DD143773A1 - PROCESS FOR PREPARING N-ARYL-N '- (3-CHLOROPROPYL) -PIPERAZINES - Google Patents

Abstract

N-aryl-Ν '- (3-chloropropyl) piperazines are prepared from the corresponding N-aryl-piperazines and 1,3-Bromchlorpropan obtained in high yields and good purity, characterized in that one from the optionally after removal of an existing aqueous-alkaline phase the N-aryl-Ν '- (3-chloropropyl) piperazines by addition of a mineral acid, preferably one Hydrohalic acid, precipitated as a salt, separated and from these compounds che N-aryl-Ν '- (3-chloropropyl) piperazine sets free.

Description

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Title of the invention

Process for the preparation of N-aryl-N ¹ - (3-chloropropyl) piperazines

Field of application of the invention

The invention relates to a process for the preparation of H-aryl-N'-C3-chloropropyl) piperazines of the general Pormel

V /

- CHp - Cl I

where R is hydrogen, halogen or a lower alkyl or alkoxy radical. These compounds are intermediates for the preparation of pharmaceuticals.

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Characteristic of the known technical solutions

Kach Bach and co-workers, J, Amer. ehem. Soc., Jjü (1957) 2221, the compounds of the general formula I can be obtained from the corresponding U-aryl-N'-O-hydroxypropyl) piperazines by chlorination with PCIn. The chlorination can also be carried out with SOCl 2 (Byk Gulden, IL-OLS 72 16 309, 2.12.71; Krieael et al., J. Pharm. Sej. Jjo (1967) 326; Bourdais, Bull. Soc. Chim. Pr * 8 (1968), 3246). These processes have the disadvantage that the yield is low and the preparation of the substituted hydroxy compounds used as starting materials is expensive »

It is also known that U-aryl-U '- (3-chloropropyl) <piperazines of the general formula I from U-aryl-piperines of the general formula

R - ^ / 7 ^. ^ CH ₂ - CH \ / CHp - CH

wherein R has the meaning given above, can be prepared by alkylation with 1,3-brorachloropropane (Pollard, J. Org · Chem. 24 ^ 764-767 (1959)) * This process has the disadvantage that the workup of the Reaktionsegemischea very cumbersome and lossy iat · Thus, after completion of the reaction, the aqueous-alkaline phase is separated _s . then the solvent is distilled off under vacuum and the remaining

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Fractionated oil in vacuo. During this distillation, decomposition and side reactions of the formed N-aryl-N'-O-chloropropyl) -piperazines of the general formula I take place, which take place in salt-like distillation residues or at higher and longer temperature; expressing stress in tar-like distillation residues, which makes it difficult in particular to make a technical application of these methods

These residues contain cracked substances, as well as unwanted by-products and no N-aryl-N'-C3-chloropropyl) -piperazine of the formula I more · The amount of residues in certain cases makes up 50 % of the piperazine of the formula I. In unfavorable cases comes for the complete decomposition of the piperazine of the formula I ·

Object of the invention:

The invention makes it possible to obtain the compounds of the formula I in high yields and good purity from the reaction mixtures obtained in the reaction of N-aryl-piperazines of the formula II with 1,3-lromochloropropane; and to avoid the side and decomposition reactions hitherto occurring in the work-up of the reaction mixture.

Instead of 40-50 % yield in the procedure described by Pollard 80-SO % yield are achieved · Another advantage is that the unreacted N-arylpiperazines of formula II can be recovered in this way and fed back into the reaction process ·.

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Explanation of the essence of the invention

The invention is based on the object H-aryl-N ^f - (3-chloropropyl) piperazines of the general formula I in which R has the abovementioned meaning to produce in high yields and good purity ·

Entaprechend of the invention, this is achieved by reacting from a reaction mixture obtained in the reaction of H-aryl pi.p.erazines of formula II with bromochloropropane in an inert organic solvent after removal of any aqueous alkaline phase, the compounds of general formula I. by adding a mineral acid, preferably a hydrohalic acid, as a salt of the general formula

^< > - ³ ^ _x ^ THH - CH ₂ - CH ₂ - CH ₂ - Cl

CHp * * CHp

III

in which R has the abovementioned meaning and X "denotes the anion of a mineral acid, preferably a halogenoanion, precipitates, separates and releases from it the compounds of general formula I,

The precipitation of the compounds of the general formula III can be carried out both in the presence and in the absence of water by adding the reaction mixture either with an aqueous solution of the acid in question, preferably by adding hydrohalic acid, or by separating the aqueous alkaline phase dry hydrogen halide in the optionally

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einleizet by an inert solvent diluted alkylation mixture, wherein the end point of the precipitation is achieved by a slight excess of the acid in question. Preferably, one works with hydrohalic acids in aqueous-organic systems, the sparingly soluble salts of formula III precipitate and optionally isolated after cooling, while the readily water-soluble salts of the starting materials of the formula

IV

R ^ / 1 \\ . CH ₂ - VXi ₂ ^ - N

V- / CH ₂ - CH

in which R and X "have the abovementioned meaning, can be introduced into the mother liquors and the corresponding piperazine bases can be obtained therefrom after alkalization and, if necessary, made accessible to a renewed alkylation reaction.

