DE1201843B - Process for the preparation of N-phenyl-piperazine derivatives - Google Patents

Description

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 p -6

Number:
File number:
Registration date:
Display day:

M47904IVd / 12p
February 2, 1961
September 30, 1965

The invention relates to a method of manufacture of N-phenyl-piperazine derivatives of the general formula

N-X- /

3 ·

(I)

wherein X is a straight-chain alkylene group with 2 to 4 carbon atoms, optionally substituted by an alkyl group, R ₁ and R _{2 are} hydrogen or halogen atoms, R _{3 is} an alkylcarbonylamino or alkanesulfonamido group in the m- or p-position with at most 4 carbon atoms and R _{4 is} a Nitro group in any position or an alkylcarbonylamino or alkanesulfonamido group with a maximum of 4 carbon atoms, as well as of the non-toxic salts of these compounds with acids.

The compounds prepared according to the invention show pharmacological and psychotropic properties, that are valuable in psychiatry; in particular, they have a beneficial effect on abnormal ones psychomotor activity. There are compounds of the general formula I preferred as a group Process for the preparation of N-phenylpiperazine derivatives

Applicant:

May & Baker Limited, Dageflham, Essex

(Great Britain)

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Brauhausstr. 4th

Named as inventor:

Anthony Stanley Fenton Ash, Epping, Essex;

Andrew Malcolm Creighton, London;

William Robert Wragg, Woodford Green, Essex

(Great Britain)

Claimed priority:

Great Britain of February 2, 1960 (3728),

dated September 9, 1960 (31218)

contain an unsubstituted or a phenyl group substituted by a single fluorine or chlorine atom and in which X is a —CH ₂ —CH ₂ - or -CH ₂ —CH ₂ —CH ₂ —CH ₂ —group. Of outstanding importance are compounds which contain an o-chlorophenyl or an o- or p-fluorophenyl group and in which X is a —CH ₂ —CH ₂ group, R _{3 is} a p-acetamido group and R _{4 is} an acetamido or nitro group, in particular 1- [2 '- (3 ", 4" -diacetamidophenyl) - ethyl] - 4 - (o - chlorophenyl) piperazine and 1- [2' - (3 ", 4" -diacetamidophenyl) ethyl] -4- (o-fluorophenyl) piperazine and its salts. The compounds of the general formula I are also valuable intermediate compounds for the preparation of other therapeutically valuable substances.

It has been shown that, for example, the compounds 1- [2 '- (3 ", 4" -diacetamidophenyl) ethyl] -4- (o-chlorophenyl) piperazine obtainable according to the invention so (A) and 1- [2 '- (4 "-methanesulfonylamido-3" -nitrophenyl) ethyl] -4- (o-chlorophenyl) piperazine (B) the known 1- (p-chlorobenzhydryl) -4- [2 '- (2 "-hydroxyethoxy) ethyl] piperazine dihydrochloride are surprisingly superior. The following comparative tests were carried out:

a) Determination of the lethal dose DL ₅₀ in mg / kg.

b) The decrease in psychomotor activity according to the Winter Flataker test, modified from Dews.

You put in a transparent cage through which a bundle of rays shines through falls on a photoelectric cell, a group of 5 mice. The psychomotor activity is measured by the number of interruptions in the beam in a certain period of time.

The products to be examined are injected subcutaneously or intraperitoneally. 30 minutes later the mice are placed in the cage and the activity is observed for 10 minutes. Four groups of control animals and two groups of treated animals are used for each dose Mice. The dose is determined in mg / kg of active ingredient that is necessary

509 689/408

to increase psychomotor activity by 50% Reduce.

c) Inhibition of the action of d-2-amino-1-phenylpropane (DA ₅₀ ).

The product to be investigated is injected subcutaneously or intraperitoneally into a group of ten mice 1 hour before the administration of such a dose of d-2-amino-1-phenylpropane (20 mg / kg subcutaneously) that a mortality of 90% in a control group of mice. The mortality in the pretreated group is compared with that of an untreated group and that of a group treated with 2 mg / kg subcutaneously 3-chloro-10- (3'-dimethylaminopropyl-phenthiazine). That dose (DA ₆₀ ) is determined in mg / kg which reduces the mortality of the group examined by 50%.

d) hypothermia test.

