Method for preparing clofibrate from sulfur hexafluoride

Abstract

The invention discloses a method for preparing clofibrate by using sulfur hexafluoride, which comprises the following steps: taking ethanol and p-chlorophenoxyisobutyric acid as raw materials, taking an alkaline substance as an additive, illuminating in the presence of sulfur hexafluoride and a photocatalyst, and reacting in a solvent to obtain clofibrate. According to the method disclosed by the invention, SF6 is activated under a photocatalytic condition, and an esterification reaction of carboxylic acid p-chlorophenoxyisobutyric acid is realized by utilizing an SF6 decomposition product, so that clofibrate is obtained; wherein the decomposition product of SF6 is used as a condensation reagent, the greenhouse gas SF6 is effectively activated by the method, the decomposition product of SF6 is fully utilized to realize esterification of p-chlorophenoxyisobutyric acid to obtain clofibrate, and the SF6 is turned into wealth from waste; the raw materials required by the method are simple and easy to obtain, the reaction conditions are simple and convenient, and the method is green and energy-saving and has higher application value.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing clofibrate by using sulfur hexafluoride. Background Art

[0002] As a common group, ester group is widely present in many drug molecules. It can not only increase the lipophilicity of drugs, but also is a necessary structure-effect group in many drug molecules. Ester compounds are also an important class of chemical products in the chemical industry and indispensable in our lives. Ester compounds are also an important class of solvents. They play a very obvious role in dissolving cellulose and also play a very important role in the field of food additives and spices. Therefore, promoting the condensation esterification reaction of alcohol and carboxylic acid has important use value. At present, the methods of esterification are:

[0003] Method 1: Fischer-Speier esterification reaction is the most classic esterification reaction. Under the action of acidic catalysts (sulfuric acid, sulfonic acid, phosphoric acid, hydrochloric acid, etc.), carboxylic acid and alcohol undergo a reversible reaction to generate ester compounds. Because it is a reversible reaction, it is often necessary to add an excess of one of the raw materials, or use a Dean-Stark device to remove water.

[0004]

[0005] This method uses an acidic catalyst, which has the characteristics of high catalytic activity, low price and easy preparation. However, the disadvantage is that the yield in the esterification of secondary and tertiary alcohols is low and the raw materials are wasted (or additional equipment is required to remove water).

[0006] Method 2: Esterification reaction catalyzed by N,N-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine

[0007]

[0008] This method has the advantages of mild reaction conditions, high yield, good selectivity, etc., but it produces dicyclohexylurea as a by-product and the post-processing is cumbersome.

[0009] Method 3: Use elemental iodine alone to catalyze the esterification reaction of carboxylic acid and alcohol.

[0010]

[0011] The advantages of this reaction system are simple operation, non-toxicity, strong applicability, relatively mild conditions and high yield; however, the post-processing is complicated and the reactant alcohol is in excess, resulting in great waste.

[0012] Therefore, there is still a need to develop a carboxylic acid esterification method that has simple and readily available raw materials, simple operation, high reaction yield, good functional group tolerance, environmental friendliness, and is easy to promote in industrial production.

[0013] And for the following reasons: SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at room temperature and pressure. It is an inert gas with high stability. It does not decompose at high temperatures of 500-600°C, and does not react with acids, alkalis, water, etc. It is also an insulating gas with excellent insulating properties. The gas can adsorb free discrete electrons in the electric field, effectively reducing ionization collisions in the gas, which actually has an insulating effect and can be used to eliminate high-voltage arcs. Therefore, SF6 is widely used in the power sector, but SF6 has a strong greenhouse effect, and its climate warming power is 23,900 times that of CO2. Secondly, because SF6 is an artificially synthesized gas with quite stable chemical properties, SF6 is extremely difficult to decompose, and its natural lifespan in the atmosphere can be as long as more than 3,000 years. With continuous accumulation in the atmosphere, the greenhouse effect it brings is also continuously increasing. SF6 is currently subject to strict emission restrictions, and the treatment of large amounts of SF6 stored in the power sector faces difficulties.

[0014] SF6 itself has a high potential for utilization. One SF6 molecule contains one sulfur atom and six fluorine atoms. The decomposition products of SF6 contain high-valent sulfur-fluorine intermediates, which can be used as condensation reagents in the field of organic synthesis.

[0015] Clofibrate, also known as clofibrate, is mainly used for hypertriglyceridemia, especially for type III and IV hyperlipoproteinemia, and also for atherosclerosis. Clofibrate can reduce the adhesion of platelets, inhibit platelet aggregation, and reduce the excessive fibrin concentration to normal, thereby reducing thrombosis. It can be used alone or in combination with anticoagulants for patients with ischemic heart disease. It can inhibit the synthesis of cholesterol and triglycerides. It promotes cholesterol excretion and reduces triglycerides more significantly than cholesterol. It also reduces blood viscosity, reduces plasma fibrinogen content, and has anti-thrombotic effects.

