Preparation method of 2-cyano thiophene compound

Abstract

The invention discloses a preparation method of a 2-cyano thiophene compound, which comprises the following steps: taking a compound shown as a formula I and a cyaniding reagent as raw materials, and carrying out cyaniding reaction in a mixed system of water and an organic solvent in the presence of a catalyst and a ligand to obtain a compound shown as a formula II, namely the 2-cyano thiophene compound, in the invention, the cyaniding reagent is wide in source, low in price, safe and stable, and the preparation method is simple and easy to operate; besides, combination of different ligands, catalysts and solvents has great influence on yield and purity, the high-purity 2-cyanothiophene compound II can be obtained through reasonable matching, cyano functional groups in the compound shown in the formula II are effectively inhibited from hydrolyzing to generate byproducts of a compound shown in a formula III (R groups in the formula III are the same as the formula II), and the yield and purity of the compound shown in the formula III are greatly improved. And the catalyst has the advantages of low dosage and high purity control in the intermediate process, and can be easily applied to large-scale production of the 2-cyanothiophene compound II.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 2-cyanothiophene compounds. Background Art

[0002] Nitrile compounds are a very important class of intermediates in organic synthesis. They are not only easily converted into various compounds such as nitrogen-containing heterocycles, aldehydes, acids and acid derivatives, but are also key components of a series of drugs, agricultural chemicals and dyes. Therefore, the preparation of nitrile compounds is of great significance.

[0003] The traditional Sandmeyer (Ber. Dtsch. Chem. Ges., 1884, 17, 2650.) and Rosenmund-von Braun (Ber. Dtsch. Chem. Ges., 1919, 2, 1749.) reactions for synthesizing aromatic nitriles have serious defects. Both use stoichiometric amounts of copper (I) cyanide as a cyaniding agent, resulting in equimolar heavy metal pollution. The Rosenmund-von Braun reaction usually also requires high temperatures (150-250°C) and uses expensive aryl iodides, while aryl chlorides and bromides have low reactivity and a narrow range of substrates for the reaction. Compared with these two methods, transition metal-catalyzed cyanidation of aryl halides is a more environmentally friendly, more efficient, and more widely applicable method. Among them, palladium catalysts have attracted widespread attention due to their advantages such as higher cyanidation efficiency, lower sensitivity to air and water, and higher functional group tolerance. However, there are two main problems that need to be solved. First, the reaction mainly uses various toxic cyanide sources. For example, the Buchwald research group reported a palladium-catalyzed cyanation reaction at low temperature (Org. Lett., 2015, 17, 202.), which has mild reaction conditions and high yield. However, toxic Zn(CN)2 is required as the cyanide source. Second, when palladium is exposed to high concentrations of cyanide ions, a stable cyanide complex is formed, which reduces the activity of the catalytic system and inhibits the formation of products (Chem. Eur. J., 2003, 9, 1828). Therefore, it is crucial to use a green and harmless cyanide source, effectively control the concentration of cyanide ions in the solution, and provide an environmentally friendly and efficient palladium-catalyzed cyanation reaction system.

[0004] At present, the concentration of cyanide ions is mainly controlled by using a two-phase mixed solvent or a solvent with low solubility of the cyaniding agent. However, these methods usually require grinding the cyaniding agent to maintain a uniform particle size, and industrial production is limited. Potassium ferrocyanide is a cyanide source that is easy to handle, non-toxic and environmentally friendly (Chem. Commun., 2004, 12, 1388.), and cyanide ions can be strongly combined in potassium ferrocyanide (II), ensuring that the release of cyanide ions is very slow, so that the cyanide concentration is maintained at a low level, which is conducive to reducing the deactivation of the catalyst. In addition, its 6 CN ions can all participate in the cyanidation reaction of aryl halides, making full use of the potential of the reagent. Compared with other cyanide sources, potassium ferrocyanide has many advantages, solves the two main problems of palladium-catalyzed aryl halide cyanidation, and becomes an ideal choice for cyanide sources. In 2014, Chatterjee et al. used K4[Fe(CN)6] as a nitrilation agent and reported a new ZnO-supported palladium catalyst for the cyanation of aryl bromides and chlorides (J.Org.Chem., 2014, 79, 5875). The reaction required a small amount of catalyst and had a high yield. However, the catalyst needed to be prepared under microwave conditions, which had great limitations for industrial application.

