DE2116213A1 - Piperazine derivatives - Google Patents

Description

Or. Ina. A. vender Weift Dr. ^r ruiwi LciöfOf

PATEN ί LAWYER!

April 2nd 1971

RAN 4008/166

F. Hoffmann-La. Roche & Co. Aktiengesellschaft, Basel / Switzerland Plural derivatives

The present invention relates to piperazine derivatives of the formula

-CH ₂ -CHOH-CH ₂ -

-OH,

in which R denotes the fluorine or chlorine atom, which are at least partially present as optical (-) antipodes, as well as acid addition salts of these compounds,

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which are prepared according to the invention by a compound of the general formula.

'-CH ₂ -CHOH-CH ₂ -R

II

in which R has the meaning given above, R means a leaving group or together with the Hydroxyl group forms an oxygen bridge,

with l- (p-methoxyphenyl) piperazine reacts, or that one Compound of the general formula

III

in which R has the meaning given above with a compound of the general formula

R ² -CH -CHOH-CH -N \

2
in the row a leaving group

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INSPECTED

means or forms an oxygen bridge together with the hydroxyl group,
is reacted, or that a compound of the formula

in which R has the above meaning, with a compound of the formula

VI

in which R denotes a leaving group , or that one is a compound of the formula

-CH ₂ -CHOH-CH ₂ -NH ₂

VII

In which R has the above meaning with a compound of the formula

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R-CH ₂ -CH ₂

R-CH ₂ -CH ₂

VIII

in which R denotes a leaving group , or that one is a compound of the formula

.CH ₂ -CHOH-CH ₂

N /

IX

in which R has the above meaning, methylated, whereupon a obtained (-f) -antipode of a compound of the formula I is carried out Racemization converted into the corresponding racemate, if desired the (-) - antipodes from a resulting racemate separates and, if desired, traps a obtained base into a Acid addition salt transferred "

The above-mentioned leaving groups are preferably halogen atoms, preferably chlorine or bromine, or else Alkylsulfonyloxy groups, for example methanesulfonyloxy, or arylsulfonyloxy groups, such as benzenesulfonyloxy or

p-toluenesulfonyloxy.

1 09845/1 926

It has been found that the compounds of the formula I which can be prepared according to the invention and their acid addition salts, which represent new compounds, are distinguished by a particularly strong psychosedative effect, the effect being predominantly linked to the (-) - antipodes. Special mention should be made of the psychosedant effect of rac. and (-) - 4- ^ 3- [4- (p-methoxyphenyl) -l-piperazinyl] -2-hydroxypropoxyj-4 ^f -fluoro-benzophenone.

The (+) - antipodes of the compounds of the formula I and their acid addition salts are also the subject matter of the present invention Invention. They are intermediate products for conversion into the corresponding racemates or (-) - antipodes. This implementation is explained in more detail below.

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The benzophenone derivatives of the formula II used as starting compounds can be prepared, for example, in such a way that a corresponding 4-halo-benzoyl halide is mixed with an alkoxybenzene according to Friedel-Crafts, ie with the aid of a Lewis acid, such as, for example, alurainium chloride, zinc chloride, boron trifluoride, etc. reacted, dealkylated and the V-halogenated 4-hydroxybenzophenone of the formula III formed, preferably with an excess of an epihalohydrine, W in particular with epichlorohydrin, preferably in the presence of a catalytically effective amount of an organic base, such as piperidine, at elevated temperature, preferably at approx. 100 ⁰ C, is reacted, the obtained crude compound of formula II, in which R represents halogen, by treatment with strong aqueous Alkallen such as caustic soda, to be closed at room temperature to an oxirane ring. If desired, this oxirane ring can be opened again by reacting with an alkylsulfonic acid (for example methylsulfonic acid) or with an arylsulfonic acid (for example p-tolylaulfonic acid). This gives ■ starting compounds of the formula II in which R is alkylsulfonyloxy or arylsulfonyloxy.

