DE2432030C3 - 1- (3-Acetylaminopropyl) -4- (2,5dichlorphenyO-plperazine, their salts, process for their preparation and pharmaceutical agents - Google Patents

Description

N N-CH ₂ CH ₂ CH ₂ NHCOCHj (I)

Cl

and its physiologically acceptable salts with acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se

a) an acylating agent on H3-aminopropyl) -4- {2,5-dichlorophenyl) piperazine lets act or

b) 4 - (2,5 - dichlorophenyl) - 1 - piperazino - propionitrile subjected to an acetylating reduction or

c) a compound of the general formula XCH ₂ CH ₂ CH _{2 NHCOCH 3} Γ in which X is a group that can be split off, allows (2,5-dichlorophenyD-piperazine to act or

Cl

d) Acedamid with a compound of the general formula

Cl

; -N N-CH ₂ CH ₂ CH ₂ X (V)

Cl

in which X is a group that can be split off,

lets react or
e) 1 - (3 - diacetyl - aminopropyl) - 4 - (2.5 - di-

chlorphenyD-piperazine of a partial acidic

or subjected to alkaline hydrolysis or 1 - (3 - acetylaminopropyl) - 4 - (m - chlorphe-

nyl) -piperazine chlorinated or o) 2,5-dichloroaniline with a compound of

general formula

XCH, CH,

NCH ₂ CH ₂ CH ₂ NHCOCh ₃ (VIII)

XCH ₂ CH ₂

in which X is a leaving group, reacts or

h) a compound of the general formula XCH ₂ CH ₂ X. in which X is a removable group. with the compound of the formula

-NHCH ₁ CH ₁ NHCh ₁ CH ₁ CH ₁ NHCOCH,

(IX)

Cl

reacts and, if appropriate, converts the compound of the formula I into its physiologically acceptable salts with acids.
3. A pharmaceutical agent, consisting of a compound according to claim 1, and pharmaceutically customary carrier substances and / or diluents.

Acylating agent (acetic anhydride, acetyl halide, ketene) to a substance of formula II

Cl

-N N-CH ₂ CH ₂ CH ₂ NH ₂ (II)

or (b) by acetylative reduction of the compound of formula III
Cl

The invention relates to 1-13-acetylaminopropyl) -4- (2.5-dichlorophenyl) piperazine the form! 1

N-Ch ₁ CH ₁ CH ₁ NHCOCH ₁ (1)

f VN. N-CH ₂ CH ₂ CN (HI)

Cl

or (C) by the action of a compound of the general formula

XCH ₂ CH ₂ Ch ₂ NHCOCH.,

wherein X is a removable group, on Di chlorophenyl-piperazine of the formula IV

Cl

its physiologically compatible salts with acids. Process for their manufacture and pharmaceutical agents.

The compounds I according to the invention can la) in a manner known per se by action: one -N NH

(IVl

■ egg

oiler Uli through the action of acetamide on a ver

3 previous year 4

Binding of the formula V _{or (f) by chlorination of the} compound of the formula VII

^ - .— ^ ■ '"( / -N N-CH ₁ CHXh ₁ NHCOCH, (Viii

/ -N "N-CHXH ₁ CH ₁ X (V) ⁵ ^ p '" ^

W- v_. _C1

Cl or (g) by the action of 2,5-dichloroaniline

, a compound of formula VIII

in which X is a removable group, or (e),, ₀

by partial acidic or alkaline hydrolysis of the XCH ₂ CH ₂

Compound of formula VI N-CH ₂ CHXH ₂ NHCOCh, (VHIi

? COCH ₁ XCH ₁ CH ₂

.-—. . — Ν / '5 "

, / ^N * —Nj N - CHXH ₁ CH ₁ N (VI)> n where X is a removable group, or lh)

X = / - "\ by the action of a compound of the formula

■ COCH XCHXH ₂ X, in which X is a leaving group.

Cl ³ to the compound of formula IX

CI

^^ - NHCHXH ₂ NHCHXHXH ^ nHCOCH, ι IXi Cl

and optionally subsequent conversion of the with a compound of formula 11 during a

Compounds of general formula i in their rather long warming period or the same

Physiologically compatible salts with mil acids can be produced by reacting diacelylamine with a

will be presented. Compound of formula V are produced.

