DE1670431A1 - Process for the preparation of new piperazine derivatives - Google Patents

Description

27 February 1967

Chinoin Gyfcgyszer Is Vegyeszeti TermÄkek Gyara Ht., Budapest IV, To utca 1-5 »Hungary

METHOD ZlJB MANUFACTURING NElIEiR

It is known that certain fiperazine derivatives have valuable therapeutic properties. In the IAteratur particularly those derivatives are described as valuable, which have an carbonyl group. In U.S. Patent No. 2,985,657 those piperazih derivatives are described which _{contain a group of the formula Ar.CO.CH 2} CH ₂ - in place 1 and a heterocyclic radical in place 4. These compounds can be prepared by alkylating the corresponding monoalkyl-pipfrazin-derivatives. According to the Belgian patent, very if t Ko. 614.151 Fhenyl-piperaein-dcirivate are brought into reaction with cyclic ketones and formaldehyde. Tue · 77/113 old.

009887/2113 BAD original

Hungarian * patent specification Ho. 152..051 b * £ »« b * «£ b * © 3» procedure to produce n ^ tw »a? Piy ^ jpQzin ^^ rivnte, after which alkyl-, Aralkylpiperazines with alkyl-, /.rclkyl-ketonen and formaldehyde be condensed.

It has been found that the new fiperasin derivatives of the general formula I. (wherein Sr is an alkyl group; R ^ is hydrogen or an alkyl group; η is an integer from 0 to 3 and

R ¹ denotes a 5- or 6-membered heterocyclic radical containing at least one nitrogen atom or a group of the general formula II in which R and Ir denote hydrogen, halogen or alkyl,

with the proviso that if n = 1 and Hr denotes hydrogen, at least one of the symbols R and Ir does not denote hydrogen) and their salts have valuable therapeutic properties. The new compounds of the formula I have a calming effect on the central nervous system and can be used in pharmacy in particular as narcotics, anesthetics and antihypertensive agents. An important advantage of the compounds prepared according to the invention is their low toxicity. The compounds of the formula I are significantly less toxic than the known alkyl or aralkyl piperczin derivatives.

The lower toxicity of our new compounds is illustrated by the following table! (The substituents A and B listed in the table are bound to positions 1 and 4 of the piperazine ring)

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AN (CH ₂ CHg) ₂ NB KD ₅₀ mgAs iv A. B. 43.5 CH ₃ (CHg) ₃ (CEg) ₂ COC ₆ H ₅ 18.5 CH ₃ (CHg) ₇ (CHg) ₂ COC ₆ H ₅ 25.5 C ₆ H ₅ O ₃₂ (CHg) ₂ COC ₆ H ₅ 222.0 O ₂ H ₅ OCO (CHg) ₂ CX> C ₆ H ₃ (OCH ₃ ) g 83.0 C ₂ H ₅ OCO (CHg) ₂ COC ₆ H ₄ Cl 95.0 C ₂ H ₅ OCO (CHg) ₂ COC ₆ H ₄ Br

From the table above it can be seen that the new compounds prepared according to the invention (last three Lines) have a significantly lower toxicity than the known connections

The substituent Br can, for example, mean lower alkyl groups with a maximum of 4 carbon atoms (such as methyl, propyl, leobutyl and advantageously ^ .thyl)

If R ^{2 stands} for an alkyl radical, this is, for example, an alkyl radical with a maximum of 4 carbon atoms, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl radical.

Ir can stand for a 5 "* or 6-membered heterocyclic radical containing at least one nitrogen atom, such as, for example, the 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, piperaainyl, thiazolyl, horpholinyl, oxazolyl radicals Di · heterocyclic radicals can contain further heteroatoms (for example oxygen, nitrogen or sulfur atoms) and can be saturated or unsaturated and optionally substituted.

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BATH ORIGINAL

ΈΓ can also stand for a substituted or unsubstituted phenyl radical of the formula II. The phenyl radical can be substituted with 1 or P. halogen atoms baw, alicyl or alkrtacy groups.

