RU2385858C2 - Method of producing high-purity 4-(2-hydroxyethyl)phenol - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing high-purity 4-(2-hydroxyethyl)phenol (thyrozol) which is suitable for parenteral, including intravenous administration of its aqueous solution to a patient suffering from cardiac failure, as well as for eliminating withdrawal syndrome in drug addict patients. The method involves oxyalkylation of 2,6-di-tert-butylphenol with ethylene oxide in the presence of a catalyst and subsequent dealkylation of the obtained 4-(2-hydroxyethyl)-2,6-di-tert-butylphenol. Oxyalkylation is carried out in the presence of anhydrous tin tetrachloride as a catalyst at a low reaction rate. Dealkylation is carried out using aqueous HBr at temperature 120-130°C with simultaneous removal of water and tert-butylbromide from the reaction mass. The obtained compound is treated successively with sodium acetate and sodium hydroxide, with subsequent acidification of the salt aqueous solution of sodium 4-(2-hydroxyetyl)phenolate and purification of the obtained aqueous solution of 4-(2-hydroxyethyl)phenol.

EFFECT: method enables obtaining 4-(2-hydroxyethyl)phenol containing not less than 99,5% basic substance.

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Description

The invention relates to the field of organic chemistry, more specifically to a method for the synthesis of 4- (2-hydroxyethyl) phenol of the formula (1):

Compound (1) of a high degree of purity (not less than 99.5%) is suitable for parenteral, including intravenous, administration of its aqueous solution into the body of patients suffering from acute heart failure, as well as for withdrawal of withdrawal symptoms in drug patients. A commercial reagent, 2- (4-hydroxyphenyl) ethanol, contains 98% of the basic substance and has a melting point of from 89 to 92 ° C [Aldrich. Directory of chemical reagents. 2007-2008. P.1450.] According to technical requirements, commercial reagent samples are not suitable for the above purpose. Another disadvantage of a commercial reagent is its high cost.

In known methods for producing 4- (2-hydroxyethyl) phenol (the trivial name is tyrosol), the high purity of the target product is achieved either by purifying it or by increasing the selectivity of individual stages of the synthesis.

Known patent [US 5003115], which describes a method for producing 4- (2-hydroxyethyl) phenol using 4-acetoxystyrene as the starting compound. The method consists in epoxidizing 4-acetoxystyrene with peroxyacetic acid to obtain 4-acetoxyphenyloxyran in 98% yield, followed by hydrogenation of the resulting intermediate with hydrogen on a Pd / C catalyst. The resulting 2- (4-acetoxyphenyl) ethanol compound was saponified with KOH to give 4- (2-hydroxyethyl) phenol in 95.9% yield. The patent describes in detail the complex purification of technical 4- (2-hydroxyethyl) phenol, including repeated extraction, subsequent processing of the evaporated NaBH ₄ extract, purification on carbon, filtration through zeolite, reprecipitation and subsequent distillation to obtain 4- (2-hydroxyethyl) phenol with a purity 99%

The disadvantage of this method is the inability to achieve the required degree of purity of 4- (2-hydroxyethyl) phenol even in the presence of complex purification.

A known method of producing compound (1) from bromophenol by reacting with a 2.5-fold excess of butyl lithium in ether or tetrahydrofuran at a temperature of 33-34 ° C, followed by reaction of the resulting intermediate with ethylene oxide at a temperature of from -15 to -12 ° C. The yield of technical 4- (2-hydroxyethyl) phenol is about 80% [RU 2151137]. The technical product is purified by crystallization from chloroform and is characterized by a melting point of 93 ° C, which indicates a rather high degree of purity. However, the disadvantages of the method are manifested in the transition to industrial production: the need to organize at the enterprise a parallel production of butyl lithium - an unstable and extremely fire hazardous compound; the use of toxic high purity p-bromophenol; the use of flammable solvents such as ether or tetrahydrofuran.

The closest technical solution is a method for producing 4- (2-hydroxyethyl) phenol starting from 2,6-di-tert-butylphenol followed by optimal de-tert-butylation of 4- (2-hydroxyethyl) -2,6- obtained in the first stage di-tert-butylphenol (2).

2,6-di-tert-butylphenol is ethoxylated with ethylene oxide in the presence of butyllithium and tri-iso-butylaluminum in toluene at 5 ° C to give 4- (2-hydroxyethyl) -2,6-di-tert-butylphenol (2) s 95% yield (99% purity). The resulting compound (2) is dealkylated using p-toluenesulfonic acid at 220 ° C. Impurities are removed by extraction with ethyl acetate and recrystallization to obtain 4- (2-hydroxyethyl) phenol of 95% purity with a yield of 95% [JP 2000319213].

