RU2699070C1 - Method of producing 2-nitroxysuccinate 3-oxy-6-methyl-2-ethylpyridine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing 2-nitroxysuccinate 3-oxy-6-methyl-2-ethylpyridine by nitration of malic acid with a sulfuric-nitric mixture until formation of nitroxy-succinic acid followed by treatment thereof with 2-ethyl-6-methyl-3-oxypyridine, where nitro-malic acid, which is synthesized as an intermediate product, is extracted from the reaction mixture in a dry form, and in form of a solution in ethyl acetate, which is then used to carry out a final reaction with 3-oxy-6-methyl-2-ethylpyridine.

EFFECT: design of an explosion-proof technology – a method of producing 2-nitroxysuccinate 3-oxy-6-methyl-2-ethylpyridine.

1 cl, 1 dwg, 2 ex

Description

The invention relates to a method for producing a physiologically active substance of 3-hydroxy-6-methyl-2-ethylpyridine 2-nitroxy succinate. The compound 3-hydroxy-6-methyl-2-ethylpyridine 2-nitroxysuccinate (structure III in Fig. 1) is a fundamentally new hybrid (from the point of view of polypharmacology) molecule that simultaneously combines antioxidant and vasodilating properties. The prospect of structure III as a potential anti-ischemic, anti-stress and anti-hypoxic drug is confirmed by the publication [RU 2394815 C2].

The prior art patent is known [RU 2250210 C1], which describes a method for producing derivatives of nitroxysuccinate. According to the proposed method, the nitration of malic acid is first carried out with a mixture of sulfuric and nitric acids, followed by the isolation of nitro malic acid. And then the obtained nitration product is treated with a pyridine derivative until the formation of the desired nitroxy succinate (Fig. 1 - Scheme of obtaining structure III). The main disadvantage of the known analogue is that the nitro-malic acid secreted in the first stage during the drying process can spontaneously detonate if the amount of secreted acid exceeds 15 g [A. Lachman // J. Am. Chem. Soc., 1921, 43 (9), pp 2084-2091].

The closest technical solution is the patent [RU 2394815 C2] which describes a method for producing structure III. The method of obtaining is similar to the patent [RU 2250210 C1], characterized in that, in this patent, a more detailed description of the conditions for the final stage of processing of nitroxy succinic acid is given: the reaction is carried out in alcohols and at elevated temperature. The main disadvantage of this method is similar to the patent [RU 2250210 C1] and also lies in the explosiveness of the technology, which complicates the implementation of the method on an industrial scale.

The objective of the present invention is the development of explosion-proof technology - a method for producing 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine. To solve the problem of obtaining structure III, nitration is carried out without isolation of the intermediate nitro-malic acid, not in dry form, but in the form of a solution in ethyl acetate, which excludes the possibility of its spontaneous detonation and allows you to safely scale the synthetic process. At the nitration stage, the degree of conversion of malic acid to nitro-malic is controlled. The final reaction of 3-hydroxy-6-methyl-2-ethylpyridine with nitro-malic acid is carried out in ethyl acetate in the temperature range from 15 ° C to 35 ° C, which provides a higher yield of the target compound in comparison with the alcohol reaction medium.

In the claimed method, ethyl acetate is used both for the extraction of the nitration product of malic acid and for the final stage of obtaining structure III. Due to the extremely low solubility of structure III in ethyl acetate, the final reaction (Fig. 1) proceeds with a significantly greater (15%) yield compared to [RU 2394815 C2]. Moreover, high yields of the final stage are achieved both during the reaction with crystalline nitro-malic acid and with its ethyl acetate extract.

The complete conversion of the nitration reaction of malic acid is also monitored, since the reaction time can vary significantly during the scaling process. The method of IR spectroscopy is used for these purposes, since a mixture of nitro-malic and malic acids is characterized by a rather intense signal in the region of 1100 cm ^-1 , which can be correlated with vibrations of the CO bond of the alcohol group of malic acid. In this regard, the complete disappearance of the signal in the region of 1100 cm ^-1 indicates the completion of the nitration reaction, i.e. the complete absence of malic acid in the reaction mixture.

NMR spectra were recorded on a Bruker DRX 500 instrument with an operating frequency of 500.13 MHz at a temperature of 298 K and using tetramethylsilane as the internal standard. IR spectra were recorded on a Bruker alfa spectrometer. Elemental analysis was performed on a Vario Micro cube CHNS / O elemental analyzer.

Below are examples characterizing the essence of the present invention.

