Method for preparing napropamide from sulfur hexafluoride

Abstract

The invention discloses a method for preparing napropamide by using sulfur hexafluoride, which comprises the following steps: by taking diethylamine and 2-(1-naphthyloxy) propionic acid as raw materials, reacting in an organic solvent under the conditions of a photocatalyst, alkali, sulfur hexafluoride and illumination to obtain napropamide. The reaction conditions are mild, the used reaction raw materials are cheap and easy to obtain, and the method has the characteristics of cost saving, environment friendliness and industrial popularization. According to the method, the greenhouse gas SF6 is effectively activated and utilized, the decomposition product SF6 is fully utilized to realize the amidation reaction of the 2-(1-naphthyloxy) propionic acid to prepare the napropamide, the SF6 is turned into wealth, the required raw materials are simple and easy to obtain, the reaction conditions are simple and convenient, the method is green and energy-saving, and the method 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 naproxenamide by using sulfur hexafluoride. Background Art

[0002] Amidation reaction is the most commonly used organic synthesis reaction. A study on drug synthesis shows that 65% of drug synthesis processes use amidation reactions. In addition, amidation products play an important role in the biomedical, pharmaceutical and food industries, and are also widely used in industrial products. For example, sulfamide can modify peptide units and proteins, and sulfamide modification can significantly improve the stability and activity of peptide drugs; tyramine-derived hydroxycinnamamide in plant-based foods can be used as a food preservative due to its natural antioxidant effect; amide greases are often used in nuclear power and aerospace fields due to their excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the synthesis of amide compounds includes:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid to catalyze the amidation reaction between carboxylic acid and amine.

[0004]

[0005] This method is not only applicable to the reaction of primary and tertiary amines with carboxylic acids, but is also applicable to some special substrates with large steric hindrance and olefin groups. However, it requires high temperature (>100°C) and anhydrous conditions, and has the problem of low atom economy.

[0006] Method 2: Using two zirconium catalysts (ZrCp 2 Cl 2 / ZrCl 4 ), in toluene solvent, heated under reflux at 110°C, it can efficiently catalyze the amidation reaction of carboxylic acid and amine.

[0007]

[0008] This method has a high yield and can achieve the synthesis of two drug molecules, acetaminophen and moclobemide, with a relatively high yield, but this method introduces metal compounds and requires high temperature conditions.

[0009] Method 3: Using active ester as acyl source and zinc powder as catalyst, the synthesis of secondary amide was achieved under the conditions of microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] The reaction has the following characteristics: simple, efficient, environmentally friendly and the catalyst can be reused. However, the substrate has a narrow scope of application and alcohol is also generated, which makes it very difficult to separate the subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation 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] SF 6 The 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 that can be used to extinguish high-voltage arcs. Therefore, SF 6 It is widely used in the power industry. 6 It has a strong greenhouse effect, and its climate warming power is CO 2 23900 times, and secondly, due to SF 6 It is a synthetic gas with fairly stable chemical properties. 6 It is extremely difficult to decompose, and its natural life span in the atmosphere can be as long as 3,000 years. As it continues to accumulate in the atmosphere, the greenhouse effect it brings is also continuously increasing. 6 The emission of SF 6 Faced with enormous pressure in handling.

[0014] N,N-diethyl-2-(α-naphthyloxy)propionamide is known as naproxil and is commonly sold under the trade name "Devrinol". It is used for pre-emergence control of annual grasses and broadleaf weeds in many crops and plantations. The application document with publication number IN1303KOL2013A discloses a non-aqueous method for preparing R-(-)-N,N-diethyl-2-(α-naphthyloxy)propionamide, comprising the following steps: i. reacting (L)-2-(-)halopropionic acid with thionyl chloride and an alkaline compound to generate (L)-2-(+)-halopropionyl chloride; ii. reacting (L)-2-halopropionyl chloride with N,N-diethylamine in the presence of a non-aqueous base and an organic solvent to form (L)-2-(+)-N,N-diethyl-halopropionamide; iii. reacting a substance containing (L)-2-N,N-diethyl-halopropionamide with α-naphthol in the presence of a non-aqueous base to form R-(-)-N,N-diethyl-2-(α-naphthyloxy)propionamide. The method has complicated reaction steps and high reaction temperature, which limits its application. Summary of the invention

[0015] The technical problem to be solved by the present invention is how to synthesize propamide simply, safely and greenly.

[0016] The present invention solves the above technical problems through the following technical means:

[0017] A method for preparing naproxenamide by using sulfur hexafluoride, wherein diethylamine and 2-(1-naphthyloxy)propionic acid are used as raw materials, and the naproxenamide is obtained by reacting in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light.

