RU2494087C1 - Method of producing omega-iodo-aliphatic carboxylic acids and esters thereof - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a method of producing ?-iodo-aliphatic carboxylic acids and esters thereof. The method involves splitting aliphatic cyclic ketones such as cyclohexanone, cycloheptanone or 4-methylcyclohexanone, under the action of hydrogen peroxide in the presence of a catalyst and iodine compounds at room temperature. The catalyst used is copper (I) chloride; production is carried out with radio of cyclic ketone: hydrogen peroxide: copper (I) chloride of 1:5:0.1, while stirring for 10-20 hours, in the presence of methanol or ethanol solutions of iodine; iodine is taken in an amount which is such that the ratio of cyclic ketones to iodine is 1:0.5. In order to extract and separate the end products, a saturated solution of sodium bicarbonate is added to the reaction mass, wherein ?-iodo-aliphatic carboxylic acids are transferred into the aqueous layer in form of sodium salts, and esters thereof are easily separated by extracting the aqueous layer with ethyl acetate. The ethyl acetate extraction is then dried with anhydrous sodium sulphate; ethyl acetate is evaporated and esters of ?-iodo-aliphatic carboxylic acids are obtained. In order to extract only ?-iodo-aliphatic carboxylic acids, the reaction mass, which contains a mixture of acids and their esters, is extracted with methylene chloride, water and trifluoroacetic acid are added, stirred at room temperature for 20-24 hours and the solvent is then evaporated.EFFECT: improved method of producing ?-iodo-aliphatic carboxylic acids and esters thereof.3 cl, 12 dwg, 17 ex

Description

The invention relates to the field of organic chemistry, in particular to methods for producing ω-iodaliphatic carboxylic acids and their esters based on the reaction of cleavage of aliphatic cyclic ketones by the action of hydrogen peroxide in the presence of iodine and copper (I) salts, corresponding to the basic principles of green chemistry (Green Chemistry ) (Fig. 1).

ω-Iodaliphatic carboxylic acids and their esters can be used in various fields of technology, including organic and pharmaceutical chemistry, biochemistry and medicine (in particular, as radiopharmaceuticals).

Little methods are known for producing iodaliphatic carboxylic acids and their esters that meet the principles of green chemistry.

A known method for producing iodaliphatic carboxylic acids described in the German patent [1]. The method consists in obtaining ω-iodaliphatic carboxylic acids from ω-bromaliphatic carboxylic acids by exchange of halogens when heated in a thin layer of an inert carrier (figure 1).

The main disadvantage of this method is the inaccessibility of ω-bromaliphatic carboxylic acids, in addition, the implementation of the method occurs when heated (80-150 ° C), it is necessary to separate the resulting product from the original substrate and the product yields are not high enough.

Another method is known where, under the conditions of the classical nucleophilic substitution reaction, sodium iodide was applied to ethyl 6-bromohexanoate in acetone, and the corresponding ω-iodaliphatic acid was obtained in low yield [2] (Fig. 2).

And in this case, the main disadvantage is that the substrates used are inaccessible reagents. In addition, the production method includes the step of chromatographic separation of ω-iodaliphatic carboxylic acids from ω-bromaliphatic carboxylic acids, heating to 80-150 ° C is necessary, and no water is allowed, since hydroxy aliphatic carboxylic acids may form . The yields of the target products are achieved no more than 75%.

Another, also the most common method for producing ω-iodaliphatic acids, is the reaction of the opening of lactones in the presence of various sources of iodine (figure 3). So, ethyl 6-iodhexanoic acid was obtained in very low yield (46%) by the action of trimethylsilyl iodide on valerolactone in ethanol [3].

In another work, a similar compound (6-iodhexanoic acid methyl ester) was obtained through the reaction of opening to hydroxy acid methyl ester, and subsequent treatment with iodine and triphenylphosphine. The obtained triphenylphosphonium iodide is used in the synthesis of prostaglandins (figure 4) [4].

However, these methods for the preparation of 6-iodohexanoic acid esters also require the use of inaccessible and environmentally unsafe reagents.

Closest to the proposed method can be considered a splitting of cycloalkane hydroperoxides by the action of Cu (II) ions (Fig. 5) [5]. The authors obtain hydroperoxides from the corresponding ketones by the action of hydrogen peroxide in the presence of Cu ²⁺ ions.