Example 1

- яблочной кислоты. После охлаждают реактор до 0°С при перемешивании добавляют 4 мл HNO₃ (d=1.45). Полученную суспензию перемешивают при 0°С в течение 2 часов. После чего прибавляют 2.5 мл концентрированной H₂SO₄, полученную смесь перемешивают в течение 1 часа при температуре 0°С, затем выливают на 40 г льда. После гомогенизации раствор обрабатывают этилацетатом (3 раза по 30 мл) в делительной воронке. Этилацетатный экстракт сушат путем добавления (~ 1% от общего объема органической фазы) безводного Na₂SO₄. Этилацетатный раствор отделяют от осадка Na₂SO₄ путем декантации с последующим упариванием растворителя. Получают 5.34 г целевой нитрояблочной кислоты. Элементный анализ. Найдено, %: С 26.93; Н 3.01; N 7.72. Расчет для C₄H₅NO₇, %: С 26.83; Н 2.81; N 7.82. ИК спектр, см^-1: 1703, 1647, 1443, 1384, 1334, 1261, 1244, 1203, 1049, 902, 862, 840, 809, 748, 693, 670, 615. ¹Н ЯМР (ДМСО-d5, δ, м.д., J/Гц): 2.90-2.95 (дд, 1Н (СН₂) J=8.0), 2.98-3.02 (дд, 1Н (СН₂) J=4.0), 5,63-5.65 (м, 1Н (СН), J₁=4.0, h=8.0), 12.0-14.0 (уш. с, НООС). ¹³С ЯМР (ДМСО-d5): 37.8 (СН2); 80.3 (CHONO₂); 172.5; 173.9 (С=O).In a flask (50 ml) equipped with a magnetic stirrer, reflux condenser, internal thermometer and cooling bath, 5 g (37.3 mmol) of d are placed,

- malic acid. After the reactor was cooled to 0 ° C, 4 ml of HNO ₃ (d = 1.45) was added with stirring. The resulting suspension was stirred at 0 ° C for 2 hours. Then add 2.5 ml of concentrated H ₂ SO ₄ , the resulting mixture is stirred for 1 hour at 0 ° C, then poured onto 40 g of ice. After homogenization, the solution is treated with ethyl acetate (3 times 30 ml) in a separatory funnel. The ethyl acetate extract was dried by adding (~ 1% of the total volume of the organic phase) anhydrous Na ₂ SO ₄ . An ethyl acetate solution was separated from the precipitate Na ₂ SO ₄ by decantation, followed by evaporation of the solvent. Obtain 5.34 g of the target nitro-malic acid. Elemental analysis. Found,%: C 26.93; H 3.01; N, 7.72. Calculation for C ₄ H ₅ NO ₇ ,%: C 26.83; H 2.81; N, 7.82. IR spectrum, cm ^-1 : 1703, 1647, 1443, 1384, 1334, 1261, 1244, 1203, 1049, 902, 862, 840, 809, 748, 693, 670, 615. ¹ N NMR (DMSO-d5, δ , ppm, J / Hz): 2.90-2.95 (dd, 1Н (СН ₂ ) J = 8.0), 2.98-3.02 (dd, 1Н (СН ₂ ) J = 4.0), 5.63-5.65 (m , 1H (CH), J ₁ = 4.0, h = 8.0), 12.0-14.0 (br.s, NOOS). ¹³ C NMR (DMSO-d5): 37.8 (CH2); 80.3 (CHONO ₂ ); 172.5; 173.9 (C = O).

In a flask (100 ml) equipped with a magnetic stirrer, a reflux condenser and an internal thermometer, 5.01 g (28 mmol) of nitro-malic acid and 30 ml of ethyl acetate are placed. A solution of 3.75 g (27.4 mmol) of 2-ethyl-6-methyl-3-hydroxypyridine in 55 ml of ethyl acetate was added to the resulting solution. The mixture was stirred at room temperature for 10 hours. The precipitate formed is filtered off, washed with ethyl acetate and dried over P ₂ O ₅ . Received 8.38 g of the target compound. Yield 98.2%. Elemental analysis. Found,%: C 45.44; H 5.18; N, 8.52. Calculation for C ₁₂ H ₁₆ N ₂ O ₈ ,%: C 45.57; H 5.10; N, 8.58. IR spectrum (cm ^-1 ): 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1058, 1038, 962, 890. 857, 813. ¹ H NMR spectrum ( DMSO-d5, δ, ppm, J / Hz): 1.13-1.16 (t, 3H, C H ₃ CH ₂ , J = 7.5); 2.36 (s, 3H, CH ₃ ); 2.68-2.73 (dd, 2H, CH ₃ C H ₂ , J = 7.5); 2.79-2.84 (dd, 1H, C (O) C H ₂ CH, J = 8); 2.94-2.99 (dd, 1H, C (O) C H ₂ CH, J = 4.3); 5.53-5.55 (m, 1H, C (O) CH ₂ C H ); 7.00-7.01 (d, 1H, Ar, J = 8.3); 7.18-7.19 (d, 1H, Ar, J = 8.2). ¹³ C NMR (DMSO-d5): 12.53; 21.87; 24.25; 34.17; 77.17; 121.98; 123.95; 145.73; 148.57; 149.36; 168.86; 170.25.