The. Reaction of compounds of the formula II with l- (p-methoxyphenyl) -plperazln takes place expediently in a

1QSSA5 / 1926

Temperature between room temperature and the boiling point of the reaction mixture, especially at about 60-100 C. It is expedient, the reaction in a polar »organic Solvent, e.g. in an alkane, such as methanol, ethanol or isopropanol, or in a cyclic ether, such as Tetrahydrofuran or dioxane to carry out.

The compounds of the formula II are preferably reacted with 1- (p-methoxyphenyl) -l-piperazine in a polar, organic solvent. The reaction temperature is expediently between room temperature and the boiling point of the reaction mixture. Preference is given to an elevated temperature worked. If R is a leaving group, the reaction is preferably carried out in the presence of an acid-binding agent such as potassium carbonate.

Compounds of the formula IV can be prepared, for example, by adding l- (p-methoxyphenyl) piperazine with an epihalohydrin in the presence of an alkanol such as

Methanol to a compound of the formula IV in which R is halogen represents, implements. Oils obtained compound can through Treat with strong aqueous alkalis at room temperature to close an «oxirane ring. If desired, can this oxirane ring again by reaction with an alkyl sulfonic "* ur" (e.g. methyl sulfonic acid) or with an aryl sulfonic acid

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(e.g. p-tolylsulfonic acid). One obtains Starting compounds of the formula IV, In which R is alkylsulfonyloxy or Aryleulfonyloxy mean «

Oils compounds of the formulas III and IV can be reacted with one another under the conditions mentioned for the reaction of the compounds of the formula II with l- (p-methoxyphenyl} -piperazine. If R ^{2 is} a leaving group, the compounds of the formula are carried out IXX in two-fluid form initially into an alkali metal salt, for example in the sodium or potassium salt.

The starting compounds of the formula V are activated by reacting the corresponding 4- (2,3-epoxy-propoxy) -Jl'-halo-foenzophenone with abhylenimine and subsequent reaction of the βrhe. 1 tenon Λ-O-aziridinyl-2-hydroxy-propoxy) ~ 4'-halobenzophenone obtained with p-anisidine. Both reaction steps are preferably carried out in a lower alkanol (z * B. Methanol) 'at a temperature between about ⁰ · O O ⁰ C and about 50. The last reaction step is preferably carried out in the presence of an acid, such as maleic acid, a hydrohalic acid (eg hydrochloric acid), trifluoroborohydrate acid or a boron trifluoride-acetic acid complex.

The starting compound of the formula V can also be obtained by 109845/1926

Reaction of the corresponding K- (2,3-epoxy-propoxy) -V-halogenobenzophenone with N- (2-aminoethyl) ~ p-methoxyanilln can be obtained.

The reaction of the compounds of Poreeln V and VI takes place with advantage in a polar, organic solvent, such as in a lower alkanol (eg «methanol, ethanol)
or in dimethylformamide, dimethyl sulfoxide or tetrahydrofuran. The reaction temperature is expedient
between approx. 50 ⁰ C and the boiling point of the reaction mixture. The reaction is advantageously carried out in the presence of an acid-binding agent, for example in the presence of an alkali metal carbonate or hydroxide, for example potassium carbonate or sodium hydroxide. According to preferred embodiments, 1,2-dichloro, 1,2-dibromo or 1,2-ditosyloxyethane are used as starting compounds of the formula VI.

The starting compounds of the formula VII are expediently prepared starting from the corresponding 4- (2,3-epoxy-propoxy) -4'-halogen-benzophenones. The latter can be converted into the corresponding N- {3-Cp- (p'-halobenzoyl) -phenoxy] -2-hydroxypropyl] -succinimides by reaction with Suoclnimld, advantageously in a lower alkanol - (3-Amino-2-hydroxy-propoxy) -4 ^t -halogenobenzophenones of the formula VII pass over. The hydrolysis can be caused by the action of acidic

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. (e.g. hydrochloric acid) as well as basic (e.g. sodium hydroxide) Funds are carried out

The subsequent reaction of the compounds of the formulas VII and VIII is preferably carried out in a polar, organic solvent, such as in a lower alkanol (for example methanol, ethanol) or in dimethylformamide, dimethyl sulfoxide or tetrahydrofuran. The W temperature is expediently between about 50 ° C. and the boiling point of the reaction mixture. The reaction is advantageously carried out in the presence of an acid-binding agent, for example in the presence of an alkali metal carbonate or hydroxide, for example in the presence of potassium carbonate or sodium hydroxide. The starting compounds of the formula VIII are preferably p- [bis- (2-chloroethyl) -amino! -Anisole, p- [bis- (2-bromoethyl) -amino] -anisole or p- [bis- (2-tosyloxyethyl) - amino] -anisole used.