The main disadvantage of this method is the low yields of the target products (only 41-72%). Low yields are due to the fact that the copper (II) chloride catalyst used and the ratio of the reagents do not completely oxidize cyclic ketones. In addition, for the introduction of iodine into carboxylic acids, the authors of the article suggest using halide salts at room temperature; under these conditions, halogenation proceeds very slowly, not completely and with the formation of by-products - ω-hydroxycarboxylic acids.

A new technical task is to simplify the method, increase the yield and purity of the target products while expanding their assortment.

To solve the problem in a method for producing ω-iodaliphatic carboxylic acids and their esters, including the decomposition of aliphatic cyclic ketones under the influence of hydrogen peroxide in the presence of a catalyst of copper ions and iodine compounds, at room temperature, cyclic ketones such as cyclohexanone or cycloheptanone are cleaved or 4-methylcyclohexanone, also copper (I) chloride is used as a catalyst; the preparation is carried out in the following ratio of components: cyclic ketones - hydrogen peroxide - copper (I) chloride - 1: 5: 0.1, with stirring, for 10-20 hours, in the presence of methanol or ethanol solutions of iodine, the amount of iodine is taken in the following ratio: cyclic ketones - iodine - 1: 0.5. A saturated sodium bicarbonate solution is also added to the reaction mass to isolate and separate the desired products, while ω-iodaliphatic carboxylic acids are transferred to the aqueous layer as sodium salts, and their esters are separated by extraction of the aqueous layer with ethyl acetate, after which the ethyl acetate extraction is dried using sodium anhydrous sulfate, ethyl acetate is distilled off and esters of ω-iodaliphatic carboxylic acids are obtained. Also, to isolate only ω-iodaliphatic carboxylic acids, the reaction mixture containing a mixture of acids and their esters is extracted with methylene chloride, water and trifluoroacetic acid are added, and stirred at room temperature for 20-24 hours. Then the solvent is distilled off and receive ω-iodaliphatic carboxylic acids that do not require additional purification.

It is proposed to use the reaction of the cleavage of aliphatic cyclic ketones by the action of hydrogen peroxide in the presence of iodine and copper (I) salts, corresponding to the basic principles of green chemistry (Green Chemistry), with the formation of ω-iodaliphatic carboxylic acids and their esters (Fig.6).

In the proposed method for producing ω-iodaliphatic carboxylic acids and their esters, aliphatic cyclic ketones under the action of hydrogen peroxide and copper salts (I) with a ratio of cyclic ketones - hydrogen peroxide - copper (I) chloride - 1: 5: 0.1 with stirring at room at a temperature of 10-20 hours, hydroperoxides form, which in the presence of alcoholic solutions of iodine (with a ratio of substrate - iodine - 1: 0.5) open up, forming ω-iodaliphatic carboxylic acids and their esters. The selected conditions, namely the ratio of reagents, reaction time and room temperature, allow to obtain products with a total yield of 80-98%.

To isolate and separate the target products, the simplest method is proposed. When a saturated sodium bicarbonate solution is added to the reaction mass, ω-iodaliphatic carboxylic acids pass into the aqueous layer in the form of sodium salts, and their esters are easily separated by extraction of the aqueous layer with ethyl acetate. Then, the ethyl acetate extraction was dried using anhydrous sodium sulfate, ethyl acetate was distilled off and ethers of ω-iodaliphatic carboxylic acids were obtained, which did not require additional purification. To isolate only ω-iodaliphatic carboxylic acids, the reaction mixture containing a mixture of acids and their esters is extracted with methylene chloride, water and trifluoroacetic acid are added, and stirred at room temperature for 20-24 hours. Then the solvent and trifluoroacetic acid are distilled off to obtain ω-iodaliphatic carboxylic acids that do not require further purification.

Distinctive features showed in the inventive methodology of the aggregate new properties that are not explicitly derived from the prior art in this field and are not obvious to a specialist.

The proposed set of features is not described in the patent and scientific literature.

Examples of specific methods for producing ω-iodaliphatic carboxylic acids

and their esters from cyclic ketones

Example 1. Obtaining methyl ester of ω-iodhexanoic acid at 20-28 ° C.

