents hydrogen, in excess (for example 0.5 mol).

Optionally, the reaction can also be carried out in the presence of acid-binding agents such as alkali carbonates (potash, soda), alkali hydroxides or tert-amines (for example triethylamine). The latter is especially true when compounds are used in which V represents a halogen atom.

If a compound of formula II is used as the starting substance wherein Y represents hydrogen, this compound can also be used in the form of a metal salt, preferably the alkali metal salt (for example the sodium or potassium salt). This is especially true when in the second reactant III in the group Z = -CH 2 -CH (OR 1) -CH 2 V the symbol V is a halogen atom.

In carrying out the reaction, the corresponding halogen hydride or a mixture of these two compounds (synthetic crude product) can also be used as the ethylene oxide starting compound instead of the ethylene oxide compound.

In the products obtained, existing amino and / or hydroxy groups as well as the middle secondary hydroxy groups (introduction of the R1-acyl group) can be obtained by acylation, ie treatment with acid of the formula R10H, wherein R1 in addition to hydrogen has glycemic reactions by treatment with corresponding acid derivatives. As the corresponding derivative derivative, there are in particular compounds 7803742-1 of the formula RW IV 1 in which W represents chlorine, bromine or iodine, the group -NEN, a group with BH, -O-PO (OH) 2. Here, R represents 'formula -OR' , -SR 'or a group of the formula -OSO -OP (OR') 2, -O-As (OR ') 2 or -OCO-R ". An alkyl group or when the groups -OR' or -SR 'are meant e.g. also a phenyl group, p-nitrophenyl group, cyanomethyl group or carboxymethyl group; R "may denote a straight or branched alkyl group, an alkoxy group, a phenoxy group, a carbobenzoxy group or even Aliphatic ketenes having 2 to 6 carbon atoms may be used. the rest Rl. as acylating agent. acid derivatives of the formula IV wherein W represents chlorine or bromine. resp. R "denotes alkyl or alkoxy groups, these are preferably low molecular weight and have 1 to 6 carbon atoms.

The acylation can, for example, take place in inert solution resp. suspending agents such as water, lower aliphatic alcohols, lower aliphatic ketones, dioxane, dimethylformamide, benzene or toluene at temperatures between 0 to 200 ° C. Optionally, the reaction is carried out with the addition of an acid-binding agent such as alkali hydroxides, alkali metal carbonates (potassium carbonate), alkali metal bicarbonates, alkali metal acetates, alkaline earth carbonates, tertiary amines (for example trialkylamine, pyridine) or alkali alcoholates (sodium ethylate). The groups to be acylated (hydroxy groups, amino groups) can also be transferred first in the compound to be reacted. The corresponding alkali compound can also be reacted by reacting them in an inert solvent such as dioxane, dimethylformamide, benzene or toluene with an alkali metal, alkali metal hydride. or alkali amide (especially sodium or sodium compounds) at temperatures between 0 and 150 ° C and add the acylating agent.

If the free acid of the formula RIOH is used, its activation is required by the presence of condensing agents such as dicyclohexylcarbodiimide, sulfuric acid bis-alkylamides (for example SO: § (CH3) å_2), N, N'-carbonyldiimidazole and so on. (Organic Reactions, Volume 12, 1962, pages 205 and 239).

Instead of the above-mentioned builder, other chemical equivalents commonly used in chemistry can also be used- (e.g. also LF and Mary Fieser "Reagents for Organic Synthesis", John 1967, volume 1, pages 1303 - 4 Of course, in the obtained pre- Wiley and Sons , Inc. New York, and volvm 2, pages 471). the acyl groups present in a known manner are also cleaved again, for example with aqueous alkali or alcoholic alkali hydroxide (for example methanolic KOH) or possibly also with mineral acids such as hydrochloric acid or sulfuric acid in alcoholic or water-alcohol solution at temperatures between 20 and 100 ° C.

