A method for preparing 2-cyanopyridines

Abstract

The application discloses a preparation method of 2-cyanopyridine compounds, which comprises the following steps: taking a compound of formula I and a cyanation reagent as raw materials, and performing a cyanation reaction in a mixed system of water and an organic solvent in the presence of a catalyst and a ligand to obtain a compound of formula II, i.e. a 2-cyanopyridine compound; in the application, the cyanation reagent is widely available, low in price, safe and stable, the preparation method is simple and easy to operate, and the catalyst consumption is low; in the application, through the combination of the catalyst, the ligand and the organic solvent, high conversion of reactants can be realized, and high-purity products can be obtained, so that the application is suitable for large-scale production and wide application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 2-cyanopyridine compounds. Background Technology

[0002] Aromatic nitriles are a class of highly valuable compounds with wide applications in pharmaceuticals, dyes, pesticides, and functional materials. Furthermore, nitriles are very useful intermediates in organic synthesis, serving as catalysts for the transformation of functional groups such as amines, amides, aldehydes, carboxylic acids, and heterocycles. More than 30 nitrile-containing drugs have been approved in the pharmaceutical field, with several more in late-stage clinical trials. These bioactive molecules containing nitriles can be used to treat various diseases, such as depression, breast cancer, HIV, and Parkinson's disease (J. Med. Chem., 2010, 53, 7902). Therefore, developing new methods for preparing aromatic nitrile compounds is of great significance.

[0003] Many methods have been developed for preparing aromatic nitriles, but the introduction of cyano functional groups remains the most direct and universal approach. Classical methods include the Rosenmund-von Braun reaction of aryl halides with stoichiometric amounts of CuCN at high temperatures (Chem. Ber., 1919, 2, 1749) and the Sandmeyer reaction of diazonium salts with CuCN (Ber. Dtsch. Chem. Ges., 1884, 17, 2650), but both inevitably use toxic cyanide reagents, resulting in stoichiometric heavy metal pollution. Currently, transition metal-mediated cyanation of aryl halides has become one of the most promising methods for preparing aryl nitriles. Takagi et al. first achieved the cyanation of aryl halides using palladium catalysis in 1973, but this method still uses potassium cyanide as the cyaniding agent, and the substrates are limited to aryl bromides and iodides (Chem. Lett., 1973, 2, 471). The industrially chosen method is ammoxidation (Adv. Synth. Catal., 2004, 346, 1407), but this method has poor functional group tolerance and harsh reaction conditions, resulting in significant limitations. Finding suitable cyano sources and mild reaction systems, while simultaneously expanding the applicable substrate range, has become an urgent problem to be solved.

[0004] K4Fe(CN)6, a chemical already produced on a ton-scale basis, possesses numerous advantages such as stability, non-flammability, ease of storage, and insensitivity to moisture. Moreover, it is lower in cost than KCN and NaCN, non-toxic, and even used in the food industry (Chem. Commun., 2004, 12, 1388), making it an ideal cyanide source. In 2008, Chen et al. developed an environmentally friendly system for the cyanation of aryl halides in Pd / C and PEG-H2O using K4Fe(CN)6 as the cyanide source (Eur. J. Org. Chem., 2008, 3524), but this method requires microwave conditions, making it difficult to apply to industrial production. Additionally, Pitchumani et al. also used this cyanide source to achieve the cyanation of aryl halides under CuI catalysis (New J. Chem., 2012, 36, 2334), but this reaction requires a high temperature above 140°C. Palladium catalysts exhibit higher activity than copper catalysts and are less sensitive to air and humidity than nickel catalysts, making them more widely used in cyanation reactions (Chem. Eur. J., 2007, 13, 6249). Therefore, using K4Fe(CN)6 as the cyanide source and a suitable palladium catalytic system to achieve large-scale production of aryl nitriles shows great promise.