To a solution of cyclohexanone in 10 ml of methanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide and sodium sulfite ceased to oxidize the iodine residue. Next, the reaction mixture was filtered, discarding a precipitate containing salts of copper (I) chlorides and iodides. The resulting filtrate was extracted with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.248 g (81%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.67 (s, 3H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( q, 2H), 1.62 (q, 2H), 1.43 (q, 2H) (Fig. 7).

Example 2. Obtaining methyl ester of ω-iodhexanoic acid at 29-35 ° C.

To a solution of cyclohexanone in 10 ml of methanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide and sodium sulfite ceased to oxidize the iodine residue. Next, the reaction mixture was filtered, discarding a precipitate containing salts of copper (I) chlorides and iodides. The resulting filtrate was extracted with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.124 g (73%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.67 (s, 3H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( q, 2H), 1.62 (q, 2H), 1.43 (q, 2H) (Fig. 7).

Example 3. Obtaining methyl ester of ω-iodhexanoic acid at 36-39 ° C.

To a solution of cyclohexanone in 10 ml of methanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , p = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide and sodium sulfite ceased to oxidize the iodine residue. Next, the reaction mixture was filtered, discarding a precipitate containing salts of copper (I) chlorides and iodides. The resulting filtrate was extracted with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.063 g (69%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.67 (s, 3H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( q, 2H), 1.62 (q, 2H), 1.43 (q, 2H) (Fig. 7).

Example 4. Obtaining ω-iodhexanoic acid at 20-28 ° C.

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.708 g (98%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 5. Obtaining ω-iodhexanoic acid at 29-35 ° C.

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.614 g (85%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 6. Obtaining ω-iodhexanoic acid at a hydrolysis temperature of 29-35 ° C.

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). To the obtained extract (10 ml) was added 5 ml of water and 1 ml of trifluoroacetic acid, stirred at a temperature of 29-35 ° C for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.578 g (80%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 7. Obtaining ω-iodhexanoic acid at a hydrolysis temperature of 36-45 ° C.

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). To the obtained extract (10 ml) was added 5 ml of water and 1 ml of trifluoroacetic acid, stirred at a temperature of 29-35 ° C for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.434 g (60%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 8. Obtaining ω-iodhexanoic acid with a hydrolysis time of 12 hours

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 12 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.390 g (54%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 9. Obtaining ω-iodhexanoic acid with a hydrolysis time of 16 hours

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 16 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.433 g (60%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 10. Obtaining ω-iodhexanoic acid at a hydrolysis time of 20 hours

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 20 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.693 g (96%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 11. Obtaining ω-iodhexanoic acid with a hydrolysis time of 28 hours

To a solution of cyclohexanone in 10 ml of methanol (3 mmol, 0.294 g, ρ = 0.946 g / cm ³ ) was added iodine (1.5 mmol, 0.381 g), a copper (I) chloride catalyst (0.3 mmol, 0.03 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (6 mmol, 0.638 g perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Next, 6 mmol (0.638 g) of perhydrol and copper (I) chloride (0.15 mmol, 0.015 g) were added, stirred at room temperature for 10 hours and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in those same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 28 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. The isolated ω-iodhexanoic acid did not require additional purification. Yield 0.708 g (98%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.19 (t, 2H), 2.38 (t, 2H), 1.85 (m, 2H), 1.63 ( m, 2H), 1.47 (m, 2H) (Fig. 8).

Example 12. Obtaining methyl ester of ω-iodhexanoic acid with a ratio of components in the reaction mixture cyclohexanone - hydrogen peroxide - copper (I) chloride - 1: 3: 0.1.

To a solution of cyclohexanone in 10 ml of methanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 3 mmol (0.319 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 3 mmol (0.319 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide and sodium sulfite ceased to oxidize the iodine residue. Next, the reaction mixture was filtered, discarding a precipitate containing salts of copper (I) chlorides and iodides. The resulting filtrate was extracted with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 0.893 g (58%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.67 (s, 3H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( q, 2H), 1.62 (q, 2H), 1.43 (q, 2H) (Fig. 7).

Example 13. Obtaining methyl ester of ω-iodhexanoic acid with a ratio of components in the reaction mixture cyclohexanone - hydrogen peroxide - copper (I) chloride - 1: 6: 0.1.