The abovementioned cleavage- The compound according to formula VIl can be obtained from the

free groups halogen atoms, such as, for example, the already known compound 1- (3-aminopropyll-

Chlorine or bromine atoms or alkyl or aryl sulfone 4- (m-chlorophynylV-piperazine by treatment with

acid groups. such as methanesulfonyl- an acetylating agent,

oxy-. Benzenesulfonyloxy-, or p-toluenesulfonyloxy- The compounds according to formula VIII can

Groups. by the action of a compound The materials used in the manufacturing process

Connections can be made as follows: ^XC " ² ^ " 2CH ₂ NHC JCH,

den: The compound (II) can by chemical or 40 in which X is a removable group on

catalytic reduction from the compound (111) or diethanolamine and subsequent treatment

by hydrolysis of a compound according to formula X with a chlorinating agent, for example

Q SOCl ₂ , or with a sulfonyl chloride, such as

CO wise toluenesulfonyl chloride, are produced.

/. \ 'y / X 45 The compound according to formula IX can by

N 'N CH ₁ CH ₁ CH ₁ N Ji j action of a compound of general

"- = ■" - \ / \ / Formula XCh ₂ CH ₂ NHCOCH ₃ , in which "X is a

Q CO p ^. Removable group means to 2.5-dichlorophenyl

Ethylenediamine can be produced, the latter

or by the action of ammonia on l- (3-chloro-50 compound of 2,5-dichloroaniline and aziridine or

propyl) -4- (2.5-dichlorophenyH-piperazine, as in the by the action of 2,5-dichloroaniline on Aeetyl-

Examples are given. Amino-propylaziridine is produced.

A compound of the formula III can be obtained by adding acrylonitrile to 2,5-dichloiphynyl-piperazine in pharmacological and clinical trials, and it was found that the compound is generally as indicated in the examples. manufactured 5 ^ mean formula I better be in the form of a salt, like . for example as the hydrochloride is used. Fs

The compound according to formula IV is already in the but can also salts with other mineral acids

Literature, such as in the journal Mcd. Chem. H. such as sulfuric acid.

P. 104 . Phosphoric acid, or with aliphatic mono- or

The compound according to formula Y can be dutch one-60 polycarboxylic acids, such as formic acid

effect of XCH ₂ CiI ₂ CH ₂ Y. where Y is: light acetic acid. Lactic acid, succinic acid. Malonic acid

Removable group as X means ¹ on 2,5-dichloro-glutaric acid. Adipic acid. Citric acid. Malein-

phenyl-pipera / in can be obtained. acid. Fumaric acid, or with aromatic acids

An example! for the reaction of the compound (IVl such as benzoic acid, salicylic acid, Püinoe-

with l-bromo-3-chloropropane in en.-r solution of 6? acid, or with mandelic acid. Diphenyl acid

Water and acetone are described below. Phenylacetic acid, or with sulfonic acids, as at

The connection according to Forme! VI can include, for example, methanesulphonic acid, ben / olsulphonic acid

Reaction a ·; '"' Excess of ii-si'jsaure.Mihvdrid toluene sulfonic acid. or with sulfamic acids. \ vi. at

Test results are given in Table II below summarized.

c) Tranquilizing effect

The tranquilizing effect of the compound according to formula 1 was determined in mice. Rats and Dogs, using the Irwin method (Irwin S., in: »Pharmacology Techniques in Drui · Evaluation »Year Book Medic; ·! Publishers. Chicago, 1964. pp. 36 to 54) or the methods of Hender s hol and Forsaith (H en de rsh ο t L. C. and J. Forsaith - J. Pharmacol, exp. Ther. 1959, 125, 237 to 240). which is the response to determine unpleasant Somali stimuli, applied would. Significant activity has been shown to be found at doses of about 5 mg kg i.d. p. and 20 mg kg p. o. was obtained.

It "was found that the compound of Formula I is hardly toxic. both in the determination of the acute as well as in the determination of chronic toxicity. so that a high therapeutic index was obtained. Accordingly the therapeutic interest for human medicine is evident. Accurate toxicity data are available summarized in table i below.

Table 1

For example cyclamic acid, or with acidic amino acids, such as aspartic acid, glutamic acid, or with heterocyclic acids such as nicotinic acid.