[0005] Heterocyclic compounds are widely distributed in nature, and many synthesized heterocyclic compounds have been successfully used as clinical drugs. It is reported that more than 75% of the drugs currently used in clinical practice contain at least one heterocycle (Eur. J. Med. Chem., 2020, 200, 112438). Thiophene is a five-membered sulfur-containing heterocyclic aromatic compound, and its derivatives are very important intermediates in science and industry. It has been reported to have a variety of biological and pharmacological properties such as antibacterial, antiviral, antioxidant, anti-inflammatory, antidepressant, antitumor, anticancer, antipyretic and analgesic (Chem. Cent. J., 2018, 12, 137). α-Substituted thiophene derivatives have been widely used in clinical practice. For example, ceftriaxone sodium is a first-generation antibacterial cephalosporin, which is clinically mainly used for respiratory tract infections, soft tissue infections, urinary tract infections and sepsis caused by penicillin-resistant Staphylococcus aureus and sensitive Gram-negative bacilli (Antimicrob. Drug News Res., 1992, 8, 75), and can also be used to prepare drugs that inhibit tumor cell metastasis and spread (CN104546863). Sufentanil is a powerful analgesic that can produce complete anesthesia with fewer side effects than fentanyl or morphine. It is mainly used in thoracotomy and major surgery for patients with severe cardiovascular disease (Chem. Pharm. Bull., 2009, 57, 1421). Azosemide, which was launched in 1981, is a long-acting sulfonamide diuretic. It is mainly used for the first-line treatment of hypertension and heart failure, and can also be used to manage hypervolemia and various electrolyte secretion disorders. Compared with furosemide, it is more potent and has a lower risk of cardiovascular cell death or heart failure (J.Mol.Struct., 2022, 1268, 133672). Tiaprofenic acid is a nonsteroidal anti-inflammatory drug used to treat rheumatic diseases such as rheumatoid arthritis and osteoarthritis. It has good effects and is well tolerated. It can also treat tonsillitis, nasal pain, eye diseases, acute sinusitis, pharyngitis, etc. It also has analgesic and antipyretic properties, and is more effective than ibuprofen and aspirin. It can be used clinically for short-term relief of postoperative pain, migraine attacks and fever in children (Clin.Phormacokinet, 1996, 31, 331; Drugs, 1995, 50, 1050).

[0006] 2-nitrile-substituted thiophene derivatives have been shown to be selective inhibitors of FMS-like tyrosine kinase 3 LTD (FLT3-LTD) mutants, used to prepare drugs for treating FLT3-LTD-related diseases, and have strong selectivity for tumor cell lines expressing FLT3-LTD, as a therapeutic drug for specific acute myeloid leukemia (CN108690006A). They can also be used as TRPA1 activity inhibitors for the treatment or prevention of fibrotic diseases, inflammatory and autoimmune diseases (CN114945408). They are also used to prepare drugs for the treatment of metabolic-related diseases, including diabetes, obesity, non-alcoholic hepatitis, etc. (CN117177970). Therefore, it is of great significance to develop and prepare α-nitrile-substituted thiophene derivatives. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 2-cyanothiophene compounds, wherein the cyano reagent is widely available, cheap, green and harmless, and the reaction conditions are simple and easy to operate; through a reasonable combination of a ligand, a catalyst and a solvent, a high-purity target product can be obtained, the hydrolysis of the target product can be effectively inhibited, and the catalyst dosage is low, the intermediate process purity is high, and it is easy to be applied to the large-scale production of 2-cyanothiophene compounds II.

[0008] In order to solve the above technical problems, the first aspect of the present invention is to provide a method for preparing a 2-cyanothiophene compound, wherein a compound of formula I and a cyaniding agent are used as raw materials, and a cyaniding reaction is carried out 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-cyanothiophene compound;

[0009]

[0010] Wherein, 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-, or para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy;

[0012] X is a halogen,

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

[0014] The ligand is selected from one or more of XantPhos, N-XantPHOS, dippf, DPEpHos, dtbpf, (rac)-BINAP, Cy-DPEPHOS, and Ad2(nBu)P;

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

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

[0017] In the present invention, the cyaniding reagent has a wide source, is low in price, is green, harmless and environmentally friendly, and the preparation method is simple and easy to operate; in addition, in the present invention, the combination of the ligand, the catalyst and the solvent has a great influence on the yield and purity, and a high-purity compound of formula II, i.e., a 2-cyanothiophene compound, can be obtained by reasonable combination, and the reaction conversion rate is high, and the hydrolysis of the cyanide functional group of the compound of formula II to generate a by-product of the compound of formula III (the R group in formula III is the same as that in formula II) can be effectively inhibited, and the amount of palladium catalyst used is small.