To a solution of cyclohexanone in 10 ml of methanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 12 mmol (1.275 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide and sodium sulfite ceased to oxidize the iodine residue. Next, the reaction mixture was filtered, discarding a precipitate containing salts of copper (I) chlorides and iodides. The resulting filtrate was extracted with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.263 g (82%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.67 (s, 3H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( q, 2H), 1.62 (q, 2H), 1.43 (q, 2H) (Fig. 7).

Example 14. Obtaining ethyl ester of ω-iodhexanoic acid.

To a solution of cyclohexanone in 10 ml of ethanol (6 mmol, 0.588 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in ethanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of ethanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) were added, stirred at room temperature for 10 hours, and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 6 hours in the same conditions.

Saturated sodium hydrogen carbonate solution was added to the reaction mixture until the evolution of carbon dioxide ceased. Then, extraction was performed with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.332 g (82%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 4.14 (q, 2H), 3.18 (t, 2H), 2.32 (t, 2H), 1.84 ( m, 2H), 1.62 (m, 2H), 1.43 (m, 2H), 1.25 (t, 3H) (Fig. 9).

Example 15. Obtaining ω-iodheptanoic acid.

To a solution of cycloheptanone in 10 ml of methanol (2 mmol, 0.228 g, ρ = 0.956 g / cm ³ ) was added iodine (1 mmol, 0.254 g), a copper (I) chloride catalyst (0.2 mmol, 0.02 g). Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (4 mmol, 0.425 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 4 ml of methanol) was added dropwise over 4 hours. Then 4 mmol (0.425 g) of perhydrol and copper (I) chloride (0.1 mmol, 0.01 g) were added, stirred at room temperature for 10 hours, and then another 2 mmol (0.212 g) of perhydrol was added with stirring for another 8 hours in the same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 0.504 g (98%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): 3.29 (t, 2H), 2.29 (t, 2H), 2.05 (m, 2H), 1.82 ( m, 2H), 1.59 (m, 2H), 1.41 (m, 2H) (Fig. 10).

Example 16. Obtaining methyl ester of ω-iodo-γ-methylhexanoic acid.

To a solution of 4-methylcyclohexanone in 10 ml of methanol (6 mmol, 0.672 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 6 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) was added, stirred at room temperature for 8 hours and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 8 hours in the same conditions.

Saturated sodium bicarbonate solution was added to the reaction mixture until the carbon dioxide evolution ceased, sodium sulfite until the iodine was discolored and filtered, discarding the precipitate. Then, extraction was performed with ethyl acetate (2 × 10 ml). The ethyl acetate extract was dried by passing through anhydrous sodium sulfate and the solvent was distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.344 g (83%). ¹ H NMR spectrum (racemic mixture) (500 MHz, CDCl ₃ , δ, ppm): 3.66 (s, 3H), 3.20 (t, 2H), 2.31 (m, 2H), 2.15 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H), 1.62 (m, 2H), 1.40 (m, 2H), 1.26 (m , 2H), 0.95 (d, 3 H), 0.94 (d, 3 H) (Fig. 11).

Example 17. Obtaining ω-iodine-γ-methylhexanoic acid.

To a solution of 4-methylcyclohexanone in 10 ml of methanol (6 mmol, 0.672 g, ρ = 0.946 g / cm ³ ) was added iodine (3 mmol, 0.762 g), a copper (I) chloride catalyst (0.6 mmol, 0.06 g ) Then, with stirring at room temperature, a solution of hydrogen peroxide in methanol (12 mmol, 1.275 g of perhydrol (32% H ₂ O ₂ , ρ = 1.125 g / cm ³ ) in 5 ml of methanol) was added dropwise over 4 hours. Then 12 mmol (1.275 g) of perhydrol and copper (I) chloride (0.3 mmol, 0.03 g) was added, stirred at room temperature for 8 hours and then another 6 mmol (0.638 g) of perhydrol was added with stirring for another 8 hours in the same conditions.

Sodium sulfite was added to the reaction mixture to oxidize the iodine residue, the precipitate was filtered off and discarded. Then, the filtrate was extracted with methylene chloride (2 × 5 ml). 5 ml of water and 1 ml of trifluoroacetic acid were added to the obtained extract (10 ml), stirred at room temperature for 24 hours and the solvents were distilled off. The resulting light yellow oily mass was dried under vacuum. Yield 1.49 g (97%). ¹ H NMR spectrum (500 MHz, CDCl ₃ , δ, ppm): (racemic mixture) 3.66 (s, 3H), 3.20 (t, 2H), 2.34 (m, 2H), 2.18 (m, 2H), 2.00 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.46 (m, 2H), 1.33 (m , 2H), 0.99 (d, 3H), 0.98 (d, 3H) (Fig. 12).