A significant drawback of this method for producing 4- (2-hydroxyethyl) phenol is the technical complexity of the method used for hydroxyethylation of 2,6-di-tert-butylphenol using flammable butyl lithium and tri-iso-butyl aluminum produced by the Japanese industry. These reagents are expensive, have a short shelf life and should be produced at the place of their consumption. The use of butyllithium causes a high degree of fire hazard in production both at the stages of its synthesis and at the stage of its use [Weigang - Hilgetag. Experimental methods in organic chemistry. Ed. Chemistry. M. 1966. S. 637-638]. The high technological equipment of such production of 4- (2-hydroxyethyl) phenol, necessary to eliminate the fire hazard of the process, creates significant difficulties for its implementation.

The objective of the invention is to develop a new safe method for producing 4- (2-hydroxyethyl) phenol of high purity (with a basic substance content of at least 99.5%) based on domestic raw materials.

The problem is solved by obtaining 4- (2-hydroxyalkyl) phenol (1) based on 2,6-di-tert-butylphenol in three stages, presented in the scheme:

Each of them is fundamentally known, but contains significant innovations that make it possible to effectively implement the process as a whole and to obtain high purity 4- (2-hydroxyethyl) phenol.

The first step is the hydroxyethylation of 2,6-di-tert-butylphenol with ethylene oxide in the presence of a SnCl ₄ catalyst to form 4- (2-hydroxyethyl) -2,6-di-tert-butylphenol (2). The known method describes a similar reaction of 2,6-di-tert-butylphenol and propylene oxide [US 4603161] to obtain 4- (2-hydroxypropyl) -2,6-di-tert-butylphenol (5) in 11% yield.

We found that olefin oxides, when rapidly added to the reaction medium containing an acid catalyst, are consumed unproductively with the predominant formation of diglycols that protonate the catalyst, resulting in the acceleration of de-tert-butylation processes with the formation of side compounds: 4-tert-butylphenol, 2,4-di-tert-butylphenol, 2,4,6-tri-tert-butylphenol and 4- (2-hydroxyethyl) -2-tert-butylphenol. A decrease in the rate of this undesirable process is achieved by the gradual introduction of catalyst and ethylene oxide into the reactor and the use of trichlorethylene as a solvent, which generally leads to an increase in the yield of compound (2) to 92% (based on the 2.6-di-tert- butylphenol).

The second stage of obtaining 4- (2-hydroxyethyl) phenol is described in the well-known patent [RU 2218326] and consists in the de-tert-butylation of compound (2) under the action of hydrobromic acid at a temperature of 120-130 ° С with simultaneous replacement of the aliphatic hydroxyl group with bromine , which leads to an almost quantitative formation of 4- (2-bromoethyl) phenol (3).

The third stage proceeds in one vessel and essentially consists in the replacement of bromine in compound (3) with a hydroxyl group to obtain 4- (2-hydroxyethyl) phenol.

The reaction is carried out by boiling bromide (3) with an aqueous solution of sodium acetate, which leads to the production of 4- (2-hydroxyethyl) phenol (1) and acetate (4) in a ratio of 1: 3. This mixture is briefly heated with an aqueous alkali solution, which leads to a salt solution of sodium 4- (2-hydroxyethyl) phenolate (Example 4), acidifying which gives 4- (2-hydroxyethyl) phenol.

It is known that the implementation of such direct substitution is not effective: the yield of 4- (2-hydroxyethyl) phenol is 30% [B. Borkowski, Z. Nololenska, E. Lada, W. Wieniawski. // Acta Polon. Pharm. V.34. No. 3 (1977). S.250-255]. The general approach is known [K. Maruyama, F. Kobayashi, A. Osuka. // Bull. Chem. Soc. Jpn. V.63 (1990). P.2672-2681], suitable for the preparation of derivatives of 4- (2-hydroxyethyl) phenol, which consists in the hydrolysis of acetates. This process is carried out in tetrahydrofuran with dilute hydrochloric acid while maintaining the reaction mass at room temperature for several days. The components of the reaction mixture are separated by column chromatography to obtain derivatives of 4- (2-hydroxyethyl) phenol with a yield of 85-90%. The disadvantage of this method is the need for the synthesis of acetate (4) described in the above article, the use of tetrahydrofuran with the difficulty of its regeneration, the complexity of the method of separation of the components of the reaction mass.