This study is described by Courvoisier and co-workers in "Archives Internationales de Pharmacie et de Therapy", Vol. 92, p. 339 (1933). Determining the dose of product, which causes a reduction in its temperature by 5 ° C in mice, which are kept in an environment of 25 ⁰ C.
The results of these tests are compiled in the following table; all doses are mg / kg. [The subcutaneous administration (process products) and the intraperitoneal administration (comparison substance) are to be regarded as equivalent in the mouse, as can be seen from a further experiment in which the results obtained for the comparison substance in test b) with subcutaneous administration 65 mg / kg and at intraperitoneal administration 55 mg / kg.]

test

Product A.

Product B

Acquaintance
Comparison substance

Toxicity (DL ₅₀ )

Psychomotor activity

Inhibition of the action of d-2-amino-l-phenyl-

propane (DA ₅₀ )

Hypothermia test

The N-phenyl-piperazine compounds of the general formula I are prepared by in an known way either

a) a phenylpiperazine of the general formula

NH

with a compound of the general formula

, Ra

Y-X

III

in which Y represents a reactive esterified hydroxyl group, converts or
b) a compound of the general formula

N-X

NH,

IV

wherein R ₃ 'has the meaning of R ₃ or represents an amino group in the m- or p-position, reacts with the anhydride of a saturated aliphatic monocarboxylic acid and optionally then converts the bases obtained into their salts with non-toxic acids.

The reaction a) is preferably carried out by heating the reagents in an inert solvent such as an alcohol, e.g. B. n-butanol, a ketone, ζ. B. acetone, a benzene hydrocarbon, e.g. B. benzene or toluene, or a halogenated carbon-300 sc
1.9 sc

10 sc
3.0 sc

240 SC
5.6 sc

13.5 s.c.

170 ip
50 ip

50 ip
50 ip

hydrogen in the presence of an acid-binding agent such as an alkali metal or a derivative thereof, z. B. an alkali metal carbonate, alkoxide, amide or hydride, or a tertiary base, e.g. B. triethylamine, executed. It is expedient to use an excess of the phenylpiperazine used general formula II as an acid-binding agent.

Suitable non-toxic salts of the compounds of general formula I are, for. B. Hydrohalides, such as Hydrochloride, phosphate, nitrate, sulfate, maleinate,

Fumarates, citrates, tartrates, methanesulphonates, ethane disulphonates and 2-hydroxyethanesulphonates. These salts can be obtained from the bases of the general formula I by customary methods. You can z. B. by mixing the base in question with an equivalent amount of a non-toxic acid in a solvent, optionally subsequent evaporation of part or all of the solvent and filter off the resulting salt. The salts can be crystallized or by any other conventional method can be cleaned. The following examples illustrate the invention.

example 1

41.1 g of 2- (4'-acetamido-3'-nitrophenyl) ethyl bromide, 48.9 g of N-phenylpiperazine and 500 ml of dry toluene were refluxed together for 18 hours. Phenylpiperazine hydrobromide (32.3 g; 93%) was filtered off from the cooled reaction mixture and the filtrate was evaporated to a yellow, crystalline residue. This was recrystallized from isopropanol-cyclohexane; crystallized upon cooling to 0 ⁰ C 43.2 g (82%) l- [2 '- (4 "Acetamido-3" -nitrophenyl) ethyl] -4-phenylpiperazinaus; 117 to 19 ° C. The starting material was prepared as follows: 2 - (ρ - aminophenyl) - ethyl bromide - methanesulfonate was obtained by catalytic hydrogenation of a solution of 2- (p-nitrophenyl) ethyl bromide (460 g) in methanol (3.5 ml), the methanesulfonic acid (139 ml) contained