Example 2

- яблочной кислоты. После охлаждения реактора до 0°С при перемешивании добавляют 4 мл HNO₃ (d=1.45). Полученную суспензию перемешивают при 0°С в течение 2 часов. После чего прибавляют 2.5 мл концентрированной H₂SO₄, полученную смесь перемешивают при температуре 0°С. Спустя 30 минут после добавления к смеси серной кислоты, с помощью шпателя из реактора отбирают небольшое количество (около 2-3 мг) реакционной смеси. Выделенный образец растворяют в 1 мл дистиллированной воды, с последующей обработкой этилацетатом с целью экстракции получаемого продукта нитрования (3×1 мл этилацетата). Полученный этилацетатный экстракт упаривался, сухой остаток анализировался с помощью ИК-спектрометрии. Полученный ИК спектр, см^-1: 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1100, 1058, 1038, 962, 890. 857, 813. Наличие на ИК спектре интенсивного сигнала в области 1100 см^-1 свидетельствовало о присутствии в реакционной смеси остатков непрореагировавшей яблочной кислоты, а также о необходимости в продолжении реакции нитрования. Спустя 65 минут после добавления к реакционной смеси серной кислоты проводят повторный анализ степени конверсии яблочной кислоты в нитрояблочную (в соответствии с вышеописанной процедурой). В результате был получен следующий ИК спектр, см^-1: 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1058, 1038, 962, 890. 857, 813. Отсутствие сигнала в области 1100 см^-1 свидетельствовало о полном завершении реакции нитрования. Полученную по окончании реакции массу выливали на 40 г льда. После гомогенизации раствор обрабатывался этилацетатом (3 раза по 30 мл) в делительной воронке. Этилацетатный экстракт сушили путем добавления (~ 1% от общего объема органической фазы) безводного Na₂SO₄. Этилацетатный раствор отделяют от осадка Na₂SO₄ путем декантации. Содержание нитрояблочной кислоты в этилацетатном экстракте определяют путем взвешивания сухого остатка после упаривания 2 мл аликвоты. Таким образом было установлено, что в 87 мл полученного этилацетатного раствора содержалось 27.9 ммоль нитрояблочной кислоты. К полученному раствору 27.9 ммоль нитрояблочной кислоты в 87 мл этилацетата при перемешивании добавляют 3.8 г (27.9 ммоль) 3-окси-6-метил-2-этилпиридина. Смесь перемешивают при комнатной температуре в течение 10 часов. Образовавшийся осадок отфильтровывают, промывают и этилацетатом и сушили над Р₂О₅. Получено 7.9 г целевого соединения. Элементный анализ. Найдено, %: С 45.63; Н 5.09; N 8.62. Расчет для C₁₂H₁₆N₂O₈, %: С 45.57; Н 5.10; N 8.58. ИК-спектр (см^-1): 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1058, 1038, 962, 890. 857, 813. Спектр ¹Н ЯМР (ДМСО-d5, δ, м.д., J/Гц): 1.13-1.16 (т, 3Н, СН ₃СН₂, J=7.5); 2.36 (с, 3Н, СН₃); 2.68-2.73 (дд, 2Н, СН₃СН ₂, J=7,5); 2.79-2.84 (дд, 1Н, С(O)СН ₂СН, J=8); 2.94-2.99 (дд, 1Н, С(O)СН ₂СН, J=4.3); 5.53-5.55 (м, 1Н, С(O)СН₂СН); 7.00-7.01 (д, 1Н, Ar, J=8.3); 7.18-7.19 (д, 1Н, Ar, J=8.2). ¹³С ЯМР (ДМСО-d5): 12.53; 21.87; 24.25; 34.17; 77.17; 121.98; 123.95; 145.73; 148.57; 149.36; 168.86; 170.25.In a flask (50 ml) equipped with a magnetic stirrer, a reflux condenser, an internal thermometer and a cooling bath, 5 g (37.3 mmol) d was placed,