The starting compounds of the formula IX can be prepared, for example, by reacting l- [p-hydroxyphenyl) piperazine with the corresponding 4- (2,3-epoxy-prop * »xy) -4 '-halo-benzophenones obtain. The reaction is advantageously carried out in a polar, organic solvent, e.g. in a lower alkanol, or in a cyclic ether such as Dloxan.

The resulting starting compounds of the formula IX are

1Q88A5 / 192S

then methylated. The methylation takes place, for example, by converting a compound of the formula IX into an alkali metal salt, e.g. the sodium or potassium salt, and this is then, preferably in wtfssrlg-alkaline solution, reacted with dimethyl sulfate * You can also convert the compound of the formula IX into an alkali metal alkanolate solution, for example in a sodium ethylate or potassium ethylate solution and the goose soaked in dimethyl sulfate or one Compound of formula

CR.X

in which X is a leaving group such as halogen, alkylsulfonyloxy or arylsulfonyloxy,

in the presence of an alkali metal hydride, preferably sodium hydride. Methyl bromide or methyl iodide are preferred used as a methylating agent. A third method consists in the methylation of a compound of formula IX with diazo "" than. The compound of formula IX then lies preferably in solution with a lower alkenol, such as Methanol, ethanol, while the diazomethane is used used in essential solution. -

The methylation described above is carried out at a low temperature. Temperatures between ⁰ ° C. and 40 ° C. are preferably used.

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If, according to the invention, an optical (+ -J-antipode of a starting compound of the formula II, IV, V, VII or IX is used, the (Ή-form of a compound of the formula I) is obtained. This has to be racemized. The racemization can be done after prior protection the keto group (by treatment with N, N-dimethylhydrazine and subsequent quaternization of the Ν, Ν-dimethylhydrazone group with methyl iodide) by oxidation of the hydroxyl group of the side chain to the oxo group * using dimethyl sulfoxide and acetic anhydride and subsequent reduction of the oxo group obtained with the aid of an alkali metal borohydride, _s are followed by removal of the quaternary Ν, Ν, Ν-Trimethylhydrazingruppe carried out by mild alkali another method consists in the Auetausch

Hydroxy group on the side chain by chlorine with the help of thionyl chloride in chloroform. After treatment with alkanoll shear Sodium hydroxide solution will restore the introduced chloro atom exchanged for hydroxyl, with the formation of a product which contains the {-) - tefclpod®n of a compound d @ r formula I.

EIr? Any hacemat that may arise can be transferred to the usual Ways to be sown, for example by implementing the Base with an optically active acid, e.g. with {+) - or (-) - tartaric acid or derivatives thereof, e.g. {+) - or {-) - 0, Q-DibenzoylweinsMur®, («* ■) - or (-) - * - bromocamphor sulfonic acid etc. The mixture of the two opti @ oh @ n isomers can be obtained by means of wisderholte, fractionated Separated crystallization and the

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desired (-) - antipode to be isolated.

The bases of the formula I obtained form salts with both inorganic as well as organic acids, e.g. with hydrogen halide acid, such as hydrochloric acid, hydrobromic acid, Hydroiodic acid, with other mineral acids such as sulfuric acid, phosphoric acid, nitric acid, as well as with organic Acids such as tartaric acid, citric acid, oxalic acid, camphorsulphonic acid, ethylsulphonic acid, tolylsulphonic acid, Salicylic acid, ascorbic acid, maleic acid, mandelic acid, etc. Preferred salts are the hydrohalides, especially those Hydrochloride. The acid addition salts are preferably in a suitable solvent, such as ethanol or acetonitrile, by treating the free base with the appropriate non-aqueous acid.

