RU2532128C1 - Method of producing o-luminolates of alkali metals - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing O-luminolates of alkali metals. The method includes reacting 3-nitrophthalic acid with hydrazine hydrate to form 5-nitro-2,3-dihydro-1,4-phthalazinedione, reducing the nitro groups and obtaining alkali metal salts. The cyclisation reaction is carried out in a medium of concentrated acetic acid at boiling point. Reduction of the nitro groups with simultaneous formation of alkali metal salts is carried out in an aqueous alkaline medium using hydrogen as a reducing agent at pressure of 1-5 atm and temperature of 90-110°C and a Raney nickel catalyst. After crystallising, separating, washing and drying the crystals, associates of hydrate forms of O-metallated luminal having the following general formula are obtained:

, M-Li, n=1; (VIIIa), M-Na, n=2; (VIIIb), M-K, n=3; (VIIIc), m=2.

EFFECT: invention enables to obtain associates of hydrate forms of O-metallated luminal using a method which improves stability of process parameters, minimises harmful impurities and provides an environmentally safe process.

7 dwg, 3 tbl, 3 ex

Description

The proposal relates to the field of organoelemental chemistry, namely to processes for the production of alkali metal salts.

The technical task and the positive result of the developed method are to increase the stability of technological parameters, the representativeness of the substance, the minimization of harmful impurities, the environmental safety of the process.

The specified problem and the technical result are achieved due to the fact that the implementation of the method involves obtaining a composition due to the interaction of 3-nitrophthalic acid with hydrazine hydrate with the formation of 5-nitro-2,3-dihydro-1,4-phthalazinedione, followed by reduction of the nitro group and alkali salts metals, characterized in that the cyclization reaction is carried out in a medium of concentrated acetic acid at a boiling point, and the subsequent reduction of the nitro group with the simultaneous formation of an alkali metal salt lumin ol is conducted in an aqueous-alkaline medium using hydrogen as a reducing agent at a pressure of 1-5 ati and a temperature of 90-110 ° C and a Raney nickel catalyst with a yield after crystallization, isolation, washing and drying of crystals, which are associates of hydrated forms of O- metallated luminol of the following general formula:

The technology is multi-stage, periodic, includes several stages. The initial “products” are 3-nitrophthalic acid, hydrazine hydrate and glacial acetic acid. The reactions proceed according to the following scheme, which reflects the possible formation of reaction by-products - the phthalimide analog of 1,4-phthalazinedione and oligomerization products:

The practice of the synthesis of phthalic acid hydrazides [1-4] showed that the formation of the ballast isomer IV at the hydrazinolysis stage can be eliminated by using more than 2-fold excess of hydrazine hydrate (II). Moreover, the isomer (IV) irreversibly isomerizes when heated to the target product (III).

The process is carried out by heating the reaction mixture to a boil and distilling off aqueous acetic acid. Upon reaching a temperature of 120 ° C, the heating is turned off and distilled water is poured into the reaction mass in an amount equal to the amount of hydrazine hydrate loaded, the mixture is cooled and filtered [1, 4, 16].

The precipitate of 5-nitrophthalyl hydrazide on the filter is washed with water until neutral according to universal indicator paper. The washed precipitate is dissolved in an aqueous NaOH solution and the resulting solution is hydrogenated with hydrogen in the presence of a Raney nickel catalyst.

The high quality of the precursor of salts of alkaline and alkaline earth metals “luminol” is also guaranteed by the use of a pure reducing agent, hydrogen, in combination with a superactive Ni-Raney catalyst [6].

According to X-ray diffraction data, “luminol” has an amide-imidole form (VI), and not, as everyone previously believed, a purely amide structure (VII):

According to XRD [5], “luminol” under normal conditions exists in the form of a stable imidol trimmer. Therefore, in the luminolates of alkaline elements (VIII), metal atoms (Li, Na, K) are not found in nitrogen, as previously thought [7–16], but in the oxygen atom:

Hydrogenation is carried out at a constant pressure of hydrogen in the range from 1 to 5 atm and a constant temperature in the range of 90-110 ° C (preferably 94-95 ° C) in a device with a high-speed turbine self-priming mixer that captures hydrogen from the upper zone of the reactor and disperses it in volume liquids.

The constancy of pressure and temperature in the reactor is a decisive factor for obtaining a quality product. Significant changes in temperature can lead to difficult fixable and even irreparable marriage, due to the occurrence of numerous adverse reactions characteristic of the process of restoration of aromatic nitro compounds.

Constant pressure is provided by an automatic reducer mounted on the line between the hydrogen cylinder and the reactor. The constant temperature in the reactor is achieved by supplying a coolant to his jacket and coil with a constant speed and temperature, but mainly the speed of rotation of the mixer.

The hydrogenation process proceeds at a very high speed, therefore, after stopping the pump dosing the supply of the 5-nitro-2,3-dihydro-1,4-phthalazinedione sodium salt solution, it immediately ends. However, for a full guarantee, mixing is carried out for another 10-15 minutes.

The hot solution is filtered off from the catalyst and adsorbed with activated carbon.