[0005] Pyridine is a six-membered heterocyclic compound containing one nitrogen atom, also known as nitrogen benzene. Its derivatives are widely found in nature and have been reported to have a variety of biological activities, including antibacterial, antiviral, antioxidant, antidiabetic, anti-inflammatory, antimalarial, analgesic and anticancer (J. Drug. Desi. Medic. Chem., 2015, 1, 1). The 2-substituted pyridine structure is also widely found in various drugs. For example, chlorpheniramine, brompheniramine and its enantiomer dexbrompheniramine, as well as carbisamine, doxylamine, and the recently approved betostine, which were approved by the US FDA as early as the 1950s, are all drugs with significant antihistamine effects (J.Med.Chem.,2014,57,10257). Betahistine hydrochloride tablets are a vasodilator with significant efficacy in treating acute ischemic cerebrovascular disease (Am.J.Transl.Res.2022,14,8183). Vimodil is the first oral antitumor drug approved by the FDA for the treatment of locally advanced or metastatic basal cell carcinoma (N.Engl.J.Med.,2012,366,2171). Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) clinically used to relieve various arthritis, gout, fever, migraine, and other diseases (Endocrine Metab Immune Disord Drug). Targets., 2021, 21, 1760; Neurol. Res., 2024, 46, 717).

[0006] 2-Cyanopyridine compounds have been shown to have therapeutic effects on chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction, and heart failure (WO2005082863A2), exhibiting a strong effect in lowering serum uric acid levels and favorable pharmacokinetic properties (Bioorg. Med. Chem. Lett. 2009, 19, 6225). They can also be used to treat prostate cancer (Drugs, 2018, 78, 699), demonstrating great potential and broad application prospects in new drug development. Therefore, developing safe and efficient methods for preparing 2-cyanopyridine compounds is of great significance to the development of human health. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 2-cyanopyridine compounds, which achieves high conversion rate of reactants and high yield and high purity of products by using a safe, stable and inexpensive cyaniding reagent, through the combination of catalyst, ligand and organic solvent, and with a small amount of catalyst.

[0008] To solve the above-mentioned technical problems, the first aspect of the present invention is to provide a method for preparing 2-cyanopyridine compounds, wherein a cyanidation reaction is carried out in a mixed system of water and organic solvent in the presence of a catalyst and a ligand using a compound of formula I and a cyanidating reagent as raw materials to obtain a compound of formula II, namely a 2-cyanopyridine compound.

[0009]

[0010] The catalyst is a transition metal catalyst, and the ligand is a phosphine ligand.

[0011] R is selected from one or more functional groups such as ortho-, meta-, and para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy groups;

[0012] X is a halogen,

[0013] Preferably, the catalyst is a palladium salt;

[0014] The phosphine ligand is selected from one or more of XantPhos,(rac)-BINAP,Ad2(nBu)P,Ph2DavePHOS,dtbpf,dppf,dippf, and N-XantPhos;

[0015] The cyaniding reagent is K4[Fe(CN)6]·3H2O, which is dissolved in water before use to form an aqueous solution with a density of 1.1-1.5 g / mL.

[0016] The organic solvent is one or more selected from dimethylacetamide, 1,4-dioxane, tert-amyl alcohol, or sulfolane.

[0017] In this invention, the cyaniding reagent is widely available, inexpensive, safe and stable, and the preparation method is simple and easy to operate, with a small amount of catalyst required. In this invention, the combination of organic solvent and ligand can achieve high conversion rate of reactants and obtain high-purity products, which is suitable for large-scale production and wide application.

[0018] In this invention, the structural formula of the ligand is as follows:

[0019]

[0020] In one specific embodiment, the organic solvent is tert-amyl alcohol (t-AmylOH), and the ligand is selected from dtbpf, XantPhos, N-XantPhos, dippf, Ph2DavePHOS; or

[0021] The organic solvent is 1,4-dioxane, and the ligand is selected from dtbpf, dppf; or

[0022] The organic solvent is dimethylacetamide (DMAc), and the ligand is selected from dtbpf, Ph2DavePHOS, dippf, (rac)-BINAP; or

[0023] The organic solvent is sulfolane, and the ligands are selected from dtbpf, Ph2DavePHOS, XantPhos, and dppf.