[0016] The currently reported synthesis methods include: synthesizing clofibrate by heating p-chlorophenol and α-bromoisobutyrate under alkaline conditions (CN 110372638 A) and the condensation reaction of phenoxyisobutyric acid and ethanol promoted by 2,4-dinitro-1-(trifluoromethoxy)benzene and 4-dimethylaminopyridine (Eur. J. Org. Chem. 2024, 27, e202400142), but there are no reports on the use of sulfur hexafluoride for preparation. Summary of the invention

[0017] The technical problem to be solved by the present invention is how to synthesize clofibrate simply and safely.

[0018] The present invention solves the above technical problems through the following technical means:

[0019] A method for preparing clofibrate by using sulfur hexafluoride, which uses ethanol and p-chlorophenoxyisobutyric acid as raw materials, uses alkaline substances as additives, irradiates with light in the presence of sulfur hexafluoride and a photocatalyst, and reacts in a solvent to obtain the clofibrate.

[0020] Preferably, the method for preparing clofibrate using sulfur hexafluoride comprises the following steps: adding p-chlorophenoxyisobutyric acid and a photocatalyst into a reaction device, adding a solvent after evacuating, bubbling sulfur hexafluoride, adding ethanol and an alkaline substance, placing the reaction device under light conditions for reaction, and obtaining the clofibrate after post-treatment after the reaction is completed.

[0021] Preferably, the photocatalyst is an organic photocatalyst or a transition metal photocatalyst, or a mixture of both; and the alkaline substance is an organic base.

[0022] Preferably, the organic base is a tertiary amine, preferably N,N-diisopropylethylamine. When the base is N,N-diisopropylethylamine, the product yield is the highest.

[0023] Preferably, the photocatalyst is 4CZIPN, Mes-Acr + ClO4 — (9-mesityl-10-methylacridine perchlorate), Ir[dF(CF3)ppy]2(dtbbpy)PF6, a mixture of one or more of Ir(dtbbpy)ppy2PF6.

[0024] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0025] Preferably, the solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

[0026] The present invention is carried out in a system with a single organic solvent; if necessary, other organic solvents may also be present in the system, but from the perspective of reaction yield and simplicity of operation, it is preferred not to add other organic solvents, that is, to use a single organic solvent as the reaction solvent.

[0027] Preferably, the solvent is tetrahydrofuran.

[0028] Preferably, the molar ratio of ethanol to p-chlorophenoxyisobutyric acid is 1:1 to 20:1.

[0029] Preferably, the molar ratio of ethanol to p-chlorophenoxyisobutyric acid is 10:1.

[0030] Preferably, the molar ratio of the alkaline substance to p-chlorophenoxyisobutyric acid is 1:1-10:1; the molar ratio of the photocatalyst to p-chlorophenoxyisobutyric acid is 0.010:1-0.002:1; and the dosage ratio of p-chlorophenoxyisobutyric acid to the solvent is 0.5-0.1 mmol:1 mL.

[0031] Preferably, the dosage ratio of p-chlorophenoxyisobutyric acid to the solvent is 0.17 mmol:1 mL; when the dosage ratio is 0.17 mmol:1 mL, the product yield is the highest.

[0032] Preferably, the light source of the illumination is blue light with a wavelength of 450 to 480 nm.

[0033] Preferably, the light source power of the illumination is 15W.

[0034] Preferably, during the reaction, the sulfur hexafluoride gas pressure is 1 atm. When the pressure is 1 atm, the yield of the product is the highest.

[0035] Preferably, the reaction temperature is 0 to 50° C. and the reaction time is 5 to 48 hours.

[0036] Preferably, the reaction temperature is room temperature and the reaction time is 20 hours.

[0037] The advantages of the present invention are:

[0038] The present invention uses easily available ethanol and p-chlorophenoxyisobutyric acid as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as photocatalysts, and cheap and easily available alkaline substances such as N,N-diisopropylethylamine as additives. Under SF6 gas, at room temperature, 15W blue light is used as a light source to simply and efficiently synthesize clofibrate. The reaction conditions of the present invention are mild, the reaction raw materials used are cheap and easily available, and it has the characteristics of cost saving, environmental friendliness, and industrial promotion. The method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition product of SF6 as a condensation reagent to realize the esterification reaction of carboxylic acid to prepare clofibrate, turning SF6 into treasure.

[0039] The invention provides a method for preparing clofibrate by carboxylic acid esterification, which has easy-to-obtain raw materials, simple and safe operation, and is green and energy-saving. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the H NMR spectrum of ethyl 2-(4-chlorophenoxy)-2-methylpropanoate described in Example 1 of the present invention;

[0041] Figure 2 This is the carbon NMR spectrum of ethyl 2-(4-chlorophenoxy)-2-methylpropanoate described in Example 1 of the present invention. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not 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.