The term "halogen" refers to all four halogens such as chlorine, bromine, fluorine and iodine, but precedes

4 S partial for chlorine or bromine. If R and Ir are alkyl, they are straight-chain or branched alkyl groups, advantageously containing at most 4 carbon atoms, such as methyl, ethyl, etc. The phenyl group can advantageously be substituted as follows: 3-, 4-, 3 _f 4-, 2.4-, 2.6, 3i5-. If B ^ is a substituted phenyl radical, then, for example, the following groups come into consideration:
5-chloro-phenyl-, 3-methyl-phenyl-,
3-iMethoxyphenyl-, 4-chlorophenyl-, 4-bromo-phenyl-, 4-methoxyphenyl-, 4-methyl-phenyl-, 3,4-dichlorophenyl-, 3,4-dimethoxy- phfcnyl-, 3,4-dimethyl-phenyl-, 2,6-dimethoxyphenyl-, 3-methoxy-4-methy 1 -phenyl, etc,

Particularly valuable compounds of the formula I are the following new piperazine derivatives:

l-carbaldioate-4- / r-oxo-l- (3,4-dimethoxyphenyl) -propyl (3 _< ^ 7- -piperazine,

-oxo-l- (4-chloro-phenyl) -propyl- (3, ^ 7-piperazine,

-o: ro-l- (4-bromophenyl) -propyl-

l-carbethoxy-4- / T-oxo-l- (4-chloro-phenyl) -ethyl- (227-piperazine,

-plperezin,

l-Carbäthoaty-4- / T-oxo-l (4-chloro-phenyl) * -butyl- (4i7-piperazine _f .. 00S8P87 / 2113

-oxo- (3-pyridyl) -propyl- (3 ^ 7-piperazine.

The free bases of the formula I can, if desired be converted into their salts formed with acids. Inorganic acids (e.g. hydrochloric acid, hydrogen bromide, Phosphoric acid, sulfuric acid) and organic acids (e.g. benzoic acid, oxalic acid, tartaric acid, lactic acid, acetic acid, Citric acid, maleic acid, etc.) can be used.

It has also been found that the compounds of general formula I and their salts can be prepared by

a.) a ketone of the general formula XII (in which «, F and η have the meaning given above and X stands for a reactive radical) with a piperazine derivative of the general formula (IV)
(wherein "Br has the meaning given above) or

b.) for the preparation of compounds of the general formula I in which η = 1, a ketone of the general formula V. (where Ir and IT have the same meaning as above) in the present of formaldehyde or substances that give formaldehyde with piperazine derivatives of the general formula IV, and the compounds obtained in this way, if appropriate, in their with Acids formed salts and / or optionally the compounds of formula I or their salts in, in pharmacy usable preparations transferred.

The symbol X can, for example, be a halogen atom or an alkylsulphonyl, Arylsulphonyl or substituted arylsulphonyl radical. X is advantageously chlorine, bromine or a methenpulphonyl, benzene sulphonyl or p-toluenesulphonyl badikal.

# 7/2113 BAD ORlGtNAU

Accordingly, the compounds of the formula III the chloride, bromide, fikthansulphonate, benzene sulphonate or p-tolaol sulphoncte of the enteps? Echend «» n ketones be.

The reaction according to method a.) Between the compounds of the formula III and the pipferazine derivatives of the formula IV can be advantageous in the presence of an acid-binding agent take place. The following types of compounds can advantageously be used for this purpose: alkali carbonates (e.g. Potassium carbonate etc.), alkali hydrogen carbonate, (e.g. sodium hydrogen carbonate etc.), alkali hydroxides (e.g. sodium hyÄroacyft), tertiary amines (e.g. triethylamine, etc.). It is advantageous to use an excess of the piperazine derivative of the formula IV, which acts at the same time as a medium and an acid-binding agent.

The compounds of the formulas III and IV can be used in an equivalent amount, but the piperazine derivative can also be used in excess. If the piperazine derivative of the formula IV is used as the acid-binding agent, it is advantageous to use this in an amount of about 2 moles (calculated on one mole of the ketone component) to be used «

The reaction can be carried out in the presence of organic solvents, e.g. non-polar. Solvents such as benzene, toluene, IyIöl etc. * can be carried out. You can get the reaction without Complete solvent.

The reaction temperature is not of major importance.

- O ··

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BAD OHiGlNAL

activityj it depends on the component used » average, Ke is advantageous, however, the reaction in the Perform reflux perpetuity of the reaction mixture. the The duration of the reaction depends on the starting material and the other Farametera. Reflux the reaction is carried out, it is generally sufficient to continue the reaction for 1-3 hours. The reaction mixture can processed according to the usual laboratory methods (e.g. extraction).

