RU2051899C1 - Process for preparing bis-quaternary salts of bis(2- dimethylaminoethyl ester) of succinic acid - Google Patents

Abstract

FIELD: chemistry of biologically active compounds. SUBSTANCE: proposed is a process for preparing such compounds which comprises using an accessible raw material. The process conditions, namely reaction of succinic anhydride with 2- dimethylaminoethanol in toluene at 110 to 120 C for 30 ± 5 hrs and a molar ratio of succinic anhydride, 2- dimethylaminoethanol and toluene of 1:(2.5-3.0):(3.5- 5.0), respectively makes it possible, without prepurification, to use intermediate bis(2- dimethylaminoethyl ester) of succinic acid to obtain the desired bis-quaternary salts. EFFECT: simplified technology, increased yield of the end products, their quality meeting the criteria of pharmacopeia. 1 tbl

Description

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Недостатками метода являются применение высокотоксичного и труднодоступного дициклогексилкарбодиимида (IV), сравнительно невысокий выход эфира (I) и трудности отделения его от N,N'-дициклогексилмочевины (V).The invention relates to the chemistry of biologically active compounds, and in particular to a new method for producing depolarizing curariform preparations of dithilin, and its analogs of listenone and muscle relaxant [1]
Several methods are known for producing these drugs [2, 3] The prototype of the method is a method for the synthesis of these drugs, based on the production of bis (2-dimethylaminoethyl ether) succinic acid (I) by the interaction of succinic anhydride (II) and dimethylaminoethanol (III) in the presence of N, N'-dicyclocarbodiimide (IV) followed by its quaternization into the target compound (VI) [4]

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The disadvantages of the method are the use of highly toxic and inaccessible dicyclohexylcarbodiimide (IV), a relatively low yield of ether (I) and the difficulty of separating it from N, N'-dicyclohexylurea (V).

 The aim of the invention is to simplify the process and increase the yield of bis-quaternary salts of succinic acid bis (2-dimethylaminoethyl ether).

Как известно, толуол образует с водой азеотропную смесь, кипящую при 85^оС, и при проведении процесса при 110-120^оС образующаяся в результате реакции янтарного ангидрида с 2-диметиламиноэтанолом вода постоянно вводится из реакционной сред, что направляет реакцию в сторону образования эфира (I). Температурный интеpвал 110-120^оС, при котором следует проводить процесс, обосновывается следующими причинами. При проведении реакции при температуре ниже 110^оС она протекает медленно, не достигается устойчивого вывода воды с толуолом и не происходит достаточно полного превращения янтарного ангидрида в эфир (I), из-за чего его выход падает. При проведении процесса при температуре выше 120^оС начинается интенсивная отгонка 2-диметиламиноэтанола (т. кип. 131-134^оС), что приводит к выводу одного из реагентов из среды реакции. При этом не достигается полного превращения янтарного ангидрида в эфир (I), и протекают побочные реакции.The goal is achieved by reaction of succinic anhydride (II) with 2-dimethylaminoethanol (III) in toluene at a temperature of 110-120 ^{° C} for 30 5 hours and molar ratio succinic anhydride, 2-dimethylaminoethanol and toluene = 1: (2 5-3.0) :( 3.5-5.0), respectively:

As it is well known, forms a water-toluene azeotrope boiling at 85 ^{° C,} and by operating at 110-120 ^{° C} formed by the reaction of succinic anhydride with 2-dimethylaminoethanol water is introduced from the reaction medium, that directs the reaction towards ester formation (I). The temperature interval of 110-120 ^C, at which the process based on the following factors should be performed. In carrying out the reaction at a temperature below ¹¹⁰ ° C, it is slow, output is not achieved stable with toluene and water does not occur sufficiently complete conversion of succinic anhydride ester (I), because of which its output drops. In carrying out the process at temperatures above 120 ° ^C. begins intensive distillation of 2-dimethylaminoethanol (t. Bales. 131-134 ° ^C), which leads to a one of the reactants from the reaction medium. In this case, complete conversion of succinic anhydride into ether (I) is not achieved, and adverse reactions occur.

