RU2088575C1 - Method of synthesis of 5,7-dibromo-8-hydroxyquinoline - Google Patents

Abstract

FIELD: chemical technology, organic chemistry. SUBSTANCE: product: 5,7-dibromo-8-hydroxyquinoline that is synthesized by interaction of 8-hydroxyquinoline with bromine excess in chloroform medium at mass ratio of chloroform to 8-hydroxyquinoline = (15-30):1. Bromine is taken at amount not exceeding 1.1-fold stoichiometry value. After termination of reaction of 8-hydroxyquinoline interaction bromine excess is bound by addition of 8-hydroxyquinoline at stoichiometric amount to bromine excess in reaction mass followed by exposition of the latter. Isolation of 5,7-dibromo-8-hydroxyquinoline is carried out by precipitate filtration. Mother liquor is recovered to cycle, precipitate is treated with water at 90-100 C, an aqueous solution is cooled and the end product is isolated from an aqueous solution. EFFECT: increased purity of the end product, decreased reagents consumption. 5 cl

Description

 The invention relates to the synthesis of polyhaloid organic compounds, and more particularly to the production of 5,7-dibromo-8-hydroxyquinoline (5,7-dibromoxine) by bromination of 8-hydroxyquinoline (oxine).

Bromination, like any halogenation, of organic compounds proceeds in such a way that a hydrogen atom is replaced by bromine, as a result of which the second atom of the bromine molecule is released in the form of hydrogen bromide:
R-H + Br ₂ __ → R-Br + HBr
Therefore, to obtain a dibromo derivative, two bromine molecules per one molecule of organic matter are required.

5,7-dibromoxin is a crystalline product, hardly soluble in water. According to [1], the solubility of 5,7-dibromoxin at 20 ^o C is (in g / l) 7.38 (chloroform), 4.77 (dichloroethane), 3.73 (benzene) and 2.08 (carbon tetrachloride ) With increasing temperature, the solubility changes little. A suitable solvent for recrystallization was not found for 5,7-dibromoxin. Therefore, all methods that use recrystallization from conventional organic solvents for the purification of 5,7-dibromoxin should immediately be considered as unsuitable for practical use.

 Known [2, 3] is a method for producing 5,7-dibromoxin, which is as follows.

20 g of oxine (about 0.14 mol) when dissolved, dissolved in water containing 160 cm ³ 2 N. hydrochloric acid, cooled and, with stirring, poured into 500-1000 cm ^{3 of} water containing about 22 g of bromine (0.14 mol). After 1 h, the precipitate formed is filtered off and washed with cold water. For cleaning, the precipitate is dissolved in a minimum amount of concentrated hydrochloric acid and poured into 2-4 liters of water. The precipitate formed is filtered off, washed with water from acid (Congo control) and dried in air, after which it is recrystallized twice from benzene using 15-20 cm ^{3 of} solvent for each gram of dry preparation. Product yield not specified.

 In the indicated recipe, the oxine was taken in a two-fold excess, i.e. half of it is lost. In addition, an excess of oxine interferes with the preparation of the dibromo derivative and promotes the formation of monobromoxins as by-products. It is with the goal of removing monobromoxins in this recipe that a huge amount of water is used and two very difficult operations are carried out to recrystallize the product from benzene.

 Known [4] an improved method of bromination of oxine.

According to this method, 50 g (0.345 mol) of oxine are dissolved in 400 cm ³ 2 N. hydrochloric acid and add a solution of 120 g (0.75 mol) of bromine and 100 g of potassium bromide in 1 liter of water. Stirred for 1 h. The precipitate was filtered off, washed with water and dried. The yield of 87% is indicated and melting point is shown. 195-197 ^o C for recrystallized from dioxane product.

In relation to oxine, bromine in this method was taken in excess of 0.06 mol (9.7 g). According to the catalogs on the reagents of various countries, 5,7-dibromoxine melts at 200 ± 1 ^o C. 195-197 ^o C indicates the low quality of the obtained product. Bromination is carried out in a 30-fold volume of water at a high flow rate of other components. It is not known what to do with a strongly acidic, containing potassium bromide and excess bromine, mother liquor and washings. Therefore, this method can be used only for a single production of a small batch of 5,7-dibromoxin, but is unsuitable for producing larger batches, and even more so for industrial use.

 Judging by the appearance of the product obtained by this method (brown powder with a low melting point), the bromination of oxine in an aqueous medium is accompanied by oxidative and other side processes.

 Oxin bromination in chloroform is known. This technique was used in [5], devoted to elucidating the effect of the oxine: bromine ratio on the yield of individual bromine derivatives. Bromination is carried out as follows.

To 10 cm ^{3 of} chloroform containing 5 mol of bromine, 1.2 or 3 milliequivalents of oxine are added. The mixture is stirred for 3 hours, after which the resulting product is analyzed for the content of individual components.