5 6

produced via platinum oxide (2%) at 29.4 at. When c) l- [2 '- (4 "-Acetamido-3" -nitrophenyl) ethyl] -4- (p-

Evaporation of the filtered solution gave a crystalline chlorophenyl) piperazine, yield: 65%> F. 157

ner residue obtained from acetone-ether at up to 160 ° C (from ethyl acetate),

was crystallized; 428 g (73%) of 2- (p-Ami-... ..

nophenyl) ethyl bromide methanesulfonate obtained; F.161 5 ß e ι s ρ ι e ι 4

up to 162 ° C. The acetylation of l- [2'-acetamido-3 "-amino-

Anhydrous sodium acetate (56 g) and then phenyl) ethyl] -4- (o-chlorophenyl) piperazine after

Acetic anhydride (750 ml) were added to a solution. The method described in Example 2 gave a

of 2- (p-aminophenyl) ethyl bromide methanesulfonate 80% yield of l- [2 '- (3 ", 4" -diacetamidophenyl) -

(180 g) in glacial acetic acid (750 ml) at about 35 ^° C. are added. io ethyl] -4- (o-chlorophenyl) piperazine; M.p. 191 to 191.5 ° C

The reaction mixture was at about 20 minutes (from isopropanol).

Stirred at 25 ° C, then cooled to 0 to + 5 ° C; In an analogous manner the following were obtained:

fuming nitric acid a) l- [2 '- (3 ", 4" -diacetamidophenyl) ethyl] -4- (m-

(66 ml; £? = 1.51) was added. After chlorophenyl) piperazine for 30 minutes, yield: 85%. F. 197

Stirring at 5 ° C and stirring at room lstündigem 15-198 ⁰ C (from isopropanol), and

temperature was the mixture in ice-water (about b) 1- [2 '- (3 ", 4" -diacetamidophenyl) ethyl] -4- (o-fluoro-

8 kg) poured. The solid 2- (4'-acetamido-3'-nitro-phenyl) -piperazine, yield: 68%, mp 193 bis

pehnyl) -äthylbromid (145 g; 83%) was filtered, 194 ⁰ C (from isopropanol).

washed with water (201) and from a mixture.

of isopropanol (1300 ml) and ethyl methyl ketone ao:

(70 ml) recrystallized; M.p. 128 to 129 ° C. The catalytic hydrogenation of l- [2 '- (4 "-Acet ~

amido-3 "-nitrophenyl) ethyl] -4- (o-chlorophenyl) -piper-

Example 2 ^ _{n nacn} ^ _sm j _m jj _e j _S pi _e i 2 for the starting materials

Acetic anhydride (12 ml) was recorded in the 10 minute procedure gave a 76% yield

at room temperature to a solution of l- [2'- 35 an l- [2 '- (4 "-acetamido-3" -aminophenyl> ethyl] -4- (o-

(4 "-Acetamido-3" -aminophenyl) ethyl] -4-phenylpiperchlorophenyl) piperazine; F. 152 to 153 ⁰ C (from Isopro-

azin (5 g, 0.014 m) in n-acetic acid (100 ml) was added. panol).

After stirring for 90 minutes at room temperature, the following were obtained in an analogous manner:

The solution was poured into an excess of ice _{- a} ) 1- [2 '- (4 "-Acetamido-3" -aminophenyl) ethyl] -4-

Poured water and by adding ammonia 30 (m-chlorophenyl) piperazine, yield: 80%, F.139

made water alkaline to pH 9. After that to 140 ° C (from isopropanol), and

Standing overnight at about 0 ⁰ C, the precipitated b) l- [2 '- (4 "Acetamido-3" -aminophenyl) ethyl] -4-

solid substance filtered off, dried and then from (o-nuophenyl) piperazine-, yield: 77%, mp 164

Isopropanol (150 ml) recrystallized. The l- [2 '- (3 ", - to 166 ⁰ C (from isopropanol).