[0018]

[0019] In the present invention, the structural formula of the ligand is as follows:

[0020]

[0021] In a specific embodiment, the catalyst is one or more of Pd2(dba)3, Pd(OAc)2, and PdCl2; the ligand is XantPhos; and the organic solvent is tert-amyl alcohol.

[0022] In a specific embodiment, 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.

[0023] In a specific embodiment, the molar ratio of the compound of formula I to K4[Fe(CN)6]·3H2O is 1:0.2-1.0; the molar ratio of the compound of formula I to the 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. Understandably, the amount of palladium catalyst used in the present invention is very low.

[0024] In a specific embodiment, the reaction temperature is 80°C-120°C or 95°C-105°C; the reaction time is 10-24h; an alkaline additive may be added during the reaction; and the reaction is carried out in an inert gas atmosphere. It can be understood that the reaction conditions in the present invention are relatively mild and suitable for industrial applications.

[0025] In the present invention, after the reaction is completed, the reaction system is cooled to room temperature, and the reaction solution is taken and the conversion rate and purity of the reaction are determined by high performance liquid chromatography. It should be noted that the 2-cyanothiophene compound prepared by the present invention can be obtained by general methods such as separation, filtration, purification, etc. to obtain the final product, which will not be repeated here.

[0026] In order to solve the above technical problems, the second aspect of the present invention is to provide a compound of formula II prepared by the above preparation method, that is, a 2-cyanothiophene compound.

[0027]

[0028] In formula II, R is selected from one or more functional groups such as ortho-, meta-, or para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solution of the present invention, the following briefly introduces the drawings required for use in the present invention. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0030] Figure 1 It is a test result diagram of Example 1 of the present invention. DETAILED DESCRIPTION

[0031] The following will be combined with the accompanying drawings to clearly and completely describe the technical solutions in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] Example 1

[0033]

[0034] Step 1: Material preparation:

[0035] 1) Dissolve 21.3 mg of PdCl2 in 3600 μL of t-AmylOH to obtain a PdCl2 t-AmylOH solution;

[0036] 2) 615.2 mg of 2-acetyl-5-bromothiophene and 79.9 mg of internal standard were dissolved in 4380 μL of t-AmylOH to obtain a t-AmylOH solution of 2-acetyl-5-bromothiophene;

[0037] 3) Take 2323.1 mg K4[Fe(CN)6]·3H2O and dissolve it in 11220 μL pure water to obtain an aqueous solution of K4[Fe(CN)6]·3H2O. At this time, the density of the aqueous solution of K4[Fe(CN)6]·3H2O is 1.083 g / mL;

[0038] Step 2: Cyanidation reaction

[0039] Add 0.579 mg XantPhos (0.579 mg, 1 μmol, 0.02 eq.), 30.1 μL (0.177 mg, 1 μmol, 0.02 eq.) of PdCl2 solution, 76.5 μL (10.254 mg, 50 μmol, 1 eq.) of 2-acetyl-5-bromothiophene solution, and 47.5 μL (10.560 mg, 25 μmol, 0.5 eq.) of K4[Fe(CN)6]·3H2O aqueous solution into the reaction bottle, adjust and control the reaction liquid temperature to 95-105°C, and stir continuously for 16 hours under a closed nitrogen environment;

[0040] Step 3: Sample testing

[0041] After the reaction is completed, sample the reaction system after it cools to room temperature, dilute it with acetonitrile and detect it by high performance liquid chromatography, using commercial reagents CAS: 88653-55-8 and CAS: 68257-89-6 as product and by-product standards. The detection conditions are: Agilent 1260 liquid chromatograph and UV detector, Eclipse Plus C18 (50×4.6mm, 1.8μm) chromatographic column, mobile phase A: 0.05% (volume percentage) formic acid in water, mobile phase B: 0.05% (volume percentage) formic acid in acetonitrile. Column temperature: 40°C, flow rate: 1.5mL / min, detection wavelength 220nm, high performance liquid chromatography results are as follows Figure 1 ;

[0042] Step 4: Calculation of conversion rate and purity

[0043] The conversion rate and the purity of the compound of formula II and the compound of formula III were calculated according to the test results of high performance liquid chromatography:

[0044] Conversion rate % = [peak area percentage of compound of formula II + compound of formula III] / [peak area percentage of compound of formula I + compound of formula II + compound of formula III] * 100% = (61.1394 + 12.5680) / (0 + 61.1394 + 12.5680) * 100% = 100%.