In general, when carrying out the process at a temperature below 110 ^{° C} and above ¹²⁰ ° C ether (I), and consequently the target bisquaternary salts (VI), can not be obtained with sufficiently high yields and required quality.

Use of 2.5-3.0 moles of 2-dimethylaminoethanol per mole of succinic anhydride, i.e. the use of an excess of 0.5-1.0 moles of 2-dimethylaminoethanol from theoretical allows you to maintain the necessary excess of amino alcohol in the reaction medium. A decrease in this amount leads to incomplete conversion of succinic anhydride, and its increase is impractical, since it does not affect the course of the reaction. The use of toluene in an amount less than 3.5 mole per mole of succinic anhydride requires an increase in reaction temperature above 120 ^C, which, as mentioned earlier, leads to losses of the amino alcohol and does not allow the target substance with high yield and satisfactory quality.

A significant advantage of the proposed method is that only three components remain in the reaction mixture after the process: the target ester (I), an excess of 2-dimethylaminoethanol and toluene. In this case, toluene and 2-dimethylaminoethanol can be easily removed by distillation without vacuum in a small factory vacuum. Bis (2-dimethylaminoethyl ether) succinic acid having a boiling point of 148-150 ^about With, while not distilled off. Thus, in the reaction mass after distillation of toluene and 2-dimethylaminoethanol there remains a sufficiently pure ether (I), which without further purification can be used to form the desired bis-quaternary salts (VI).

 Based on the ester (I) obtained under the described conditions, during quaternization with methyl halides, curariform preparations were synthesized: bis-chloromethylate bis (2-dimethylaminoethyl ester) succinic acid (listenone), bis-bromomethylate bis (2-dimethylaminoethyl ester) succinic acid (myorelax) and bis (2-dimethylaminoethyl ester) succinic acid bis-iodomethylate (dithiline), fully corresponding to those described in the literature [3] When quaternizing ether (I) with dimethyl sulfate, bis (2-dimethylaminoethyl ether) bismethyl sulfonate was obtained amber acid.

 The proposed method is illustrated by examples of its implementation.

PRI me R 1. Obtaining bis-iodomethylate bis (2-dimethylaminoethyl ether) succinic acid. 25 g (0.25 mol) of succinic anhydride and 92 g (1.0 mol, 106 ml) of toluene are charged into a 250 ml three-necked round-bottom flask equipped with a thermometer, stirrer and Dean-Stark nozzle. To the resulting suspension 55.8 g (0.625 mol, 83 ml) of 2-dimethylaminoethanol are added with stirring. The reaction mixture was heated in an oil bath and maintained at a mixture temperature of 115 ^{° C} for 30 hours, collecting water in a stand-water separator (Dean-Stark trap). After completing the excess toluene was distilled off and 2-dimethylaminoethanol at a bath temperature of about 130 ^{° C} without vacuum first and then at vacuum approximately 50 mmHg The residue is 63.8 g of a light brown liquid (n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1.4570) which is dissolved in 100 ml of ethyl alcohol. To the resulting solution was added dropwise with stirring at 15-20 ^C 86.5 (0.81 mole, 38 ml) methyl iodide for 30 min. After standing for 3 hours at a temperature of 20-25 ^{° C} the precipitate was filtered off, washed with ethyl alcohol (30 ml) and recrystallized from 80 ml of 80% ethanol.

125.3 g (92% based on succinic anhydride) of bis (2-dimethylaminoethyl ester) succinic acid bis-iodomethylate are obtained, with a melting point of 244-245 ^о С, literature data: mp 243-245 ^about C [3]
PRI me R s 2-7. Obtaining bis-iodomethylate bis (2-dimethylaminoethyl ether) succinic acid is carried out analogously to example 1, but take different molar ratios of the starting reagents, change the temperature and time. The results are shown in the table.