For the reduction of one or even two nitrogen groups, catalytic hydrogenation is particularly important. Examples of catalysts are: raney nickel, precious metals such as palladium and platinum and compounds thereof with or without carriers such as, for example, barium sulphate, calcium sulphate, etc. It may be convenient to carry out the hydrogenation of the nitro groups at temperatures between 20 and 80 ° C and a pressure of about 5 to 50 atm in a solvent, for example alcohols, dioxane, tetrahydrofuran, etc. For the subsequent isolation of the reduced compounds, it can in many cases be advantageous to initially add drying agents to the hydrogenating mixture, such as anhydrous sodium or magnesium sulphate.

However, the reduction can also be carried out with atomic hydrogen, for example zinc / hydrochloric acid, tin / hydrochloric acid, iron / hydrochloric acid or with salts with hydrogen sulphide in alcohol / water at about 70-120 ° C or with activated aluminum in aqueous ether at 20-40 ° C. or with stannous chloride / hydrochloric acid.

The compounds of the invention can generally be obtained as racemates. The optically active antipodes are obtained either by using optically active starting materials or by racemic cleavage over salts of optically active acids such as, for example: L - (+) - tartaric acid, D - (-) - tartaric acid, (+) - 0.0 '-dibenzoyl-D-tartaric acid, (-) - 0,0'-dibenzoyl-L-tartaric acid, (-9-0,0'-di-p-tolyloyl-L-tartaric acid, (+) - 0,0' -di-p-toluoyl-D-tartaric acid, (+) - camphor-10-sulfonic acid and others.

Z The compounds of general formula I can be converted into the salts according to known methods. As anions for their salts, there are known and therapeutically useful acid residues. Examples of such acids are: H 2 SO 4, phosphoric acid, hydrohalic acid, ethylenediaminetetraacetic acid, sulfamic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, guajazulensulfonic acid, maleic acid, fumaric acid, tartaric acid, tartaric acid, tartaric acid gluconic acid, benzoic acid, citric acid, acetaminoacetic acid and oxyethanesulfonic acid.

From the salts of the compounds, the free bases can be prepared in the usual way, for example by treating a solution with an organic agent such as alcohols (methanol) with soda or sodium hydroxide. The composition according to the invention is suitable for the preparation of pharmaceutical preparations. The pharmaceutical preparations resp. the medicaments may contain one or more compounds according to the invention or even mixtures thereof with other pharmaceutically active substances. For the preparation of the pharmaceutical preparations, customary pharmaceutical carriers and excipients can be used. The drugs can be used enterally, parenterally, orally: or perlingually. For example, the dosage may be in the form of tablets, capsules, pills, dragees, suppositories, ointments, gels. creams, powders, liquids, powders or aerosols. Suitable liquids are, for example: oil or water solutions or suspensions, emulsions, injectable water and oil solutions or suspensions.

The starting compounds of the formula III in which Z represents the group -CH2-CH (OH) -CH2-V, can be obtained, for example, in the usual manner by reaction of epichloro- or epibromohydrin with the corresponding piperazine containing the group R 2 in the 4-position, in alcohol, preferably methanol with the addition of about 5% water at 10 ° C. The reaction time is ~, for example, half an hour.

Then heat to 30 - 400 and stir for 5 hours.

The ratio of piperazine to hydrin is, for example, 1z1 - 1: 5, preferably 1: 1 - 1: 2. The water content can also be between 1 and 10%, preferably 2 and 6%.

In the compounds thus obtained, the group R1 can be introduced by acylation with a compound R1w under the conditions already given. Similarly, R 1 may also be introduced into the starting compounds of formula II wherein Y represents the group -CH 2 -CH (OH) -CH 2 -V.

The other starting compounds are known.

The invention is further illustrated by the following examples in which the temperatures refer to CO.

