A process for the preparation of clofibrate using sulfur hexafluoride

Abstract

This invention discloses a method for preparing chlorofibrate using sulfur hexafluoride (SF6). The method uses ethanol and p-chlorophenoxyisobutyric acid (p-chlorophenoxyisobutyric acid) as raw materials, with an alkaline substance as an additive. The reaction is carried out in a solvent under light irradiation in the presence of SF6 and a photocatalyst to obtain chlorofibrate. In this method, SF6 is activated under photocatalytic conditions, and the esterification reaction of p-chlorophenoxyisobutyric acid with SF6 decomposition products is achieved to obtain chlorofibrate. The SF6 decomposition products serve as a condensation reagent. This method effectively activates SF6, a greenhouse gas, and fully utilizes the SF6 decomposition products to achieve the esterification of p-chlorophenoxyisobutyric acid to obtain chlorofibrate, turning SF6 waste into a valuable resource. The raw materials required by this method are simple and readily available, the reaction conditions are simple, green, and energy-saving, and it has high application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a method for preparing chlorofibrate using sulfur hexafluoride. Background Technology

[0002] Ester groups, as common functional groups, are widely present in many drug molecules. They not only increase the lipophilicity of drugs but are also essential structure-activity groups in many drug molecules. Ester compounds are also an important class of chemical products in the chemical industry and indispensable in our daily lives. Ester compounds are also important solvents, playing a significant role in the dissolution of cellulose, and hold a vital position in the fields of food additives and flavorings. Therefore, promoting the condensation esterification reaction of alcohols and carboxylic acids has significant practical value. Currently, esterification methods include:

[0003] Method 1: The Fischer-Speier esterification reaction, as the most classic esterification reaction, involves a reversible reaction between a carboxylic acid and an alcohol under the action of an acidic catalyst (sulfuric acid, sulfonic acid, phosphoric acid, hydrochloric acid, etc.) to produce ester compounds. Because it is a reversible reaction, it often requires the addition of an excess of one of the raw materials, or the use of a Dean-Stark apparatus to remove water.

[0004]

[0005] This method uses an acidic catalyst, which is characterized by high catalytic activity, low cost, and ease of preparation. However, its disadvantages include low yields and wasted raw materials in secondary and tertiary alcohol esterification (or the need for additional equipment for water removal).

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

[0007]

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

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

[0010]

[0011] The advantages of this reaction system are that it is simple to operate, non-toxic, widely applicable, relatively mild under mild conditions, and has a high yield; however, the post-processing is complicated, and the excess of reactant alcohol results in a great deal of waste.

[0012] Therefore, there is still a need to develop a carboxylate esterification method that uses readily available raw materials, is easy to operate, has a high reaction yield, good functional group tolerance, is environmentally friendly, and is easy to promote in industrial production.

[0013] Furthermore, SF6 is a colorless, odorless, non-toxic, non-flammable, and non-corrosive gas at normal temperature and pressure. It is an inert gas with high stability, not decomposing even at high temperatures of 500-600℃, and does not react with acids, alkalis, or water. It is also an insulating gas with excellent insulating properties. This gas can adsorb free electrons in an electric field, effectively reducing ionization collisions in the gas, thus achieving an insulating effect and being used to extinguish high-voltage arcs. Therefore, SF6 is widely used in the power sector. However, SF6 has a powerful greenhouse effect, with a global warming potential 23,900 times that of CO2. Secondly, because SF6 is a synthetic gas with remarkably stable chemical properties, it is extremely difficult to decompose, and its natural lifespan in the atmosphere can reach over three thousand years. With continuous accumulation in the atmosphere, its greenhouse effect continues to intensify. SF6 is currently subject to strict emission restrictions, and the disposal of large quantities of SF6 stored in the power sector faces significant challenges.

