Method for preparing aclifinin by using sulfur hexafluoride

Abstract

The invention discloses a method for preparing aclidinine by using sulfur hexafluoride, which comprises the following steps: by taking diethylaminoethanol and 2, 2-diphenylacetic acid as raw materials and an alkaline substance as an additive, carrying out esterification reaction in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and illumination to obtain the aclidinine. According to the method disclosed by the invention, SF6 is activated under a photocatalytic condition, and an esterification reaction of 2, 2-diphenylacetic acid is realized by utilizing an SF6 decomposition product, so that an ester compound aclidinine is obtained; wherein the decomposition product of SF6 is used as a condensation reagent, the greenhouse gas SF6 is effectively activated by the method, carboxylic acid esterification is realized by fully utilizing the decomposition product of SF6 to prepare aclifinin, 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 adifenine 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 a by-product, dicyclohexylurea, 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] Adifenine is an oral drug that can be used to treat gastric and duodenal ulcers, cholelithiasis, etc. The literature reports that there are three synthesis techniques for adifenine. One is to use thionyl chloride to convert 2,2-diphenylacetic acid into the corresponding acyl chloride, and then react with diethylaminoethanol (J.Med.Chem.1987,30,273-278). There are many reaction steps and the reagents are highly corrosive; the second is to react 2,2-diphenylacetic acid with N,N-diethylethylenediamine under the action of 2,2-dimethylpropylene glycol dinitrite (Chem.Commun.2020,56,10938-10941). The reagents used are expensive and difficult to synthesize; the third is to obtain 2,2-diphenylacetic acid and diethylamine by heating in 1,2-dichloroethane (Chem.Eur.J.2020,26,5648–5653), and the reaction energy consumption is high. As an ester compound, there is currently no report on its preparation using sulfur hexafluoride. Summary of the invention

[0016] The technical problem to be solved by the present invention is how to synthesize adifenine simply and safely.

[0017] The present invention solves the above technical problems through the following technical means:

[0018] A method for preparing adifenine using sulfur hexafluoride, which uses diethylaminoethanol and 2,2-diphenylacetic acid as raw materials, uses an alkaline substance as an additive, and performs an esterification reaction in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and light to obtain the adifenine.

[0019] Preferably, the method for preparing adifenine using sulfur hexafluoride comprises the following steps: adding 2,2-diphenylacetic acid and a photocatalyst into a reaction device, adding a solvent after vacuuming, adding diethylaminoethanol and an alkaline substance after bubbling sulfur hexafluoride, placing the reaction system under light conditions for reaction, and obtaining the adifenine through post-treatment after the reaction is completed.

[0020] Preferably, the alkaline substance is an organic base.

[0021] Preferably, the organic base is a tertiary amine, preferably N,N-diisopropylethylamine. When the organic base is N,N-diisopropylethylamine, the product yield is the highest.

[0022] Preferably, the photocatalyst is an organic photocatalyst or a transition metal photocatalyst, or a mixture of both.

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

[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 diethylaminoethanol to 2,2-diphenylacetic acid is 1:1 to 20:1.

[0029] Preferably, the molar ratio of diethylaminoethanol to 2,2-diphenylacetic acid is 10:1.

[0030] Preferably, the molar ratio of the alkaline substance to 2,2-diphenylacetic acid is 1:1-10:1; the molar ratio of the photocatalyst to 2,2-diphenylacetic acid is 0.010:1-0.002:1; and the dosage ratio of the 2,2-diphenylacetic acid to the solvent is 0.5-0.1 mmol:1 mL.

[0031] Preferably, the molar ratio of the alkaline substance to 2,2-diphenylacetic acid is 5:1.

[0032] Preferably, the molar ratio of the photocatalyst to 2,2-diphenylacetic acid is 0.005:1.

[0033] Preferably, the usage ratio of the 2,2-diphenylacetic acid and the solvent is 0.17 mmol:1 mL; when the usage ratio is 0.17 mmol:1 mL, the product yield is the highest.

[0034] Preferably, the light source is blue light with a wavelength of 450 to 480 nm; the pressure of sulfur hexafluoride gas is 1 atm, the reaction temperature is 0 to 50° C., and the reaction time is 5 to 48 hours.

[0035] Preferably, the light source power of the illumination is 15W.

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

[0037] 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.