If you translate the moles into grams, it turns out that 0.8 g of bromine is dissolved in 10 cm ^{3 of} chloroform. To obtain the dibromo derivative from this amount of bromine, 0.3625 oxine is required. In relation to the latter, chloroform is used in a 30-fold volume. Although in the stated form this method is not even a preparatory prescription, since it does not provide for the isolation of 5,7-dibromoxin itself in its pure form, nevertheless it is he who was chosen as a prototype. Unlike all previous methods, where water was used and where the number one problem was the conversion of bromine to a soluble state, chloroform dissolves bromine and sufficiently oxine, which according to previous methods also required to be converted to a water-soluble state. In addition, methods are indicated for how to get rid of free excess bromine and the resulting hydrogen bromide, which was not provided for by the previous methods. Another work [6] of the same authors describes how the reaction mass is treated, namely: the chloroform mass is washed 3 times in 5 cm ³ portions ^{of an} aqueous solution containing 5% sodium acetate (to bind hydrogen bromide) and 5% sodium bisulfite ( to bind free bromine). Then the chloroform solution is evaporated, the residue is dissolved in acetonitrile, transferred to trimethylsilyl derivatives, which are analyzed by chromatography. In [5, 6], the degree of conversion of oxine to the dibromo derivative was indicated, which allows one to indirectly evaluate the yield and quality of the product.

 The objective of the invention is to reduce the consumption of reagents and the selection of the target product in its pure form.

In the proposed method, the problem is solved in that the preparation of 5,7-dibromo-8-hydroxyquinoline, including 8-hydroxyquinoline in a solution of excess bromine, stirring the reaction mixture, chloroform and oxine are taken in a mass ratio (15-30): 1, from the reaction mixture after the interaction of bromine with oxine is completed by filtration, a precipitate containing 5,7-dibromoxin hydrobromide is isolated. The mother liquor is returned back to the cycle, the precipitate is treated with water at 90-100 ^o C and after cooling the water mass, the target product is isolated from it.

 The problem is also solved by the fact that in relation to 8-hydroxyquinoline bromine is taken in an amount not exceeding 1.1 times the excess from stoichiometry.

 The problem is solved in that 8-hydroxyquinoline is introduced into the chloroform solution of bromine in parts, followed by a temporary exposure of the reaction mass.

 The problem is also solved by the fact that after the end of the interaction of the oxine with an excess of bromine, oxine is introduced into the reaction mass in a stoichiometric amount to bind free bromine and the reaction mass is mixed for 0.5-1.5 hours.

 The problem is also solved by the fact that the solution, after isolation of the target product from it, is evaporated, and the residue is returned back to the bromination cycle.

 When using 15-30 g (by weight) of chloroform or a mother liquor for 1 hour of oxine, the reaction of the latter with bromine proceeds easily with the formation of mainly 5,7-dibromoxine hydrobromide, which, after isolation from the reaction mass, is transferred under the conditions described below to target product 5,7-dibromoxin.

 At a lower consumption of chloroform, part of the oxine is not brominated and falls into the precipitate of 5,7-dibromoxin hydrobromide. Although in an acidic aqueous solution it is easily separated from the dibromo derivative, this leads to a drop in the yield of the target product. A strong increase in solvent consumption does not affect the yield of the target product.

 The chloroform mother liquor remaining after separation of the precipitate contains a certain amount of oxine and monobromo derivatives in the form of hydrobromides. It returns to the cycle and under the conditions of bromination, the target product is also obtained from the above substances, which eliminates the need for its processing to remove impurities.

Using the above amount of solvent leads to the fact that the bulk of the target product of 5,7-dibromoxine hydrobromide is in the form of a precipitate. As impurities, it may contain hydrobromides of oxine and monobromoxoxins or even crystals of oxine. The method used by the author to separate the precipitate by filtration, followed by treating it with water at 90-100 ^o C allows the hydrolysis of 5,7-dibromoxin hydrobromide to a free base. Hydrobromides of oxine and monobromoxins are resistant to hydrolysis under these conditions and remain in solution. Random oxine crystals dissolve in an acidic medium and turn into a hydrobromide.

 A lower water treatment temperature reduces the degree of hydrolysis of 5,7-dibromoxin hydrobromide and reduces the yield of the free base. To carry out hydrolysis in more severe conditions, the use of special equipment that provides for pressure work is required.

As a result of hydrolysis of the hydrobromide, the free base 5,7-dibromoxin precipitates. After washing and drying, the product has so pl. 200 ± 1 ^o C.

 An increase in the excess of bromine above 1.1-fold practically does not affect the yield and quality of the target product, but complicates the stage of binding of free bromine. A decrease in bromine consumption below stoichiometric naturally leads to a drop in the yield of 5,7-dibromoxin. The quality of the product is deteriorating by increasing the number of monobromo substituted.