To do this, activated carbon is added to the reaction mass purified from the catalyst at the rate of 3% of this mass. When the stirrer is running, the process is carried out for 5-10 minutes. After that, the suspension is filtered and ethanol is added to the filtrate in a volume of up to 30% of the volume of the reaction mass. The mixture is cooled with a working stirrer to minus 5-10 ° C and kept for 5-6 hours, as a result, the sodium salt of 5-nitro-2,3-dihydro-1,4-phthalazinedione (VIIIb) precipitates. The precipitate is filtered off on a cooled filter and washed first with ice water and then ethanol cooled to minus 10 ° C.

The filter cake - sodium luminolate (VIIIb) is dried in an oven at a temperature of 40-50 ° C until the weight change stops.

The obtained sodium O-luminolate is a stable hydrated form in the form of a dimeric associate (VIIIb).

The unit structural cell of luminolates is characterized by the parameter Z = 4, i.e. it contains four molecules of matter. The architecture of the crystal lattice is characterized by an abundance of hydrogen bonds (m≥2).

Thus, the proposed method allows you to:

- receive a high quality drug substance in the complete absence of mechanical and chemical impurities;

- receive a substance with a yield of up to 95% of theoretical;

- receive the substance of the drug in pure dry form or in the form of stable crystals;

- receive a basic precursor of high purity white;

- to obtain crystalline hydrates of alkali metal luminolates with a variable substance / water molar ratio with accurate fixation of the amount of water in the associate.

Besides:

- the method is characterized by extremely high regiospecificity of the reactions of hydrazinolysis of 3-NFC and hydrogenation of the obtained hydrazide;

- the method is characterized by a reduction in the consumption of toxic hydrazine hydrate and other raw materials, high conversion, increased ergonomics and environmental friendliness.

In addition to the aforementioned, in the method due to the stage of recovery at Nickel Raney other high indicators are achieved:

- the recovery time of the nitro group is reduced to 0.5-1.5 hours;

- the formation of resinous substances, linear oligo- and polyimides, isomeric phthalimides is completely suppressed;

- it is possible to equally efficiently obtain aqueous solutions of Li, Na and K for the O-metallization of luminol from the corresponding alkalis, salts of carbonic acid, metal hydrides;

- Any order of mixing reagents is allowed.

The technical result - the preparation of alkali metal salts in the form of hydrates and free water form is achieved due to the absence therein of trace isomeric N-type aminoizomera (IV) and linear oligomers (V) due to the application of NO ₂ reduction step -intermediata in NH ₂ -analogue is an individual, pure white luminol - a) the application of the thermo / strain gauge technique during the process from the stage of mixing the reagents to the process itself, b) super-active Nickel Raney, c) super-fast (at least 150 rpm ) stirring g heterogeneous reaction mixture, d) the use of environmentally friendly hydrogen as a reducing reagent.

Example 1. The double associate of sodium luminolate dihydrate is the product (VIIIb).

Into a three-necked 1 L flask equipped with a stirrer, a refrigerator, a mantle heater and a thermometer, 250 g of 3-NFC were charged, the stirrer was turned on and 250 g of glacial acetic acid was poured, then 125 g of hydrazine hydrate was poured in small portions, avoiding strong boiling of the mass . After adding all of the hydrazine hydrate, the temperature of the reaction mass rose to 70-80 ° C due to the thermal effect of the reaction of neutralizing the hydrazine hydrate with an acid and a clear yellowish solution formed.

The mantle was turned on and the contents of the flask were heated to a boil, cooling water was allowed into the refrigerator. Acetic acid was distilled off, while the temperature of the reaction mixture gradually increased, and a yellow precipitate of 5-nitro-2,3-dihydro-1,4-phthalazinedione began to precipitate. When the mass temperature reached 120 ° C, the mantle was turned off and 125 g of distilled water was poured into the flask to prevent crystallization of the liquid phase with the formation of a monolith. The mantle was replaced with a container with flowing cooling water or ice and the mass was cooled to room temperature with the stirrer on.

A suspension of 5-nitro-2,3-dihydro-1,4-phthalazinedione was filtered through filter paper on a vacuum filter (Buchner funnel with a Bunsen flask). The precipitate of 5-nitrophthalyl hydrazide on the filter was washed with water until neutral according to universal indicator paper, squeezed and dried in an oven to constant weight. Received 210-220 g of a yellow crystalline powder of 5-nitro-2,3-dihydro-1,4-phthalazinedione, with a yield of 85-90%.

A 2-liter autoclave equipped with a high-speed shielded electric drive, a self-priming turbine stirrer, a jacket and a coil for heating and cooling, a thermocouple sleeve built into the autoclave and loading and unloading fittings, as well as for supplying nitrogen and hydrogen, was charged with 15 g of catalyst and 200 ml of distilled water. The shirt and the coil were connected to a liquid thermostat. The discharge line of the precision metering pump was connected to the loading choke, and its suction line to a container with a solution of 210 g of 5-nitro-2,3-dihydro-1,4-phthalazinedione in 1200 g of a 3.4% aqueous solution of sodium hydroxide. Before joining the autoclave, turning on the pump, the discharge and suction lines were filled with solution.

