CH651031A5 - PROCESS FOR THE PREPARATION OF (TRIALCOXY BENZYL) -1 PIPERAZINES. - Google Patents

Description

The invention relates to a process for preparing (trial-

According to a preferred embodiment of the process, in a first phase, a reaction is carried out in a first solvent.

3

651031

mole of a trialkyl benzyl chloride of general formula: OR,

(ii)

in which Ri, R2 and R3 have the meanings defined above, on two moles of piperazinone-2 of formula:

r <

HN N:

(ìli)

to obtain a (trialcoxybenzyl) -4 piperazinone-2 of general formula:

aA

CH0 - N NE

2 \ /

(iv)

then, in a second phase, this compound of general formula IV is reduced in a second solvent, by means of a hydride, to obtain the compounds of structure (I).

It will be noted that, in the first phase, an excess of piperazinone-2 (2 moles) is used relative to the stoe-chiometrically necessary amount (1 mole); this increases the yield; the additional mole of piperazinone-2 is recovered.

Advantageously, the first solvent is toluene, the second solvent is ether, or preferably tetrahydrofuran, and the hydride is AlLiHU or B2H6.

The process according to the invention is particularly applicable to the preparation of (2,3,4,4-trimethoxy benzyl) -1 piperazine starting from 2,3,4-trimethoxy-benzyl chloride, the intermediate piperazinone being ( trimethoxy-2,3,4 benzyl) -4 piperazinone-2.

We will now give two examples of implementation of the process according to the invention for the preparation of (2,3,4-trimethoxybenzyl) -1 piperazine.

Example 1

In a first phase, one mole of 2,3,4,4-benzyl trimethoxy chloride is reacted with two moles of piperazinone-2 in toluene at reflux, and the (2,3,4-benzeth trimethoxy) is thus obtained. -4 piperazinone-2, which melts at 112 ° C.

In a second phase, the latter compound is reduced to obtain (2,3,4,4-benzeth trimethoxy) -1 piperazine as follows.

To a suspension of 2 g of AlLitU in 100 ml of anhydrous tetrahy-5 drofuran is added, under a nitrogen atmosphere and at a temperature not exceeding 10 ° C, a solution of 14 g (0.05 mole) of (trimethoxy -2.3.4 benzyl) -4 piperazinone-2 (obtained in the first phase) in 150 ml of tetrahydrofuran.

When the addition of said solution is complete, the mixture is heated at reflux for twelve hours. Then cooled and added to the suspension successively 2 ml of water, 2 ml of 2N NaOH and 6 ml of water, cooling. Then the alumina is filtered, rinsed with tetrahydrofuran and evaporated under reduced pressure.

An oily residue is finally obtained which is rectified under vacuum. 9 g of (2,3,4-trimethoxy benzyl) -1 piperazine are thus isolated, the boiling point of which is 200 to 205 ° C. (under reduced pressure of 2 mm of mercury) and of which the dichlorhy-20 drate melts at 235-238 ° C (Kofler method).

Example 2

The first phase of Example 1 is repeated.

As for the second phase, it consists in adding, to 100 ml of a molar solution of B2H6 in tetrahydrofuran, a solution of 14 g (0.05 mole) of (2,3,4-trimethoxy benzyl) -4 piperazinone-2 (obtained in the first phase) in 50 ml of anhydrous tetrahydrofuran, this addition taking place in one hour under a nitrogen atmosphere and at a temperature not exceeding 5 ° C.

Then allowed to stand for one hour at room temperature, then heated for one hour at reflux. At the end of this period of time, 100 ml of water are added while cooling to 0 ° C. and the solvent is evaporated off under reduced pressure.

A residue is thus obtained which is treated with 50 ml of water and which is extracted with chloroform. The chloroform solution is washed with a 10% solution of COsHNa, then dried and evaporated under reduced pressure.

40 The oily residue is rectified under vacuum and 10 g of (2,3,4-trimethoxy-benzyl) -1 piperazine-30 are obtained, the boiling point of which is 200 to 205 ° C (under reduced pressure of 2 mm mercury) and whose dihydrochloride melts at 235-238 ° C (Kofler method).