The bases of the formula I are crystalline, solid substances that are in Dlmethylsulfoxid, dimethylformamide or in chlorinated Hydrocarbons such as chloroform, methylene chloride, soluble and in water, methanol, ethanol, benzene and petroleum ether are relatively insoluble.

The acid addition salts of the bases of the formula I are likewise crystalline, solid substances. You are in Dimethylsulfoxld and dimethylformamide and soluble in water, methanol, ethanol, benzene, petroleum ether and in chlorinated hydrocarbons

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Substances such as chloroform, methylene chloride are relatively insoluble.

To demonstrate the psychosedant effect, the preparations to be tested were on the rat in the so-called "open field" · Test [Psychopharmacologia 1, 3Ö9-392 (i960)] tested. the Dose showing a 50 # decrease in the number of diameter crossings (diameter crossings) compared to untreated controls is reported as ED. Result: rac. 4-p- C4- (p-methoxyphenyl) -1-piperazinyl] -2-hydroxypropoxyj-V-fluoro-benzophenone: ED = 1.8 mg / kg p.o. (-) -4- | 3-E4- (p-methoxyphenyl) -1-piperazinyl] -2-hydroxypropoxyj ^ '- fluoro-benzophenone: ED = 1.8 mg / kg p.o.

The psychosedant effect of the process products was also proven by hand. The preparation rac. 4- [3- [4- (p-Methoxyphenyl) -1-piperazinyl] ] -2-hydroxy-propoxy i-4 '-f luoro-benzophenone administered orally (with the stomach tube). When applied, the preparation was dispersed in gum arabic. Three different Dogs received a dose of 10 mg of active ingredient per kg of body weight. They all showed the following Behavior that is typical of a psychosedated state:

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After about 1/2 hour

Onset of action: The previously lively dogs are very quiet, but still respond to call.

After about 1-1 1/2 hour

Effect maximum: The dogs lie with closed Eyes and do not respond to call *

After approx. 2 1/2 - 6 1/2 hours

Wirkungsqjnde t The dogs are, but are quieter than before the experiment.

The following day all dogs behaved as they did before the experiment. Adverse side effect / could occur during and after Attempt cannot be determined.

Even with the administration of 3 mg of active ingredient per kg of body weight the behavior described above could be clearly observed.

The absence of adverse side effects is consistent with the low acute toxicity measured in mice:

rac. 4-13-C4- (p-methoxyphenyl) -1-piperazinyl] -2-hydroxypropoxy | -4'-fluoro-benzophenone:

LD ₅₀ PO »3700 mg / kg (after 2k hours)

LD ₅₀ p, o. * 2100 mg / kg (after 10 days). 109845/1926

The compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations which use them or their salts in admixture with one for the enteral Application of suitable pharmaceutical, organic or inorganic inert carrier material, such as gelatin, Gum arabic, lactose, starch, magnesium stearate, talc contain vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations are preferably in solid form fc e.g. as tablets, coated tablets, suppositories or capsules. They can also contain other therapeutically valuable substances.

Contain optional pharmaceutical dosage forms about 5 to 100 mg of a compound of the formula I «Expedient oral dosage ranges are about 0.1 mg / kg per day up to about 10 sng / kg per day. Up to the ranges mentioned can, however, be extended upwards or downwards, depending on the individual needs of the patient and those of the specialist given instruction.

example 1

27 * 2 g ^ - (2 _i 3-epoxy-prepoxy) -4'-fluorine .ber! Sophenon and 19.2 g »(p-methxy-ph @ nyl) -piperazine are added together with 500 ml of ethanol Heated under reflux conditions for 1 hour. After cooling Kardas filtered the deposited crystals

and washed with a little ether. Rac. k- (3-1 k ~ (p-

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Methoxyphenyl) -1-piperazinyl] -2-hydroxy-propoxyj-4'-fluorobenzophenone, which melts ^{at 149-150 o C after recrystallization from acetonitrile.}

The 4- (2,3-epoxypropoxy) -4'-fluoro-benzophenone used as the starting material can be made as follows:

23 g of 4-methoxy-4'-fluoro-benzophenone are in a hot Mixture of 30 ml of glacial acetic acid and 60 ml of 65 # hydrobromic acid entered with stirring and heated under reflux conditions with further stirring. The still hot solution will open Poured approx. 200 ml of water, whereby a precipitate forms. The mixture is filtered after cooling. The residue is washed neutral with water and in excess, warm, 3-N sodium hydroxide solution dissolved. The solution is extracted with chloroform. The aqueous phase is acidified with concentrated hydrochloric acid. The crude product which separates out is filtered, washed neutral with water and made from a mixture of water and Recrystallized ethanol (1: 3). 4-Hydroxy-4'-fluorobenzophenone is obtained in the form of crystals that melt at 170-172 ° C.

21.6 g of 4-hydroxy-4'-fluoro-benzophenone, 40 ml of epichlorohydrin and 0.3 ml of piperidine are stirred at 100 ° C. for 12 hours. The excess of epichlorohydrin is evaporated under reduced Druek at 80 ⁰ C. The residue is dissolved in about 50 ml of chloroform and with a solution of 4 g of sodium hydroxide in

1098A5 / 192B

10 ml of water shaken for one hour. The aqueous phase is separated off, ma the organic phase is washed with water until a neutral reaction *, dried over potassium carbonate and evaporated. After recrystallization from methanol, 4 "# (2 _i 3-epoxy-» propoxy) -4 ^t -fluoro-benzophenone is obtained in the form of crystals which melt at 10-5-1O6 ° C.

Example 2

In the same way as indicated in Example 1, 4- (2,3-epoxy-propoxy) -4 ^l -chloro-benzophenone and l- (p-methoxyphenyl) -piperazine rac are obtained. 4- {3-f ^ T (p-methoxyphenyl) -1-piperazinyl1-2-hydroxy-propoxyt-4 "-chlorobenzophenone, which melts at 150-151 ⁰ C after recrystallization from ethanol.

The 4- (2,3-epoxy-propoxy) -4! -Chlorobenzophenone used as starting material can be prepared in analogy to the information in Example 1. Melting point 116-117 ° C (from ethanol)

Example 3

1 g of ty-hydpoxy-V-fluoro-benzophenone is dissolved in a solution entered of 120 mg of sodium in 20 ml of absolute ethanol. A solution of 1.4 g of rac is added to this solution. 1- (2-Hydroxy-3-chloro-propyl) -4- (p-methoxyphenyl) -piperazine in 10 ml of absolute ethanol. The mixture thus obtained is then 1.5 hours

109845 / 192S

heated under reflux conditions, after cooling, rac · 4-f 3-lk- (p-methoxyphenyl) -l-piperazinyl] -2-hydroxypropoxy ^ -4'-fluoro-benzophenone is obtained in the form of crystals, which after the Recrystallize from acetonitrile at 149-150 C melt.

The rac used as starting material. 1- (2-Hydroxy-3-chloro-propyl) -4- (p-methoxyphenyl) -piperazine can be made as follows:

3.8 g of l- {p-methoxyphenyl) piperazine are in 20 ml Dissolved methanol and treated with 2 g of epiohlorohydrin. That The reaction mixture remains at room temperature for 24 hours, the crude product separating out in crystalline form. To filtration and recrystallization from methanol gives pure rac. l- (2-Hydroxy-3-ehlor-prx> pyl) -4- (p-methoxyphenyl) -piperazine, which melts at 111-111.5 ° C.

Example 4

In the same way as indicated in Example 3, using 4-hydroxy-4'-chloro-benzophenone and rac. 1- (2-Hydroxy-3-chloro-propyl) -4- (p-methoxyphenyl) -piperazine rac. 4- (3- [4- (p-methoxy-phenyl) -1-piperazinyl] -2-hydroxyprops "3TY ^ -4 ^f -ohlor-benzophenone, the sohmilzt after recrystallization Äethanol at 150-151 ⁰ C.