As far as pharmacological properties are concerned, the compound is dor Formula I and its Salts endowed with interesting activities: the compounds show, in particular, a hypotensive effect Effect on internal pressure in the eyes. Also show an adrenolytic effect from ulph; 'type and a tranquilizing effect.

a) Hvpotential effect on internal pressure
of the eyes

The compound of formula i reduces the internal pressure of the eyes both after systematic administration as well as in the case of ocular administration in the form of an eyewash. The trials were with Rabbits carried; the test conditions were already described by B u r b e r i S .. D. P i c c i η e 11 i lind B. SiI vest rini in Arzneimittel-Forsehun;:. 1970. 20. 1143. described.

A significant effect occurs even with intravenous administration of a dose of 0.15 mg / kg. without any side effects. or even at concentrations of about 0.05 ° o. The data show that a remarkable advance in the therapy of glaucoma can be realized with the help of this compound. The test results are summarized in, ₀ Table III below.

b) Adrenolytic effect

The adrenolytic effect has been demonstrated using some of the most well known procedures that normally used for such examinations as the study of the arterial high blood pressure (hypertension) caused by epinephrine.

The compound has been shown to be effective in doses of about 0.15 mg / kg when administered intravenously in rabbits and 0.35 mg / kg when administered intravenously to rats.

These data indicate that there is potential therapeutic use for the compound of Formula 1 is given. both for the treatment of some types of arterial hypertension as well as for the treatment of other vascular diseases such as headaches. the

Table II

Effect of the compound of the invention and trazodone hydrochloride on arterial pressure and on the hypertension induced by adrenaline in rabbits.

The minimum effective dose and the dose immediately above it are shown for each compound. Dilution factor = 2.

Acute toxicity of I
proper connection Type of
Appointment
reaching "ra / odon and the inventive Animal species i D .., in mc kg LD ₅ ,,
Tnizodon
hvdro-
chloride i. V. Tra / o-
Don-
tmiro-
chlond crtin-
apprenticeship
Ver
bmdung LD ₅ ,, erlin-
manure
πκίβε
Ver
binding Rabbits i. V. 52 39 1.33 rat l.p. 91 40 2.27 p. O. 178 122 1.46 i. v. 690 415 1.66 mouse i.p. 91 46 1.98 i. m. 210 113 1.86 ρ. ο. 475 225 2.11 610 230 2.65

Investigated connections dose Arterial pressure Attempt
length of time Adrenaline-induced 1 change Hypertensic number of
tries acceptance
of blood
pressure (Minutes) number of
tries i%) Attempt
length of time (mg kg iv) Imm hg) 9 -29 ! Minutes) According to the invention 0.15 4th 25th 20th 4th -31 > 15 connection 0.31 4th 13th 15th 4th -30 > 30 Trazodone hydrochloride 1.25 2 24 30th 1 -61 15th 2 5 5 20th 5 :> 60

Table 111

Effects of the compound of the invention and trazodone hydrochloride on internal pressure in rabbits' eyes. Each compound was tested in at least two different amounts, one amount being the minimum active dose.
Dilution factor = 2.