A method for producing ω-iodaliphatic carboxylic acids and their esters is proposed, which consists in the fact that aliphatic cyclic ketones under the action of hydrogen peroxide and copper salts (I) with a ratio of cyclic ketones - hydrogen peroxide - copper (I) chloride - 1: 5: 0, 1 with stirring at room temperature for 10-20 hours form hydroperoxides, which in the presence of alcoholic solutions of iodine (substrate to iodine ratio - 1: 0.5) open up, forming ω-iodaliphatic carboxylic acids and their esters. The selected conditions, namely the ratio of reagents, reaction time and room temperature, allow to obtain products with a total yield of 80-98%.

To isolate and separate the target products, the simplest method is proposed. When a saturated sodium bicarbonate solution is added to the reaction mass, ω-iodaliphatic carboxylic acids pass into the aqueous layer in the form of sodium salts, and their esters are easily separated by extraction of the aqueous layer with ethyl acetate. Then, the ethyl acetate extraction was dried using anhydrous sodium sulfate, ethyl acetate was distilled off and ethers of ω-iodaliphatic carboxylic acids were obtained, which did not require additional purification. To isolate only ω-iodaliphatic carboxylic acids, the reaction mixture containing a mixture of acids and their esters is extracted with methylene chloride, water and trifluoroacetic acid are added, and stirred at room temperature for 20-24 hours. Then the solvent is distilled off and receive ω-iodaliphatic carboxylic acids that do not require additional purification.

Thus, the claimed invention, in comparison with known analogues, allows, through a single step, to obtain a mixture of ω-iodaliphatic carboxylic acids and their esters and in a simple way to separate the acid from its ether with a total yield of 80-98%.

As can be seen from the experimental part, the proposed production method does not involve the use of expensive reagents and the use of complex manipulations and allows one to obtain ω-iodaliphatic carboxylic acids and their esters in two stages, while the total yield of products is 80-98%. Also, upon the preparation of ω-iodaliphatic carboxylic acids and their esters, the stage of product purification is not required and the procedure for their isolation is maximally simplified.

Thus, the proposed method has the following advantages over other methods for producing iodaliphatic carboxylic acids and their esters:

1) aliphatic cyclic ketones are cheap, commercially available substrates that do not have toxicity;

2) high yields of target products;

3) the use of low toxicity reagents and solvents;

4) carrying out the reaction without heating;

5) without the formation of by-products;

6) there is no need for additional purification of the target products;

7) simple methods for isolating the target products;

8) obtaining in one way acids and their esters (methyl and ethyl);

9) lack of multi-stage, ease of receipt.

Justification of the regime

The optimal temperature regime for obtaining ω-iodaliphatic carboxylic acids and their esters was experimentally selected (examples 1-5). It was found that the reaction should be carried out at a temperature of 20-28 ° C, while the total yield of products is 80-98%, and an increase in temperature to 29-35 ° C leads to a decrease in yield by 8-14%.

The optimal ratio of components in the reaction mixture is cyclic ketones - hydrogen peroxide - copper (I) chloride - 1: 5: 0.1. This ratio allows almost completely to oxidize cyclic ketones, which is necessary to achieve high yields of target products (examples 1, 12-13).

For the hydrolysis stage, the temperature regime and the time of hydrolysis were found to be fundamental. It is optimal to carry out hydrolysis at room temperature, while the yield of ω-iodaliphatic carboxylic acids is more than 95%. So, at a higher temperature (more than 30 ° C), yields decreased significantly (by 10-15%), since in addition to hydrolysis, nucleophilic replacement of iodine by a hydroxyl group or a hydrogen atom in the target products occurred, which led to the formation of by-products (examples 4 , 6, 7).

The output of ω-iodaliphatic carboxylic acids is achieved the greatest during hydrolysis for 20-24 hours (examples 4, 8-11). Reducing the reaction time (less than 20 hours) leads to incomplete hydrolysis of the esters and, consequently, to a decrease in the yield of the target acids.