The autoclave was sealed, purged with nitrogen to remove air, and then with hydrogen to remove nitrogen. Using a gearbox, a hydrogen pressure of 5 at.

A liquid thermostat filled with water was turned on, a temperature of 90 ° C was set, and the autoclave was heated to this temperature, recorded using a thermocouple installed in the sleeve, and a secondary device, a potentiometer with a regulator, acting on the frequency controller of the agitator drive current.

The drive of the mixer and the metering pump were turned on. A slight drop in the pressure of hydrogen in the autoclave (up to 4–4.5 at) and an increase in temperature were observed, which indicated the beginning of the hydrogenation process. When the temperature in the autoclave reached 95 ° C, the thermostat was triggered and the heater was turned off. When the temperature dropped below 95 ° C, the heater turned on again. In this mode, the entire solution of 5-nitro-2,3-dihydro-1,4-phthalazinedione was pumped into the autoclave for about 1 hour, after which the metering pump was turned off and the mixture was allowed to stand for 10-15 minutes. The hydrogen pressure in the autoclave again rose to 5 atm and the temperature dropped to 90 ° C, which signaled the end of the reduction reaction.

Hydrogen pressure was released, the autoclave was purged with nitrogen, and the reaction mixture was discharged together with the catalyst through the lower discharge nozzle into a receiving tank.

The hot solution was filtered from the catalyst on a vacuum filter through filter paper and cleaned of impurities with activated carbon.

For this, 40 g of activated carbon was added to the reaction mass purified from the catalyst, the mass was stirred and the extract was allowed to stand for 5-10 minutes. After that, the suspension was filtered on a vacuum filter through filter paper and 500 ml of ethanol was added to the filtrate and all this was transferred to a crystallizer. The mixture was cooled with a working stirrer to minus 5 ÷ 10 ° C and kept for 5-6 hours, as a result, the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (VIIIb) crystallized. The precipitated salt was filtered on a cooled vacuum filter and washed first with ice water, then ethanol cooled to minus 10 ° C and squeezed out carefully. After that, it was dried in an oven at a temperature of 40-60 ° C to constant weight.

Received 158 g of a white crystalline powder of the product (VIIIb) with a purity of not less than 99% and a yield of 80%. Elemental analysis and thin layer chromatography are given in Appendix 1.

According to X-ray diffraction data (see Appendix 3), the C1 – N2 bond length in the Na salt became shorter (1.304 Å) —the C = N double bond, and in the amide part of the molecule, the N3-C4 bond is 1.338 Å, i.e. she's a single N-C bond.

Correspondingly, the C1 – O1 bond extended to 1.310 Å in comparison with the remaining bond length of the atoms of the carbonyl group C4 – O4 (1.274 Å).

Illustration of the drying process in Appendix 2.

Example 2. Double associate lithium luminolate monohydrate - product (VIIIa).

The lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (VIIIa) was obtained analogously to the sodium salt with a yield of 89% of theoretical.

Appendix 1 shows the data of elemental analysis, pH values of aqueous solutions, data on thin-layer chromatography (Rf 0.24).

Appendix 2 contains graphs of TGA and DTA characterizing the process of dehydration of molecules.

Appendix 3 provides information on the molecular and crystalline structure of compound (VIIIa).

Example 3. Double associate potassium luminolate monohydrate - product (VIIIc).

The potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (VIIIc) was obtained analogously to lithium and sodium salts with a yield of 94% of theoretical.

Table 1 shows the data of elemental analysis, pH values of aqueous solutions, data on thin-layer chromatography (Rf 0.24). Appendices 1, 2, 3 show graphs of TGA and DTA, illustrating the process of dehydration of molecules. Tables 2 and 3 provide information on the molecular and crystalline structure of the obtained compounds in hydrated and anhydrous forms.

As a result, in general terms, the obtained new forms of alkali metal salts based on luminol can be represented as follows:

The indicators of the method of obtaining the desired composition are summarized in tables 1, 2, 3

Appendices 1, 2, 3 show the graphs of the study process of the obtained o-luminolate and its structure, where:

figure 1, 2 and 3 are graphs of the dehydration of the molecules of TGA, DTP;

4 and 5 graphs of DTA records;

figure 6 - structure of Na luminolate;

Fig.7 - the structure of luminolate Li.

Claims (1)

The method of producing alkali metal O-luminolates by reacting 3-nitrophthalic acid with hydrazine hydrate to form 5-nitro-2,3-dihydro-1,4-phthalazinedione, followed by reduction of the nitro group and obtaining alkali metal salts, characterized in that the cyclization reaction is carried out in a medium concentrated acetic acid at boiling point, and the subsequent reduction of the nitro group with the simultaneous formation of the alkali metal salt of luminol is carried out in an aqueous-alkaline medium using hydrogen as a reducing agent at a pressure of 1-5 ati and a temperature of 90-110 ° C and a Raney nickel catalyst with a yield after crystallization, isolation, washing and drying of crystals, which are associates of hydrated forms of O-metallized luminol of the following general formula:

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