TesHerbindiini! Doms Quantity *** l / eil in Minu th + 30 17.6 i 0.X5 + 90 + 120 + 300 the Kc- 1X.6 - 1.03 20.6 + 0.61 17.7 + 0.90 17.6 t 1.30 21.2 ± 0.31 • ■ iiim- 20.3 t 0.56 -3.0 * · *) 20.2 ± 0.56 21.1 i: 0.56 20.0 ± 1.15 niun ^ cn -1.7 -2.5 * 1 -3.5 * 1 + 1.2 Img ki!
i. \. -20 15.9 -. 0.92 Invention classes 0.15 14th 23.6 - 0.6S 16.6 ± 0.X4 21.5 i 1.34 16.7 ± 0.63 18.2 i 0.X4 20.1 ± 1.11 Connection in physio / 14th 23.7 τ. 0.64 19.7 χ 1.22 -5.6 ***) 20.1 + 0.94 20.1 ± I. (X) 20.0 ± 1.44 logical table salt -0.1 -3.1 -3.4 ***) -1.9 + 0.1 solution 15.3 i 0.81 Inventiveness 0.31 X 23.0 t 1.02 15.9 ± 0.35 21.1 i 1.14 17.0 ± 0.00 18.9 ι 0.4 21.1 + 1.45 Connection in physio / X 23.0 ί 1.02 21.5 χ 1.10 -5.8 ***) 22.4 ± 0.88 22.9 - 0.97 25.8 ± 0.00 logical table salt 0.0 -5.6 ***) -5.4 ****) -4.0 ***) -4.7 *) solution 17.1 ± 0.63 Inventiveness 0.62 , 4 23.4: 1.43 18.0 ι 0.69 20.1 ± 0.59 17.5 ± 0.63 17.6 ± 0.62 19.3 ± 0.69 Connection in physio / 4th 23.4: 1.43 19.5 ± 0.44 -3.0 ***) 20.4 ± 0.44 19.7 ± 0.53 20.0 + 0.72 logical table salt 0.0 -1.5 17.1 ± 0.X2 -2.9 ** ·) -2.1 ***) -0.7 solution 17.6 ± 0.70 21.5 ± 0.81 18.0 ± 0.72 18.9 ± 0.90 22.6 ± 1.36 Trazodone hydrochloride 1.25 IK 21.5 ± 0.63 21.4 ± 0.79 -4.4 * ···) 21.6 ± 0.72 20.7 ± 0.87 21.9 ± 0.94 in physiological / IS 21.5 r 0.63 - 3.8 ***) -3.6 *** ') -LX + 0.7 Saline solution > ***) P> 0.001. Trazodone hydrochloride 5 12th 22.1 ± 0.97 in physiological / 12th 22.1 i 0.97 Saline solution ·) P> 0.05. **) P > 0.02. P> 0.01

by means of, chromatographed on an aluminum oxide column. The solution was made with a mixture of cyclohexane and benzene in a ratio of 1: 1. which contained 40 0.3% rriäthyiamin. There were 2 g 4 - (2.5 - dichlorophenyl) - 1 - piperazino - propionitrile was obtained.

Example 2

1- (3-Acetylaminopropyl) -4- (2.5-dichlorophenyl) piperazine

50 g of 1 - (3 - aminopropyl) - 4 - (2,5 - dichlorophenyl) piperazine were dissolved in 500 ml of CH ₂ Cl ₂ and the

example 1

1- (3-Acetylaminopropyl) -4- (2,5-dichlorophenyl) piperazine

A mixture of 20 g of 4- (2.5-dichlorophenyl) -l-piperazinopropionitrile, 100 ml of acetic anhydride, 12 g of anhydrous sodium sulfate and 6 ml of a 50% Solution of Raney nickel was in a Farr apparatus at 60 ° C and at a pressure of 4.22 kg / 45 60 pounds per inch (cm) hydrogenated. After about half an hour there was absorption of hydrogen completed. The reaction mixture was cooled, the catalyst was filtered off and the solution was concentrated

small volume refluxed in a 50 solution in a rotary evaporator. 25 ml

steamed. The residue was washed with an NaOH acetic anhydride, dissolved in 500 ml of CH ₂ Cl ₂ , while

Treated solution and added several times with CHCl ₃ extra- rend about an hour while stirring,

here. The organic layer was washed. The solution was heated for an additional hour

dried ιιηϊ evaporated. The residue was taken up on a rotary evaporator to dryness

crystallized from ethyl acetate. 14 g of the 55 were evaporated. The residue was washed up with water

Product treated with a melting point of 114 C, whereby a solid substance was obtained,

keep. The hydrochloride had a melting point which was separated off, washed and dried ^{at 50 D C.}

of 229 ° C. The oxalate showed a melting point. This solid substance was then in 350 ml

of 162 ° C. The maleate showed a melting point of dissolved ethyl acetate, treated with animal charcoal and

of 104 ° C. The benzylate had a melting point of 60 crystallized. It was 1 - (3-acetylaminopropyl) -

from 145 to 146 ° C. The phosphate showed a melting 4- {2,5-dichlorophenyl) piperazine in almost quantitative

point of 179 ° C. Yield obtained. The melting point was 114 ° C.