The next step is the purification of 4- (2-hydroxyethyl) phenol, from the aqueous solution of which volatile impurities are distilled off with water vapor: phenol, o- and p-tert-butylphenols. Next, an aqueous solution of 4- (2-hydroxyethyl) phenol was concentrated and the residue was extracted with methyl tert-butyl ether. To separate from acetic acid, the extract is washed with an aqueous solution of sodium bicarbonate until neutral or the solvent is evaporated first, and then acetic acid is removed under vacuum at a moderate temperature (not higher than 50-70 ° C). The solid residue is distilled in vacuo, collecting the fraction with so kip. 158-168 ° C / 2-3 mmHg, followed by crystallization of the distilled product (1) from a mixture of chloroform and ethanol to give 4- (2-hydroxyethyl) phenol (1), mp 93-94 ° C with a purity of 99.5-99.7%.

Thus, the selection of the conditions of the 1st stage (hydroxyethylation) of the 3-stage synthesis of 4- (2-hydroxyethyl) phenol in combination with the conditions of the 2nd and 3rd stages leads to the production of 4- (2-hydroxyethyl) phenol with a purity 99.5%, suitable for the creation of a parenteral agent (iv) for the treatment of acute heart failure.

The advantage of the proposed method is:

- the lack of high fire hazard of the method of obtaining the target products;

- use of affordable domestic raw materials;

- obtaining 4- (2-hydroxyethyl) phenol according to the claimed method allows the production of biologically active substances also important for medical chemistry: 4- (2-methoxyethyl) phenol - the active principle of metoprolol, and tyramine (according to patent RU 2218326) high degree of purity.

The invention is illustrated by the following examples.

EXAMPLE 1. 72.5 g (0.35 g / mol) of 2,6-di-tert-butylphenol are loaded into a 0.3 liter reactor with a stirrer, dropping funnel, thermometer and dissolved in 75 ml of trichlorethylene, the solution is cooled to - 10 ° C. 16 ml of SnCl ₄ are added to the reactor and a solution of 16 ml of ethylene oxide in 20 ml of trichlorethylene is metered in over 45 minutes at a temperature in the reactor of not higher than 0 ° C. Then a new portion of 16 ml of SnCl ₄ is introduced into the reactor and a portion of a solution of 16 ml of SnCl ₄ in 20 ml of trichlorethylene is added over 45 minutes at a temperature not exceeding 2 ° C. 16 ml of SnCl ₄ are again introduced and a further portion of a solution of 16 ml of ethylene oxide in 20 ml of trichlorethylene is dosed for 30 minutes at + 5 ° C. The reaction mass is heated, stirring, to room temperature, incubated for 20 minutes and then add 70 ml of water. Stirring is continued for 20 minutes, the lower acid layer is separated, and the organic part is washed with water (3 times 150 ml) until neutral. Then, the organic part is evaporated in half a volume on a vacuum rotary evaporator. The concentrated solution is left overnight at a temperature of -10 ° C. The precipitate formed is filtered off and the filter residue is washed with 100 ml of chilled petroleum ether. Obtain 63.5 g (0.253 mol) of 4- (2-hydroxyethyl) -2,6-di-tert-butylphenol (2), so pl. 99-101 ° C. According to GLC, the resulting product contains at least 98% of the main substance. The filtrates were evaporated from the solvent and the residue, oil, (17 g) was distilled under vacuum, collecting 10.8 g (i.e. boiling point 97-105 ° C / 2-3 mmHg) of 2,6-di-tert distillates butylphenol and 2,4,6-tri-tert-butylphenol, which are returned to a new operation. Continuing the distillation of the bottom residue, 5 g of compound (2) are obtained with so on. 140-160 ° C / 2 mmHg It is purified by crystallization from petroleum ether. The total yield of purified compound (3) is 66.0 g (74%).