Example 1. (E) -1-: E- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl-4- (2-methoxyphenyl) -piperazine. 12 g (0.05 mol) of 3,4,5-trimethoxyphenoxy-glycidyl ether were boiled with 9.6 g (0.05 mol) of 1- (2-methoxyphenyl) -piperazine in 100 ml of isopropanol for 5 hours under reflux. Then most of the solvent was distilled off and the residue was treated with an excess of isopropanol-containing HCl and the dihydrochloride of 1: 3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl-4- (2-methoxyphenyl) -piperazine was precipitated by addition of diethyl ether. 18.4 g (73% of theory) were obtained as a colorless crystalline substance, m.p. 196 DEG-197 DEG. The 3,4,5-trimethoxyphenoxy glycidyl ether can be prepared, for example, as follows: In a suitable reaction vessel with an azeotropic water separation device, 18.4 g (0.1 mol) of 3,4,5-trimethoxyphenol were heated with 37 g (0.4 mol). epichlorohydrin to boiling and within 30 minutes 10 g (0.1 mol) of 40% sodium hydroxide were added dropwise, at the same time the water was separated azeotropically. After the addition of the sodium hydroxide was completed, the mixture was allowed to react for one hour at boiling temperature, diluted with about 100 ml of toluene and filtered off separated NaCl. The filtrate was fractionated first under normal pressure, then in vacuo. The 3,4,5-trimethoxyphenoxyglycidyl ether was obtained at kp1'0 = 175-150 ° C as a colorless one; yield: 19.2 g corresponding to 80% yield, calculated on the trimethoxyphenol.

The process Preparation of the process product can also be carried out as follows: 0.05 mol of sodium (3,4,5-trimethoxy) phenolate was heated with 0.05 mol of 1- (3-chloro-2-hydroxy-propyl) -4- (2-methoxyphenyl) -piperazine (prepared by reacting 1- (2-methoxyphenyl} piperazine with epichlorohydrin) in 50 ml of dioxane, 8 hours under reflux, until boiling.

After cooling, the precipitated NaCl was filtered off and the filtrate was evaporated. The residue was treated with isopropanol-containing hydrochloric acid and otcr and the crystalline solid was recrystallized from methanol. 8.2 g (32% of theory) of (i) -1-: §- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl: -4- (2-methoxyphenyl) -piperazine were obtained as dihydrochloride with melting point l94 - 1960.

Another possibility of carrying out the process is as follows: A mixture of 0.05 moles of 3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl bromide, 0.05 moles of 1- (2-methoxyphenyl) -piperazine and 0, 06 moles of triethylamine were heated in 100 ml of toluene for 5 hours under reflux to boiling. Then the precipitated triethylammonium bromide was filtered off and the filtrate was evaporated. The residue was taken up in a small amount of isopropanol and with isopropanol-containing hydrochloric acid and ether the dihydrochloride precipitated from (f) -1-: š- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl: -4- (2-methoxyphenyl) - piperazine.

After recrystallization from methanol, 1.0 g of the pure compound (40 .mu.l of theory) were obtained, m.p. 195 DEG-197 DEG.

In an analogous manner to the first section of Example 1, from each of the 0,05 moles of 3,4,5-trimethoxyphenoxyglycidyl ether and 0,05 moles of a compound of formula III were obtained the compounds of the formula 9 listed in Table 1. - \ ca oo - (m2 - cH (oH) - C112 - N _ N-nz Example 22. (i) -1- [3- (3,4,5-trimethoxyphenoxy) -2- (nicotinoyloxy) -propyl ] - 4- (2-methoxyphenyl) -piperazine 13.0 g (o, o3 moi) (in-1-β- (β-trimethogyphenoxy) -z-nyaroxypropyl:] - 4- (2-methoxyphenyl) - piperazine was dissolved together with 3.34 g of triethylamine (0.033 mol) in 80 ml of anhydrous benzene and added within 30 minutes to a solution of 4.67 g (0.033 mol) of nicotinic acid chloride in 50 ml of anhydrous benzene, stirring for a further 2 hours at room temperature and finally heated the mixture for another hour to 70-800. After cooling, the mixture was shaken several times with water, washed with aqueous NaHCO 3 and water and the benzene-containing phase was dried over magnesium sulphate and evaporated. and dioxane. After addition of excess isopropanolic hydrochloric acid and ether, 13.0 g (67% of theory) of the above compound were obtained as trihydrochloride (colorless crystals). Melting point 187 - 1920 (decomposition).

