RU2757109C1 - Method for producing an acidic potassium salt of d-glucaric acid and an installation for its implementation - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to the production of an acidic potassium salt of D-glucaric acid used in the production of medicines, as well as pharmaceutical and cosmetic compositions. The method for producing the acidic potassium salt of D-glucaric acid is implemented by oxidation of D-glucose, during which a solution of D-glucose in weak nitric acid and a solution of D-glucose in concentrated nitric acid are prepared, which is then heated to 98-103°C, then the temperature is decreased to 60-65°C and a solution of D-glucose is dosed in weak nitric acid, after which the reaction mass is kept and mixed for 3.5-4.5 hours at a temperature of 60-65°C, after which the temperature of the reaction mass is reduced to room temperature and potassium hydroxide is dosed until a pH of 10.0-11 is reached, after that, it is neutralized with concentrated nitric acid, and then the target product is filtered, characterized in that a solution of D-glucose in weak nitric acid is dosed through a bubbler, regulating the reaction temperature. The system for producing the acidic potassium salt of D-glucaric acid includes a mixer, a reactor, an apparatus and a filter connected in series, while a Nutch filter is used as a filter, and the reactor includes a housing, a jacket, a stirrer, a bottom drain valve, a bubbler and a dephlegmator-condenser.

EFFECT: increase in the yield of the target product while increasing the efficiency of safety management of the D-glucose oxidation process with a nitric acid solution.

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Description

The invention relates to organic chemistry, in particular to the production of an acidic potassium salt (CCS) of D-glucaric acid used in the production of medicines, as well as pharmaceutical and cosmetic compositions.

Compositions containing D-glucaric acid or calcium salt of D-glucaric acid are used to remove toxins and harmful substances in order to prevent diseases or disorders; increasing the supply of glutathione; removing or improving hangover and alcohol intoxication [WO 2015148317, WO 2005089412, US 20040248818]. There, and for the same purposes, the use of CCC of D-glucaric acid, as well as 1,4- and 3,6-lactones of D-glucaric acid, is described [WO 2005089412, US 20040248818].

CCC D-glucaric acid can find application as a non-toxic inhibitor of colon cancer [International Journal of Oncology (2000), 16 (1), 43-48.]. The process was studied on the example of rats and presumably proceeds through the formation of the corresponding 1,4-lactone D-glucaric acid.

The ability of a derivative of an acidic potassium salt - 1,4-lactone D-glucaric acid - to inhibit breast, prostate and colon cancer in humans has been described [Cancer Detection and Prevention (1997), 21 (2), 178-190].

Known compositions for inhibiting the activity of β-glucuronidase based on derivatives of D-glucaric acid - 1,4- and 3,6-lactones with water-soluble electrolytes for the primary prevention of the initiation of bladder tumors [RU 2062100 and RU 2723999].

The most accessible and widespread raw material for the production of D-glucaric acid and its derivatives is D-glucose. Oxidation of the latter is the main method for obtaining the acidic potassium salt of D-glucaric acid.

Closest to the claimed invention is a method of obtaining by oxidation of D-glucose in a solution of 43-56% nitric acid, followed by processing the resulting mass with 45% aqueous potassium hydroxide solution, acidification with nitric acid, filtration, washing and drying. Achieved yields of CCC of D-glucaric acid are 18.8-34.6% [RU 2024485].

As features of the prototype method, the implementation of the process of oxidation of D-glucose in a cascade of two reactors can be distinguished. The first reactor is a flow reactor and serves to initiate oxidation. The second is periodic for the main process.

According to the prototype, D-glucose is preliminarily dissolved in 43-56% nitric acid at a temperature of 20-22 ° C and a molar ratio of D-glucose: nitric acid 1: (3-3.85), respectively.

The resulting solution is fed into a flow reactor, the device of which provides a filling factor of its volume of no more than 0.2 (with a reactor volume of 250 ml). The initiation of D-glucose oxidation is achieved by heating the reaction mixture prior to the start of the oxidation reaction. From the flow-through reactor, the reaction mass enters a batch reactor (main reactor) with a capacity of 2000 ml, where the oxidation is completed at a temperature of 50-70 ° C. The total time of the process is 3 hours. With such an organization of the process, the safety of the process is ensured due to the short residence time of small volumes of the reaction mass in the zone of initiation of oxidation.

