CH449629A - Process for the preparation of piperazine compounds - Google Patents

Description

  

  



  Process for the preparation of piperazine compounds
The present invention relates to a process for the preparation of N- (2-OR-2-Ph-ethyl) -N'-arpiperazines of the formula I.
EMI1.1
 where Ph is a halophenyl or trifluoromethylphenyl radical, R is lower alkyl, Ri is hydrogen or methyl and Ar is phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl or pyridyl, or their acid addition salts.



   The halogen substituent in the radical Ph is e.g. B.



  Fluorine, chlorine or bromine.



   The lower alkoxy group OR in the 2-position of the ethyl radical of the above formula has 1-7, preferably 1-4 carbon atoms and is primarily methoxy or ethoxy, but also n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy or n-heptyloxy.



   The symbol Ar means primarily an unsubstituted phenyl radical or one by lower alkyl, e.g. B.



  Methyl, ethyl, n-propyl, isopropyl or tert-butyl, lower alkoxy, e.g. B. methoxy, ethoxy, n-propyloxy, iso propyloxy or n-butyloxy, or halogen, e.g. B. fluorine, chlorine or bromine substituted phenyl radical. The group Ar can also represent pyridyl, e.g. B. 2-pyridyl, 3-pyridyl or 4-pyridyl stand.



   The compounds of the present invention have above all anti-inflammatory, but also antihypertensive, adrenolytic, diuretic and saliuretic effects and can accordingly be used as anti-inflammatory agents or as vasodilators in peripheral vascular diseases such as Reynaud's disease or causalgia. The new substances are also antagonists of compounds which have a strong effect on the tissue, such as e.g.

   B. the norepinephrine. Furthermore, they can be used as a diagnostic means to control the adrenal function, since they suppress the excretion of substances that increase blood pressure such as epinephrine or norepinephrine in the normally functioning adrenal glands. The new compounds can also be used as hypotensive, diuretic or saliuretic agents.



   Particularly valuable compounds are those of the formula II
EMI1.2
 where R is lower alkyl, preferably with 1-4 carbon atoms, the radical R is hydrogen or methyl, Ra is a halogen atom, preferably with an atomic weight of 19 to 80, and the group R "is hydrogen, lower alkyl, preferably having 1-4 carbon atoms, lower alkoxy, preferably having 1-4 carbon atoms, or halogen, preferably having an atomic weight of 19 to 80, and their acid addition salts.



   The compounds of the formula III show particularly strong anti-inflammatory properties
EMI1.3
 where R has the meaning given above, Rta is halogen, in particular chlorine, R, is hydrogen or methyl and R'b is hydrogen, methyl, methoxy or chlorine, and their acid addition salts, in particular 1- [2- (4-chlorine phenyl) -2-ethoxyethyl] -4- (2-methoxyphenyl) piperazine and its acid addition salts.



   The process according to the invention for preparing the new compounds is characterized in that an N-Ar-piperazine of the formula IV
EMI2.1
 wherein Ar and Ri have the meaning given above, or its salts with a reactive ester of a 2-OR-2-Ph-ethanol of the formula V
EMI2.2
 where R and Ph have the meaning given above and Y is a reactive esterified hydroxyl group. If desired, obtained acid addition salts can be converted into the free compounds or obtained free compounds can be converted into their acid addition salts.



   Salts of the piperazine compound of the formula IV used as starting material are mainly metal salts, such as alkali metal, e.g. B. lithium, sodium or potassium salts. These salts can be prepared by methods known per se. So z. B. the N-Ar piperazine compound, wherein Ar has the meaning given above, dissolved in a suitable solvent or solvent mixture and the solution with an alkali metal, e.g. B. sodium, with an alkali metal hydride or amide, such as lithium, sodium, potassium hydride or amide, with an alkali metal carbonate, e.g. B. sodium carbonate or potassium carbonate, or with an alkali metal lower alkoxide, if desired, with cooling or heating and / or in an inert gas atmosphere, e.g. B. treated under nitrogen.

   However, it is also possible to convert a metal salt-forming reagent to the mixture of the two starting materials or, preferably, to their solution, the salt being formed in the reaction mixture.



   Reactive esters of a 2-OR-2-Ph-ethanol, in which R and Ph have the meaning given above, are primarily esters of strong inorganic acids, in particular hydrohalic acids such as hydrochloric or hydrobromic acid, also sulfuric acid, or a strong organic sulfone - acid, e.g. B. methane sulfonic acid or p-toluene sulfonic acid. Preferred starting materials are the 2-OR-2-Ph ethyl halides of the formula VI
EMI2.3
 where Ph and R have the meaning given above and Hal stands for a halogen atom, in particular with an atomic weight of 35 to 80, in particular chlorine, but also bromine.



   The reaction can be carried out in a manner known per se. If the free piperazine compound of the formula IV is used, the acid which forms can be neutralized with an excess of the said perazine compound or with another basic agent, such as sodium acetate, sodium carbonate or potassium carbonate. The basic condensation agent can also be added to the mixture of the two starting materials. The reaction is preferably carried out in the presence of a diluent (e.g.