Example 23. (ï) -1E§- [§, 4,5-trimethoxyphenoxy: -2-: B, 4,5-trimethoxybenzooxy: -propyl] -4- (2-methoxyphenyl) -piperazine (i) -1 I: 3- (3,4,4-Trimethoxyphenoxine-2-hydroxy-propyl-4- (2-methoxyphenyl) -piperazine was reacted analogously to Example 20 with 3,4,5-trimethoxybenzoyl chloride in the presence of triethylamine. as dihydrochloride, m.p. 193 - 1950 (decomposition).

Yield 38 å.

Example 24. (i) -1-: §- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl: -4- (2-acetamidophenyl) -piperazine 4 g (ï) -1- [§- (3, 4,5-Trimethoxyphenoxy-2-hydroxypropyl-4- (2-aminophenyl) -piperazine (monohydrochloride) was dissolved in 20 ml of dioxane and added with 10 ml of triethylamine, then added dropwise with stirring at -50 0.9 ml of acetyl chloride. hours after-reaction at room temperature, the solution was filtered and the solvent was removed under reduced pressure.Through column column chroma- 10 @ H ~ oHxoHw>: fl @ ^ ** U fl H0HMon¶> J0: 0 = ~ A * mm ^ * æmp H> cwwoHu fl c | N: fl NmHmm fi m | ^ fi> Gwm0HuH: | Nv | ~ FN Fw ^ mømv -np Hæcmu fl xonwæslm c fl wmumß fl mx ^ fi> cwm fl N0nwwnïNv | P ON N: ^ **: ww. | Www fl nw | m ^ | wV | H> w fi ~> m | P mp.

Pw ^ * n: N | Næm ^ Hvw fi> ummc Q fl Nmumm fl m | ^ Hv | H> ummc | _ w- mw ^ ** NhF I mwp H> cmwHw # wEH0dam fl nu | fi n fl NmHwm fi m | ^ H>: mmH> uoEu0ø fi m fi uuïnv | now H> = wwH> @ weHo = HwH ~ u | w. ø fl wmuwm fl ml ^ H> = «wH> wwa» oøH «fl Hw | wv | - w, Ammmv. mn w fi p I ßnw H> nwmHæ # w0m \: s fi wmHmmHQ | A fi bømm fi numomtavlw m fi Fb ^ * O fi N. | mmm H> cwmH> umE fl w | w.N c fl wmnmm fl ßl ^ H> cmmH> uwE fl U | m.mvl fi av om ^ ** ww. | wwp H> cmwH> »wa fl ø |« .n n fl wmuwm fl mn ^ ~> nwwH> »waHw1w.nv | _. n. ww ^ ** wm, _ | www H> = w «H>» we | n .wc fi wm ~ wm fi @ | ^ H> = ww fi> pws | nv | _ w. .rm ^ * mmP | mm- Hmcmm fl wuwëlm Q fl mmnmmwml ^ H> nmw fl æwoE | Nv | ~ P- mw Åämwf | nw ~ Hæ: wwOumduHwEH> umE | N c fl wmumm fl ml ^ HMGwmoumm0nmEH> uwE | NvI ~ O »mc fi s fi mwnwwsæm: w ^ ** øoN I wav fl> cmm fl x0um | m: fi wmuwm fl m | | M | * 0PN I mom H>: ww fl xouwET: c fl wmnmm fl Q | ^ H> c @ w fl NOuwE |: v | P w mm ^ **: oN | mom H> nwmHxouoE | n c fl wmu @ Q fi m | ^ H> cmm fl xouwE | nv | ~ N av & ** POm | am, H> cmmnOHx |: c fl wmH®m fi m¿H>: mmHoHM |: v | ~ w ww ^ * fi NF l NN- H> cmmH0HM | fl c fl umnwc fl ßn ^ fl> GwMn0HM | nv | - M ww ^ * nmF 1 mm H> = wwHoHx | w s fi wmnwm fl @ | ^ H> ø @ «HoHM | wv | F z nu ^: xn0N | Now Hæcwwuoø fl mne c fl wmnøa fi ml ^ H> nmmH0øHw |: v | F G mw ^ ** mæ_ 1> æ_ H>: @ w q fi wm ~ wmHm fi> = ww | _ w mxm fi uanoow o o. _ now> m & Hwäuou HHH s fi wëncw wmí ac .o ~> J @ D. Qxcslu fl mëm 0vswwuwcm> O A Nå a: a: 02E3zwm: mauu _HQæÜmq. 1sez142-1 OH F fifi wßdà H 7803742 ~ 1 topography on silica gel (eluent re-etvïàëÉtat'å 151) išblèrades the desired compound. Recrystallization was from acetone-ether. yield: so%. melting point 128 - 130 °.