Sources of information taken into account when compiling the description:

1. LAUFER; PETER MACHULLA; YURGEN STOCKLIN; GERHARD.

METHOD OF MAKING 1. SUP. 123 LABELED FATTY ACIDS. Publication number: 4290965, Publication date: 1981-22-09.

2. C. Hardouin, M.J. Kelso, F.A. Romero, T.J. Rayl, D. Leung, I. Hwang, B. F. Cravatt, D. L. Boger // J. Med. Chem. 2007, 50, P.3359.

3. P. Kraft, R. Cadalbert. The Thia-Analog of Ambrettolide. Synthesis and Odor of 1,8-Oxathiacyclohexadecan-2-one // Synlett 1997; No. 5: P 600-602.

4. S. El. Fangour, A. Guy, V. Despres, J.-P. Vidal, J.-C. Rossi, T. Durand. Total Synthesis of the Eight Diastereomers of the Syn-Anti-Syn Phytoprostanes Fl Types I and II // J. Org. Chem. 2010, 69, No. 7. P.2498-2503.

5. G.I. Nikishin, A.B. Alexandrov, A.B. Ignatenko, E.K. Starostina. Synthesis of ω-haloaliphatic acids by the catalytic decomposition of cycloalkane hydroperoxides by copper ions // Izvestiya AN SSSR, Chemical Series. 1984. No. 11. S.2628-2630.

APPENDIX

Figure 1 - Scheme for producing 6-iodhexanoic acid.

Figure 2 - Scheme for obtaining ethyl ester of 6-iodhexanoic acid from ethyl ester of 6-bromohexanoic acid.

Figure 3 - Scheme of obtaining ethyl ester of 6-iodhexanoic acid from lactone.

Figure 4 - Scheme for the preparation of methyl ester of 6-iodhexanoic acid from lactone.

Figure 5 - Scheme for producing ω-derivatives of carboxylic acids from cyclic ketones.

Figure 6 - Scheme for the preparation of ω-iodaliphatic carboxylic acids and their esters from cyclic ketones.

Figure 7 - NMR Spectrum ¹ H methyl ester of ω-iodhexanoic acid (500 MHz, solvent CDCl ₃ ).

Figure 8 - NMR spectrum of ¹ H ω-iodhexanoic acid (500 MHz, solvent CDCl ₃ ).

Figure 9 - ¹ H NMR Spectrum of ω-iodhexanoic acid ethyl ester (500 MHz, solvent CDCl ₃ ).

Figure 10 - NMR Spectrum of ¹ H ω-iodoheptanoic acid (500 MHz, solvent CDCl ₃ ).

Figure 11 - ¹ H NMR Spectrum of ω-iodo-γ-methylhexanoic acid methyl ester (500 MHz, CDCl ₃ solvent).

Figure 12 - NMR Spectrum of ¹ H ω-iodine-γ-methylhexanoic acid (500 MHz, solvent CDCl ₃ ).

Claims (3)

1. A method of producing ω-iodaliphatic carboxylic acids and their esters, comprising splitting aliphatic cyclic ketones under the influence of hydrogen peroxide in the presence of a catalyst of copper ions and iodine compounds, at room temperature, characterized in that cyclic ketones such as cyclohexanone or cycloheptanone or 4-methylcyclohexanone; copper (I) chloride is also used as a catalyst; the preparation is carried out in the following ratio of components: cyclic ketones - hydrogen peroxide - copper (I) chloride 1: 5: 0.1, with stirring, for 10-20 hours, in the presence of methanol or ethanol solutions of iodine, the amount of iodine is taken in the following ratio: cyclic ketones - iodine 1: 0.5. 2. The method according to claim 1, characterized in that a saturated sodium bicarbonate solution is added to the reaction mass to isolate and separate the desired products, while ω-iodaliphatic carboxylic acids pass into the aqueous layer in the form of sodium salts, and their esters are separated by extraction of aqueous layer with ethyl acetate, after which the ethyl acetate extraction is dried using anhydrous sodium sulfate, ethyl acetate is distilled off and esters of ω-iodaliphatic carboxylic acids are obtained. 3. The method according to claim 1, characterized in that for the isolation of only ω-iodaliphatic carboxylic acids, the reaction mass containing a mixture of acids and their esters is extracted with methylene chloride, water and trifluoroacetic acid are added, stirred at room temperature for 20-24 hours, then the solvent is distilled off to obtain ω-iodaliphatic carboxylic acids that do not require further purification.

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