The disadvantages of the prototype include the control of the D-glucose oxidation process solely by the feed rate of the reagents through the flow reactor without the possibility of using external heat exchange to adjust the reaction temperature. In addition, as indicated in the patent, the use of dilute nitric acid (solution with a concentration of 25 wt.%) Is the reason for a reduced yield of the CCC of D-glucaric acid (18.8%, with a purity of 95.4%). Obtaining the target product with a yield of 28.2-34.6% and a purity of 91-99% is achieved only in the case of using 43-56% nitric acid. However, the use of the latter concentrations makes the accumulation and storage of large amounts of D-glucose solution in nitric acid more hazardous.

In view of these shortcomings of the prototype method, obtaining CCS of D-glucaric acid in medium and large-scale production by this method will lead to significant material costs and limit the consumption of the target product.

A technical problem is the need to develop a method for producing the acidic potassium salt of D-glucaric acid and an installation for its implementation, devoid of the above disadvantages and providing an efficient and safe production of the acidic potassium salt of D-glucaric acid.

The technical result consists in increasing the yield of the target product while increasing the efficiency of managing the safety of the process of oxidation of D-glucose with a solution of nitric acid.

The technical result is achieved by the fact that in the method of obtaining the acidic potassium salt of D-glucaric acid by oxidation of D-glucose, during which a solution of D-glucose in weak nitric acid and a solution of D-glucose in concentrated nitric acid are prepared, which is then heated to 98-103 ° C, then the temperature is reduced to 60-65 ° C and a solution of D-glucose in weak nitric acid is dosed, after which the reaction mass is kept and stirred for 3.5-4.5 hours at a temperature of 60-65 ° C, after which the temperature of the reaction mixture is reduced to room temperature and potassium hydroxide is dosed until a pH of 10.0-11 is reached, after which it is neutralized with concentrated nitric acid, and then the target product is filtered; according to the invention, a solution of D-glucose in weak nitric acid is dosed through a bubbler, adjusting the reaction temperature.

The technical result is also achieved due to an installation for obtaining an acidic potassium salt of D-glucaric acid, including a series-connected mixer, a reactor, an apparatus and a filter, while a suction filter is used as a filter, and the reactor includes a housing, a jacket, a stirrer, a bottom drain valve , bubbler and reflux condenser.

A distinctive feature of the proposed method is the oxidation of D-glucose in one reactor with the separation of the process into two stages. The initiation of oxidation is carried out by preheating a solution of D-glucose (from 10 to 20 wt.% Of the total amount introduced into the reaction) in nitric acid with a concentration of 63-70% in a reactor equipped with a stirrer, heat-removing elements and a bubbler to a temperature of 83-87 ° C and with a volume filling factor of 0.29-0.32.

At the second stage, the main part of D-glucose (from 80 to 90 wt.% Of the total amount used in the process) is dosed into the same reactor in the form of a solution of it in 10-25% nitric acid through a bubbler under a layer of a pre-initiated solution of D- glucose in 63-70% nitric acid. The dosage time of the entire solution can vary from 1 to 1.5 hours, depending on the current controlled temperature of the reaction mass. The process temperature is maintained from 60 to 65 ° by regulating the supply of the D-glucose solution and the heat exchange elements of the reactor. The yield of the isolated CCC of D-glucaric acid is from 42.5 to 46% (for the loaded D-glucose, in terms of 100% substance).

In the proposed method for the oxidation of D-glucose, a higher yield of the acidic potassium salt of D-glucaric acid is realized in comparison with the prototype with a safe conduct of the process.

Oxidation safety is due to a number of technological methods:

- the initial stage of initiation of the reaction takes place in concentrated solutions of nitric acid (63-70%). Significant mass modulus for nitric acid in relation to D-glucose, small amounts of oxidizable D-glucose, regulation of the process temperature due to external cooling of the reactor, allow you to control the course of the reaction;

- the bulk of oxidized D-glucose is supplied in the form of its solution in 10-25% nitric acid (RU 2024485 states that solutions of D-glucose monohydrate in 25% nitric acid are completely safe when stored at a temperature of 5-7 ° C);

- the main mass of oxidized D-glucose is supplied by bubbling, which contributes to an increase in the rate of generation of oxidation catalysts (nitrogen oxides), and effective heat and mass transfer in the reactor ensures the reliability of the process control.