[0043] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0044] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0045] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means known in the art before use when necessary.

[0046] 1 H NMR and 13 C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the reference was selected: 1 H NMR: CHCl3 7.260 ppm; 13 C NMR: CHCl3: 77.000 ppm.

[0047] In the following examples, irradiation and stirring were performed at room temperature under SF6 gas at one atmosphere pressure.

[0048] Example 1

[0049] Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester (clofibrate)

[0050] 4-Chlorophenoxyisobutyric acid (107.3 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 3.0 mL of anhydrous tetrahydrofuran was added, and bubbled for 3 minutes. Ethanol (291.8 μL) and diisopropylethylamine (434.6 μL) were then added, and the reaction system was placed under a 15W 465 nm blue LED light source for irradiation and stirring for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1). That is, clofibrate, 107.7 mg, with a yield of 89%.

[0051] The H NMR and C NMR spectra of the product 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester are as follows Figure 1-2 The specific data are as follows: 1 H NMR (400MHz, CDCl3) δ7.08–7.05(m,2H),6.69–6.66(m,2H),4.08(q,J=7.2Hz,2H),1.45(s,6H),1.09(t,J=7.2Hz,3H)ppm. 13 C NMR (101MHz, CDCl3) δ173.3,153.7,128.6,126.6,120.0,78.9,61.0,24.8,13.6ppm.

[0052] As can be seen from Example 1, the present invention uses easily available ethanol and p-chlorophenoxyisobutyric acid as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and cheap and easily available N,N-diisopropylethylamine as a base. Under an atmospheric pressure of SF6 gas, at room temperature, 15W of 465nm blue light is used as a light source to simply and efficiently synthesize clofibrate. The method is a method for synthesizing clofibrate with mild conditions, simple operation, and easy industrial promotion. In addition, the method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of the decomposition product of SF6 to realize the esterification reaction of carboxylic acid to prepare clofibrate, turning SF6 into treasure.

[0053] Example 2

[0054] Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester (clofibrate)

[0055] 4-Chlorophenoxyisobutyric acid (107.3 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (5.6 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 3.0 mL of anhydrous tetrahydrofuran was added, and bubbling was performed for 3 minutes. Subsequently, ethanol (583.6 μL) and diisopropylethylamine (88 μL) were added, and the reaction system was placed under a 15W 480 nm blue LED light source for irradiation and stirring for 5 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1).

[0056] Example 3

[0057] Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester (clofibrate)

[0058] 4-Chlorophenoxyisobutyric acid (107.3 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 5.0 mL of anhydrous tetrahydrofuran was added, and bubbled for 3 minutes. Ethanol (29.2 μL) and diisopropylethylamine (869.2 μL) were then added, and the reaction system was placed under a 15W 450 nm blue LED light source for irradiation and stirring for 48 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1).

[0059] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing clofibrate using sulfur hexafluoride, characterized in that: The method uses ethanol and p-chlorophenoxyisobutyric acid as raw materials, uses alkaline substances as additives, irradiates with light in the presence of sulfur hexafluoride and a photocatalyst, and reacts in a solvent to obtain the clofibrate.

2. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The following steps are involved: p-Chlorophenoxyisobutyric acid and a photocatalyst are added to a reaction device, and a solvent is added after vacuuming. After sulfur hexafluoride is bubbled, ethanol and an alkaline substance are added, and the reaction device is placed under light conditions for reaction. After the reaction is completed, the clofibrate is obtained through post-treatment.

3. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The alkaline substance is N,N-diisopropylethylamine.

4. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is a mixture of one or more of 4CZIPN, 9-mesityl-10-methylacridine perchlorate, Ir[dF(CF3)ppy]2(dtbbpy)PF6, and Ir(dtbbpy)ppy2PF6.

5. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

6. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the ethanol to p-chlorophenoxyisobutyric acid is 1:1 to 20:

1.

7. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the alkaline substance to p-chlorophenoxyisobutyric acid is 1:1-10:1; the molar ratio of the photocatalyst to p-chlorophenoxyisobutyric acid is 0.010:1-0.002:1; and the dosage ratio of p-chlorophenoxyisobutyric acid to the solvent is 0.5-0.1mmol:1mL.

8. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: The light source is blue light with a wavelength of 450 to 480 nm.

9. The method for preparing clofibrate using sulfur hexafluoride according to claim 1, characterized in that: During the reaction, the pressure of sulfur hexafluoride gas was 1 atm.

10. The method for preparing clofibrate using sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The reaction temperature is 0-50°C and the reaction time is 5-48h.

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