[0024] In this specific embodiment, the combination of organic solvent and ligand can achieve the highest possible reactant conversion rate, as well as high yield and high purity of Formula II compound.

[0025] In one specific formulation, the volume / mass ratio of the organic solvent to the compound of formula I is 5-20 mL / g; the volume / mass ratio of water to the compound of formula I is 2-5 mL / g. More specifically, the volume / mass ratio of the organic solvent to the compound of formula I is 10 mL / g; the volume / mass ratio of water to the compound of formula I is 3 mL / g. It should be noted that K4[Fe(CN)6]·3H2O and water are pre-prepared into an aqueous solution of K4[Fe(CN)6]·3H2O for use.

[0026] In one specific embodiment, the molar ratio of compound I to K4[Fe(CN)6]·3H2O is 1:0.2-1.0; the molar ratio of compound I to catalyst is 1:0.001-0.1; and the molar ratio of compound I to ligand is 1:0.001-0.2. More specifically, the molar ratio of compound I to K4[Fe(CN)6]·3H2O is 1:0.5; the molar ratio of compound I to catalyst is 1:0.02; and the molar ratio of compound I to ligand is 1:0.02. Understandably, in this invention, the amount of palladium catalyst is relatively low.

[0027] In one specific embodiment, the reaction temperature is 80℃-120℃ or 95℃-105℃; the reaction time is 10-24 hours; and the reaction is carried out in an inert gas atmosphere. Understandably, the reaction conditions in this invention are relatively mild and suitable for industrial applications.

[0028] In this invention, after the reaction is completed and the reaction system is cooled to room temperature, the conversion rate and purity of the reaction solution are determined by high-performance liquid chromatography (HPLC). Commercially available reagents are used as product standards, such as the commercially available reagent with CAS number 1620-77-5 in Example 1. It should be noted that the 2-cyanopyridine compounds prepared in this invention can be obtained as final products through general methods such as separation, filtration, and purification, which will not be elaborated here.

[0029] To address the aforementioned technical problems, a second aspect of the present invention is to provide a compound of formula II prepared by the aforementioned preparation method, namely a 2-cyanopyridine compound.

[0030]

[0031] In Formula II, R is selected from one or more functional groups such as ortho-, meta-, and para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy groups. Attached Figure Description

[0032] To more clearly illustrate the technical solution of the present invention, the accompanying drawings used in the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 This is a test result diagram of Embodiment 1 of the present invention. Detailed Implementation

[0034] The technical solutions of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0035] Example 1

[0036]

[0037] Step 1, Material Preparation:

[0038] 1) Dissolve 21.3 mg of PdCl2 in 3600 μL of t-AmylOH to obtain a t-AmylOH solution of PdCl2;

[0039] 2) Dissolve 516.1 mg of 2-bromo-5-methylpyridine and 79.9 mg of internal standard in 3360 μL of t-AmylOH to obtain a t-AmylOH solution of 2-bromo-5-methylpyridine;

[0040] 3) Dissolve 2323.0 mg of K4[Fe(CN)6]·3H2O in 9460 μL of pure water to obtain an aqueous solution of K4[Fe(CN)6]·3H2O. The density of the aqueous solution of K4[Fe(CN)6]·3H2O is 1.128 g / mL.

[0041] Step 2, cyanidation reaction

[0042] Under a nitrogen atmosphere, 0.474 mg dtbpf (0.474 mg, 1 μmol, 0.02 eq.), 30.1 μL (0.177 mg, 1 μmol, 0.02 eq.) of PdCl2 solution, 59.0 μL (8.602 mg, 50 μmol, 1 eq.) of 2-bromo-5-methylpyridine solution, and 47.5 μL (10.559 mg, 25 μmol, 0.5 eq.) of K4[Fe(CN)6]·3H2O aqueous solution were added to the reaction flask. The temperature of the reaction solution was adjusted and controlled at 95-105 °C, and the mixture was stirred continuously for 16 hours under a closed nitrogen atmosphere.