The claimed invention is illustrated by a drawing, where FIG. 1 shows a block diagram of the inventive installation, and FIG. 2 shows the rector used in the method and installation.

The inventive plant for producing the acidic potassium salt of D-glucaric acid includes a series-connected mixer 1, a reactor 2, an apparatus 3 and a filter 4. Mixer 1 and apparatus 3 are boilers equipped with mixing devices and heat-removing elements. Reactor 2 includes a reactor vessel 5, a reactor jacket 6, a stirrer 7, a bottom drain valve 8, a bubbler 9 and a reflux condenser 10. The bubbler 9 is a hollow tube with an inner diameter of 30-40 mm, the lower part of which is spirally bent along the shape of the inner diameter of the reactor vessel and oriented in the plane of the cross-section of the reactor. Along the entire surface of the lower part, there are holes with a diameter of 3-3.5 mm in the amount of 90-100 pcs. A suction filter is used as filter 4. Mixer 1 is connected to reactor 2 through a bubbler 9 for dosing a solution of D-glucose in 10-25% nitric acid. The transfer of the solution from the mixer 1 to the reactor 2 through the bubbler 9 is carried out by gravity due to the placement of the apparatuses at different levels. The reactor 2 is connected through the bottom drain valve 8 to the apparatus 3 for overflowing the finished reaction mass by gravity. Apparatus 3 is connected to filter 4 to discharge the sediment suspension.

The inventive method is carried out as follows.

Mixer 1 is charged from 41.27 to 52.96 dm ³ 10-25% nitric acid. With stirring and a temperature of 20 to 25 ° C, 35.01 to 40.95 kg of D-glucose (from 35.01 to 40.95 kg in terms of 100% substance; 80-90 wt.% from the total amount used in the process). Each portion of D-glucose is added after complete dissolution of the previous one.

A 38.4-44.6% solution of D-glucose in 10-25% nitric acid is obtained. The solution can be stored at a temperature not exceeding 25 ° C for 2 days.

In reactor 2, load from 39.44 to 50.07 dm ³ 63-70% nitric acid. With stirring and a temperature of 20 to 25 ° C, from 4.55 to 9.48 kg of D-glucose (from 4.55 to 9.48 kg in terms of 100% substance; from 10 to 20 wt. % of the total amount used in the process). Get 6.9-14.8% solution of D-glucose in 63-70% nitric acid. The solution is heated to a temperature of 83 to 87 ° C. When this temperature range is reached, the oxidation reaction begins, which proceeds at an increasing rate, which manifests itself in a rapid rise in temperature to 98-103 ° C and a violent release of nitrogen oxides. The process temperature is reduced to 60-65 ° C by supplying cooling water to the reactor jacket 6. After reducing the rate of release of nitrogen oxides, from 78.51 to 98.67 kg of 38.4-44.6% solution of D-glucose in 10-25% nitric acid is dosed into reactor 2 from mixer 1 through bubbler 9 so that the temperature of the reaction the mass was in the range from 60 to 65 ° C. At the end of the dosing, the reaction mass is maintained at the indicated temperature and stirring by means of stirrer 7 for 3.5-4.5 hours.

At the end of the exposure, the reaction mass is cooled to a temperature of 20-25 ° C and discharged into apparatus 3. A 45 wt% aqueous solution of potassium hydroxide is dosed into apparatus 3 to neutralize acidic products so that the temperature does not exceed 35-40 ° C. Neutralization is carried out to pH 10.0-11.5. When this pH value is reached, the resulting solution is kept for 25-35 ° minutes without external cooling, cooled to 20 ° C and again neutralized with 70 wt% nitric acid, maintaining the temperature at no higher than 25 ° C to pH 3.7-3.9.

The precipitate that formed is washed twice with water on filter 4 and dried. The yield of the acidic potassium salt of D-glucaric acid is from 42.5 to 46.0%.

The rest of the examples are presented in a similar way.

The claimed invention is illustrated by examples.

Example 1.

The mixer is charged with 48.12 dm ³ 20% nitric acid. With stirring and a temperature of 20 to 25 ° C, 40.95 kg of D-glucose (40.95 kg in terms of 100% substance; 90 wt.% Of the total amount used in the process) are added in portions to the mixer. Each portion of D-glucose is added after complete dissolution of the previous one.

Get 43.3% solution of D-glucose in 20% nitric acid. The solution can be stored at a temperature not exceeding 25 ° C for 2 days.