[0018] Preferably, the method for preparing propamide using sulfur hexafluoride comprises the following steps: adding 2-(1-naphthyloxy)propionic acid and a photocatalyst into a reaction device, adding an organic solvent after evacuation, introducing sulfur hexafluoride gas, and then adding diethylamine and a base, placing the reaction system under a light source to react and obtain the propamide.

[0019] Preferably, the photocatalyst is an organic photocatalyst or a mixture of one or more transition metal photocatalysts.

[0020] Preferably, the organic photocatalyst is 4CZIPN, Mes-Acr + C1O 4 — (9-mesityl-10-methylacridinium perchlorate) or a mixture of two thereof.

[0021] Preferably, the transition metal photocatalyst is Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 ,Ir(dtbbpy)ppy 2 PF 6 One or a mixture of two.

[0022] Preferably, the photocatalyst is Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 .

[0023] Preferably, the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

[0024] Preferably, the organic solvent is acetonitrile.

[0025] 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.

[0026] Preferably, the base is an organic base.

[0027] Preferably, the organic base is a tertiary amine.

[0028] Preferably, the base is N,N-diisopropylethylamine. When the base is N,N-diisopropylethylamine, the product yield is the highest.

[0029] Preferably, the molar ratio of diethylamine to 2-(1-naphthyloxy)propionic acid is 1:1 to 20:1.

[0030] Preferably, the molar ratio of diethylamine to 2-(1-naphthyloxy)propionic acid is 10:1.

[0031] Preferably, the molar ratio of the 2-(1-naphthyloxy)propionic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 2-(1-naphthyloxy)propionic acid to the base is 1:1-1:10.

[0032] Preferably, the molar ratio of the 2-(1-naphthyloxy)propionic acid to the base is 1:5.

[0033] Preferably, the molar ratio of the 2-(1-naphthyloxy)propionic acid to the photocatalyst is 100:0.5.

[0034] Preferably, the illumination uses blue light with a wavelength of 450-480nm as a light source.

[0035] Preferably, blue light with a wavelength of 465 nm is used as the light source.

[0036] Preferably, during the reaction, SF 6 The gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

[0037] Preferably, the yield of the product is highest when the gas pressure is 1 atm.

[0038] Preferably, the reaction temperature is room temperature and the reaction time is 20 hours.

[0039] Preferably, the usage ratio of the 2-(1-naphthyloxy)propionic acid and the organic solvent is 0.5-0.1 mmol:1 mL.

[0040] Preferably, the usage ratio of 2-(1-naphthyloxy)propionic acid and organic solvent is 0.5 mmol:3 mL; the product yield is the highest.

[0041] Preferably, during the reaction, SF 6 The decomposition products are used as condensation reagents.

[0042] The advantages of the present invention are:

[0043] In the present invention, diethylamine and 2-(1-naphthyloxy)propionic acid, which are easily available, are used as reaction substrates, and commercially available Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 As photocatalysts, cheap and readily available N,N-diisopropylethylamine was used as base. 6 The method can be used to synthesize propamide simply and efficiently under the condition of SF. The reaction conditions of the present invention are mild, the reaction raw materials used are cheap and easy to obtain, and it has the characteristics of cost saving, environmental friendliness, and industrial promotion. 6 This greenhouse gas, fully utilizing SF 6 The decomposition product is subjected to the amidation reaction of carboxylic acid to prepare propamide, and SF 6 Turning waste into treasure, the required raw materials are simple and easy to obtain, the reaction conditions are simple, green and energy-saving, and it has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the H NMR spectrum of (±)N,N-diethyl-2-(naphthalen-1-yloxy)propionamide described in Example 1 of the present invention;

[0045] Figure 2 This is the NMR carbon spectrum of (±) N, N-diethyl-2-(naphthalen-1-yloxy)propionamide described in Example 1 of the present invention. DETAILED DESCRIPTION

[0046] 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.

[0047] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0048] 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.

[0049] 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.

[0050] 1 H NMR and 13C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the references were: 1 H NMR:CHCl 3 7.260ppm; 13 C NMR:CHCl 3 It is 77.000ppm.

[0051] Example 1

[0052] Synthesis of (±)N,N-diethyl-2-(naphthalen-1-yloxy)propionamide (Napropamide)

[0053] 2-(1-Naphthyloxy)propionic acid (108.1 mg), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.8 mg) was added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and plugged with SF 6 Then, 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Diethylamine (517.3 μL) and N,N-diisopropylethylamine (434.6 μL) were then added, and the reaction system was placed under a 15 W, 465 nm blue LED light source, irradiated and stirred at room temperature for 20 hours, wherein, at an atmospheric pressure of SF 6 The mixture was stirred under a gas atmosphere. After the reaction was completed, the organic solvent was removed under vacuum and separated by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 3:1) to obtain (±) N, N-diethyl-2-(naphthalen-1-yloxy)propionamide. That is, 89.4 mg of the racemic form of propamide, with a yield of 66%.