The compound used as the starting substance The compound used as the starting substance

was made as follows: can be made by one of the following methods

A solution of 5 g of 4- (m-chlorophenyl) -l-piper- 65 will be:

Azino-propionitrile in 100 ml of CHCl ₃ was mixed with 5.4 ga) 143 g of 1- (2,5-dichlorophenyl) piperazine. the on

Chlorosuccinimide added. The solution was ^{heated some 55 0} C, were slowly stirring Heated for hours and, after removal of the solution, admixed with 33 g of acrylonitrile. The solution was

609641/327

Maintained at 55 ° C for 2 hours, then were a further 33 g of acrylonitrile were slowly added. The reaction mass was then reduced under Distilled pressure. 160 g of 4- (2.5-dichlorophyll-1-pipera / .ino-propiuiiiln! obtained with a boiling point of 205 ° C at 2.5 mm.

A solution of KX) g of 4- (2.5-dichlorophenyl-1-piperazinopropionitrile in 560 ml of methanol was admixed with 18 ml of a 50% strength nickel-Raney suspension. The solution was stirred and heated to 50 ° C. At the same temperature, a A solution of 18 g of Na ^- BH ₄ in 60 ml of SN NaOH was added over the course of 30 minutes. The reaction was complete after heating for a further 15 minutes. The catalyst was filtered off, the solution concentrated to dryness in a rotary evaporator and the residue obtained with Water and solid potassium carbonate. The precipitate was _{extracted with CH 2} Cl ₂ , washed and dried. The solvent was eliminated and the solution was distilled under reduced pressure. 95 g of 1- (3-aminopropyl) -4- (2.5 dichlorophenyl) piperazine, which had a boiling point of 181 ° C. at 0.6 mm. The dihydrochloride had a melting point of 270 ° C. with decomposition.

b) A mixture of 23 g of N- (3-chloropropyl) phthalimide. 24 g of 1- (2.5-dichlorophenyl) piperazine. 14 g of anhydrous sodium carbonate and 130 ml of toluene was added heated with stirring for 30 hours. The solution was then cooled, filtered, evaporated to dryness and the residue treated with water and ether. The essential extract was washed, dried and evaporated to dryness. The residue was treated with ethyl acetate and poured into the Hydrochloride converted with the help of ethanolic HCL. 30 g of N- [3- 4- (2,5-dichlorophenyl) - 1 - piperazinyl - propyl] - pbthalimide hydrochloride with a melting point of 233 C (below Decomposition).

The same product was obtained from the action of 1- (3-chloropropyl) -4- (2.5-dichlorophenyl) piperazine on potassium diium chloride in dimethylformamide. 15 g of N- [3- 4-12.5-dichlorophenyl) -! -piperazinyl propyl] phthalimide and 2 ml of 99% hydrazine hydrate were refluxed for 90 minutes. 115 ml of 5N HCl were then added and the solution heated under reflux for an additional 30 minutes. The solution was cooled, filtered and concentrated to a small volume. The residue was diluted with water, made alkaline with a NaOH solution and extracted _{with CH 2} Cl _2. The organic layer was dried, evaporated and distilled under reduced pressure. There were obtained 7 g of l- -4- (2.5-dichlorphenyll-piperazine (aminopropyl-3).

c) A mixture of 46 g of l- (2.5-dichlorophynyl) piperazine and 46 ml of acetone were added to a solution of 20 g of NaOH in 40 ml of water at 15 ^° C. A solution of 40 g of 1-bromo-3- chloropropane in 40 ml of acetone was added over the course of 30 minutes. The solution was kept at 15 ° C. for 30 minutes and then at room temperature for 24 hours. The acetone layer was separated and the aqueous layer extracted with a further amount of acetone. The organic layers were collected and evaporated to dryness. The residue was dissolved in ethyl acetate and treated with ethanolic HCl. The 1- (3-chloro propyl) -4 - (2.5-dichlorophenyl) -piperazine-hydrochloride precipitated out. which crystallized from anhydrous ethanol. The yield was 30 si. the melting point was 227 C.