Oxine is introduced into the chloroform solution of bromine at such a rate that the temperature of the reaction mass does not exceed 45 ^o C to prevent loss of bromine and solvent. But since oxine is introduced into the reaction in solid form, the completeness of the process largely depends on the degree of fragmentation of the crystals. Therefore, it is advisable to carry out the process and increase the yield of the product to load the oxide in portions with subsequent exposure to time. For example, with an initial load of approximately 2/3 of the total amount of oxine, the reaction proceeds under favorable conditions (in terms of bromine concentration) and ends in 1-1.5 hours. For the remaining third of the oxine, increase the time to 2-2.5 hours.

 To bind the remaining excess of bromine in the proposed method uses the ability of the oxine to react with the formation of mainly dibromo derivative. It is enough to add the amount of oxine calculated on the formation of the monobromo derivative to ensure complete binding of free bromine. Possible by-products (monobromo derivatives, oxine) are the same as in the main reaction. Thanks to this technique, there is no need to regenerate chloroform and to use extraneous agents such as sodium bisulfite. A relatively small excess of bromine does not allow the formation of a noticeable amount of monobromo derivatives, which adversely affects the quality of the target product.

 The binding of free bromine then allows you to carry out operations to filter the reaction mass using paper, fabrics and other materials. In the presence of free bromine, not a single material, except glass, can withstand its action.

 The filtrate obtained after separation of 5,7-dibromoxin is an aqueous solution of hydrobromides, monobromoxins and the oxine itself. According to the proposed method, the filtrate is not discarded, but evaporated to dryness. The dry residue can be probromiruyut under the same conditions separately or in a mixture with oxine and to obtain an additional amount of the target product. The consumption of bromine for processing monobromo derivatives is 2 times lower than in the case of oxine. The yield of 5,7-dibromoxin is approximately 2/3 of the loaded solids by weight.

 If in all known methods the excess of bromine is irretrievably lost, then the proposed method is based on the maximum use of bromine. Therefore, the product yield should be calculated by bromine.

Example. To 1500 cm ^{3 of} chloroform mother liquor, previously used for repeated operations on the bromination of oxine, add 80 cm ³ (1.56 mol) of liquid bromine. Then add 70 g of oxine in powder form, making sure that the temperature of the reaction mixture does not exceed 40-45 ^o C. In the solution a yellow precipitate very quickly appears. Stirred for 1 h without forced cooling. Then again add 40 g of oxine (110 g total or 0.76 mol) and the mixture is stirred for another 2 hours. Then, to bind the excess bromine (about 0.04 mol), 5 g (0.034 mol) of oxine are added and stirred for another 1 hour. the mixture is filtered. The chloroform mother liquor is recycled. The yellow precipitate of 5,7-dibromoxin hydrobromide is hydrolyzed 1,600 cm ^{3 of} water by heating (about 100 ^° C.) and stirring while distilling off the chloroform adsorbed by the precipitate. The resulting colorless precipitate of the free base of 5,7-dibromoxin is filtered off, washed 3 times with cold water of 150 cm ³ and dried to constant weight at 100-105 ^o C. Product yield 219 g, so pl. 199.5-200.5 ^o C. For bromine, the product yield is 93.2% and for oxine taken only for bromination, 95.2%
After evaporation of the aqueous mother liquor, 32.5 g of a dry residue is obtained, from which after bromination an additional 22 g of 5,7-dibromoxin can be obtained.

 The distilled chloroform is separated from the water and attached to similar shoulder straps. As accumulation is carried out, drying is carried out by distillation of a part of chloroform (an azeotrope with water) and returned to the cycle to replenish the chloroform mother liquors.

 The proposed method for producing 5,7-dibromoxin is technologically advanced and suitable for producing the product on a large scale.

Claims (5)

1. The method of producing 5,7-dibromo-8-hydroxyquinoline, including the introduction of 8-hydroxyquinoline in a solution of excess bromine in chloroform, stirring the reaction mixture, characterized in that chloroform and 8-hydroxyquinoline are taken in a mass ratio of (15-30) 1, from the reaction mass, after completion of the interaction of bromine with 8-hydroxyquinoline, a precipitate containing 5.7-dibromo-8-hydroxyquinoline hydrobromide is isolated by filtration, the mother chloroform solution is returned to the cycle, the precipitate is treated with water at 90-100 ^° C and, after cooling, the precipitate of the target product is isolated .  2. The method according to claim 1, characterized in that in relation to 8-hydroxyquinoline bromine is taken in an amount not exceeding a 1.1-fold excess from stoichiometry.  3. The method according to claim 1, characterized in that 8-hydroxyquinoline is introduced into the chloroform solution of bromine in parts, followed by a temporary exposure.  4. The method according to claim 1, characterized in that after the end of the interaction of 8-hydroxyquinoline with an excess of bromine, 8-hydroxyquinoline is introduced into the reaction mass in a stoichiometric amount with respect to the free bromine contained in the reaction mass and mixed for 0.5 1.5 hours  5. The method according to claim 1, characterized in that the aqueous filtrate after separation of 5,7-dibromo-8-hydroxyquinoline is evaporated and the dry residue is returned to the bromination cycle.