RU2616974C1 - METHOD OF PRODUCTION ω-(BIS(PYRIDINE-2-ILMETHYL)AMINO)ALIPHATIC ACIDS - PRECURSORS WITH HELATERAL CENTERS FOR BINDING METALS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a process for preparing ω-(bis (pyridin-2-ylmethyl)amino)aliphatic acids, which are precursors with chelating centers for metal binding. The process involves the preparation of esters ω-derivatives of aliphatic acids, followed by reaction with a reagent containing a picolyl substituent, and consists of two steps. In the first stage, intermediate synthesis products - esters iodaliphatic ω-carboxylic acids by oxidative cleavage of aliphatic cyclic ketones under the action of hydrogen peroxide in the presence of a catalyst of copper ions and iodine compounds at room temperature. Is subjected to cleavage of cyclic ketones used as catalyst copper (I) chloride, the preparation is carried out at a ratio of cyclic ketones components: hydrogen peroxide: copper (I) chloride=1:5:0.1, with stirring for 10-20 hours in the presence methanolic or ethanolic iodine solutions. The amount of iodine taken in a ratio of cyclic ketone: iodine=1:0.5. Further, a saturated solution of sodium hydrogencarbonate is added to the reaction mass, transferring ω-Iodaliphatic carboxylic acids into the aqueous layer in the form of sodium salts, and their esters are separated by extraction of 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 ωcarboxylic acids are obtained. In the second stage in esters ω-iodaliphatic carboxylic acids, the iodine atom is replaced by bis(pyridin-2-ylmethyl)amino group, for which di-2-picolylamine is used. The second step is carried out at a component ratio of ethers ω-iodaliphatic carboxylic acids: di-2-picolylamine: triethylamine=1:1.16:1, respectively, with stirring at 50°C for 24 hours. After that, ethers are isolated ω-(bis(pyridin-2-ylmethyl)amino)aliphatic acids, for which a saturated solution of sodium hydrogen carbonate is added to the reaction mass and extracted with ethyl acetate. The ethyl acetate extract was dried with sodium sulfate anhydrous, ethyl acetate was distilled off, the residue was purified by column chromatography on silica gel using hexane-ethyl acetate (1:1) as the eluent, gradually increasing the gradient of the latter, and ether ω-(bis(pyridin-2-ylmethyl)amino)aliphatic acid. The ester obtained is hydrolyzed in acetonitrile under concentrated hydrochloric acid for 2 hours at a temperature of 50°C, the solvent was distilled off in vacuo to give ω-(bis(pyridin-2-ylmethyl)amino)aliphatic acids, which do not require additional purification.

EFFECT: increase in the yield of these acids.

9 dwg, 16 ex

Description

The invention relates to the field of organic chemistry, in particular to methods for producing ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids - precursors with chelate centers for metal binding based on the cleavage reaction of cyclic ketones that comply with the principles of green chemistry (Green Chemistry ), which can be used in various fields of technology, including in organic and pharmaceutical chemistry, biochemistry and medicine, in particular, as radiopharmaceuticals (Fig 1).

Radiopharmaceuticals based on the technetium-99 and rhenium-188 isotopes occupy a significant place in diagnosis and therapy, respectively. The main thing in the development of the synthesis of such radiopharmaceuticals is the introduction of precursors into their structures - a ligand with high chelating ability for strong binding of technetium-99 or rhenium-188, which are used successfully ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids. Thus, the development of a new method for the preparation of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids as precursors for the binding of metals is based on the cleavage reaction of aliphatic cyclic ketones.

A known method of producing derivatives of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids, based on the synthesis of omega-aminopropanoic and omega-aminohexanoic acids and 2-picolyl chloride hydrochloride (Fig. 2). The starting acids and 2-picolyl chloride hydrochloride are dissolved in water and stirred for 5 days at room temperature. Next, the reaction mixture is subjected to sequential treatment with acid and alkali and extracted with chloroform. The crude product is purified by recrystallization, and the product yield is not more than 41%. The main disadvantage of this method is the length of the production process and low yields of final products [2].

A known method of producing ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids, based on the synthesis of omega-aminoaliphatic acids and pyridine-2-carbaldehyde in the presence of sodium triacetoxyborohydride and dichloroethane. The synthesis is carried out with stirring for 8 hours at room temperature, followed by isolation of the products by extraction with chloroform and purification by flash chromatography (Fig. 3) [3]. The yields of products are low (40-80%), reagents inaccessible.