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Example 5

0.5 g rac. 4-p- £ (2-p-anisidinoethyl) amino] -2-hydroxypropoxy) -4'-fluoro-benzophenone and 0.2 g of 1,2-dibromoethane are heated on the steam bath for 24 hours. After cooling, it will Reaction mixture mixed with ether and filtered from insoluble components. After evaporation of the ether, the residue becomes mixed with chloroform and 3N ammonia solution. the organic phase is dried over potash and the solvent is evaporated under reduced pressure. The residue becomes ail silica gel with absolute ether as the mobile phase chromatographed. The pure rac.4- / 3- [4- (p-methoxyphenyl) -1-piperazinyl] -2-hydroxypropoxy obtained j-4 '-fluorobenzophenone melts at 142 ° C.

The rae.4- | 3 - [(2-p-anisidinoethyl) used as starting material amino] -2-hydroxy-propoxy j-4 '-f luoro-benzophenone can be made as follows:

8.1 g of 4- (2,3-epoxy-propoxy) -4'-fluoro-benzophenone and 30 g of ethyleneimine are stored in 200 ml of methanol for 24 hours at room temperature. The excess Aethylenlmin and the solvent is evaporated under reduced pressure and the residue is recrystallized from ethyl acetate-petroleum ether. The obtained rac.4- [3- (1-aziridinyl) -2-hydroxypropoxy] -4'-fluoro-benzophenone melts after a second

117-118 c. 109845/1926

crystallization at 117-118 C.

2,6-g rac.4- [3- (1-aziridinyl) -2-hydroxy-propoxy] -4'-fluorobenzophenone, 1.1 g of p-anisldine and 2.5 g of maleic acid are stored in 18 ml of methanol for 4 days at room temperature, with crude rac.4- / 3 - [(2-p-Anisidlnoethyl) amino] -2-hydroxy-propoxyJ-4'-fluorobenzophenone maleate crystallized out. Crystallization is completed by refrigeration. That Product melts after recrystallization from ethanol

Example 6

1,6-g rac.4- (3-amino-2-hydroxypropoxy) -4'-fluorobenzophenone hydrochloride, 1.7 g of bls-N, N- (2-bromoethyl) -p-anie ± din and 0.6 g of sodium hydroxide in 30 ml of n-butanol are added for 24 hours heated under reflux conditions and filtered hot. The rac.4- {3- [4- (p-methoxyphenyl) -l-piperazinyl] -2-hydroxy-propj »xy which crystallizes on cooling and trituration j-4'-fluorobenzophenone melts after recrystallization from methanol at 147 ° C.

The rac.4- (3-amino-2-hydroxypropoxy) -4'-fluoro-benzophenone hydrochloride used as starting material can be made as follows:

2.7 g of 4- (2,3-epoxy-propoxy) -4'-fluoro-benzophenone and 1.0 g of succinimide are heated in 20 ml of ethanol for 5 hours under reflux conditions. That crystallizes out on cooling

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N- | 3- [P- (p-fluoro-benzoyl) -phenoxy] -2-hydroxy-propylI-succinimide melts after recrystallization from ethanol

13 * 6 g of N- {3- £ p- (p-Flu ° ^r benzoyl) -phenoxy] -2-hydroxypropyl ^ -succinimide are added to 100 ml.konzentrierter hydrochloric acid and heated for 16 hours under reflux conditions. After the excess hydrochloric acid has been evaporated off under reduced pressure, the residue is made alkaline with 1N sodium hydroxide solution. The crude base is filtered, dissolved in methanol and converted into the corresponding hydrochloride by adding ethanolic hydrochloric acid. The resulting rac.4- (3-amino-2-hydroxypropoxy) -4'-fluoro-benzophenone hydrochloride melts after recrystallization from methanol at 250-251 ° C.

Example 7

0.5 g of rac.4- ^ 3- [4- (p-Hydroxy-phenyl) -l-piperazinyl] -2- w hydroxy-propoxyl-V-fluoro-benzophenone are dissolved in 100 ml of methanol and with excess solution of Diazomethane added to ether. The solution remains at room temperature for about 12 hours and is evaporated under reduced pressure until crystallization begins. The resulting rac.4- / 3- [4- (p-methoxyphenyl) -1-piperaziny 1] -2-hydroxy-propoxyf -4'-fluorobenzophenone melts after recrystallization from methanol

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The rac.4- £ 3-f4- (p-hydroxyphenyl) used as starting material -1-piperazinyl] ^ -hydroxy-propoxyi ^ '- fluorobenzophenone can be made as follows.