   B. a solvent used in the production of the metal compound), if desired, carried out with cooling or preferably heating, in an inert gas, such as nitrogen atmosphere, or in a closed vessel.



   The starting materials are known or can be prepared by methods known per se. So z. B. the 2-OR-2-Ph-ethyl halides, where R and Ph have the meaning given above, by reacting the magnesium Grignard reagent of a Ph halide, e.g. B. bromide, with a 1-Niederalkoxy ethylene-1, 2-dihalide, z. B. dichloride.



   Depending on the process conditions and starting materials, the end product can be obtained in free form or in the form of its acid addition salts, which is also included in the invention. For example, basic, neutral, acidic or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner known per se, e.g. B. exchange with basic agents such as alkalis or ions. On the other hand, the free base obtained can form salts with organic or inorganic acids.



  For the preparation of acid addition salts, in particular therapeutically useful acids can be used, eg. B. hydrohalic acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, vinegar, propionic, amber, glycol, milk, apple, wine, lemon and ascorbic acid. n-, maleic, hydroxymaleic or pyruvic acid;

     Phenylacetic, benzoic, p-amino-benzoic, anthranil, b-hydroxy-benzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.



   These or other salts of the new compound, such as. B. the picrates, can also be used to purify the free compound obtained by converting the free compound into salts, separating them and in turn liberating the free compound from the salts.



   As a result of the close relationship between the new compound in free form and in the form of its acid addition salts, in the preceding and in the following the free compound is to be understood, meaningfully and appropriately, also to mean the corresponding acid addition salts.



   The new compounds can be present as racemates or mixtures of racemates, which can be resolved by methods known per se.



   In the process of the present invention it is preferred to use those starting materials which lead to the compounds described at the beginning as being particularly valuable.



   The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations can be used, which these compounds together with phar pharmaceutical, organic or inorganic, solid or liquid excipients, which for enteral, z. B. oral or parenteral administration are suitable.



   Example 1 E: n mixture of 10.05 g of 1- (2-methoxyphenyl) - prperazine and 11.5 g of 2- (4-chlorophenyl) -2-ethoxy-ethyl chloride in 200 ml of butanol is on Refluxed for 24 hours in the presence of 40.0 g of sodium carbonate, boiled with stirring. The inorganic material is filtered off, the filtrate is evaporated to dryness and the residue is distilled. 1-12- (4-chloro-phenyl) -2-ethoxy-ethyl] -4- (2-methoxyphenyl) piperazine of the formula is obtained
EMI3.1
 at 190-200 / 0.3 mm.



   A solution of the free base in ethanol is treated with a saturated solution of hydrogen chloride in ethanol and diluted with diethyl ether. The 1- [2- (4-chloro-phenyl) -2-ethoxy-ethyl] -4- (2-methoxyphenyl) -p-perazine dihydrochloride obtained melts, after recrystallization from isoropanol, at 229-231.



   The 2- (4-chloro-phenyl) -2-ethoxy-ethyl chloride used as starting material is prepared as follows: (To a mixture of 8.16 g of magnesium in 75 ml of diethyl ether, a total of 76.4 g is added 4-chloro-bromobenzene in diethyl ether is added. The reaction mixture is refluxed and treated with most of the 4-chloro-bromobenzene in diethyl ether (the total amount of ether is about 200 ml). The reaction mixture is refluxed until all of the magnesium reacts has, then cools and adds 48.0 g of 1,2-dichloro-diethyl ether with cooling in one hour. The reaction mixture is then stirred for 30 minutes at room temperature, refluxed for one hour and left to stand overnight.

   Then it is poured onto a mixture of hydrochloric acid and ice. The organic material is extracted with diethyl ether, the organic solution quickly washed with 20% aqueous sodium hydroxide solution and twice with water, dried and evaporated. The desired 2- (4-chloro-phenyl) -2-ethoxy- Ethyl chloride is obtained by distillation at 122-140 / 12 mm.



     Example 2
A quantity of 16.0 g of 2- (4-chlorophenyl) -2-ethoxy-ethyl chloride and 11.8 g of 1-phenyl-piperazine in 200 ml of n-butanol is refluxed for 24 hours in the presence of 40.0 g Boiled sodium carbonate. The inorganic material is filtered off, the filtrate is evaporated and the residue is distilled. The 1- [2- (4-chlorophenyl) -2-ethoxy-ethyl] -4-phenyl-piperazine of the formula is obtained
EMI3.2
 at 90-91 / 0.3 mm. The product is converted into its dihydrochloride which, after recrystallization from acetonitrile, melts at 203-205.



