A process for the preparation of benzocaine from sulfur hexafluoride

Abstract

The application discloses a method for preparing benzocaine from sulfur hexafluoride, which uses ethanol and 4-amino benzoic acid as raw materials, uses an alkaline substance as an additive, and carries out a reaction in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and light to obtain the benzocaine. In the method, SF6 is activated under the photocatalytic condition, and the esterification reaction of a carboxylic acid is realized by using a decomposition product of SF6 to obtain the benzocaine; wherein the decomposition product of SF6 is used as a condensation reagent, the method effectively activates the greenhouse gas SF6, fully utilizes the decomposition product of SF6 to realize the esterification of the carboxylic acid to obtain the benzocaine, and changes the SF6 into treasure from waste; the raw materials required by the method are simple and easy to obtain, the reaction condition is simple, green and energy-saving, and the method 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 benzocaine 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 dehydration).

[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 and good selectivity, but it produces the 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 there is an excess of alcohol as a reactant, resulting in a lot 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] Benzocaine is a synthetic local anesthetic that plays an important role in clinical applications. On one hand, it blocks nerve conduction, thereby reducing pain and sensory abnormalities. Therefore, it can be used for local anesthesia in areas such as the mouth, ear, nose, and throat, and in surgical procedures. On the other hand, benzocaine also has some anti-allergic effects, reducing the incidence of symptoms such as skin redness, swelling, and itching. Furthermore, benzocaine can also be used as an anti-inflammatory drug to treat skin diseases, traumatic inflammation, and other conditions.

[0016] Several methods for preparing benzocaine have been disclosed in the prior art. For example, Chinese patent application CN 118005521 A discloses a method for synthesizing benzocaine, including the following steps: S1, using p-nitrotoluene as a raw material, adding an oxidant and concentrated sulfuric acid, and undergoing an oxidation reaction under the catalysis of catalyst A to generate p-nitrobenzoic acid; S2, using p-nitrobenzoic acid as a raw material, undergoing an esterification reaction with ethanol under the catalysis of catalyst B to generate ethyl p-nitrobenzoate; S3, using ascorbic acid to reduce ethyl p-nitrobenzoate under alkaline conditions to obtain benzocaine. This method uses ascorbic acid for reduction, avoiding the use of iron powder or zinc powder, and does not produce difficult-to-treat amine-containing iron sludge or amine-containing zinc sludge, thus avoiding environmental impact and being environmentally friendly. Furthermore, ascorbic acid is low in cost, and the resulting benzocaine has a high yield and few impurities. However, its complex steps limit its application. Summary of the Invention

[0017] The technical problem to be solved by this invention is how to synthesize benzocaine simply and safely.

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

[0019] A method for preparing benzocaine from sulfur hexafluoride, wherein ethanol and 4-aminobenzoic acid are used as raw materials, and an alkaline substance is used as an additive, and the reaction is carried out in a solvent under the conditions of sulfur hexafluoride, photocatalyst and light irradiation to obtain the benzocaine.

[0020] Preferably, the method for preparing benzocaine from sulfur hexafluoride includes the following steps: adding 4-aminobenzoic 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 benzocaine by 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 organic 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 4-aminobenzoic acid is 1:1 to 20:1.

[0029] Preferably, the molar ratio of ethanol to 4-aminobenzoic acid is 10:1.

[0030] Preferably, the molar ratio of the alkaline substance to 4-aminobenzoic acid is 1:1 to 10:1; the molar ratio of the photocatalyst to 4-aminobenzoic acid is 0.010:1 to 0.002:1; and the ratio of 4-aminobenzoic acid to solvent is 0.5 to 0.1 mmol: 1 mL.

[0031] Preferably, the molar ratio of the alkaline substance to 4-aminobenzoic acid is 5:1.

[0032] Preferably, the molar ratio of the photocatalyst to 4-aminobenzoic acid is 0.005:1.

[0033] Preferably, the light source is blue light with a wavelength of 450–480 nm.

[0034] Preferably, the power of the light source is 15W.

[0035] Preferably, the sulfur hexafluoride gas pressure is 1 atm during the reaction. The product yield is highest when the gas pressure is 1 atm.

[0036] Preferably, the reaction temperature is 0–50°C and the reaction time is 5–48 h.

[0037] Preferably, the reaction is carried out at room temperature for 20 hours.

[0038] Preferably, the ratio of 4-aminobenzoic acid to solvent used in the reaction is 0.17 mmol: 1 mL; the yield is highest when the ratio is 0.17 mmol: 1 mL.