5.5 g 4- (2,3-epoxy-propoxy) -4'-fluoro-benzophenone and 3.6 g of l- (p-hydroxyphenyl) piperazine are dissolved in 40 ml of ethanol Maintained under reflux conditions for 1 hour. The solvent is evaporated off under reduced pressure, the oily residue acidified with ethanolic hydrochloric acid and crystallized with ethyl acetate. The thus obtained rao.4- £ 3- [4- (p-hydroxyphenyl) -1-piperazinyl] -2-hydroxypropoxy} 4'-fluoro-benzophenone melts after recrystallization Water at 134-186 ° C.

Example 8

A hot solution of 3 * 9 S rac.4- {3 - [^ - (p-Methoxyphenyl) -l-piperazinyl] -2-hydroxy-propoxyj-4'-fluoro-benzophenone and 3.1 g of (+) - 0,0-dibenzoyltartaric acid in 350 ml of methanol are allowed to cool slowly to room temperature. The separating Salt of (-) - 4- {3- [4- (p-Methoxyphenyl) -1-piperazinyl] -2-hydroxy-propoxyj-4'-fluoro-benzophenone with (+) - 0,0-dibenzoyltartaric acid is suction filtered and recrystallized from methanol. Melting point 178-180 ° G (dec.).

- + 51.6 ° (m dioxane, c = l).

1098A5 / 1926

2118213

Example 9

Production of capsules with the following composition:

rac .4- [3- [4- (p-Methoxyphenyl) -1-piperazinyl] -2-hydroxy-

propoxyj-4 ^! -fluoro-benzophenone IQ mg

Mannitol 110 mg

Talc 5 mg

fc The active ingredient becomes homogeneous with the talc and mannitol mixed, through a No. 5 (mesh size about 0.23 now) happened and mixed again. The mixture obtained is filled into gelatin capsules No. 4.

Example 10

Production of coated tablets with the following composition:

rac.4- {3- [4- (p-Methoxyphenyl) -1-piperazinyl] -2-

hydroxy-propoxyj-fyi-fluoro-benzophenone 25 mg

Mannitol 100 mg

Painting starch 20 mg

Talc 5 mg

150 mg

The active ingredient is mixed with mannitol and poured through a Sieve N0.5 (mesh size about 0.23 now) happened. From the corn starch a 10 | 5 aqueous paste is prepared and

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mixed homogeneously with the ManAit ^ active ingredient mixture. The slightly moist liquid is filtered through a No. 2 (mesh size about I mm ₄ O) happens. The granulate obtained is dried and, after adding the talc, is pressed into biconvex cores weighing 150 mg. The kernels can be coated with a sugar layer in the usual way by sugar-coating.

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Claims (1)

