Way to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl) piperazine


(57) Abstract:

The invention relates to the field of synthesis of medicinal substances, specifically, to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine (I), which is the substance of a drug Trimetazidine. The compound (I) is produced by interaction of 2,3,4-trimethoxybenzaldehyde with piperazine by catalytic hydrogenation with hydrogen on the catalyst palladium on coal at a temperature of 80-85C, and 2,3,4-trimethoxybenzaldehyde injected into the reaction gradually. Also it is possible to conduct the reaction in the presence of catalytic amounts of acetic acid. This method can be developed on an industrial scale.

The invention relates to the field of synthesis of medicinal substances and specifically to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine (I), which is the substance of a drug Trimetazidine.

A method of obtaining the compound (I), which 2,3,4-trimethoxybenzaldehyde (II) and an excess of piperazine dissolved in an alcohol solvent or methyl tert-butyl ether and hydronaut hydrogen in the presence of palladium on coal at 45-75S, and the basis of (I) transferred to dihydrochloride ether for this process in the production of virtually eliminated due to the properties of the solvent, in was taken as a prototype example, with an alcoholic environment.

78,4 g 2,3,4-trimethoxybenzaldehyde (II), 137, 6mm g of anhydrous piperazine, 400 ml of ethanol and 4 g of 5% Pd/C contribute to the reactor, rinsed with nitrogen and hydrogen, and then as soon as possible heated to 70C, creating upon reaching 45C a hydrogen pressure of 10 bar, and stop the hydrogenation after 70 minutes the Reaction mixture at 20 C is filtered, the filtrate is evaporated to dryness, the residue make 200 ml) cooled to (-5) - (-10)With toluene and filtered. To the filtrate was added 200 ml of water, adjusted to pH 6 by addition of concentrated hydrochloric acid, the organic layer separated and the aqueous extracted twice with 120 ml of toluene. To the aqueous layer was added 42 g of sodium hydroxide, extracted three times with 120 ml of toluene, and the combined extracts evaporated to dryness and receive the base (I) with the release of 92% and a content of the basic substance to 96.8% (by HPLC).

Us study has found that the aldehyde (II) and piperazine take the polycondensation with the formation of oligomers (VI) (see diagram transformations):

The reaction is already cold, greatly accelerating when heated, and to exclude it in terms of the said patent cannot. In addition to the output of the aldehyde (II) from the target healthy lifestyles who you and deposited on the catalyst surface and equipment. The latter, in particular, leads to jamming of the rotor stirrer autoclave with induction drive and in principle is contraindicated for production. The prototype is likely to reduce the formation of oligomers, the solution of both reagents is heated as quickly as possible to 70C and start hydrogenation at 45C. However, production cannot quickly be heated using traditional methods of heating, because of thermal inertia of large amounts of active mass. And when simulating production conditions, the reaction mixture turns into a gel-like mass.

The disadvantage of this method is that it is absolutely impossible to use in a production environment due to leakage in the above adverse reactions.

The present invention is to provide a method which can be utilized in an industrial scale. This is achieved by 2,3,4-trimethoxybenzaldehyde (II) is introduced into the reaction gradually at a temperature of 80-85C.

A solution of the aldehyde (II) is gradually added to a solution of piperazine containing Pd/C, heated to 80-85C at an operating pressure of hydrogen (5-10 ATA). As a solvent used isopropanol. In order to advance) is rapidly converted into the target product (I), that reduces the probability of formation of the gem-diamine (V) and further polycondensation. The reaction is terminated during the addition of hydrogen (30 min), as indicated by cessation of pressure drop of hydrogen. At the same time the gradual addition of the aldehyde and reduces the degree of leakage other adverse reactions leading to the formation of 1,4-di(2,3,4-trimethoxybenzyl)piperazine (III), because it creates a huge excess of piperazine in each point of the process over time.