The closest to the proposed one can be considered a method for producing 6- (bis (pyridin-2-ylmethyl) amino) hexanoic and 11- (bis (pyridin-2-ylmethyl) amino) undecanoic acids, which involves the reaction of nucleophilic substitution of hydrogen atoms in amino groups 6-aminocaproic acid or 11-aminoundecanoic acid to 2-picoline bromide (Fig. 4) [4]. In this method, in the first step, the starting substrates 6-aminohexanoic acid or 11- (bis (pyridin-2-ylmethyl) amino) undecanoic acid are esterified with methyl alcohol using toxic thionyl chloride. Product yields amounted to no more than 45%. In the second stage, methylated products are reacted with a twofold excess of 2-picoline bromide for 5 days with stirring at a temperature of 50 ° C. The yields of target products 34-41%. The disadvantages of the method are the need to carry out a pre-laborious reaction to the esterification of the starting substrates using toxic thionyl chloride, low yields of reaction products, high consumption of the reagent 2-picoline bromide and the duration of the synthesis.

A new technical problem is the simplification of the method, increasing the selectivity of the method, increasing the yields of products, the versatility of the method.

To solve the problem in a method for producing ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids, including the preparation of esters of ω-derivatives of aliphatic acids, followed by interaction with a reagent containing picolyl substituent, at the first stage, intermediate synthesis products are obtained - esters ω-iodaliphatic carboxylic acids by oxidative cleavage 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, while cyclic ketones such as cyclopentanone, cyclohexanone, or cycloheptanone, or 4-methylcyclohexanone, or any other cyclic ketone, are also cleaved; 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, also, the amount of iodine is taken in the following ratio: cyclic ketones - iodine - 1: 0.5. To isolate and separate the intermediate products, a saturated solution of sodium bicarbonate is added to the reaction mass, 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 anhydrous sodium sulfate, ethyl acetate is distilled off and esters of ω-iodaliphatic carboxylic acids are obtained. At the second stage of the method, in the esters of ω-iodaliphatic carboxylic acids, the iodine atom is replaced by a bis (pyridin-2-ylmethyl) amino) group, for this di-2-picolylamine is used. The second stage is carried out with the following ratio of components: esters of ω-iodaliphatic carboxylic acids - di-2-picolylamine - triethylamine - 1: 1.16: 1, with stirring at 50 ° C for 24 hours. To isolate the esters of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids, a saturated sodium bicarbonate solution is added to the reaction mass and extracted with ethyl acetate, the ethyl acetate extraction is dried using anhydrous sodium sulfate, and ethyl acetate is distilled off. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter, and ω-bis (pyridin-2-ylmethyl) amino) aliphatic acid ester was isolated. The resulting ether is subjected to hydrolysis in acetonitrile under the action of concentrated hydrochloric acid for 2 hours at a temperature of 50 ° C. The solvent is distilled off in vacuo to give ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids that do not require further purification.

Distinctive features showed in the claimed combination of the proposed method 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-bis (pyridin-2-ylmethyl) amino) aliphatic acids

Example 1. Obtaining methyl ester of ω-iodhexanoic acid

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

A 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 is 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. 5).

Example 2. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 30 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 30 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 32%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 3. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 40 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 40 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 61%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 4. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 45 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 45 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 83%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 5). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (FIG. 6).

Example 5. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 50 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 50 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 90%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 6. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 55 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 55 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10%) soda solution was added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 86%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 7. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 60 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 60 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 64%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 8. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 70 ° C

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37 mmol) of triethylamine. The reaction mass is stirred at 70 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 42%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 9. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, add 500 μl (2.76 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 165 μl (1.86 mmol) of triethylamine. The reaction mass is stirred at 50 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 32%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 10. Obtaining methyl ester of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid

To the ω-iodhexanoic acid methyl ester (2.37 mmol, 0.6068 g) obtained in Example 1, 430 μl (2.37 mmol) of 2- (dipicalyl) amine, 2 ml of isopropanol and 330 μl (2.37) are added. mmol) of triethylamine. The reaction mass is stirred at 50 ° C for 24 hours. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate-ethanol = 10: 3).

After that, 5 ml of a 10% soda solution are added to the reaction mass and extracted with ethyl acetate (2 × 5 ml). The ethyl acetate extract was washed with brine, dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting product was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as the eluent, gradually increasing the gradient of the latter. The product yield was 32%.