4 "-Diacetamidophenyl) ethyl] -4-phenylpiperazine became 35

obtained as fibrous white needles (4.4 g, 79%); R eisηiel 5

M.p. 202 to 204 ° C. ^P

The starting material was prepared as follows: 2- (4'-Methanesulfonamido-3'-nitrophenyl) -äthylbro-

The catalytic hydrogenation of a solution of amide (18 g), N- (o-chlorophenyl) piperazine (10.3 g), 1- [2 '- (4 "-acetamido-3" -nitrophenyl) ethyl] -4 -phenyl- 40 dry triethylamine (6.4 g) and dry benzene piperazine (30 g) in methanol (300 ml) over Raney (250 ml) were together for 16 hours under RückNickel (10%) at 4.9 at heated to evaporation, then cooled and filtered. The filtrate from the filtered solution and the recrystallization was washed with water (ml three times 100), then the compound from isopropanol-petroleum ether l- [2 '(bp 40 dried over magnesium sulfate and an oil to 6O ⁰ C.) - (4' -Acetamido-3- "aminophenyl) -äthyl- 45 evaporated, the treatment with cold ethanol 4-phenylpiperazine (23.9 g, 87%); F. 160 to 161 ⁰ C. slowly crystallized. Recrystallization twice

from ethanol gave 8.7 g (27%) l- [2 '- (4 "-methanesulfone-

Example 3 amido-3 "-nitrophenyl) ethyl] -4- (o-chlorophenyl) -piper-

Azine in the form of a yellow, microcrystalline solid

2- (4'-Acetamido-3'-nitrophenyl) ethyl bromide (20 g), 50 substance; F. 107 to 108 ⁰ C.

N- (o-chlorophenyl) piperazine (12.8 g), dry tri- The starting material was produced as follows

ethylamine (9.6 ml) and dry benzene (300 ml):

were refluxed together for 17 hours. 59 _g 2- (p-aminophenyl) ethyl bromide methanesulfo-

The cooled reaction mixture was filtered and _na t, dry triethylamine (20 g) and dry

the filtrate was washed with water (150 ml twice). 55 benzene (400 ml) were mixed together for 2 hours at 5 bis

When evaporating the 10 ⁰ C getrock- with magnesium sulfate stirred. Then suddenly a dry tri

Neten benzene solution, a solid residue was obtained äthylamine (22.5 g) and then immediately a solution of

th, which recrystallized twice from isopropanol methanesulfonyl chloride (17.5 ml) in dry benzene

became. There were 16 g of l- [2 '- (4 "Acetamido-3" -nitro- (50 _m L) was added in 20 minutes at 5 to 8 ⁰ C Die.

phenyl) ethyl] -4- (o-chlorophenyl) piperazine (57%) of the 60 reaction mixture was 1 hour at room temperature

Melting point Hl ⁰ C obtained. stirred temperature, then refluxed for 45 minutes

The following were obtained in an analogous manner: heated, ^{cooled to 0 °} C. and filtered. The filtrate

a) 1- [2 '- (4 "-Acetamido-3" -nitrophenyl) ethyl] -4- (m- was washed with water (twice 500 ml), over chlorophenyl) -pjperazine, yield: 59%. F. 80 magnesium sulfate dried and ^{evaporated to a light brown to 8I 0} C (from ethanol-ligroin (bp 60 to 80 ° C), 65 crystalline residue.

b) 1- [2 '- (4 "-Acetamido-3" -nitrophenyl) ethyl] -4- (o- sieren from ethyl acetate-ligroin (bp. 60 to fluorophenyl) -piperazine, yield: 53%, F. 135 8O ⁰ C) was added 2- (p-Methansuh "onamidophenyl) -äthylbis 136 ° C (from isopropanol), and - bromide (34.5 g, 67%) was obtained,. F. 102-103 ° C.

A solution of 2- (p-methanesulfonamidophenyl) - recrystallized; the l- [2 '- (3 ", 4" -dipropionamidophe-

ethyl bromide (18.2 g) in a mixture of glacial acetic acid ethyl] -4- (o-chlorophenyl) piperazine (6.2 g, 48%)

(120 ml) and acetic anhydride (120 ml) were melted at 134-135 ° C.