As a less polar by-product, which by increasing the amount of acetyl chloride can be obtained as the main product, (t) -1- [§- (3,4,5-trimethoxyphenoxy) -2-acetoxypropyl] -4- (2-acetamidophenyl) - piperazine.

Melting point 540.

Example Gel 25. (-) - 1E§- (3,4,5-trimethoxyphenoxy) -2-acetoxypropyl] -4- (2-acetoxyphenyl) -piperazine 6 g (0,143 moi) (ï) -1 ~ [; - (3,4,5-S-trifluoromethylphenyl) -2-hydroxypropyl] -4- (2-hydroxyphenyl) -piperazine and 2.9 g (0.0286 mol) of triethylamine were dissolved in 80 ml of absolute methylene chloride and added to 0 ° dropwise with a solution of 2.24 g (0.0286 mol) of acetyl chloride in 20 ml of absolute methylene chloride. The reaction mixture was stirred for 2 hours at room temperature and the precipitated triethylamine hydrochloride was filtered off. Then the solvent was distilled off in vacuo and the residue was recrystallized from ether / petroleum ether. Yield: 57%, melting point 700.

Example Gel 26. - (i) -1- [[(3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-aminophenyl) -piperazine 6 g (0.0124 mol) (i) -1E ? - (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-nitrophenyl) -piperazine was dissolved in 300 ml of methanol and hydrogenated in the presence of 0.5 g of Pd-C (10%). at room temperature. After filtering off the catalyst and removing the solvent in vacuo, the product was recrystallized from ethanol. Yield: 94%. Melting point of monohydrochloridenz 181 - 1s3 °.

Examples of racemate cleavage (+) - 1- [1-3 (3,4,5-trimeaoxyphenoxy) -2-nyaroxypropyl] -4- (2-methoxyphenyl) piperazine (base = compound 1a) and (-) - 1- [§ - (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl-4- (2-methoxyphenyl) -piperazine (base = compound 1b). 4.32 g (0.005 mol) of the racemic compound prepared according to Example 1 were dissolved hot in 80 ml of butyl acetate and at 800 4.04 g (0.005 mol) - (-) - di-p-toluoyl-L were added portionwise with vigorous stirring. tartaric hydrate whereby the left-handed diastereomeric salt pair precipitated. The mixture was then heated to 110 DEG C. for a further 10 minutes, the mixture was allowed to cool to 100 DEG C. and the precipitate was filtered off. The salt pair was recrystallized from 50 DEG-374 DEG C. in acetone-dimethylformamide-gasoline (EAJ 20-48.60; 1% in dimethyl-D-formamide) and then cleaved by treatment with concentrated ammonia. Base was extracted with ether and the crucible was evaporated.

The solid residue was recrystallized from isopropanol; 1a-base colorless crystal, m.p. 103 DEG-104 DEG; EQQJ: O + 7.20 (concentration in 2% in CH 3 OH). By dissolving the base in methanol and adding isopropanol-containing hydrochloric acid and ether, the dihydrochloride of the compound Ia was obtained in the form of colorless crystals, m.p. 189-193 °; E¿ [{š ° - 11.4 ° (concentration = 2% 1 cn3on).

The filtrate of the salt pair precipitate containing the right-turning diastereomeric salt pair was evaporated on a rotary evaporator, the viscous residue was slurried in water, added with concentrated ammonia and the base extracted therefrom with ether. The ethereal solution was dried and evaporated and the solid residue was recrystallized from isopropanol: 1b base, colorless crystals, m.p. 100-110 °; Ep] 20 - s.a ° (concentration = 2% 1 cH 3 OH).

D, by dissolving the base in methanol and treating the mixture with isopropanol-containing hydrochloric acid and ether, the dihydrochloride of compound 1b was obtained in the form of colorless crystals, m.p. 182-178 °; EC]: ° + 11, o ° (koooontration = 2% 1 çH3oH).