To identify the synthesized methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized ether (300 MHz, CDCl ₃ , δ, ppm, J, Hz ): 8.48 (d, 2H _arom , J = 4.8 Hz), 7.61 (t, 2H _arom ), 7.48 (d, 2H _arom , J = 7.8 Hz), 7.11 ( t, 2H _arom ), 3.8 (s, CH ₂ ), 3.67 (s, CH ₃ ), 2.52 (t, CH ₂ ), 2.24 (t, CH ₂ ), 1.52 ( m, CH ₂ ), 1.25 (m, CH ₂ ) (Fig. 6). MS (ESI) -m / z: (M + H) ⁺ - found: 328.2032, (M + H) ⁺ - calculated: 328.2020 (Fig. 7).

Example 11. Method for the synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 50 ° C

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 2 hours at a temperature of 50 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 96%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, a ¹ H-NMR spectrum was obtained, the shape of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, J, Hz): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9.1 Hz), 7.89 (t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9)

Example 12. Method for the synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 40 ° C

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 2 hours at a temperature of 40 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 76%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, J, Hz): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9.1 Hz), 7.89 (t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9).

Example 13. Method for the synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 45 ° C

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 2 hours at a temperature of 45 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 95%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, a ¹ H-NMR spectrum was obtained, the shape of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, J, Hz): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9.1 Hz), 7.89 (t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9).

Example 14. Method for the synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 55 ° C

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 2 hours at a temperature of 55 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 96%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, J, Hz): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9, l Hz), 7.89 (t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9).

Example 15. Method for the synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid at 60 ° C

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 2 hours at a temperature of 50 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 90%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, ¹ H-NMR spectrum was obtained, the shape of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, 7 Hz ): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9.1 Hz), 7.89 ( t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9)

Example 16. The method of synthesis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid

Methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate 0.053 g (0.16 mmol) was dissolved in 2 ml of acetonitrile and 50 μl of HCl (36%) was added. The reaction mass is stirred for 1.5 hours at a temperature of 50 ° C. The end of the reaction is determined by thin layer chromatography (eluent: ethyl acetate - ethanol = 10: 3). After hydrolysis is complete, the solvents are distilled off under reduced pressure. The product yield was 86%. To identify the synthesized 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid, a ¹ H-NMR spectrum was obtained, the form of which corresponds to the structure of the synthesized acid (300 MHz, H ₂ O, δ, ppm, 7 Hz ): 8.65 (d, 2H _arom , J = 5.7 Hz), 8.4 (t, 2H _arom ), 7.97 (d, 2H _arom , J = 9.1 Hz), 7.89 ( t, 2H _arom ), 4.24 (s, CH ₂ ), 2.20 (t, CH ₂ ), 1.40 (m, CH ₂ ), 1.10 (m, CH ₂ ). (Fig. 8). MS (ESI) -m / z for C ₁₈ H ₂₄ N ₃ O ₂ : (M + H) ⁺ - found: 314.1879; (M + H) ⁺ - calculated: 314.1869 (Fig. 9)

Justification of the regime

The optimal temperature regime for obtaining ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids was experimentally selected (examples 2-8). It was found that the reaction for the production of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acid esters must be carried out at a temperature of 45-55 ° C, while the yield of products is 80-90%, and an increase in temperature to 60-70 ° C leads to to reduce output by 20-40%.

The optimum ratio of the components in the reaction mixture is the esters of ω-iodaliphatic carboxylic acids - di-2-picolylamine - triethylamine - 1: 1.16: 1. This ratio allows you to almost completely replace the iodine atoms on the remainder of di-2-picolylamine, which is necessary to achieve high yields of target products (examples 5, 9-10).

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 a temperature of 45-55 ° C, while the yield of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids is more than 98%. So, at a higher temperature (more than 60 ° C), yields were significantly reduced (by 10-15%), since in addition to hydrolysis, by-products were formed (examples 11-15).

The yield of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids is achieved the greatest during hydrolysis for 2-3 hours (examples 11, 16). Reducing the reaction time (less than 2 hours) leads to incomplete hydrolysis of the esters and, consequently, to a decrease in the yield of the target acids.

Thus, the proposed method has fundamental advantages over the known methods for producing ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids. Firstly, the availability of substrates - esters of ω-iodaliphatic carboxylic acids, which are proposed to be obtained from cheap, commercially available, non-toxic cyclic ketones. The remaining synthesis components used also meet the principles of green chemistry. Secondly, the selected conditions, namely the ratio of reagents, reaction time and reaction temperature, allow to obtain products with yields of 80-95%). Also, according to the results of experiments, it was found that the yield of the labeled complex of ^99m Tc with ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids was 83.6% at a radiochemical purity of 90.3%, which allows us to successfully propose ω-bis ( pyridin-2-ylmethyl) amino) aliphatic acids obtained by the developed method for binding of technetium-99 m

Information sources

1. Patent No. 2494087 dated 09/27/2013. A method of obtaining ω-iodaliphatic carboxylic acids and their esters / Yusubov M.S., Zhdankin V.V., Larkina M.S., Drygunova L.A.