According to method b.) Of our process, the compounds of general formula I (in which n = l) can be prepared by reacting a ketone of general formula V with a piperazine derivative of general formula IV in the presence of formaldehyde or a formaldehyde-releasing agent. The compound of the formula V and the formaldehyde are advantageously used in excess (calculated on the piperazine derivative). The formaldehyde used in the reaction can be used in the form of an aqueous formalin solution or a formaldehyde-releasing agent (for example paraformaldehyde, formaldehyde dimethyl acetal or formaldehyde diacetate.) The reaction can be carried out in the presence of an organic solvent or an aqueous medium; Aqueous alcohols, such as aqueous methanol or ethanol, can advantageously be used. The reaction can be accelerated by heating, advantageously C is carried out between 60-80 ^0th To carry the implementation it is particularly beneficial at. the reflux temperature to work. The reaction is advantageously continued for 0.5-5 hours, especially 2-4 hours. It is

.., ......, ■; ■. λκ- 009887/2113

BAD ORJGINAL

advantageously the reaction in an acidic medium of one. Provide a pH value of 2-4. Po. " ReakttonegÄmisch kait a mineral acid, e.g. hydrochloric acid or sulfuric acid.

The salts of the compounds of the formula I can be prepared by methods known per se. One can advantageously proceed in such a way that the free bases with an equivalent amount of the corresponding acid in the presence of a organic solvent are implemented.

For example, alcohols, acetone, benzene or ethers can be used as organic solvents.

Further details of the procedure can be found in the examples.

Examples

1.) 9.48 g of l-Oarbäthoagr-piperazine are in 30 ml 7O £ Lgem alcohol dissolved. The pH of the solution is adjusted with conc. Hydrochloric acid is adjusted to 3, 10.8 g of aoetoveratrone are added and the solution is brought to the boil. 1.8 g of paraforaaldehyde are added to the boiling reaction mixture and after boiling for two hours, the alcohol is distilled off under reduced pressure. The residue is taken up in water, the aqueous solution is made alkaline with ammonia and washed with Benzene shaken out. From the organic phase it becomes Benzene is driven off under reduced pressure, the residue is dissolved in methanol, the solution with hydrochloric acid methanol acidified, filtered the precipitated product and washed with methanol and benzene. 12.6 g of 1-Carbäthoaty- <4-2T-oxo- (3 »4-dimetho ^? - phenyl) -propyi -» (3 ^ 7-piperazine-

009887/2113

hydrochloride obtained. Melting point: 185-186 0.

Analysis: Wo = 7.61 (calc. 7.48).

2.) 47.8 g of l-carbethoxypiperazine are dissolved in 160 ml of ethanol containing 40% water. The solution is acidified, whereupon 46.8 g of p-chloro-acetophenone and 9.0 g of paraformaldehyde are added. The reaction mixture is boiled for 2 hours. After the solvent has been evaporated off, the residue is taken up in benzene and the hydrochloride, as indicated in Example 1, is isolated. 55.45 g of l-Garbäthozy-4- _i / r-oxo-l (4-chlorophenyl) propyl (3X7-plperazine hydrochloride) are obtained. Sehmp.,.: 177-178 ⁰ O, analysis: Ή% = 7.85 (calc. 7 »76).

3.) The procedure is as described in Example 2, but p-bromo-acetophenone is used as the starting material. L-carbethoxy-4- ^ T-oxo-1- (4-bromophenyl) propyl- (3. ^ 7-pipfcrazine hydrochloride is obtained. Melting point: 179-180 ⁰ O, analysis: N% = 6.95 (calc. 6.90).

4.) 18.9 g of l-carbethoxy-piperazine are in a mixture of 27 ml of water and 41 üJ. Dissolved ethanol. -The pH the solution is with conc. Hydrochloric acid set to 2, and 15.7 g of propiophenone are added. The mixture becomes the Bred to the boil and 3.52 g of paraformaldehyde are added to the boiling mixture added in portions, the reaction mixture is boiled for 1 hour and concentrated in vacuo ■ The residue is dissolved in water and the aqueous solution nit Benzene shaken out. The base is accordingly released in aqueous solution idlt sodium hydroxide and in 50.0 ml of benzene solved. The benzene solution is washed out several times with water

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BATH

and narrowed. There are 19.25 g of the l-Carbäthoacy - *! .- ^ Γ- -1-phenyl -P-meth ^ l-prcpyl - (3,} 7 -; obtained piporazine,

19fO g of the product β thus prepared are dissolved in 20.0 ml of ethanol containing hydrochloric acid, whereupon the solution is concentrated in vacuo and the hydrochloric acid salt is precipitated with 30 ml of acetone. The melting point of the hydrochloride is 161-163 ⁰ C. Analysis "M ^ a 8.14 (calc. 8.24).