[0038] The advantages of the present invention are:

[0039] The present invention uses easily available diethylaminoethanol and 2,2-diphenylacetic 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 adifennin. The reaction conditions of the present invention are mild, the reaction raw materials used are cheap and easily available, and the method 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 products of SF6 to react and prepare adifennin, turning SF6 into treasure. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The H NMR spectrum of ethyl 2-(diethylamino)-2,2-diphenylacetate described in Example 1 of the present invention;

[0041] Figure 2This is the NMR carbon spectrum of ethyl 2-(diethylamino)-2,2-diphenylacetate 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 Adifenin (2-(Diethylamino)2,2-Diphenylacetic Acid Ethyl Acetate)

[0050] 2,2-diphenylacetic acid (106.1 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, and a SF6 balloon was inserted after vacuuming, and 3.0 mL of anhydrous tetrahydrofuran was added and bubbled for 3 minutes. Subsequently, diethylaminoethanol (662.8 μL) and diisopropylethylamine (434.6 μL) were 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 113.5 mg of ethyl 2-(diethylamino)-2,2-diphenylacetate was obtained by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 20:1), with a yield of 73%.

[0051] Product ethyl 2-(diethylamino)-2,2-diphenylacetate The H-NMR and C-NMR spectra are as follows Figure 1-2 The specific data are as follows: 1 H NMR (400MHz, CDCl3) δ7.34–7.25(m,10H),5.06(s,1H),4.69–4.66(m,2H),3.24–3.21(m,2H),2.98–2.83(m,4H),1.23–1.21(m,6H)ppm. 13 CNMR (101MHz, CDCl3) δ171.6,137.6,128.8,128.5,127.6,59.0,56.9,49.6,47.0,8.5ppm.

[0052] As can be seen from Example 1, the present invention uses easily available diethylaminoethanol and 2,2-diphenylacetic 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 adifennin. This method is a method for synthesizing adifennin with mild conditions, simple operation, and easy industrial promotion. In addition, this method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of the decomposition products of SF6 to realize the esterification reaction of carboxylic acid to prepare adifennin, turning SF6 into treasure.

[0053] Example 2

[0054] Synthesis of Adifenin (2-(Diethylamino)2,2-Diphenylacetic Acid Ethyl Acetate)

[0055] 2,2-Diphenylacetic acid (106.1 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, and a SF6 balloon was inserted after vacuuming. 5.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, diethylaminoethanol (66.8 μL) and diisopropylethylamine (869.2 μL) were added, and the reaction system was placed under a 15W 450 nm blue LED light source and stirred for 48 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 2-(diethylamino)-2,2-diphenylacetic acid ethyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1).

[0056] Example 3

[0057] Synthesis of Adifenin (2-(Diethylamino)2,2-Diphenylacetic Acid Ethyl Acetate)

[0058] 2,2-Diphenylacetic acid (106.1 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, and a SF6 balloon was inserted after vacuuming. 3.0 mL of anhydrous dichloromethane was added and bubbled for 3 minutes. Subsequently, diethylaminoethanol (1325.6 μL) and diisopropylethylamine (87.5 μL) were added, and the reaction system was placed under a 15W 480 nm blue LED light source and stirred for 5 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 2-(diethylamino)-2,2-diphenylacetic 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 adifenine using sulfur hexafluoride, characterized in that: The method uses diethylaminoethanol and 2,2-diphenylacetic acid as raw materials and alkaline substances as additives, and carries out an esterification reaction in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and light to obtain the adifenine.

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

3. The method for preparing adifenine using sulfur hexafluoride according to claim 1, characterized in that: The alkaline substance is an organic base.

4. The method for preparing adifenine using sulfur hexafluoride according to claim 3, characterized in that: The organic base is N,N-diisopropylethylamine.

5. The method for preparing adifenine using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is an organic photocatalyst or a transition metal photocatalyst, or a mixture of the two.

6. The method for preparing adifenine using sulfur hexafluoride according to claim 5, characterized in that: The organic photocatalyst is one of 4CZIPN and 9-mesityl-10-methylacridine perchlorate or a mixture of two thereof; the transition metal photocatalyst is one of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ir(dtbbpy)ppy2PF6 or a mixture of two thereof.

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

8. The method for preparing adifenine using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the diethylaminoethanol to the 2,2-diphenylacetic acid is 1:1 to 20:

1.

9. The method for preparing adifenine using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the alkaline substance to 2,2-diphenylacetic acid is 1:1 to 10:1; the molar ratio of the photocatalyst to 2,2-diphenylacetic acid is 0.010:1 to 0.002:1; and the dosage ratio of the 2,2-diphenylacetic acid to the solvent is 0.5 to 0.1 mmol: 1 mL.

10. The method for preparing adifenine using sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The light source is blue light with a wavelength of 450-480nm; the pressure of sulfur hexafluoride gas is 1atm, the reaction temperature is 0-50°C, and the reaction time is 5-48h.

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