In this way, the relatively difficult to obtain U-arylpiperazines of formula II are largely utilized for the alkylation reaction to form the desired compounds of formula I. The compounds of the general formula III are well-crystallizing salts which are sparingly soluble in organic-aqueous systems and which are suitable for gentle isolation or purification of the compounds of the formula I. In particular their solubility properties permit, in most cases, selective separation from the corresponding salts Unreacted starting materials of the formula IV, which is of crucial importance for the purity of the desired compounds of the formula I because of the abovementioned lifting reactions in the case of distillative workup.

The precipitated salts of formula III are filtered off, washed, possibly recrystallized and then suspended in water in the presence of an inert water-immiscible organic solvent and released with the addition of a base, using as bases the hydroxides, carbonates or hydrogen carbonates of the metals of the Periodic Table I and II.

The liberated U-aryl-IT ^l - (3-chloropropyl) piperazine bases of the formula I are taken up by the respectively used organic solvents. These solutions are dried in the usual way. Each of the separation of the Trockeniaittels remain the NrAryl-H'-O-chloropropyl) piperazine bases of the formula I in the inert organic solvent and can be used immediately for the next step in the synthesis or in case of need also be recovered by distillation, with significantly higher yields than when directly distilled from the alkylation mixture according to the conventional procedure.

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Exemplary embodiments Example 1

Preparation of H- (3-chlorophenyl) -H ^l - (3-chloropropyl) -piperazine-HCl

98.5 g (0.50 mol) of N- (3-ethylphenyl) piperazine, 100 ml of acetone, 100 g (0.64 mol) of 1,3-bromochloropropane and 75 ml of 25% sodium hydroxide solution are stirred for 20 hours the first 2 hours, a temperature increase to 35 - 40 ⁰ G, being cooled when reaching 40 ⁰ C. After the reaction time has ended at room temperature, the lower aqueous alkaline layer is separated off and discarded. 250 ml of water are added to the upper organic phase. A pH of 2-3 is now set with about 45 ml of concentrated hydrochloric acid, during which the temperature rises to about 40 ^° C. It is then cooled and filtered off with suction at 5-10. The mixture is washed twice with 100 ml of cold water and then dried, yield: 138 g (90 % of theory) of crude KCl salt of U- (3-chlorophenyl) "H" - (3-chloropropyl) -piperazine, Pp; 192 - 200 ° C ·

Ucrystallization from water or chloroform yields the pure salt with an Mn 195-200 ⁰ C. By alkalization of the aqueous mother liquor 5-7 g of unreacted n- (3-chlorophenyl) -piperasin can be recovered.

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Example 2:

Preparation of U '' f (3-chlorophenyl) -H ^l - (3-chloropropyl) -piperazine-HBr

The alkylation is carried out analogously to Example 1. For salt precipitation concentrated hydrobromic acid is used under the same volume ratios "are obtained 160 g HBr salt of H- (3-Chlorphe.nyl) -U '- (3-chloropropyl) -piperazine having a melting point 197-202 ⁰ G (90 % of theory) · Recrystallization from water yields the pure salt with a Pp of 200 - 203 ⁰ C _β

Example 3:

Preparation of U - (. 3-chlorophenyl) -H ^t - (3-chloropropyl) piperazine

From the salts of the lT- (3-chlorophenyl) -N '- (3-chloropropyl) -piperazine, prepared according to Example 1 and 2, the corresponding bases are obtained, in each case with 150 ml of toluene, 75 ml of water and 75 ml concentrated aqueous sodium hydroxide solution to 60 - 70 ⁰ C until a bare 2-phase system was present The phases are then separated at 40 - 50 ⁰ C · The aqueous alkaline phases are discarded · Hach distilling off the toluene left behind 120 g lT- (3-chlorophenyl ) -lJ ¹ - (3-chloropropyl) -piperazine, which can be purified by distillation. Yield: 100-110 g of pure product, corresponding to 77-80 % of theory based on Έ- (3-chlorophenyl) -piperazine.

Kp _n ς -: 162-170 ⁰ C.

Claims (2)

claims 1 · Process for the preparation of N-aryl-N'-O-ethyl-propyl) -piperazines of the general formula I. CH ₂ -CH ₂ N-CH ₂ -CH ₂ -CH ₂ -Cl I in which R is hydrogen, halogen or a lower alkyl or alkoxy group, by alkylating the corresponding N-arylpiperazines of the general formula CH ₂ -CH ₂ NH - CHo SI in which R has the abovementioned meaning, with 1,3-bromochloropropane, in an inert organic solvent, characterized in that the compounds of general formula I are obtained from the reaction mixture obtained, optionally after removal of an aqueous-alkaline phase, by addition of a mineral acid, preferably a hydrogen halide acid salt of the general formula - N. CHo - - 205 8 67 in which R has the abovementioned meaning and X "" denotes the anion of a mineral acid, preferably a halogenoanion, precipitates, separates and releases therefrom the compounds of the general formula I · 2, process according to item 1, characterized in that the compounds of general formula I are obtained from the salts of general formula III by reaction with hydroxides, carbonates or bicarbonates of the metals of Groups I and II of the Periodic Table.