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

[0015] Clofibrate, also known as Atorvastatin, is mainly used for hypertriglyceridemia, especially for type III and IV hyperlipoproteinemia, and is also used for atherosclerosis. Clofibrate can reduce platelet adhesion, inhibit platelet aggregation, and lower excessively high fibrinogen levels to normal, thus reducing thrombus formation. It can be used alone or in combination with anticoagulants for ischemic heart patients. It can inhibit the synthesis of cholesterol and triglycerides, promote cholesterol excretion, and its effect on lowering triglycerides is more significant than its effect on lowering cholesterol. It also reduces blood viscosity, lowers plasma fibrinogen levels, and has an antithrombotic effect.

[0016] Currently reported synthetic methods include: the synthesis of chlorofibrate by heating p-chlorophenol with α-bromoisobutyrate under alkaline conditions (CN 110372638 A) and the condensation of phenoxyisobutyric acid with ethanol promoted by 2,4-dinitro-1-(trifluoromethoxy)benzene and 4-dimethylaminopyridine (Eur. J. Org. Chem. 2024, 27, e202400142), but there are no reports of preparation using sulfur hexafluoride. Summary of the Invention

[0017] The technical problem to be solved by this invention is how to synthesize chlorofibrate in a simple and safe way.

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

[0019] A method for preparing chlorofibrate using sulfur hexafluoride involves using ethanol and p-chlorophenoxyisobutyric acid as raw materials, an alkaline substance as an additive, and irradiating the mixture in the presence of sulfur hexafluoride and a photocatalyst, followed by a reaction in a solvent to obtain the chlorofibrate.

[0020] Preferably, the method for preparing chlorofibrate using sulfur hexafluoride includes the following steps: adding p-chlorophenoxyisobutyric acid and a photocatalyst into a reaction apparatus, adding a solvent after evacuation, adding ethanol and an alkaline substance after bubbling with sulfur hexafluoride, placing the reaction apparatus under light conditions for reaction, and obtaining the chlorofibrate after post-processing after the reaction is completed.

[0021] Preferably, the photocatalyst is one or a mixture of two of the following: an organic photocatalyst or a transition metal photocatalyst; the alkaline substance is an organic base.

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

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

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

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

[0026] This invention is carried out in a system with a single organic solvent; other organic solvents may be present in the system if necessary, but from the perspective of reaction yield and simplicity of operation, it is preferable 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 to 10:1; the molar ratio of the photocatalyst to p-chlorophenoxyisobutyric acid is 0.010:1 to 0.002:1; and the ratio of p-chlorophenoxyisobutyric acid to solvent is 0.5 to 0.1 mmol: 1 mL.

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

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

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

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

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

[0036] Preferably, the reaction is carried out at room temperature for 20 hours.

[0037] The advantages of this invention are:

[0038] This invention uses readily available ethanol and p-chlorophenoxyisobutyric acid as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and inexpensive and readily available basic substances such as N,N-diisopropylethylamine as additives. Under SF6 gas conditions at room temperature, using 15W blue light as the light source, chlorofibrate is synthesized simply and efficiently. This invention features mild reaction conditions, inexpensive and readily available raw materials, cost-effectiveness, environmental friendliness, and industrial applicability. This method effectively activates and utilizes SF6, a greenhouse gas, fully utilizing SF6 decomposition products as condensation reagents to achieve the esterification reaction of carboxylic acids to prepare chlorofibrate, turning SF6 waste into a valuable resource.

[0039] This invention provides a method for preparing chlorofibrate by carboxylic acid esterification, which uses readily available raw materials, is simple and safe to operate, and is green and energy-saving. Attached Figure Description

[0040] Figure 1 The 1H NMR spectrum of ethyl 2-(4-chlorophenoxy)-2-methylpropionate described in Example 1 of this invention;

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

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0044] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0045] All raw materials used in the following specific examples are commercially available, and each reagent is purified using methods known in the art when necessary.

[0046] 1 H NMR and 13 All C NMR measurements were performed using a Bruker Avance 400 spectrometer. The test temperature was room temperature, and the solvent was deuterated chloroform. (Reference selection follows.) 1 ¹H NMR: CHCl₃ was 7.260 ppm; 13 C NMR: CHCl3 was 77,000 ppm.