In the reactor, load 44.36 dm ³ 65% nitric acid. With stirring and a temperature from 20 to 25 ° C, 4.55 kg of D-glucose (4.55 kg in terms of 100% substance; 10 wt.% Of the total amount used in the process) is added in portions to the reactor. A 6.9% solution of D-glucose in 65% nitric acid is obtained. The solution is heated to a temperature of 83 to 87 ° C. When this temperature range is reached, the oxidation reaction begins, which proceeds at an increasing rate, which manifests itself in a rapid rise in temperature to 98-103 ° C and a violent release of nitrogen oxides. The process temperature is reduced to 60-65 ° C by supplying cooling water to the reactor jacket. After reducing the rate of release of nitrogen oxides, 94.60 kg of a 43.3% solution of D-glucose in 20% nitric acid is dosed into the reactor from the mixer through a bubbler so that the temperature of the reaction mass is in the range from 60 to 65 ° C. At the end of dosing, the reaction mass is kept at the specified temperature and stirring for 3.5-4.5 hours.

At the end of the exposure, the reaction mass is cooled to a temperature of 20-25 ° C and discharged into the apparatus. A 45 wt% aqueous solution of potassium hydroxide is dosed into the apparatus for neutralizing acid impurities so that the temperature does not exceed 35-40 ° C. Neutralization is carried out to pH 10.0-11.5. When this pH value is reached, the resulting solution is kept for 25-35 ° minutes without external cooling, cooled to 20 ° C and again neutralized with 70 wt% nitric acid, maintaining the temperature at no higher than 25 ° C to pH 3.7-3.9.

The precipitate that formed is filtered, washed twice with water on a filter, and dried. The yield of the acidic potassium salt of D-glucaric acid is 42.5%.

The rest of the examples are presented in a similar way.

Example 2.

Implemented under the conditions of example 1 except: for the preparation of a solution of the main part of D-glucose in a mixer, 52.96 dm ^{3 of} 25% nitric acid and 37.92 kg of D-glucose (37.92 kg in terms of 100% substance; 80 wt. .% of the total amount used in the process); for the preparation of the initiating solution in the reactor used 39.44 dm ³ 63% nitric acid 9.48 kg of D-glucose (9.48 kg in terms of 100% substance; 20 wt.% of the total amount used in the process).

The yield of the acidic potassium salt of D-glucaric acid is 46.0%.

Example 3.

Implemented under the conditions of example 1 except: for the preparation of a solution of the main part of D-glucose in a mixer, 41.27 dm ^{3 of} 10% nitric acid and 35.01 kg of D-glucose (35.01 kg in terms of 100% substance; 82 wt. .% of the total amount used in the process); for the preparation of the initiating solution in the reactor used 50.07 dm ³ 70% nitric acid 6.41 kg of D-glucose (6.41 kg in terms of 100% substance; 18 wt.% of the total amount used in the process).

The yield of the acidic potassium salt of D-glucaric acid is 43.4%.

Claims (4)

1. A method of obtaining an acidic potassium salt of D-glucaric acid by oxidation of D-glucose, during which a solution of D-glucose in weak nitric acid and a solution of D-glucose in concentrated nitric acid are prepared, which is then heated to 98-103 ° C, then the temperature reduced to 60-65 ° C and dosed with a solution of D-glucose in weak nitric acid, after which the reaction mass is kept and stirred for 3.5-4.5 hours at a temperature of 60-65 ° C, after which the temperature of the reaction mass is reduced to room temperature and potassium hydroxide is dosed until a pH of 10.0-11 is reached, after which it is neutralized with concentrated nitric acid, and then the target product is filtered, characterized in that a solution of D-glucose in weak nitric acid is dosed through a bubbler, adjusting the reaction temperature. 2. The method according to claim 1, characterized in that when preparing a solution of D-glucose in concentrated nitric acid, an acid with a concentration of 63-70 wt. %. 3. The method according to claim 1, characterized in that the solution of D-glucose in weak nitric acid contains acid with a concentration of 10-25 wt. %. 4. Installation for obtaining the acidic potassium salt of D-glucaric acid according to any one of paragraphs. 1-3, including a series-connected mixer, a reactor, an apparatus and a filter, while a suction filter is used as a filter, and the reactor includes a housing, a jacket, a stirrer, a bottom drain valve, a bubbler and a reflux condenser.

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