[0054] The NMR spectrum of the product (±) N, N-diethyl-2-(naphthalen-1-yloxy) propionamide is as follows Figure 1 and 2 As shown, the NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ8.31–8.29(m,1H),7.81–7.78(m,1H),7.51–7.43(m,3H),7.35–7.32(m,2H),6.83–6.82(m,1H),5.1 2(q,J=6.8Hz,1H),3.62–3.53(m,1H),3.46–3.35(m,3H),1.73(d,J=6.8Hz,1H),1.13–0.98(m,6H)ppm. 13 C NMR (101 MHz, CDCl 3)δ170.2,153.1,134.5,127.4,126.4,125.7,125.6,125.3,122.0,120.9,105.7,41.0,40.3,17.9,14.1,12.6ppm.

[0055] As can be seen from Example 1, the present invention uses easily available 2-(1-naphthyloxy)propionic acid and diethylamine as reaction substrates, and uses commercially available Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 As a photocatalyst, cheap and readily available N,N-diisopropylethylamine was used as a base in an atmospheric pressure of SF 6 Under the condition of gas, at room temperature, using 15W 465nm blue light as the light source, the synthesis of propamide was simple and efficient. This method is a method for synthesizing propamide with mild conditions, simple operation, and easy industrial promotion. In addition, this method effectively activates and utilizes SF 6 This greenhouse gas, fully utilizing SF 6 The decomposition product is subjected to the amidation reaction of carboxylic acid to prepare propamide, and SF 6 Turn waste into treasure.

[0056] Example 2

[0057] Synthesis of (±)N,N-diethyl-2-(naphthalen-1-yloxy)propionamide (Napropamide)

[0058] 2-(1-Naphthyloxy)propionic acid (108.1 mg), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (5.6 mg) was added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and plugged with SF 6 A balloon was added, and then 2.0 mL of anhydrous tetrahydrofuran was added and bubbled for 3 minutes. Subsequently, diethylamine (51.7 μL) and N,N-diisopropylethylamine (87.5 μL) were added, and the reaction system was placed under a 15 W, 450 nm blue LED light source, irradiated and stirred at room temperature for 48 hours, wherein, at an atmospheric pressure of SF 6 The reaction mixture was stirred under a gas atmosphere. After the reaction was completed, the organic solvent was removed under vacuum and separated by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=3:1) to obtain (±) N,N-diethyl-2-(naphthalen-1-yloxy)propanamide.

[0059] Example 3

[0060] Synthesis of (±)N,N-diethyl-2-(naphthalen-1-yloxy)propionamide (Napropamide)

[0061] 2-(1-Naphthyloxy)propionic acid (108.1 mg), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (1.2 mg) was added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and plugged with SF 6 A balloon was added, and then 5.0 mL of anhydrous dichloromethane was added and bubbled for 3 minutes. Subsequently, diethylamine (1029 μL) and N,N-diisopropylethylamine (869.2 μL) were added, and the reaction system was placed under a 15 W, 480 nm blue LED light source, irradiated and stirred at room temperature for 5 hours, wherein, under an atmospheric pressure of SF 6 The reaction mixture was stirred under a gas atmosphere. After the reaction was completed, the organic solvent was removed under vacuum and separated by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=3:1) to obtain (±) N,N-diethyl-2-(naphthalen-1-yloxy)propanamide.

[0062] 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 naproxenamide using sulfur hexafluoride, characterized in that: The method uses diethylamine and 2-(1-naphthyloxy) propionic acid as raw materials, and reacts in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light to obtain the propamide.

2. The method for preparing naproxenamide using sulfur hexafluoride according to claim 1, characterized in that: The method comprises the following steps: adding 2-(1-naphthyloxy)propionic acid and a photocatalyst into a reaction device, adding an organic solvent after vacuuming, introducing sulfur hexafluoride gas, then adding diethylamine and a base, and placing the reaction system under a light source to react and obtain the naproxenamide.

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

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

5. The method for preparing naproxenamide using sulfur hexafluoride according to claim 1, characterized in that: The base is N,N-diisopropylethylamine.

6. The method for preparing naproxenamide using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the diethylamine to 2-(1-naphthyloxy)propionic acid is 1:1 to 20:

1.

7. The method for preparing naproxenamide using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the 2-(1-naphthyloxy)propionic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 2-(1-naphthyloxy)propionic acid to the base is 1:1-1:

10.

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

9. The method for preparing naproxenamide using sulfur hexafluoride according to claim 1, characterized in that: During the reaction process, the SF6 gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

10. The method for preparing naproxenamide using sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The usage ratio of the 2-(1-naphthyloxy)propionic acid and the organic solvent is 0.5-0.1 mmol:1 mL.

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