[0039] The advantages of this invention are:

[0040] This invention uses readily available ethanol and 4-aminobenzoic 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. Benzocaine is synthesized simply and efficiently under SF6 gas at room temperature using 15W blue light as the light source. 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 the decomposition products of SF6 to achieve the esterification reaction of carboxylic acids to obtain benzocaine, turning SF6 waste into a valuable resource. Attached Figure Description

[0041] Figure 1 The 1H NMR spectrum of ethyl 4-aminobenzoate described in Example 1 of this invention;

[0042] Figure 2 This is the carbon NMR spectrum of ethyl 4-aminobenzoate described in Example 1 of the present invention. Detailed Implementation

[0043] 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.

[0044] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] Example 1

[0049] Synthesis of ethyl 4-aminobenzoate (benzocaine)

[0050] 4-Aminobenzoic acid (68.5 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) 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, ethanol (291.8 μL) and diisopropylethylamine (434.6 μL) were added. The reaction system was placed under a 15 W 465 nm blue LED light source and irradiated and stirred at room temperature for 20 hours, with stirring under SF6 gas at one atmosphere. After the reaction, the organic solvent was removed under vacuum, and ethyl 4-aminobenzoate, i.e., benzocaine, was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1). 38.0 mg, yield 46%.

[0051] The 1H NMR and 1C NMR spectra of the product ethyl 4-aminobenzoate are as follows: Figure 1-2 As shown, the specific data is as follows: 1 HNMR (400MHz, CDCl3) δ7.87–7.84(m,2H),6.64–6.62(m,2H),4.31(q,J=7.2Hz,2H),4.07(br,2H),1.36(t,J=7.2Hz,3H)ppm. 13 C NMR (101MHz, CDCl3) δ166.7, 150.7, 131.5, 120.0, 113.7, 60.3, 14.4ppm.

[0052] As shown in Example 1, this invention uses readily available ethanol and 4-aminobenzoic 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 basic substance. Benzocaine is synthesized simply and efficiently 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 synthesis method for benzocaine. 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 benzocaine, thus turning SF6 waste into a valuable resource.

[0053] Example 2

[0054] Synthesis of ethyl 4-aminobenzoate (benzocaine)

[0055] 4-Aminobenzoic acid (68.5 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, and 5 mL of anhydrous tetrahydrofuran was added, followed by bubbling for 3 minutes. Then, ethanol (29.2 μL) and diisopropylethylamine (869.2 μL) were added. The reaction system was placed under a 15 W 450 nm blue LED light source and irradiated and stirred at room temperature for 48 hours, with stirring under SF6 gas at one atmosphere. After the reaction was completed, the organic solvent was removed under vacuum, and ethyl 4-aminobenzoate, i.e., benzocaine, was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1).

[0056] Example 3

[0057] Synthesis of ethyl 4-aminobenzoate (benzocaine)

[0058] 4-Aminobenzoic acid (68.5 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (5.6 mg) 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, ethanol (583 μL) and diisopropylethylamine (88 μL) were added. The reaction system was placed under a 15 W blue LED light source at 480 nm and irradiated at room temperature with stirring for 5 hours. During the stirring, the mixture was stirred under SF6 gas at one atmosphere. After the reaction was completed, the organic solvent was removed under vacuum, and ethyl 4-aminobenzoate, i.e., benzocaine, 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 benzocaine from sulfur hexafluoride, characterized in that: The benzocaine is obtained by reacting ethanol and 4-aminobenzoic acid as raw materials and alkaline substances as additives in a solvent under the conditions of sulfur hexafluoride, photocatalyst and light irradiation. 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 benzocaine from sulfur hexafluoride according to claim 1, characterized in that: The process includes the following steps: adding 4-aminobenzoic 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 benzocaine by post-processing after the reaction is completed.

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

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

5. The method for preparing benzocaine from 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 benzocaine from sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of ethanol to 4-aminobenzoic acid is 1:1 to 20:

1.

7. The method for preparing benzocaine from sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the alkaline substance to 4-aminobenzoic acid is 1:1 to 10:1; the molar ratio of the photocatalyst to 4-aminobenzoic acid is 0.010:1 to 0.002:1; and the ratio of 4-aminobenzoic acid to solvent is 0.5 to 0.1 mmol: 1 mL.

8. The method for preparing benzocaine from 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 benzocaine from 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 benzocaine from 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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