- malic acid. After cooling the reactor to 0 ° C., 4 ml of HNO ₃ (d = 1.45) was added with stirring. The resulting suspension was stirred at 0 ° C for 2 hours. Then add 2.5 ml of concentrated H ₂ SO ₄ , the resulting mixture is stirred at a temperature of 0 ° C. 30 minutes after adding sulfuric acid to the mixture, a small amount (about 2-3 mg) of the reaction mixture was taken from the reactor using a spatula. The isolated sample is dissolved in 1 ml of distilled water, followed by treatment with ethyl acetate to extract the resulting nitration product (3 × 1 ml of ethyl acetate). The resulting ethyl acetate extract was evaporated, and the dry residue was analyzed by IR spectrometry. The obtained IR spectrum, cm ^-1 : 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1100, 1058, 1038, 962, 890. 857, 813. The presence on the IR spectrum an intense signal in the region of 1100 cm ⁻¹ indicated the presence of unreacted malic acid residues in the reaction mixture, as well as the need to continue the nitration reaction. 65 minutes after adding sulfuric acid to the reaction mixture, a repeated analysis of the degree of conversion of malic acid to nitro-malic acid is carried out (in accordance with the above procedure). As a result, the following IR spectrum was obtained, cm ^-1 : 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1058, 1038, 962, 890. 857, 813. No signal in the region of 1100 cm ^-1 testified to the complete completion of the nitration reaction. The mass obtained at the end of the reaction was poured onto 40 g of ice. After homogenization, the solution was treated with ethyl acetate (3 times 30 ml) in a separatory funnel. The ethyl acetate extract was dried by adding (~ 1% of the total organic phase) anhydrous Na ₂ SO ₄ . An ethyl acetate solution was separated from the precipitate Na ₂ SO ₄ by decantation. The content of nitro-malic acid in the ethyl acetate extract is determined by weighing the dry residue after evaporation of a 2 ml aliquot. Thus, it was found that in 87 ml of the obtained ethyl acetate solution contained 27.9 mmol of nitro-malic acid. To the resulting solution of 27.9 mmol nitro-malic acid in 87 ml of ethyl acetate, 3.8 g (27.9 mmol) of 3-hydroxy-6-methyl-2-ethylpyridine was added with stirring. The mixture was stirred at room temperature for 10 hours. The precipitate formed is filtered off, washed with ethyl acetate and dried over P ₂ O ₅ . Received 7.9 g of the target compound. Elemental analysis. Found,%: C 45.63; H 5.09; N, 8.62. Calculation for C ₁₂ H ₁₆ N ₂ O ₈ ,%: C 45.57; H 5.10; N, 8.58. IR spectrum (cm ^-1 ): 1723, 1643, 1618. 1560, 1466, 1439, 1398, 1331, 1309, 1274, 1229, 1188, 1058, 1038, 962, 890. 857, 813. ¹ H NMR spectrum ( DMSO-d5, δ, ppm, J / Hz): 1.13-1.16 (t, 3H, C H ₃ CH ₂ , J = 7.5); 2.36 (s, 3H, CH ₃ ); 2.68-2.73 (dd, 2H, CH ₃ C H ₂ , J = 7.5); 2.79-2.84 (dd, 1H, C (O) C H ₂ CH, J = 8); 2.94-2.99 (dd, 1H, C (O) C H ₂ CH, J = 4.3); 5.53-5.55 (m, 1H, C (O) CH ₂ C H ); 7.00-7.01 (d, 1H, Ar, J = 8.3); 7.18-7.19 (d, 1H, Ar, J = 8.2). ¹³ C NMR (DMSO-d5): 12.53; 21.87; 24.25; 34.17; 77.17; 121.98; 123.95; 145.73; 148.57; 149.36; 168.86; 170.25.

Claims (2)

1. The method of obtaining 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine by nitration of malic acid with a sulfur-nitric mixture to form nitroxy succinic acid, followed by its treatment with 2-ethyl-6-methyl-3-hydroxypyridine, characterized in that nitro-malic acid, synthesized as an intermediate product, is isolated from the reaction mixture not in dry form, but in the form of a solution in ethyl acetate, which is then used to carry out the final reaction with 3-hydroxy-6-methyl-2-ethylpyridine. 2. A method of producing 3-hydroxy-6-methyl-2-ethylpyridine 2-nitroxysuccinate according to claim 1. characterized in that the reaction of 3-hydroxy-6-methyl-2-ethylpyridine with nitro-malic acid is carried out in ethyl acetate in the temperature range from 15 up to 35 ° C.

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