In the above conditions is not observed complications associated with the formation of oligomers. Moreover, their formation can be ruled out altogether. It is established that the oligomers (VI) is rapidly hydrolyzed by acid catalysis. Water is always present in the reaction mixture, since it is allocated by the reaction and in certain amounts to be paid with reagents. In the process, the hydrolysis should be gem-diamine (V) in the moment of formation, which eliminates the subsequent polycondensation. However, it can be either hydrolyzed and amerosport (IV). Therefore, the number and strength of acid must be optimal. So, when introduced into the reaction mixture with acetic acid in the amount of 1-2% by weight of the aldehyde (II) increasing the yield of the final product (up to 5%), which indicates istwa reaction medium. In nonpolar environments, it flows much more slowly that in the light of the above undesirable. However, the addition of, for example, toluene has virtually no effect on the process. This is important because it allows one to use toluene solution of the aldehyde (II), resulting in the previous phase synthesis of substance Trimetazidine and not containing other impurities, in addition to the original 1,2,3-trimethoxybenzene (through clearing). The introduction of the toluene in the reaction mixture is well combined then replace them with isopropanol. The admixture of inert in the reaction of 1,2,3-trimethoxybenzene remains in toluene in the translation product in the aqueous layer.

The invention is illustrated by the following examples of specific performance.

Example 1

In the autoclave make 100 ml isopropanol, 34.4 g of piperazine and 2 g of 5% palladium on coal is blown with nitrogen and hydrogen to create a hydrogen pressure of 5 ATA, heated to 80-85C and gradually for 30 min was added a solution of 38.2 g of 2,3,4-trimethoxybenzaldehyde, after 15 minutes, cool, relieve pressure and separate the catalyst. Distilled isopropanol, the residue is dissolved in 150 ml of toluene, cooled to-5 C and filtered piperazine. To the filtrate was added with stirring 100 ml Floola. From the extract is distilled toluene, was added 100 ml of isopropanol and gradually added a solution of 30 g of 35% hydrochloric acid in 150 ml of isopropanol is distilled off 150 ml of a mixture of isopropanol - water, cooled to 0-5C, stirred for 1 h, filtered crystalline precipitate, washed with isopropanol, dried and receive 54,9 g of the dihydrochloride of 1-(2,3,4-tri-methoxybenzyl)piperazine, yield 81%, the content of 99.9-100% (by HPLC).

Example 2

Carried out analogously to example 1, but in the presence of 0.5 g of acetic acid. Get the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine with the release of 85%.

Example 3

The complex obtained by mixing 120 g of dimethylformamide and 220 g of phosphorus oxychloride is added 160 g of 2,3,4-trimethoxybenzaldehyde, heat 9 h at 80 C, cooled, poured onto 1.5 kg of a mixture of ice - water, stirred for 4-5 h and extracted with 400 g of toluene. The extract is washed with twice 150 ml of 10% sodium hydroxide solution and twice with 150 ml of a saturated aqueous solution of sodium chloride is distilled off 200 g of toluene, and a little water, and determine the content 2,3,4-trimethoxybenzaldehyde by GLC. Part of the obtained solution (80-85 g) containing 38,2 g 2,3,4-trimethoxybenzaldehyde, gradually over 30 min add to 34.4 g of piperazine and 2 g of 5% Pd/C in re 1-(2,3,4-trimethoxybenzyl)piperazine with yields of 80%, the content of 99.9-100% (by HPLC).

The inventive method obtain the dihydrochloride of 1-(2,3,4-trimetoksi-benzyl)piperazine can be developed on an industrial scale.

1. Way to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)-piperazine interaction 2,3,4-trimethoxybenzaldehyde with piperazine by catalytic hydrogenation with hydrogen on the catalyst palladium on coal when heated, followed by separation of the reaction product and processing it with hydrochloric acid, characterized in that 2,3,4-trimethoxybenzaldehyde injected into the reaction gradually at a temperature of 80-85C.

2. The method according to p. 1, characterized in that the reaction is carried out in the presence of catalytic amounts of acetic acid.


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