5.) 15 »7 S l-carbathoxy-piperazine are in one Dissolved mixture of 15 μl of water and 60 ml of ethanol. The pH the solution is with conc. Hydrochloric acid adjusted to 4, whereupon 16.2 g valerophenone are added. 3.0 g of paraformaldehyde are dissolved in the reaction mixture with heating and the mixture is heated for an additional 11 hours. That Solvent is distilled off, the residue is dissolved in water and the aqueous solution is extracted twice with benzene. The product precipitated from the aqueous solution after cooling is suction filtered, dried and removed 80 ml abs. Recrystallized ethanol. 9.9 g of 1-carba

hydrochloride obtained. Schmp.i 165-166 ⁰ C. Analysis: (calc. 8.42) W> = 8.36.

6.) IA-, 15 g of 1-carbethoatypiperazine and 1.35 g of paraformaldehyde are in 30 ul abs. Dissolved ethanol. 5.45 g methyl 3-pyridyl ketone are measured in 30 ml. Ethanol dissolved and the pH of the solution is adjusted to 4 with 5 n nitric acid. The solution of the ketone is added to the reaction mixture Added boiling, keeping the pH at 3.5-4. The reaction mixture is boiled under boiling for 2 hours «

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^BATH ORIGINAL

The solvent-nitride is distilled off, the ba "k * tand la!"> ■ »* * is dissolved, the aqueous solution is made alkaline with 40% sodium hydride and the oily phase which separates is extracted with benzene. The benzene solution is washed with water until the pH of the wash water no longer reacts alkaline to phenolphthalein. After drying over sodium sulphate, the benzene is distilled off, the residue is dissolved in isopropanol and the hydrochloride of the product is precipitated with isopropenol containing hydrogen bromide. The precipitated salt is sealed off and dried in a desiccator _{over P 2 ^ 5.}

After recrystallization from isopropanol, one obtains 2.8 g of l-carbethoxy - * - / T-oxo-l- (3-pyridyl) -propyl- (3) -piperazine-dihydrotiouiWJ. M.p .: 154-156 ° C (decomposition). Analysis »NJl = 9, Λ (calc. 9.3). "

7.) 9.45 g of 4-ciaophenyl-chloromethyl-ketone become old 1517 β l-carbethoxy-pipe-razin mixed. Since «BeaktiOBSgeadseli heats up strongly. After the warning development is finished, the reaction mixture was heated for 1 hour and then cooled 50 ml of benzene are added. The part insoluble in benzene is sucked off (9.42 g of l-carbethoxy-piperasine hydrochloride). The benzene oil is evaporated to dryness and the residue is absorbed in water containing hydrochloric acid. The oily one Part is ejet removed by traction with benzene. That from the aqueous phase at room temperature for each product -

bit

is abgenutecht, acetone washed, dried and made of one 1: 2 acetone-alcohol mixture crystallizes »JCb werdwi 7 * 7 β dee l-Oxbethoxy-4 - »/ T-oxo-l (4Mihlor-phenyl) ^ 1d | fi- (2 ^ -p hydrochloride obtained. Mp 197-198 ° C. (Decomposition)"

Analysis: K% = 8 _f O5 (calc. 8.07).

8J7 / 211 3

BATH ORIGINAL

8 *) 7 »5 g of 4-CiilorpixcBjO-oi-brompiiopgrl-kötron mixed with 9.41 s of 1-carbethoxy-piperazine. The reaction mixture heats up strongly after the end of heat development the mixture is heated on a hot water bath for 2 hours and, after cooling, 50 ml of benzene are added. .

The part which is insoluble in benzene (6 g of l-carbethoxy-pi ^ i · Ό perazine-hydrobromide) is filtered. The pil is evaporated to dryness and taken up in ethanol. The mixture is acidified with ethanol containing hydrochloric acid and evaporated to dryness. The residue is taken up in water and the oily part which separates out is extracted with benzene. The aqueous phase is clarified with activated carbon ©, filtered, evaporated to dryness and recrystallized from a 1: 2.5 alcohol-acetone mixture. 7.2 g of 1-carbethoxy -4- / Γ-0Χ0-1- (4-chloro-phenyl) -2-methyl-ethyl- (2) ^ 2-piperazine hydrochloride are obtained. Mp: 206-207 ° C (decomposition) Analysis: NJS = 7.69 (calculated: 7.76).

9.) 5.22 g of 4-chlorophenyl-f'-bromopropyl-ketone and 6.29 β 1-carbethoxypiperazine are dissolved in 30 ml of benzene. The reaction mixture is refluxed for 2 hours and the benzene-insoluble part (4.5 g) is filtered off. The filtrate is evaporated to dryness and the residue is taken up in hydrochloric acid-thinning water. The solution is extracted twice with benzene, and the product which separates out of the aqueous phase at room temperature is filtered off with suction, washed with acetone and dried.