[0047] In the following examples, the gas was irradiated and stirred at room temperature under SF6 gas at one atmosphere.

[0048] Example 1

[0049] Synthesis of ethyl 2-(4-chlorophenoxy)-2-methylpropionate (chlorofibrate)

[0050] 107.3 mg of p-chlorophenoxyisobutyric acid and 2.8 mg of Ir[dF(CF3)ppy]2(dtbbpy)PF6 were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, and 3.0 mL of anhydrous tetrahydrofuran was added, followed by bubbling for 3 minutes. Then, 291.8 μL of ethanol and 434.6 μL of diisopropylethylamine were added. The reaction system was irradiated under a 15 W blue LED light source at 465 nm and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and ethyl 2-(4-chlorophenoxy)-2-methylpropionate 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 1H NMR and 1C NMR spectra of the product 2-(4-chlorophenoxy)-2-methylpropionate are as follows: Figure 1-2 As shown, the specific data is 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 shown in Example 1, this invention synthesizes chlorofibrate simply and efficiently using readily available ethanol and p-chlorophenoxyisobutyric acid as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and inexpensive and readily available N,N-diisopropylethylamine as a base, under SF6 gas at one atmosphere, at room temperature, and using 15W 465nm blue light as the light source. This method is a mild, simple, and easily industrially applicable method for synthesizing chlorofibrate. Furthermore, this method effectively activates and utilizes SF6, a greenhouse gas, fully utilizing the decomposition products of SF6 to achieve the esterification reaction of carboxylic acids to prepare chlorofibrate, thus turning SF6 waste into a valuable resource.

[0053] Example 2

[0054] Synthesis of ethyl 2-(4-chlorophenoxy)-2-methylpropionate (chlorofibrate)

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

[0056] Example 3

[0057] Synthesis of ethyl 2-(4-chlorophenoxy)-2-methylpropionate (chlorofibrate)

[0058] 107.3 mg of p-chlorophenoxyisobutyric acid and 1.2 mg of Ir[dF(CF3)ppy]2(dtbbpy)PF6 were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, and 5.0 mL of anhydrous tetrahydrofuran was added, followed by bubbling for 3 minutes. Then, 29.2 μL of ethanol and 869.2 μL of diisopropylethylamine were added. The reaction system was irradiated under a 15 W blue LED light source at 450 nm and stirred for 48 hours. After the reaction was completed, the organic solvent was removed under vacuum, and ethyl 2-(4-chlorophenoxy)-2-methylpropionate 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, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing chlorofibrate using sulfur hexafluoride, characterized in that: The chlorofibrate is obtained by reacting ethanol and p-chlorophenoxyisobutyric acid as raw materials, with alkaline substances as additives, under the conditions of sulfur hexafluoride and photocatalyst in a solvent. The photocatalyst is one or a mixture of 4CZIPN, 9-trimethylmethyl-10-methylacridine perchlorate, Ir[dF(CF3)ppy]2(dtbbpy)PF6, and Ir(dtbbpy)ppy2PF6. The light source is blue light with a wavelength of 450~480nm.

2. The method for preparing chlorofibrate using sulfur hexafluoride according to claim 1, characterized in that: Includes the following steps: p-Chlorophenoxyisobutyric acid and a photocatalyst were added to the reaction apparatus. After evacuation, a solvent was added, followed by bubbling with sulfur hexafluoride and then adding ethanol and an alkaline substance. The reaction apparatus was placed under light conditions for the reaction to proceed. After the reaction was completed, post-treatment was performed to obtain the chlorofibrate.

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

4. The method for preparing chlorofibrate using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

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

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

1.

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

8. The method for preparing chlorofibrate using sulfur hexafluoride according to claim 1, characterized in that: The light source is blue light with a wavelength of 465nm.

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

10. The method for preparing chlorofibrate using sulfur hexafluoride according to any one of claims 1-9, characterized in that: The reaction is carried out at a temperature of 0-50°C for a duration of 5-48 hours.

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