EXAMPLE 2. In a glass flask with a stirrer and a dropping funnel, 100 g (0.49 g / mol) of 2,6-di-tert-butylphenol and 50 ml of trichlorethylene are placed. 40 ml (0.345 g / mol) of SnCl ₄ and a cooled solution of 40 ml of ethylene oxide (0.8 g / mol) in 40 ml of trichlorethylene are added to the resulting solution at -5 ° C over 70 min in two dropping funnels. The reaction mass is kept at room temperature for 20 minutes and 100 ml of water are added to the reactor, an aqueous solution of the catalyst is separated, and the organic layer is washed with water until neutral and evaporated. 130 g of an oil are obtained containing 58% 4- (2-hydroxyethyl) -2,6-di-tert-butylphenol (2) and 32% of the original 2,6-di-tert-butylphenol. 30 g of 2,6-di-tert-butylphenol are separated from it by vacuum distillation, and the residue is crystallized from hexane. Get 75 g of a white product (2) with so pl. 97-100 ° C.

EXAMPLE 3. To a melt of 0.3 kg of 97% 4-hydroxyethyl-2,6-di-tert-butylphenol (1.24 mol), 600 ml of a 20% solution of HBr are added with vigorous stirring for 3 hours while distillation from the reactor of a 1% aqueous solution of HBr. Then, 300 ml of a 40% HBr solution are gradually added to the reactor with vigorous stirring over 3 hours, 122 ml of tert-butyl bromide and 260 ml of diluted hydrobromic acid are distilled off from the reactor. The boiling point of the distillate increases and by the end of the process is 123-125 ° C.

40 ml of unreacted hydrobromic acid are separated from the reaction mass, from which 2 g of 4- (2-bromoethyl) phenol are precipitated upon cooling. The residue, a solid, is washed with water and dried. 238 g of 96.5% 4- (2-bromoethyl) phenol containing 1.5% 4- (2-hydroxyethyl) phenol are obtained. The total yield of 4- (2-bromoethyl) phenol is 93%.

EXAMPLE 4. Into a 2.5 L flask, 308 g of 96.5% 4- (2-bromoethyl) phenol (3) obtained in Example 3 were charged, 184 g of anhydrous sodium acetate and 1 L of water, and the mixture was boiled for 3 hours According to GLC, the organic layer of the obtained reaction mass contained 30% 4- (2-hydroxyethyl) phenol (1), 65% 4- (2-acetoxyethyl) phenol (4), 2% of the starting compound (3) and 3% of unidentified impurities buildings.

A solution of 80 g of granular NaOH in 150 ml of water is added to the reaction mass with stirring for 10 minutes and then the mixture is boiled for 30 minutes. The reaction mass is evaporated under vacuum to a volume of 550 ml with distillation with water vapor traces of phenol and p-tert-butylphenol. The residue was acidified with 15% sulfuric acid to pH 4-5 and extracted with 200 ml of methyl tert-butyl ether. The organic layer was washed with NaHCO ₃ solution to pH 6-7, then with 50 ml of water and the solvent was removed in vacuo. 189 g of a yellowish solid are obtained containing, according to GLC, 86% 4- (2-hydroxyethyl) phenol and 14% high boiling impurities. By distillation in vacuo, 140.7 g of a fraction with a boiling point are isolated. 160-175 ° C (1-3 mmHg) containing 96% 4- (2-hydroxyethyl) phenol (1).

EXAMPLE 5. The method of obtaining 4- (2-hydroxyethyl) phenol of high purity

To 24 g of distilled 96% 4- (2-hydroxyethyl) phenol was added 15 ml of 95% ethanol and heated until melted. The hot melt is poured in a thin stream into a glass containing 150 ml of chloroform, while stirring the solution. The solution was cooled to room temperature with periodic stirring.

Crystals of 4- (2-hydroxyethyl) phenol are filtered off, washed with a filter of 50 ml of chloroform and dried in air. 17.3 g of 4- (2-hydroxyethyl) phenol are obtained with a basic substance content of at least 99.5-99.7% according to GLC, so pl. 93.0-94.0 ° C.

Claims (1)

A method of producing 4- (2-hydroxyethyl) phenol by oxyalkylation of 2,6-di-tert-butylphenol with ethylene oxide in the presence of a catalyst and subsequent dealkylation of the obtained 4- (2-hydroxyethyl) -2,6-di-tert-butylphenol, characterized in that hydroxyalkylation is carried out in the presence of anhydrous tin tetrachloride as a catalyst at a low reaction rate, dealkylation is carried out using aqueous HBr at a temperature of 120-130 ° C, while removing water and tert-butyl bromide from the reaction mass, the obtained compound ops successively sodium acetate and sodium hydroxide, followed by acidification of the aqueous solution of the salt of 4- (2-hydroxyethyl) sodium phenolate and purification of the resulting aqueous solution of 4- (2-hydroxyethyl) phenol.