> 3.4 g of the hydrochloride obtained above were suspended in 16 ml of ethanol and 16 ml of a 2N Bo solution. The solution was heated to 80 ° C., and while this temperature was maintained, 30 ml of NH ₄ OH and 30 ml of ethanol were slowly added within

ίο added about an hour. The solution was evaporated under reduced pressure and the residue made strongly alkaline with concentrated NaOH. The solution was extracted with ether, washed, dried and with alcoholic HCl

is treated until an acidic pH is reached. After a few hours the precipitate was filtered off and again from 15 ml of boiling ethanol crystallized. A small amount of the insoluble matter was filtered off. as long as "the solution is hot was. It became I- (3-amopropyl) -4- (2.5-dichlorophenyl) -piperazine dihydrochloride obtained, which had a melting point of 270 C (with decomposition).

Example 3

! -l- ^v Acetyiaminopropyl) -4- (2.5-dichlorophenylpiperazine

N-f 3- 4- | 2.5-dichlorophenyD-1 -piperazinyl-propyl ] -diaeetamid were 1 hour lain: in a solution of 0.9 g of KOH in 25 ml of water and 25 ml of ethanol heated under reflux. The solution was evaporated to dryness in a rotary evaporator and treated with water and dichloromethane. The organic layer was washed off and evaporated to dryness. There were 3.5 ti <5 H-3-Acctylaminopropyl) -4-12.5-dichlorophenyl | -pipcr "-azinmn a melting point of 114 ° C.

The connection used as the exit subsian » can be closed using one of the following methods will:

a) 20 g of 1- (3-aminopropyl) -4- (2.5-dichlorophycnyD-piperaz.in hydrochloride were 1 hour lan. ' With 60 ml of acetic anhydride heated. The solution was concentrated under reduced pressure and the residue with water. Ice and a NaOH solution treated. The solution was extracted with CHXU. After emptying the solvent it boils the product obtained at 228 C at 0.6 mm. The product is converted into the monohydrochloride by means of ethanolic HCl converted that has a melting point

of 204 C (with decomposition

b) A mixture of 10 g of 1- (3-chloropropyl) -4- (2 5-dichlorophenyD-piperazine hydrochloride, _{4 g of anhydrous K 2} CO., and 4 g of diacetamide was heated to 150 ° C. for several hours with stirring Lösune was ifr c u u ^{hlt and} treated ^{with Els and water and} then with t H ₂ CH _2. The organic layer is dried and evaporated. The product was purified by distillation under reduced pressure.

Example 4 M3-Acety] aminopropyl) -4- (2.5-dichlorophenyl) -

piperazine

A mixture of 10 g of H3-chloropropyl) -4- <2,5-dichlorophenyD-p.pcrazm. 10 g of K ₂ CO ₃ and 40 g of acetamide were heated to 150 ° C. for a few hours while stirring. The solution was cooled, treated with ether and dilute HCl, and the acidic phase was separated off. The solution was made alkaline and

extracted with CH ₂ Cl _2. The organic; Layer was washed, dried and evaporated. Crystallization of the residue gave 1- '3-acetylaminopropyl) -4- (2.5-dichlorophenyll-pipera / yne.

Example 5
l- (3-acetylaminopropyll-4- (2.5-diehlophenyl) -

piperazine

L-in (iemisch from 21 g of chloropropyl acetamide. Which was prepared according to Israel .1. Of Chem. 5. 59 (1967). 36 g of l- (2.5-dichlorophenyl | -piperazine. 19.5 g of Na ₂ CO, and 13OmI of toluene for 24 hours HEAT reflux with stirring / t. the solution was cooled, ^r washed with wat and evaporated to dryness. the residue was treated with dilute HCI and washed with ether. the base was prepared from the hydrochloride Solution with K ₂ CO, powder was obtained and was _{extracted with CH 2} Cl. The organic layer was washed, dried and evaporated. The residue was crystallized from ethyl acetate. 18 g of 1- (3-acetylaminopropyl) -4- (2.5 dichlorophenyl) piperazine with a melting point of 113 C.

Example 6

1- (3-Acetylaminopropyl) -4- (2.5-dichloropheny!) - piperazine

7 g of chlorosuccinimide were added to a solution of 10 g of 1- (3-acetylaminopropyl) -4- (m-chlorophenyl) -pipcrazine in 100 ml CHCl., added. The solution was then heated to reflux for 15 minutes. The solvent was removed, the residue treated with dilute NaOH and extracted with ether. The residue from this solvent (9.9 g} consisted of a mixture containing 40% 1- (3-acetylaminopropyl) -4- (2.5-dichlorophenyl) piperazine contained. By crystallizing the picrate it was possible to obtain pure 1- (3-acetylaminopropyl) -4- (2,5-dichlorophenyl) -piperazine-picrate to isolate. The latter salt became the title substance by alkalinization obtained which had a melting point of 114.degree.

