Background and overview of application examples of pyridine-2,6-dicarboxylic acid
Pyridine-2,6-dicarboxylic acid is an important pharmaceutical synthesis intermediate. Very extensive. Can be used to synthesize 2,6-diacetylpyridine, 2,6-diamino-4-chloropyridine, (6-methoxyformamido-4-chloropyridin-2-yl)carbamate methyl ester, 6 -Aminomethylpyridine-2-carboxylic acid, 4-chloropyridine-2,6-dicarboxylic acid hydrazide, 4-chloropyridine-2,6-dicarboxylic acid methyl ester, 6-aminoethylpyridine-2-carboxylic acid Hydrazine, dimethyl pyridine-2.6-dicarboxylate, ethyl 6-chloromethylpyridine-3-carboxylate, ethyl 6-hydroxymethylpyridine-2-carboxylate, 4-chloropyridine-2,6-dicarboxylate Acid, 2,6-pyridinedicarboxylic acid chloride, N-methyl–pyridine-2,6-dicarboxylic acid dimethyl pyridine salt, and then further synthesize metal ligand compounds, functional materials, and pharmaceutical intermediates wait.
Application example preparation of pyridine-2,6-dicarboxylic acid
In industry, it is generally prepared by oxidizing 2,6-dimethylpyridine : 1. Use stoichiometrically strong oxidants, including potassium permanganate, potassium dichromate, nitric acid, etc., but these methods will produce a large amount of wastewater that seriously pollutes the environment with ammonium carbonate, and these oxidants have strong oxidizing capabilities and can easily lead to peroxidation. The product is not easy to separate. 2. Gas-phase catalytic oxidation is used, but it requires high-temperature and high-pressure reactions, which has the disadvantages of large equipment investment, high technical difficulty, and high energy consumption. Therefore, developing a green oxidation process that is environmentally friendly, has mild reaction conditions, and has a high conversion rate has obvious economic and social benefits.
Scientists at home and abroad have made many attempts. For example, in the literature “Synthetic Communications, 22 (18), 26941-6; 1992”, potassium tert-butoxide and oxygen are used instead of potassium permanganate, and 18-crown ether-6 is also used as a phase transfer catalyst in the reaction. , and ethylene glycol dimethyl ether as solvent. In Japanese Patent “Jpn. Kokai Tokkyo Koho, 11343283, 14 Dec 1999”, 2,-dimethylpyridine is oxidized with ozone in the presence of some catalyst, thereby preparing pyridine-2,6-dicarboxylic acid. However, these reported methods all have shortcomings such as difficult processes, high catalyst prices, low conversion rates, and poor selectivity, making them unsuitable for industrial production. Liquid phase catalytic oxidation is a new technology developed in recent years. The use of new catalysts can reduce the reaction temperature and pressure. The oxidation reaction can be carried out at normal temperature to 100°C and normal pressure, which greatly saves equipment investment costs and improves energy consumption. Utilization rate reduces energy consumption and waste water and gas emissions, and is an environmentally friendly technology. At present, research on liquid-phase catalytic oxidation at home and abroad mainly focuses on the oxidation of methyl groups on benzene rings and the oxidation of alcohols and aldehydes. The oxidation of methyl groups on heterocyclic rings has not been reported.