The product is made from a mixture of 5 ml of acetone

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and 25 ml of ethanol recrystallized. There are 2.5 β des

hydrochloride obtained. M.p .: 226-227 ° 0 Analysis »N% = 7.43 upper. 7.46).

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Claims (1)

PATEifEA-KSPRÜCHB 1.) Process for the production of »· * λφ> J> ip »raziJ> · the ■ Derivatives general foraiel!, (In which. an alkyl group ·! Hydrogen or an alkyl group · f η an · whole number from 0 to 3l and R ^{1 is} a 5- or similar heterocyclic radical containing at least one nitrogen atom or a · group of the general form »! II means, in which B * and B * mean hydrogen, halogen, alkyl or alkoxy, with the proviso that if η = 1 and Br denotes hydrogen, at least one of the symbols B ⁴ and B ^ does not denote hydrogen) and their salts, characterized by la, * 5 weh a.) a ketone of the general formula III (in which Br, ΈΓ and η have the meaning given above and X is a reactive Badikal) with a piperazine derivative of the general formula (IV) (in which Br has the meaning given above) implements or b.) for the preparation of compounds of the general formula I in which η = 1, a ketone of the general formula V. (where B; and B ** have the same meaning as above) in the presence of clay formaldehyde or formaldehyde-releasing substances Piperasln-Iferivaten of the general formula IV converts, and the compounds obtained in this way are optionally converted into their salts formed with acids and / or if necessary Compounds of the formula I or their salts converted into preparations which can be used in pharmacy. - 14 -009887/2113 2.) A process according to Method * b.) Dee knopi & ohu 1, characterized in that one al "formaldehyde? Rt> £ fcb" ndes ^T = ^ edium Pear foraaldehyd. "used. 3.) Method according to method t>.) Of claim 1 and according to claim 2, characterized in that the reaction is carried out in an aqueous alcohol as all solvents, is expediently carried out in aqueous methanol or ethanol. 4.) Method according to method b.) Of claim 1 and according to claims 2-3, characterized thereby rejects, that * the reaction in an acidic medium, expedient a pH value of 2-4 is carried out « 5.) Method according to method b.) Of claim 1 and claims 2-4-, characterized in that that one ice ketone of the general formula V Acetoveratrone, p-chlorccetophenone, p-bromoacetophenone, fropiophenone, valerophenone or ethyl 3-pyridyl ketone are used. 6.) Method according to Metdiode a.) Of claim 1, characterized in that compounds of the general formula III are used as the starting material, wherein X is a halogen atom, an alkylsulphonyl or axyleulphonyl group. 7.) The method according to claim 6, characterized in that X is a chlorine atom, bromine atom or a Methanesulphonyl, benzenesulphonyl or toluenesulphonyl group stands. 8 Λ method naeh method a) of claims 1 and naeh Claims 6-7, characterized in that - 15 - 009887/2113 BAD OBIQiNAt the reaction γ> ί i .. equivalent tinoo acid-binding agent performed wxrd, 9.) The method according to claim 8, characterized in that g e k e η η, that the acid-binding agent used is alkali metal hydroxides , Alkali carbonates, or alkali hydrogen carbonates are used, 10.) The method according to claim 8, characterized in that there is one as an acid-binding agent Excess of the piperazine derivative of the formula IV is used. 11.) Method according to Ilethode a.) Of claim 1 and according to claims 6-8, characterized in that the reaction in the presence of an organic solvent, advantageously benzene or toluene is carried out. 12.) Method by method:, a.) Of claim 1 and claims 6-8, characterized in, that the reaction takes place in the absence of a solvent to be led. 15.) The method according to any one of claims 1-12, characterized characterized in that the free bases of the Formula I in yours, with hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, benzoic acid, oxalic acid, lactic acid, Citric acid, or salts formed by maleic acid are transferred * 14.) The method according to any one of claims 1-13 »characterized in that the compounds of formula I or their salts, optionally after. . Addition of additives, in the form of tablets, dragees, emulsions _f suspensions, solutions, or injectable preparations for immediate medical use. - 16 - .. 009887/2113 R ¹ - CO-- CH - / GH ₂ ^ ₁ - ff. \ - COOS ⁵
ο \ / _ CO - CH ₂ R ² HN N- COOK ⁵ . IV. V / 00S887 / 2113 'originally inspected