[0043] Step 3, Sample Testing

[0044] After the reaction was complete and the reaction system cooled to room temperature, a sample was taken, diluted with acetonitrile, and analyzed by high-performance liquid chromatography (HPLC). A commercially available reagent (CAS: 1620-77-5) was used as the product standard. The detection conditions were: Agilent 1260 HPLC system and UV detector; Eclipse Plus C18 (50 × 4.6 mm, 1.8 μm) column; mobile phase A: 0.05% (v / v) formic acid aqueous solution; mobile phase B: 0.05% (v / v) formic acid acetonitrile solution. Column temperature: 40℃; flow rate: 1.5 mL / min; detection wavelength: 220 nm. The HPLC results are as follows: Figure 1 .

[0045] Step 4: Conversion rate and purity calculation

[0046] The conversion rate and the purity of compound II were calculated based on the results of high performance liquid chromatography (HPLC). The results are shown in Table 1.

[0047] Conversion rate % = Peak area percentage of compound II / Peak area percentage of [compound I + compound II] * 100% = 90.3234 / (90.3234 + 0.6941) * 100% = 99.2%.

[0048] The IPC purity (%) of compound II = percentage of peak area of ​​compound II / [100 - percentage of peak area of ​​internal standard] * 100% = 90.3234 / (100 - 8.9825) * 100% = 99.2%;

[0049] In this embodiment, calculations show that the reactant conversion rate is high, the product yield is high, and the purity of the compound of formula II is also high.

[0050] Examples 2-4

[0051] The reaction steps in Examples 2-4 are the same as in Example 1, except that the types of ligands are different. Details of the materials, conversion rates, and purity test results of the target product are shown in Table 1.

[0052] Table 1

[0053] Example Phosphine ligand types Phosphine ligand dosage Conversion rate / purity Example 1 dtbpf 0.474 mg, 1 μmol, 0.02 eq. 99.2％ / 99.2％ Example 2 dippf 0.418 mg, 1 μmol, 0.02 eq. 69.8％ / 69.8％ Example 3 XantPhos 0.579 mg, 1 μmol, 0.02 eq. 100％ / 99.2％ Example 4 <![CDATA[Ph2DavePHOS]]> 0.763 mg, 2 μmol, 0.04 eq. 99.6％ / 99.0％

[0054] Table 1 shows that when the organic solvent is t-AmylOH, selecting dtbpf, XantPhos, and Ph2DavePHOS as the phosphine ligands yields high conversion rates and high purity of the target product, with conversion rates exceeding 99% and purity above 99%. When the phosphine ligand is dippf, the conversion rate and purity of the target product are not high, approaching 70%.

[0055] Examples 5-14

[0056] The reaction steps in Examples 5-14 are the same as in Example 1, except for the type and amount of phosphine ligand and the type of organic solvent. Details of the materials, conversion rates, and purity test results of the target product are shown in Table 2.

[0057] Table 2

[0058]

[0059]

[0060] Referring to Tables 1 and 2, keeping other reaction conditions constant, and using t-AmylOH as the solvent, the choice of phosphine ligand has a significant impact on the reaction. When dtbpf, XantPhos, and N-XantPhos are used, the reaction conversion rate and the purity of the target product are all greater than 99%. When (rac)-BINAP and dppf are used as phosphine ligands, the reaction conversion rate is less than 15%. When Ad2(nBu)P is used as the ligand, the target product is not obtained.

[0061] Table 2, Examples 9-14, shows that when dtbpf is used as the ligand, both the conversion rate and the purity of the target product are high, with a conversion rate of 30-62% and a purity higher than 30%. However, when N-XantPHOS is chosen as the phosphine ligand, both the conversion rate and purity of the target product are significantly reduced, falling below 5%. This demonstrates that the choice of ligand and solvent is crucial for the reaction.