35 ° C, then cooled to 0 ° C and in 5 Mi- The starting material was prepared as follows

utes while stirring with a solution of fuming 5 represents:

Nitric acid (7 ml, d = 1.51) in glacial acetic acid (15 ml) and 1- [2 '- (4 "-acetamido-3" -nitrophenyl) ethyl] -4- (o-

Acetic anhydride (15 ml) added at -5 to 0 ° C. chlorophenyl) piperazine (30 g) was refluxed

The mixture was stirred for 1 hour at -5 to + 3 ° C. with a solution of potassium hydroxide for 30 minutes

stir and then heated in an excess of crushed (10.5 g) in ethanol-water (360 ml, 1: 1)

Poured ice. The solid substance was filtered off with 10% upon dilution with water (250 ml) and cooling

Washed with water and then from isopropanol (200 ml) to ⁰ ° C. the precipitated oil crystallized. The l- [2'-

recrystallized; 2- (4'-Methanesulfonamido-3'-nitro- (4 "-amino-3" -nitrophenyl) ethyl] -4- (o -chlorophenyl>

phenyl) ethyl bromide was filtered off in the form of yellow micro- piperazine (22.4 g, 87%), with water

crystalline needles (19 g, 90%) obtained; F. 101 until washed, dried and made from isopropanol — petroleum

102 ° C. 15 ether (boiling point 40 to 6O ⁰ C) recrystallized; F. 104 to

Example 6 106 ⁰ C.

The catalytic hydrogenation of a solution of l- [2'-

1- [2 '- (3 "-amino-4" -methanesulfonamidophenyl) - (4 "-amino-3" -nitrophenyl) ethyl] -4- (o -chlorophenyl) ethyl] -4- (o -chlorophenyl ) -piperazine (8.9 g) was obtained with piperazine (40 g) in methanol (350 ml) above Raney room temperature in a solution of glacial acetic acid 20 nickel (10%) at 32.2 atm after evaporation (60 ml) dissolved in water (150 ml). The reaction of the filtered solution and the recrystallization of the mixture was cooled to about 5 ⁰ C, with acetic compound from isopropanol-ligroin (treated Kp. 60 to acid anhydride (15 ml) and then for 2 hours 8O ⁰ C) l- [2 '- (3 ", 4" -diaminophenyl) -ethyl] -4- (o -chlorine left at room temperature. The temperature phenyl-piperazine) (33.5 g, 91%); F. 97 to 98 ⁰ C. The was by adding crushed ice again to ₂₅ melting point can be lowered by further recrystallization 5 ° C, the pH of the reaction mixture can be increased to 98 to 99 ⁰ C, by careful addition of Ammonia solution with a density of 0.880 was adjusted to 10. The examples precipitated solid substance was made with chloroform

. extracted, and the chloroform solution then-acetamido-2'-nitro-4'manner worked up in conventional ₃₀ In the reaction of 2- (The l- [2 '- (3' acetamido-4 "-me- phenyl) -äthylbromid with 2 equivalents of N-phenylthanesulfonamidophenyl) ethyl] -4- (o-chlorophenyl) -pipiperazine according to the verperazine described in Example 1, l- [2 '- (4 "-Acetamido-2" -nitrophenyl) -nen needles (6.3 g 63%) after recrystallization ethyl] -4-phenylpiperazine a melting point of from 137 to methyl ethyl ketone-ligroin (bp 60 to 8O ⁰ C) ₃₅ 139 ° C (from isopropanol-cyclohexane. ) obtained with 26% iger; F. 174 to 175 ⁰ C. Yield obtained.