The compound used as the starting material was prepared as follows:

A solution of 16 g of 1- (3-aminopropyl) -4- (m-chlorophenyl) piperazine in 115 ml of CH ₂ Cl ₂ . which were kept at the boiling point, a solution of 7.7 ml of acetic anhydride in 30 ml of CH ₃ Cl ₂ was slowly added. After the addition, the solution was heated for an additional 30 minutes, then evaporated to dryness and treated with water and 2N NaOH. The solution was _{extracted with CH 2} Cl ₂ , washed with water and dried _{over Na 2} SO _4. The solvent was evaporated and the resulting oil solidified by adding a few drops of water. The residue was crystallized from a mixture of hexane and ethyl acetate. The l- (3-acetylaminopropyl> 4- (m-chlorophenyl) -piperazm thus obtained had a melting point of 51 to 53 ° C.

Example 7

1 -P-AcetylaminopropylM-fZS-dichlorophenyl (-piperazine

2 g of N- (3-acetylaminopropyl) diethanolamine were mixed with 2 ml of thionyl chloride for 30 minutes

UOU

70 C treated. The excess of reactant component was eliminated in a rotary evaporator and the residue was dissolved in amyl alcohol. then 1.2 g of 2,5-dichloroaniline were added to the solution, which was heated for 8 hours at 150 ° C. under a stream of nitrogen. The basic products were extracted and distilled by steam distillation. The residue from the distillation was extracted with ethyl acetate and used as

ίο Hydrochloride precipitated with essential HCI. That so The hydrochloride obtained was identical to the product described in Example 1.

The exit connection was made as follows:

is a mixture of 10.5 g diethanolamine. 16.2 g N- (3-chloropropyl) acetamide, 60 ml acetone and 25 ml 6-N NaOH were added under vigorous pressure for 16 hours Stir under reflux. The solution was cooled, and after adding more acetone the organic layer was separated. The solution became dry under reduced pressure evaporated and the residue distilled. The N - (3 - acetylaminopropyl) diethanolamine obtained boiled at 138 "C and 0.2 mm.

Example 8

l- (3-acetylaminopropyl) -4- (2.5-dichlorophenyl | -
piperazine

2 g of N- (2.5-dichlorophenyl) ethylenediamine and 1.5 g

N- (3-chloropropyl) acetamide was dissolved in 10 ml of acetone. Then 2.5 ml of 6N NaOH were added and the solution was refluxed for 10 hours while stirring. The mixture was then cooled to room temperature and. after separation of the acetone layer. evaporated to dryness. 1 g of 1,2-dibromoethane was added to the residue and the solution was heated on a water bath for 24 hours; then it was cooled, treated with ether, and a small amount of an insoluble product filtered off. The ether was evaporated and the residue treated with CHCl and aqueous ammonia. The organic phase was dried and the solvent eliminated. The residue was _{chromatographed on an SiO 2} column in anhydrous ether solution. 1- (3-Acetylaminopropyl) -4- (2.5-dichiorphcnyi) piperazine was obtained which had a melting point of 114.degree

so exhibited.

The starting compound was prepared as follows:

33.5 g of AlCl ₃ in 40 ml of tetralin were mixed with 55 g of 2,5-dichloroaniline at room temperature. The solution was heated to 180 ° C. and 19.4 g of aziridine vapors were introduced into the reaction vessel. The solution was stirred for an additional 30 minutes, then cooled and decomposed with ice. 110 g of KOH were then added, the tetralin layer was separated off and the water layer was extracted with benzene. The solution was dried and, after eliminating the solvents, distilled under reduced pressure. N- (2,5-dichlorophenyl-ethylenediamine was obtained, which boiled at 138 ° C. and 1 mm. The hydrochloride had a melting point of 265 to 267 ° C.

£ "856 /

Claims (1)

Patent claims: 24 030 I. 1 - (3 - Acetylaminopropyl) - 4 - (2.5 - dichlorophenyl) piperazine the formula Cl