Example gel gl (f) -1- [3- (3,4,5-trimethoxy-phenoxy% 2-hydroxy-propyl] -4- (2-acetoxy-phenyl) -piperazine CH3O f - \ cH3o o - cnz- CH (OH) - CH 2 - N. N 3 cH 30 f OCO - C53 0.03 mol 1- (2-acetoxy-phenyl) -piperazine (crude product) and 7.2 g (0.03 mol) 3,4,5 -trimethoxy-phenoxy-glycidyl ether was heated in 150 ml of isopropanol until refluxing was complete by thin layer chromatography control.After distilling off the solvent, the hydrochloride was obtained by treatment with isopropanol-containing hydrochloric acid and purified by recrystallization from isopropanol. Yield 18% 7a-os42 42-1 The starting 1- [2-acetyloxy-phenyl] -piperazine was obtained as follows: 192.8 g (1-mol) of 2-methoxyphenylpiperazine, 130 ml (1.1 mol) of bone syl chloride and 150 g (1.0 mol) of potassium carbonate were heated in 300 ml of xylene under reflux until the reaction is complete by thin layer chromatography control, the product is filtered, the solvent is removed in vacuo and the product is transferred was dissolved in the hydrochloride in the usual manner with isopropanol-containing hydrochloric acid (yield: 70%). 60 g (0.2 mol) of the hydrochloride thus obtained were heated in 800 ml of 63% aqueous hydrobromic acid under reflux until the ether cleavage was complete (thin layer chromatography control). Then the solvent was removed in vacuo and the resulting crystalline residue was washed with ether (yield: 70%). From the dihydrobromide, the free base with dilute aqueous ammonia was liberated in the usual manner. 10 g (0.029 mol) of the free base thus obtained and 15 ml of triethylamine were cooled in 50 ml of dioxane to 50 and added dropwise with 0.032 mol of acetyl chloride at a temperature of not more than 10 °.

After stirring for one hour at 100 DEG C., the precipitated triethylamine hydrochloride was filtered off with suction and the solvent was distilled off in vacuo. In the resulting oily free base, the benzyl group was dehydrated without further purification as follows: 0.04 mol of the free base was dissolved in 150 ml of methanol and hydrogenated in the presence of 2 g of 10% palladium on carbon at 500 and 5 bar.

After complete hydrogen uptake, the catalyst was filtered off and the solvent was removed in vacuo. The 1- (2-acetoxy-phenyl) -piperazine thus obtained can be reacted directly without further purification.

In an analogous manner to the above examples, 0.03 mol of 3,4,5-trimethoxyphenoxy glycidyl ether and 0.03 mol of the corresponding piperazine compound each obtained the compounds listed in Table 2. The starting piperazine was obtained on each occasion in an analogous manner to the starting compound in the previous example, using in the acylation step instead of acetyl chloride corresponding to other acid chlorides (benzoyl chloride, cyclohexanecarboxylic acid chloride).

TABLE 2 Piperazine-Rzi formula I o Melting point Yield in% Example starting compound R1 = H (hydrochloride) of the theoretical "1- (2-benzoyl-2-benzoyloxy-194-, 196 ° C 31% 28 oxyphenyl) - piphenyl perazine 1- (2-eyk1 ° - 2-cycloonexy1-151 - 152 ° c 22 z 29 hexylcarbocarbonyloxyinyloxyphenyl) - phenyl piperazine Ekemgel 30 (3) -1- [3- (3,4,5 -trimethoxy-fi-emxy) -2-acetoxy-propyl] -4- (2-methoxy-phenyl) -piperazine io g (0.23 ml) (i) -1- [3- (3,4, s-trimethoxy- phenoxy) -2-nyaroxypropyl] -4- (2-methoxy-phenyl) -piperazine was suspended in 100 ml of xylene, 10 ml of triethylamine was added to the product and then 9 ml of acetyl chloride were slowly added dropwise at room temperature.