 PRI me R 8. Obtaining bis (iodomethylate bis- (2-dimethylaminoethyl ether) succinic acid is carried out analogously to example 1, but after distillation of the solvent and excess 2-dimethylaminoethanol, the residue is dissolved instead of ethyl alcohol in the same amount of acetone and after filtering the precipitate washed with ethanol instead of ethyl alcohol with the same amount of acetone.

123.8 g (91%) of bis- (4-dimethylaminoethyl ester) succinic acid bis-iodomethylate are obtained with a melting point of 244-245 ^about S.

PRI me R 9. Obtaining bis-chloromethylate bis (2-dimethylaminoethyl ether) succinic acid is carried out analogously to example 1, but after distillation of the solvent and excess 2-dimethylaminoethinol to a solution of the residue in 80 ml of ethyl alcohol is added dropwise at a temperature of 10-15 ^about With a solution of 31 g (0.61 mol) of methyl chloride in 20 ml of ethyl alcohol for 20 minutes. After standing for 3 hours at a temperature of 20-25 ^{° C,} the precipitate was filtered off, washed with ethyl alcohol (30 ml) and recrystallized from 50 ml of 80% ethanol.

Obtain 73.1 g (81% based on succinic anhydride) of bis (2-dimethylaminoethyl ether) bis-chloromethylate succinic acid with so pl. 159-163 ^about C. Literature data: so pl. 156-163 ^about C [3]
PRI me R 10. Obtaining bis-bromomethylate bis (2-dimethylaminoethyl ether) succinic acid is carried out analogously to example 1, but after distillation of the solvent and excess 2-dimethylaminoethanol to a solution of the residue in 80 ml of ethyl alcohol is added dropwise with stirring at a temperature of 10- A 15 ^° C solution of 58 g (0.61 mol) of methyl bromide in 20 ml of ethyl alcohol for 30 minutes. After holding at a temperature of 2-25 ^{° C} for 3 h, the precipitate was filtered off, washed with ethyl alcohol (30 ml) and recrystallized from 60 ml of 80% ethanol.

Receive 96.8 g (86% based on succinic anhydride) bis-bromomethylate bis (2-dimethylaminoethyl ether) succinic acid with so pl. 224-225 ^about C. Literature data: so pl. 225 ^about S.

PRI me R 11. Obtaining bis-methylsulfonate bis (2-dimethylaminoethyl ether) succinic acid is carried out analogously to example 1, but after distillation of the solvent and excess 2-dimethylaminoethanol to a solution of the residue in 100 ml of ethyl alcohol is added dropwise with stirring at a temperature of 20- 25 ^C. 77.3 g (0.61 mol, 58 ml) of dimethyl sulfate for 20 minutes. After holding for 3 hours at this temperature, the precipitate is filtered off, washed with ethanol (30 ml) and recrystallized from 70 ml of 80% ethanol.

Obtain 119.1 g (93% based on succinic anhydride) of bis (2-dimethylaminoethyl ether) bis-methylsulfonate succinic acid with so pl. 169-170 ^about S.

 Found C, 37.32; H 6.91; N, 5.29; S 12.49.

C ₁₆ H ₃₆ N ₂ O ₈ S ₂
Calculated, C 37.50; H 7.03; N, 5.47; S 12.50.

Claims (1)

METHOD FOR PRODUCING BIS-QUATERTABLE SALTS OF BIS (2-DIMETHYLAMINOETHYL ETHER) SUCCINIC ACID by reacting succinic anhydride with 2-dimethylaminoethanol in an organic solvent followed by quaternization of the resulting bis (2-dimethylaminoethanoic acid aminobutyric acid-yl-aminobutyrate) 2-dimethylaminoethanol is carried out in toluene at 110 - 120 ^o C for (30 ± 5) h with a molar ratio of succinic anhydride: 2-dimethylaminoethanol: toluene 1: (2.5 - 3.0): (3.5 - 5, 0), but as e quaternizing agent is methyl halide or dimethyl sulfate.

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