     The following compounds are also prepared according to the process described above: 1-, [2-Ethoxy-2- (3-trifluoro-methyl-phenyl) -Ïthyl] -4 phenyl-p! perazine (boiling point 128-140 / 0.35 mm), the dihydrochloride of which melts at 182-185; 1- [2- (3, 4-dichlorophenyl) -2-ethoxy-ethyll-4- (2-methoxy-phenyl) -piperazine (distilled at 210-220 /
0.7 mm), the dihydrochloride of which, after recrystallization from ethanol and diethyl ether, melts at 221-225;

     4- (2-chloro-phenyl) -1- [2- (4-chloro-phenyl) -2-ethoxy-ethyl] -piperazine (distilled at 185-190 / 0.2 mm), its hydrochloride, after recrystallization
Ethanol, melting at 240-244; 1- [2- (3,4-dichloro-phenyl) -2-Ïthoxy-Ïthyl] -4-phenyl piperazine (distilled at 210-220 / 0.7 mm), its
Dihydrochloride, after recrystallization from ethanol and diethyl ether, melts at 211-213; 1-, [2- (3-chloro-phenyl) -2-ethoxy-ethyl] -4- (2-methoxyphenyl) piperazine (distilled at 170-190 / 0.7 mm), its dihydrochloride, after recrystallization from ethanol and diethyl ether, melts at 213-217;

   1- [2- (3-chloro-phenyl) -2-Ïthoxy-Ïthyl] -4-phenyl piperazine (distilled at 180-200 / 0.7 mm), its
Dihydrochloride, after recrystallization from ethanol and diethyl ether, melts at 192-193; and 1- [2-ethoxy-2- (4-fluoro-phenyl) -ethyl] -4- (3-methyl-phenyl) -piperazine (distilled at 160-165 / 0.8 mm), its hydrochloride, after Recrystallization from lithanol and diethyl ether, melting at 193-196.



     Example 3 En mixture of 10.0 g of 2-ethoxy-2- (4-fluorophenyl) ethyl chloride and 8.9 g of 2-methyl-1-phenyl-piperazine in 200 ml of butanol, which a few drops of water and Contains 10.0 g of sodium carbonate, is refluxed for 72 hours. The reaction mixture is filtered, the filtrate is evaporated under reduced pressure and the residue is taken up in ether. The insoluble material is filtered off, the filtrate is washed with water, dried and evaporated under reduced pressure.

   The desired 1- [2-¯thoxy-2- (4-fluoro phenyl) ethyl] -3-methyl-4-phenyl-piperazine of the formula
EMI3.3
 is obtained by distillation at 170-175 / 0.6 mm and converted into its dihydrochloride by treatment with a solution of hydrogen chloride in ethanol. After recrystallization from ethanol and diethyl ether, the salt melts at 228-232.



   The raw material is produced as follows:
The Grignard reagent is prepared by treating a mixture of 8.16 g of magnesium turnings in 275 ml of ether with 70 g of 4-bromo-fluorobenzene. The reagent is stirred for one hour with cooling and then 48 g of 1,2-dichloroethyl-ethyl ether are added dropwise. After the addition of the last-mentioned compound has ended, the reaction mixture is stirred for 30 minutes at room temperature, then refluxed for one hour and left to stand overnight at room temperature. Then the reaction mixture is poured onto ice. The aqueous mixture is acidified with concentrated hydrochloric acid and extracted with ether. The organic solution is dried, evaporated and the residue is distilled.



  At 110-115 / 12 mm, 2-sithoxy-2- (4-fluorophenyl) ethyl chloride is obtained.

 

Claims (1)

PATENT CLAIM Process for the preparation of N- (2-OR-2-Ph-ethyl) -N'-Ar-piperazines of the formula EMI4.1 where Ph is a halophenyl or trifluoromethylphenyl radical, R is lower alkyl, Ri is hydrogen or methyl and Ar is phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl or pyridyl, or their acid addition salts, characterized in that an N-Ar-piperazine of the formula EMI4.2 wherein Ar and R have the meanings given above, or their salts with a reactive ester of a 2-OR-2-Ph-ethanol of the formula EMI4.3 where R and Ph have the meaning given above and Y is a reactive esterified hydroxyl group. SUBClaims 1. Process according to claim, characterized in that an alkali metal salt of an N-Ar piperazine of the formula IV specified in claim is used as the starting material. 2. The method according to claim, characterized in that the sodium salt of an N-Ar-piperazine of the formula IV specified in the claim is used as the starting material. 3. The method according to claim, characterized in that halides are used as the reactive ester. 4. The method according to claim, characterized in that chlorides are used as reactive esters. 5. The method according to claim, characterized in that compounds of the formula EMI4.4 where R denotes lower alkyl, the radical Ri denotes hydrogen or methyl, Ra denotes a halogen atom and the group Rb denotes hydrogen, lower alkyl, lower alkoxy or halogen. 6. The method according to claim, characterized in that compounds of the formula EMI4.5 where R is lower alkyl, R 'is halogen, Ri is hydrogen or methyl and R'b is hydrogen, methyl, methoxy or chlorine. 7. The method according to claim, characterized in that compounds of the formula EMI4.6 where R is lower alkyl, R 'is chlorine, Rt is hydrogen or methyl and R' ,, is hydrogen, methyl, methoxy or chlorine. 8. The method according to claim, characterized in that 1- [2- (4-chloro-phenyl) -2-ethoxy-ethyl] -4- (2-methoxy-phenyl) piperazine is prepared. 9. The method according to claim or one of the dependent claims 1-8, characterized in that the piperazines are produced in free form. 10. The method according to claim or one of the sub-claims 1-8, characterized in that the piperazines are produced in the form of their acid addition salts.