[0045] IPC purity (%) of the compound of formula II = peak area percentage of the compound of formula II / [100-peak area percentage of the internal standard]*100%=61.1394 / (100-25.0142)*100%=81.5%;

[0046] IPC purity (%) of the compound of formula III = peak area percentage of the compound of formula III / [100-peak area percentage of internal standard]*100%=12.5680 / (100-25.0142)*100%=16.8%.

[0047] In this example, according to calculation, complete conversion was achieved, and the purity of the compound of formula II in the product reached 81.5%. The calculation results are shown in Table 1.

[0048] Example 2-11

[0049] The reaction steps of Example 2-11 are the same as those of Example 1, except that the ligand type, dosage and solvent are different. The material details, conversion rate and target product purity test results are shown in Table 1:

[0050] Table 1

[0051]

[0052]

[0053] As can be seen from Table 1, the selection of ligands, dosage and type of solvent have a great influence on the conversion rate and purity. When XantPhos is the ligand and t-AmylOH is the solvent, the conversion rate is the highest and the purity of compound II is also the highest. When the ligand is XantPhos and the solvent is one of Sulfolane, Dixane and DMAc, the conversion rate decreases, that is, the catalyst activity is significantly reduced.

[0054] Examples 12-18

[0055] The reaction steps of Examples 12-18 are the same as those of Example 1, except that the type and amount of catalyst and the amount of water used are different. At the same time, alkaline additives are added to some examples. The material details and conversion rate and target product purity test results are shown in Table 2:

[0056] Table 2

[0057]

[0058] Combining Table 1 and Table 2, it can be seen that the difference between Example 1 and Example 12 is that the amount of water used is different. The amount of water used in Example 12 is less than that in Example 1 (at this time, the cyaniding reagent is an aqueous solution of K4[Fe(CN)6]·3H2O with a density of 1.161 g / mL), but the conversion rate and purity of compound II in Example 12 are significantly higher than those in Example 1. It can be seen that when the amount of catalyst remains unchanged, increasing the concentration of the cyaniding reagent is beneficial to inhibiting the formation of the by-product (compound of formula III) and is beneficial to increasing the purity of the compound of formula II.

[0059] It can also be seen from Table 2 that in Examples 13-15, the addition of the alkaline additive has little effect on the conversion rate, but will affect the purity of the compound of Formula II to a certain extent. In addition, by comparing Examples 12, 16 and 17, it can be seen that when the catalyst is PdCl2, the purity of the compound of Formula II is higher than that of Pd(OAc)2 and Pd2(dba)3; from Example 18, when the catalyst is PdCl2, even if the amount of the ligand is reduced to 0.005 equivalents, the conversion rate is still relatively high and the purity is also high.

[0060] 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 in the scope of protection of the present invention.

Claims

1. A method for preparing a 2-cyanothiophene compound, characterized in that: Using a compound of formula I and a cyaniding agent as raw materials, a cyaniding reaction occurs 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-cyanothiophene compound; Wherein, the catalyst is a transition metal catalyst, and the ligand is a phosphine ligand; R is selected from one or more functional groups such as ortho-, meta-, or para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy; X is a halogen, 2. The preparation method according to claim 1, characterized in that The catalyst is a palladium salt; The ligand is selected from one or more of XantPhos, N-XantPHOS, dippf, DPEpHos, dtbpf, (rac)-BINAP, Cy-DPEPHOS, and Ad2(nBu)P; The cyaniding reagent is K4[Fe(CN)6]·3H2O, which is dissolved in water before use to form a solution with a density of 1.1-1.5 g / mL for standby use; The organic solvent is one or more selected from dimethylacetamide, 1,4-dioxane, tert-amyl alcohol or sulfolane.

3. The preparation method according to claim 2, characterized in that: The catalyst is one or more of Pd2(dba)3, Pd(OAc)2, and PdCl2; The ligand is XantPhos; The organic solvent is tert-amyl alcohol.

4. The preparation method according to claim 3, characterized in that: The volume / mass of the organic solvent and 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.

5. The preparation method according to claim 4, characterized in that: The volume / mass of the organic solvent and 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.

6. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula I to K4[Fe(CN)6]·3H2O is 1:0.2-1.0; The molar ratio of the compound of formula I to the 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.

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 80°C-120°C or 95°C-105°C; the reaction time is 10-24h; the reaction is carried out in an inert gas atmosphere; and an alkaline additive may also be added during the reaction.

8. A compound of formula II prepared by the method for preparing a 2-cyanothiophene compound according to any one of claims 1 to 7; In formula II, R is selected from one or more functional groups such as ortho-, meta-, or para-substituted cyano, carbonyl, ester, alkyl, olefin, amide, and alkoxy.

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