Claims . Process for the preparation of piperazine derivatives of the formula -CH ₂ -CHOH-CH ₂ - -OH. in which R denotes the fluorine or chlorine atom, at least some of which are present as optical (-) antipodes, and acid addition salts of these compounds, characterized in that a compound of the general formula -CH-CHOH-CH-R ' II in which R has the meaning given above, R means a leaving group or an oxygen bridge together with the hydroxyl group forms, reacts with l- (p-methoxyphenyl) piperazine, or that nan a Compound of the general formula 109845/1926 III in which R has the meaning given above with a compound of the general formula R ² -CH -CHOH-CH -N \ in the row a leaving group means or forms an oxygen bridge together with the hydroxyl group,
converts, or that a compound of the formula , 0-CH ₂ -CHOH-Ch-NH-CH ₂ -CH ₂ -NH- ^ in which R has the above meaning, with a compound of the formula R ⁵ -CH ₂ -CH ₂ -R ⁵ VI 109845/1926 in which R- ^{5 means} a leaving group, converts, or that a compound of the formula '-CH ₂ -CHOH-CH ₂ -NH ₂ in which R has the above meaning with a compound of the formula 4th
R-CH ₂ -CH ₂ VII VIII in which R means a leaving group,
converts, or that a compound of the formula '-CH ₂ -CHOH-CH ₂ - IX in which R has the above meaning, me thy Her t, whereupon one obtained a (+) - antipode of a compound of the formula I. 109845/1926 Racemization converted into the corresponding racemate, if desired the (-) - antipodes are separated off from a resulting racemate and, if desired, a base obtained is converted into one Acid addition salt transferred. 2. The method according to claim 1, characterized in that that one uses a starting compound, in which one at most oxy leaving group present halogen, alkylsulfonyl / or aryloxy sulfony l / represents. 3. The method according to claim 2, characterized .gekiert, that you have a starting compound of formula II, III, V, VII or IX uses, in which R represents the fluorine atom. 4. The method according to claim 2, characterized in that that 4- (2,3-epoxy-propoxy) -4'-fluoro-benzophenone with converts l- (p-methoxyphenyl) piperazine. 5. The method according to claim 2, characterized in that 4- (2-hydroxy-3-halo-propoxy) -4 * -fluoro-benzophenone, 4- (2-hydroxy-3-mesyloxy-propoxy) -4'- fluon-tenzophenone or 4- ^ 2-hydroxy-3-tosyloxy-propoxy) -4 ^f -fluoro-benzophenone with 1- (p-methoxyphenyl) -piperazine. 6. The method according to claim 2, characterized in that 4-hydroxy-4'-fluoro-benzophenone is reacted with 1- (2,3-epoxypropyl) -4- (p-methoxyphenyl) piperazine. 109845/1: 926, γ. Process according to claim 2, characterized in that 4-hydroxy-4 ^l -fluoro-benzop] aenone with 1- (2-hydroxy-3-halo-propyl) -4- (p-methoxyphenyl) -piperazine, 1 - (2-Hydroxy-3-mesyloxypropyl) -4- (p-methoxyphenyl) -piperazine or 1- (2-hydroxy-3-tosyloxypropyl) -4- (p-methoxyphenyl) -piperazine implements · · 8. The method according to claim 2, characterized in that that 4-hydroxy-4'-fluoro-benzophenone with 1- (2-hydroxy-3- chloropropyl) -4- (p-methoxyphenyl) piperazine converts. 9. The method according to any one of claims 2-8, characterized in that a racemate of the starting compound of the formula II, IV, V, VII or IX is used and the end product of the formula I is isolated as a racemate. • 10. Method according to one of claims 2-9, characterized in that * indicates that a racemate can be converted into a Compound of formula I by fractional crystallization, e.g. 3, with (+) -OiO-dibenzoyl white acid, the (-) - antipodes of the compound of the formula I separates. - ■ ..- " 109845/1926 11. A process for the production of preparations effective on the nervous system, characterized in that that you can get a compound of the formula -CH ₂ -CHOH-CH ₂ - -OH, in which R denotes the fluorine or chlorine atom, which is at least partially present as an optical (-) antipode, or an acid addition salt of this compound using solid or liquid carriers customary in pharmacy in a form suitable for medical administration, preferably in the form of tablets, coated tablets, suppositories, etc. brings. 12. Preparation with activity on the nervous system, characterized in that it contains a compound of the formula CH ₂ -CHOH-CH ₂ - OCH. 109845/1926 in which R denotes the fluorine or chlorine atom, which is at least partially present as an optical (-) antipode, or an acid addition salt of this compound. 109845/1926 COPY 13. Piperazine derivatives of the formula , 0-CH ₂ -CHOH-CH ₂ -N -OCH- in which R denotes the fluorine or chlorine atom, at least some of which are present as optical (-) antipodes, and acid addition salts of these compounds. 14. rac. h- [j> - [h- (p-methoxyphen "!) - 1-piperazinyl 1 -2-hydroxypropoxyl-4'-fluoro-benzophenone, and acid addition salts of this compound. 15. (-) - 4- [j5- [4- (p-Methoxyphenyl) -1-piperazinyl] -2-hydroxy-propoxyj-4'-fluoro-benzophenone, as well as acid addition 'y * salts of this compound. COPY
BATH ORIGINAL