CN201310472482.6 provides a method for preparing pyridine-2,6-dicarboxylic acid using liquid phase catalytic oxidation with low pollution, low energy consumption and environmental friendliness. The overall technical solution of the present invention is: a method for preparing pyridine-2,6-dicarboxylic acid by liquid phase catalytic oxidation, which includes the following process steps: A. Using oxygen-containing gas as the oxidant, metal porphyrin compounds as the catalyst, and water As a solvent, it is made by catalytically oxidizing 2,6-dimethylpyridine under the action of an initiator; the metalloporphyrin compound is selected from the group consisting of Co(OTHPHA)2, MnTPP, CoTPPCl, CuTPP, and ZnTPP One of the above; B. Filter the reaction solution in step A, add sodium hydroxide solution dropwise to the filtrate, let it stand for stratification, separate the liquids, acidify the lower water layer with hydrochloric acid and precipitate, filter to obtain a filter cake, and filter the filter cake. Dry to obtain pyridine-2,6-dicarboxylic acid. Specific examples are as follows:
Put 500ml of water into a 1000ml three-neck flask with a thermometer, 2.0g of initiator ammonium persulfate, 1.0g of catalyst CuTPP, 100g of raw material 2,6-dimethylpyridine, and open Stir, introduce air (until the end of the reaction), heat to 80°C, and control the temperature to 80°C. After 3 hours of reaction, HPLC detection shows that the conversion rate is: 98.0%. Stop flowing the air, filter and recover the catalyst, and add mass percentage dropwise to the filtrate. Adjust the pH to 9 with a sodium hydroxide solution with a concentration of 15%, let it stand for stratification, separate the liquids, acidify the lower water layer with hydrochloric acid with a concentration of 15% by mass, adjust the pH to 5, precipitate, filter, and reduce the filter cake to room temperature. Press and dry to obtain 150.3g of product. Molar yield: 96.4%. After HPLC testing, the product purity was 99.84%.
Examples of application of pyridine-2,6-dicarboxylic acid Application [2]
To combat bacteria resistant to calcium bicarbonate Drug properties. In clinical practice, a combination therapy of inhibitors and antibiotics is often used. The inhibitor inhibits β-lactamase activity to restore bacterial sensitivity to antibiotics. For example, the inhibitors clavulanic acid, sulbactam, and tazobactam have been widely used in clinical anti-infective treatment because they can inhibit serine-β-lactamase activity. However, this type of inhibitor does not inhibit NDM-1 with zinc ions as the active center, so the development of clinically available NDM-1 inhibitors has important clinical value. Current research shows that some compounds containing sulfhydryl groups and carboxylic acids can effectively inhibit the activity of NDM-1 enzyme in vitro, but the effect on NDM-1 at the cellular level is not obvious, limiting their clinical application and development.
CN201810152383.2 provides the use of the small molecule carboxylic acid compound pyridine-2,6-dicarboxylic acid in the preparation of NDM-1 enzyme inhibitors. Pyridine-2,6-dicarboxylic acid can effectively inhibit NDM- 1 activity, thus protecting β-lactam antibiotics from hydrolysis. Furthermore, a combination therapy of this inhibitor and antibiotics can be used to sterilize bacteria and improve antibiotic sensitivity. CN201810152383.2 Using pyridine-2,6-dicarboxylic acid as NDM-1 enzyme inhibitor to protect β-lactam antibiotics from being hydrolyzed by NDM-1 enzyme. The β-lactam antibiotics are selected from penicillins, cephalosporins, carbapenems or monocyclic β-lactam antibiotics. Amide antibiotics, preferably carbapenems and imipenem. The pyridine-2,6-dicarboxylic acid of the present invention can be used as a lead compound for the development of clinically available NDM-1 inhibitors.
The present invention screens out pyridine-2,6-dicarboxylic acid, which effectively inhibits the activity of NDM-1, from a series of small molecule carboxylic acid compounds, and tests the IC50 value of this compound on the purified NDM-1 enzyme. It was verified that it can effectively inhibit the activity of NDM-1 enzyme, and finally the inhibitory effect of its combination with imipenem on clinical NDM-1-resistant bacteria was tested to verify that the two compounds can improve the sensitivity of clinical drug-resistant bacteria to imipenem. Sexual efficacy. Positive effects of the present invention: The inventor found that pyridine-2,6-dicarboxylic acid can effectively reduce and eliminate the hydrolysis and destruction of antibiotics by NDM-1, thereby protecting the bactericidal effect of antibiotics and providing a precursor to the development of clinically available inhibitors. Compounds that aid in the treatment of drug-resistant bacterial infections. Figure 4 is a graph showing the remaining active fraction of NDM-1 versus inhibitor concentration under the action of pyridine-2,6-dicarboxylic acid.