The solution was left for 2 hours at room temperature. Then the triethylammonium hydrochloride was filtered off and the solvent was distilled off in vacuo. The obtained crude product was purified by dry layer column chromatography on silica gel (eluent chloroform / methanol 98: 2). The hydrochloride was obtained in the usual manner by treatment with isopropanol-containing hydrochloric acid and recrystallized from isopropanol. Melting point of the hydrochloride 178 - 179 ° C; yield: eo%.

Example gel 31 and 32 - (j) -1- [3- (3,4,5-trimethoxy-phenoxy) -2- (thienyl- (2) -carbonyloxy) propyl] -4- (2-methoxy-phenyl) - piperazine 7863742-1 15 l _cn3o °° 3a; CH 0 O - CH - CH - CH - O - CO - Jis> 15 g (0.0319 mol) (1) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4 - (2-Methoxyphenyl) -piperazine dihydrochloride and 3.3 g of triethylamine were suspended in 100 ml of xylene. With stirring, the mixture was added dropwise with 4.7 g (0.03 l9 mol) of thiophene-2-carboxylic acid chloride at room temperature. Stir for another hour at room temperature. The precipitated triethylammonium hydrochloride was then filtered off and the solution was evaporated under reduced pressure. The residue was taken up in ether and added with isopropanol-containing HCl. The resulting dihydrochloride was recrystallized from isopropanol.

Melting point of the dihydrochloride 198-199 ° (the substance contained 1 mole of isopropanol as crystal solvent). Yield: 42% The corresponding thienyl (3) compound took place in an analogous manner.

Melting point of the dihydrochloride 193 - 1940. Yield: 48% Example gel 33 (i) -1- [3- (3,4,5-trimethoxy-phenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4 - [2- (thienyl- (2) -carbonyloxy) -phenyl] ~ piperazine II oco-lys / Ü H-co oc s 9 / \ I c NN _ -C _ __ * fl sco __ cH2 H H2 Hjco Man suspended 7 g (0.0l67 mol) (1) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-hydroxy-phenyl) -piperazine in 100 ml of dioxane and 4 ml of triethylamine. 5 g (0.034 mol) of thiophene-2-carboxylic acid chloride were added portionwise with stirring at room temperature. After the addition was complete, the mixture was stirred for a further 6 hours and then allowed to stand at room temperature. The triethylammonium hydrochloride formed was filtered off and the solvent was distilled off in vacuo. The residual oily product was taken up in 100 ml of ether, added with isopropanol-containing hydrochloric acid to an acid reaction and the precipitated hydrochloride was filtered off with suction. For purification, the mixture was recrystallized from isopropanol. Yield: 61%. Melting point of the hydrochloride 221 - 222 °.

Claims (3)

'? 7eaz742-1 CLAIM Process for the preparation of compounds of the general formula 'CH 1. 3. cnao o-cnz-gn-cna-N n-nz I I cnao OR, \ - / wherein R 1 represents hydrogen, alkanoyl with 2. - 6 carbon atoms, alkenoyl med 3 to 6 carbon atoms, benzoyl, alkoxybenzoyl having 1 to 4 carbon atoms, nicotinoyl or thienylcarbonyl and R 2 represents a phenyl, naphthyl or pyridyl group optionally substituted by the groups R 3 and R 4, wherein R 3 and R 4 are the same or different and represent hydrogen , hydroxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, amino, acylamino or acyloxy, wherein in the latter two groups acyl may be an acyl group indicated for R1, and their salts, characterized in that a compound of the formula cußc ~ is reacted. _ j 01130 / \ or II _ cußo '__ with a compound of the formula' / I 2 z-N NR '^ III \ __ /. wherein Y and Z are always different and either represent hydrogen or the group -CH 2 -CH (OR 1) -CH 2 -V, wherein V represents chlorine, bromine or iodine or, if R 1 represents hydrogen, together with the hydroxy group also -_... ......._ .. 7. - ...........- _ 1aas742-1 f * - _. 'I s nu nu - »» .- -. form an ethylene oxide ring, and optionally reduce one or two nitro groups to amino groups and / or acylate the obtained compounds with an acid resp. an acid derivative corresponding to the group R1, and that the compounds obtained are optionally transferred to their acid addition salts.