A process for the preparation of alendronate using sulfur hexafluoride

Abstract

The application discloses a method for preparing adifonine by using sulfur hexafluoride, which takes diethylaminoethanol and 2,2-diphenylacetic acid as raw materials, takes an alkaline substance as an additive, and carries out an esterification reaction in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and light to obtain the adifonine. In the method, SF6 is activated under the photocatalysis condition, and the esterification reaction of 2,2-diphenylacetic acid is realized by using the decomposition product of SF6, so that the ester compound adifonine is obtained; 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 prepare the adifonine, and changes the SF6 into treasure from waste; the raw material required by the method is 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 adefenine 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] Aldefenac is an oral medication used to treat gastric and duodenal ulcers, cholelithiasis, etc. Three synthetic techniques for adefenac have been reported in the literature. The first involves converting 2,2-diphenylacetic acid to the corresponding acyl chloride using thionyl chloride, followed by reaction with diethylaminoethanol (J.Med.Chem.1987,30,273-278). This method involves multiple reaction steps and highly corrosive reagents. The second method involves reacting 2,2-diphenylacetic acid with N,N-diethylethylenediamine in the presence of 2,2-dimethylpropanediol dinitrite (Chem.Commun.2020,56,10938-10941). This method uses expensive reagents and is difficult to synthesize. The third method involves heating 2,2-diphenylacetic acid and diethylamine in 1,2-dichloroethane (Chem.Eur.J.2020,26,5648–5653), which requires high energy consumption. As an ester compound, there are currently no reports of it being prepared using sulfur hexafluoride. Summary of the Invention

[0016] The technical problem to be solved by this invention is how to synthesize aldefenine in a simple and safe way.

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

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

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

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

[0021] 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.

[0022] Preferably, the photocatalyst is one or a mixture of two of organic photocatalysts or transition metal photocatalysts.

[0023] Preferably, the organic photocatalyst is 4CZIPN or Mes-Acr. + ClO4 — The photocatalyst is one or a mixture of two of (9-trimethylmethyl-10-methylacridinium perchlorate); the transition metal photocatalyst is one or a mixture of two of 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 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 to 10:1; the molar ratio of the photocatalyst to 2,2-diphenylacetic acid is 0.010:1 to 0.002:1; and the ratio of 2,2-diphenylacetic acid to solvent is 0.5 to 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 ratio of 2,2-diphenylacetic acid to solvent is 0.17 mmol: 1 mL; the product yield is highest when the ratio is 0.17 mmol: 1 mL.

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

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

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

[0037] Preferably, the sulfur hexafluoride gas pressure is 1 atm during the reaction. The product yield is highest when the gas pressure is 1 atm.

[0038] The advantages of this invention are:

[0039] This invention uses readily available diethylaminoethanol and 2,2-diphenylacetic 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. Aldehydefenidine 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 SF6 decomposition products to prepare aldefenidine, turning SF6 waste into a valuable resource. Attached Figure Description

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

[0041] Figure 2This is the carbon NMR spectrum of ethyl 2-(diethylamino)2,2-diphenylacetate as described in Example 1 of this 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 Aldefenac (2-(diethylamino)-2,2-diphenylethyl acetate)

[0050] 106.1 mg of 2,2-diphenylacetic 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, 662.8 μL of diethylaminoethanol and 434.6 μL of diisopropylethylamine were added. The reaction system was irradiated with 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 113.5 mg of ethyl 2-(diethylamino)-2,2-diphenylacetic acid (73%) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1).

[0051] Product 2-(diethylamino)2,2-diphenylethyl acetate The proton and carbon NMR spectra are as follows Figure 1-2 As shown, the specific data is 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 shown in Example 1, this invention synthesizes adefenine simply and efficiently using readily available diethylaminoethanol and 2,2-diphenylacetic 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 adefenine. 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 adefenine, thus turning SF6 waste into a valuable resource.

[0053] Example 2

[0054] Synthesis of Aldefenac (2-(diethylamino)-2,2-diphenylethyl acetate)

[0055] 106.1 mg of 2,2-diphenylacetic 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 5.0 mL of anhydrous acetonitrile was added, followed by bubbling for 3 minutes. Then, 66.8 μL of diethylaminoethanol and 869.2 μL of diisopropylethylamine were added. The reaction system was irradiated under a 15 W 450 nm blue LED light source and stirred for 48 hours. After the reaction was complete, the organic solvent was removed under vacuum, and ethyl 2-(diethylamino)2,2-diphenylacetate was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1).

[0056] Example 3

[0057] Synthesis of Aldefenac (2-(diethylamino)-2,2-diphenylethyl acetate)

[0058] 106.1 mg of 2,2-diphenylacetic 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 3.0 mL of anhydrous dichloromethane was added, followed by bubbling for 3 minutes. Then, 1325.6 μL of diethylaminoethanol and 87.5 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 complete, the organic solvent was removed under vacuum, and ethyl 2-(diethylamino)2,2-diphenylacetic acid 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 adefenine using sulfur hexafluoride, characterized in that: The product, aldefenine, is obtained by esterification in a solvent under the conditions of sulfur hexafluoride, photocatalyst, and light irradiation, using diethylaminoethanol and 2,2-diphenylacetic acid as raw materials and alkaline substances as additives. The photocatalyst is one or a mixture of two organic photocatalysts or transition metal photocatalysts. The organic photocatalyst is one or a mixture of two of 4CZIPN and 9-trimethylmethyl-10-methylacridine perchlorate. The transition metal photocatalyst is one or a mixture of two of 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 adefenidine using sulfur hexafluoride according to claim 1, characterized in that: Includes the following steps: 2,2-Diphenylacetic acid and a photocatalyst were added to the reaction apparatus. After evacuation, a solvent was added, followed by bubbling of sulfur hexafluoride, and then diethylaminoethanol and an alkaline substance were added. The reaction system was placed under light conditions for reaction. After the reaction was completed, the aldefenine was obtained through post-treatment.

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

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

5. The method for preparing adefenine using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is a transition metal photocatalyst.

6. The method for preparing adefenidine using sulfur hexafluoride according to claim 5, characterized in that: The transition metal photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

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

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

1.

9. The method for preparing adefenine 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 ratio of 2,2-diphenylacetic acid to solvent is 0.5 to 0.1 mmol: 1 mL.

10. The method for preparing adefenine using sulfur hexafluoride according to any one of claims 1-9, characterized in that: The light source is blue light with a wavelength of 465nm; the sulfur hexafluoride gas pressure is 1 atm; the reaction temperature is 0~50℃; and the reaction time is 5~48h.

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