2. Amino Acid and Peptide Bioconjugates of Copper (II) and Zinc (II) Complexes with a Modified N, N-Bis (2-picolyl) amine Ligand / Srecko I. Kirin, Pierre Dubon, Thomas Weyhermuller, Eckhard Bill, and Nils Metzler-Nolte // Inorganic Chemistry, Vol. 44, No. 15, 2005. P. 5405-5415.

3. Synthesis and Evaluation of a Series of 99mTc (CO) 31 Lisinopril Complexes for In Vivo Imaging of Angiotensin-Converting Enzyme Expression / Frank J. Femia, Kevin P. Maresca, Shawn M. Hillier, Craig N. Zimmerman, John L. Joyal, John A. Barrett, Omer Aras, Vasken Dilsizian, William C. Eckelman, and John W. Babich // The journal of nuclear medicine. Vol. 49. No. 6. June 2008. P. 970-977.

4. Huahui, Z. Synthesis, characterization and biodistribution of new fatty acids conjugates bearing N, N, N-donorsincorporated [ ^99m Tc / Re (CO) ₃ ] ⁺ / Dalton Transaction. - 2012. - Vol. 42. - P. 2894.

Figure 1 - Scheme for the preparation of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids - precursors with chelate centers for metal binding

Figure 2 - Scheme for the preparation of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid

Figure 3 - Scheme of obtaining derivatives of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids

Figure 4 - Scheme of obtaining derivatives of ω-bis (pyridin-2-ylmethyl) amino) aliphatic acids

Figure 5 - ¹ H-NMR spectrum of methyl 6-iodohexanoate (300 MHz, CDCl ₃ , δ, ppm, J, Hz)

Figure 6 - ¹ H-NMR spectrum of methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate (300 MHz, CDCl ₃ , δ, ppm, J, Hz)

Figure 7 - Elemental analysis of methyl 6- (bis (pyridin-2-ylmethyl) amino) hexanoate

Figure 8 - ¹ H-NMR spectrum of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid (as hydrochloride) (300 MHz, H ₂ O, δ, ppm, J, Hz)

Figure 9 - Elemental analysis of 6- (bis (pyridin-2-ylmethyl) amino) hexanoic acid

Claims (1)

A method of producing ω- (bis (pyridin-2-ylmethyl) amino) aliphatic acids, comprising the preparation of esters of ω-derivatives of aliphatic acids, followed by reaction with a reagent containing picolyl substituent, characterized in that at the first stage, synthesis intermediates are obtained - esters ω-iodaliphatic carboxylic acids - by oxidative cleavage 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, then subjected to cyclic ketones, 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 also taken in the following ratio : cyclic ketones: iodine = 1: 0.5, then a saturated sodium bicarbonate solution is added to the reaction mass, converting ω-iodaliphatic carboxylic acids into the aqueous layer in the form of sodium salts, and their esters are separated by extraction of the aqueous layer with ethyl acetate, then ethyl acetate is extracted of dried with anhydrous sodium sulfate, ethyl acetate was distilled off to give ω-iodalifaticheskih esters of carboxylic acids; in the second stage in the esters of ω-iodaliphatic carboxylic acids, the iodine atom is replaced by a bis (pyridin-2-ylmethyl) amino group, for this, di-2-picolylamine is used, and the second stage is carried out in the following ratio of components: esters of ω-iodaliphatic carboxylic acids: di -2-picolylamine: triethylamine = 1: 1.16: 1, respectively, with stirring at 50 ° C for 24 hours, then the esters of ω- (bis (pyridin-2-ylmethyl) amino) aliphatic acids are isolated, for which a saturated solution of sodium bicarbonate is added to the reaction mass and extracted with ethyl acetate tatom, the ethyl acetate extraction was dried using anhydrous sodium sulfate, the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as an eluent, gradually increasing the gradient of the latter, and ω- (bis ( pyridin-2-ylmethyl) amino) aliphatic acid, the obtained ether is subjected to hydrolysis in acetonitrile under the influence of concentrated hydrochloric acid for 2 hours at a temperature of 50 ° C, the solvent is distilled off under vacuum and ω- ( uc (pyridin-2-ylmethyl) amino) aliphatic acids, not requiring further purification.

Images