The same process, with the operations detailed in Examples 1 and 2, applies for the preparation of other (trialkoxy benzyl) -1 piperazines.

The compounds obtained according to the invention, and in particular (2,3,4,4-trimethoxy benzyl) -1 piperazine, have pharmacological properties, in particular vasodilatory properties on the vessels of the general circulation, in particular on the coronaries. They also exhibit, according to the above-mentioned BSM 805 M, an adrenolytic and noradrenolytic action.

B

Claims (9)

651031 CLAIMS 1. Process for the preparation of a (trialcoxybenzyl) -1 pipé-razine of general formula: (I) coxy benzyl) -l piperazines of general formula: gold, / \ ck_-n nh 2 \ / (I) in which Ri, R2 and R3 are identical or different alkyl radicals up to C4, characterized in that a trialkyl benzyl halide of general formula is reacted: 10 in which Ri, R2, R3 are alkyl radicals which may or may not be identical up to C4, and in particular the (trimethoxybenzyl) -1 piperazine of formula 15 C ^ -halogen (ii) ck och3 och3 / \ ch „-n nh \ / in which Ri, R2 and R3 are as defined in claim 1, and the piperazinone-2 of formula: (III) Hî ^ îp to obtain a (trialcoxybenzyl) -4 piperazinone-2 of general formula: ° iRi â ° r. £> - ch_ - n (iv) r3 ° then reducing, in a second phase, said piperazinone-2. 2. Method according to claim 1, characterized in that the halide of formula II is bromide or chloride, preferably the latter. 3. Method according to claim 2, characterized in that, in the first phase, reacting, in a first solvent, one mole of trialkyl benzyl chloride with two moles of piperazinone-2 and, in the second phase, reducing the compound of general formula IV, in a second solvent, by means of a hydride. 4. Method according to claim 3, characterized in that the first solvent is toluene. 5. Method according to claim 3 or 4, characterized in that the second solvent is tetrahydrofuran. 6. Method according to one of claims 3 to 5, characterized in that said hydride is AILÌH4. 7. Method according to one of claims 3 to 5, characterized in that said hydride is B2H6. 8. Method according to one of the preceding claims, characterized in that the (2,3,4,4-benzyl trimethoxy) -l piperazine is prepared starting from 2,3,4-trimethoxy benzyl chloride, the intermediate piperazinone being (2,3,4,4-benzyl trimethoxy) -4 piperazinone-2. v-Cr 20 whose dihydrochloride is the subject of the special drug patent M 805 M filed on June 30, 1960. The process for the preparation of (2,3,4,4-trimethoxybenzyl) -l piperazine, recommended in the above-mentioned BSM No. 805 M consists of condensing, with monoformylpiperazine, 2,3-trimethoxy chloride, 4 benzyl obtained by chloromethylation of 1,2,3,3 trimethoxy benzene, after which the condensation product is hydrolyzed to obtain the (2,3,4,4-benzyl trimethoxy) -l-piperazine which is treated with gaseous hydrochloric acid. We have also described in French Patent No. 1,302,958, filed March 21, 1961, a process for the preparation of the compounds of formula (I), characterized in that one of the starting materials belongs to the category derivatives of trial-35 coxy benzene corresponding to the general formula: 40 in which Ri, R2, R3 have the specifications indicated above, the possible second product being either a body of the piperazine family (piperazine or N-mono-substituted piperazine or their addition compounds with a mineral acid) , either ammonia, one of its derivatives or the addition product of the latter with an acid. 50 According to a particular mode of implementation of this prior process (called third mode or scheme 3 in said patent 1 302 958 and forming the subject of Example 3 of this patent), the chloride of trialcoxy acid was condensed -benzoic acid corresponding to piperazine and the amide obtained 55 was reduced by an excess double alkaline hydride, preferably in an inert atmosphere, in an aliphatic or heterocyclic ether, such as, for example, tetrahydrofuran, the latter being more advantageous because of its better dissolving power and its high boiling point. The process according to the invention, in short, consists in preparing the piperazinone-2 corresponding to the (trialkoxy benzyl) -l piperazine which it is desired to obtain, then in reducing said piperazinone; said process is defined in claim 1. The halide of formula II is, in general, chloride or bromide, preferably chloride.