The starting material was produced as follows The starting material was produced as follows: posed:

1 - [2 '- (4 "- methanesulfonic onamido - 3" - nitr ophenyl) - A mixture _VO n fuming nitric acid (5.9 ml,

ethyl] -4- (o-chlorophenyl) piperazine (4g) was in Te- 40 rf = 1.51) and sulfuric acid (4ml, d = 1.84) was trahydrofuran (200 ml), the hydrazine hydrate contained dropwise in a half an hour at 0 to + 2 ° C (3 ml, 98 to 100%), dissolved. The red solution with vigorous stirring to a solution of 2- (p was heated to 40 ° C and a catalytic amount of aminophenyl) ethyl bromide hemisulfate (30 g) in sulfur Raney nickel was added. Fiscal acid (100 ml, d = 1.84) was added to the reaction mixture. The reaction was kept at about 40 ° C for 10 minutes and the mixture was then left to stand at 0 to +2 ⁰ C for 1 hour at room temperature. Let it; then the temperature was allowed in 2 hours, excess Raney nickel rising to the mixture slowly to 2O ⁰ C. The dark red reac was added, which was then boiled for a few minutes and then filtered through ionic mixture dropwise under vigorous kieselguhr. While the mixture was evaporated to dryness while stirring to a mixture of crushed filtrate, 1- [2 '- (3 "-amino-4" -me-50 ice and water (about 500 g); the temperathansulfonamidophenyl) ethyl] -4 - (o-chlorophenyl) -pi- door was kept below 5 ° C by frequent addition of small amounts of perazine in the form of a white, microcrystalline solid, finely powdered dry ice. Obtained the substance (3.6 g, 94%); F. 189 to 191 ⁰ C. fine yellow precipitate was quickly filtered off, washed with the melting point by recrystallizing some ice-cold water (about 100 ml), geaus aqueous ethanol increased to 193 to 195 ° C and then dried in glacial acetic acid (250 ml ) will be resolved. Acetic anhydride (100 ml) and then water

free sodium acetate (100 g) was added to the solution

Example 7 was added, which was then placed on a water bath for 15 minutes

was heated. The greater part of acetic acid and des

Propionic anhydride (30 ml) became in 10 minutes ^6o anhydrides were evaporated under reduced pressure at room temperature with stirring to a solution and the residue on crushed ice of 1- [2 '- (3 ", 4" -diaminophenyl) -ethyl] -4 - (o-chlorphe- (about 500 g) poured. The pale orange-colored Niedernyl) -piperazine (10 g) in n-propionic acid (100 ml) additive was filtered off and dissolved in chloroform, added. After 2 hours of standing at about 25 ⁰ C. The chloroform solution was washed with water, the solution into an excess of ice-water, ⁶ 5 dried over magnesium sulfate and of which the ammonia water crude (45 ml, d = 0.88) was contained, Ge solid Pour 2- (4'-acetamido-2'-nitrophenyl) ethyl bromide. The precipitated solid substance was evaporated (21.5 g, 62%), which was filtered from ethyl acetate, dried and then recrystallized from isopropanol (90 ml) ester-cyclohexane; the Ver-

binding was obtained in the form of bright orange yellow microcrystals of melting point 108 to 110 ⁰ C.

Claims (1)

Claim: Process for the preparation of N-phenyl-piperazine derivatives the general formula - N N - X - IO in which X stands for a straight-chain alkylene group with 2 to 4 carbon atoms, optionally substituted by an alkyl group, R ₁ and R _{2 represent} hydrogen or halogen atoms, R ₃ an alkylcarbonylamino or alkanesulfonamido group with at most 4 carbon atoms in the m- or p-position and R _{4 is} a nitro group in any position or an alkylcarbonylamino or alkanesulfonamido group with a maximum of 4 carbon atoms, as well as of the non-toxic salts of these compounds with acids, characterized in that either 20th 10 a) a phenylpiperazine of the general formula R ₁ . - N NH with a compound of the general formula -R ₃ Y-X in which Y represents a reactive esterified hydroxyl group, converts or
b) a compound of the general formula - N N-X NHo wherein R ₃ 'has the meaning of R ₃ or represents an amino group in the m- or p-position, reacts with the anhydride of a saturated aliphatic monocarboxylic acid, and any bases obtained subsequently converted into their salts with non-toxic acids. A priority document was displayed at the time of the announcement. 509 689/408 9.65 © Bundesdruckerei Berlin