[0062] Examples 15-21

[0063] Examples 15-21 follow the same reaction steps as Example 1, except that XantPhos is used as the ligand, the type and amount of catalyst are changed, and the reaction time is extended to 24 hours. Details of the materials, conversion rates, and target product purity test results are shown in Table 3.

[0064] Table 3

[0065] Example catalyst Phosphine ligand reaction time Conversion rate / purity Example 15 <![CDATA[0.02eq.PdCl2]]> 0.02eq.XantPhos 24h 100％ / 97.9％ Example 16 <![CDATA[0.01eq.Pd2(dba)3]]> 0.02eq.XantPhos 24h 84.6％ / 81.8％ Example 17 <![CDATA[0.02eq.Pd(OAc)2]]> 0.02eq.XantPhos 24h 83.5％ / 81.4％ Example 18 <![CDATA[0.01eq.PdCl2]]> 0.01eq.XantPhos 24h 100％ / 96.3％ Example 19 <![CDATA[0.005eq.PdCl2]]> 0.005eq.XantPhos 24h 87.1％ / 84.1％ Example 20 <![CDATA[0.0025eq.PdCl2]]> 0.0025eq.XantPhos 24h 26.2％ / 25.9％ Example 21 <![CDATA[0.001eq.PdCl2]]> 0.001eq.XantPhos 24h 11.8％ / 11.8％

[0066] Table 3, in conjunction with Examples 15-17, shows that all three catalysts, with an equivalent amount of palladium, can achieve good conversion rates and purity, with PdCl2 showing better performance as the catalyst.

[0067] In Table 3, in conjunction with Examples 17-21, PdCl2 was used as a catalyst and XantPhos as a ligand, used in equivalence amounts, with the amount of equivalents varying from 0.001 to 0.02. At 0.01 equivalents, complete conversion was achieved, and the purity of compound II was high. When the amount was reduced to 0.0025 equivalents or below, the conversion rate decreased significantly, and the purity of compound II also decreased.

[0068] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a 2-cyanopyridine compound, characterized in that, Using the compound of formula I and the cyaniding reagent as raw materials, a cyanidation reaction is carried out in a mixed system of water and organic solvent in the presence of a catalyst and ligand to obtain the compound of formula II, namely 2-cyanopyridine compounds. ， The catalyst is PdCl2, and the ligand is phosphine ligand. The phosphine ligand is selected from one of XantPhos, Ph2DavePHOS, dtbpf, and N-XantPhos. R is selected from one or more of the ortho-, meta-, and para-substituted cyano, alkyl, olefin, and alkoxy functional groups; X is a halogen; The cyaniding reagent is K4[Fe(CN)6]·3H2O, which is dissolved in water before use to form an aqueous solution with a density of 1.1-1.5 g / mL. The organic solvent is tert-amyl alcohol.

2. The preparation method according to claim 1, characterized in that, The volume / mass ratio of the organic solvent to the compound of formula I is 5-20 mL / g; The volume-to-mass ratio of water to compound of formula I is 2-5 mL / g.

3. The preparation method according to claim 2, characterized in that, The volume / mass of the organic solvent and the compound of formula I is 10 mL / g; The volume-to-mass ratio of water to compound I is 3 mL / g.

4. The preparation method according to claim 1, characterized in that, The molar ratio of compound I to K4[Fe(CN)6]·3H2O is 1:0.2-1.0; The molar ratio of compound I to catalyst is 1:0.001-0.1; The molar ratio of the compound of formula I to the ligand is 1:0.001-0.

2.

5. The preparation method according to claim 1, characterized in that, The reaction temperature is 80℃-120℃; the reaction time is 10-24h; the reaction is carried out in an inert gas atmosphere.

6. The preparation method according to claim 5, characterized in that, The reaction temperature is 95℃-105℃.

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