A process for the preparation of cx546 using sulfur hexafluoride

Abstract

The application discloses a method for preparing CX546 by using sulfur hexafluoride, which takes hexahydropyridine and 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid as raw materials, and performs a reaction under the conditions of a photocatalyst, an alkali, sulfur hexafluoride and light irradiation in an organic solvent to obtain the CX546. The method has the characteristics of mild reaction conditions, cheap and easily obtained reaction raw materials, cost saving, environmental friendliness and industrial promotion. The method effectively activates and utilizes the greenhouse gas SF6, fully utilizes the SF6 decomposition product to realize the amidation reaction of the carboxylic acid to prepare the CX546, changes the SF6 from waste to treasure, the required raw materials are simple and easily obtained, the reaction conditions are simple, green and energy-saving, and the method has high application value.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of drug synthesis, in particular to a method for preparing CX546 by using sulfur hexafluoride. BACKGROUND

[0002] Amidation reaction is the most commonly used organic synthesis reaction. According to a research on drug synthesis, 65% of drug synthesis processes use amidation reaction. In addition, amidation products play an important role in the biological medical, pharmaceutical and food industries and have wide application in industrial products. For example, thioamide can modify peptide units and proteins, and thioamide modification can significantly improve the stability and activity of peptide drugs; hydroxycinnamic acid amide derived from tyramine in plant food can be used as a food preservative due to its natural antioxidant effect; and amide grease is often used in the fields of nuclear power and aerospace due to its excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the synthesis of amide compounds is mainly achieved by the following methods.

[0003] Method one: 3,4,5-trifluorobenzene boronic acid is used to catalyze the amidation reaction of carboxylic acid and amine.

[0004]

[0005] The method is suitable for the reaction of primary amine and tertiary amine with carboxylic acid, and is also suitable for some special substrates with large steric hindrance and olefin groups, but requires high-temperature (> 100 DEG C) and water-free conditions, and has the problem of low atomic economy.

[0006] Method two: two kinds of zirconium catalysts (ZrCp2Cl2 / ZrCl4) are used to catalyze the amidation reaction of carboxylic acid and amine under the conditions of toluene solvent and 110 DEG C heating reflux.

[0007]

[0008] The method has high yield and can realize the synthesis of acetaminophen and moricizine two drug molecules at a high yield, but the method introduces metal compounds and requires high-temperature conditions.

[0009] Method three: active ester is used as an acyl source, and zinc powder is used as a catalyst to realize the synthesis of secondary amide 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 reusable catalyst. However, the scope of the substrate is relatively narrow, and alcohol is also generated, which causes great difficulty in the separation of subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation method which is simple and easy to obtain raw materials, simple operation, high reaction yield, good functional group tolerance, environment-friendly, and easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at normal temperature and pressure. It is an inert gas with very high stability, which does not decompose at high temperatures of 500-600℃, and does not react with acids, bases, water, etc. It is also an insulating gas with excellent insulating properties and can be used to eliminate high-voltage arcs, so SF6 is widely used in the field of electric power. However, SF6 has a strong greenhouse effect, with a climate warming power of 23900 times that of CO2. Secondly, SF6 is a synthetic gas with very stable chemical properties, and it is extremely difficult to decompose. Its natural life in the atmosphere can last for more than 3,000 years. With the continuous accumulation in the atmosphere, the greenhouse effect it brings is also increasing. Therefore, the emission of SF6 is strictly limited, and the large amount of SF6 stored in the field of electric power is facing great pressure in handling.

[0014] CX546 is a typical ampakine drug, a selective positive modulator of the glutamate receptor alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), which has antipsychotic function and is a potential drug for the treatment of schizophrenia. In addition, CX546 has the effect of enhancing synaptic plasticity, can induce neuroprotection and promote the expression of neurotrophic factors. At present, there is no report on the preparation of CX546 from sulfur hexafluoride. SUMMARY

[0015] The technical problem to be solved by the present application is how to simply, safely and greenly prepare CX546.

[0016] The present application solves the above technical problems by the following technical means:

[0017] A method for preparing CX546 from sulfur hexafluoride, which uses piperidine and 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid as raw materials, reacts in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light to obtain the CX546.

[0018] Preferably, the method for preparing CX546 from sulfur hexafluoride comprises the following steps: adding 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid and a photocatalyst into a reaction device, vacuumizing, then adding an organic solvent, introducing sulfur hexafluoride gas, and then adding piperidine and a base, and placing the reaction system under a light source to obtain the CX546.

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

[0020] Preferably, the organic photocatalyst is a mixture of one or both of 4CZIPN, Mes-Acr + ClO4 — (9-cymene-10-methylacridine perchlorate).

[0021] Preferably, the transition metal photocatalyst is a mixture of one or both of Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6.

[0022] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

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

[0024] Preferably, the organic solvent is acetonitrile.

[0025] The present application is carried out in a system of a single organic solvent; if necessary, other organic solvents can also be present in the system, but from the perspective of reaction yield and the simplicity of operation, it is preferred that no other organic solvents are added, i.e. a single organic solvent is used 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 hexahydropyridine to 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid is 1:1-20:1.

[0030] Preferably, the molar ratio of hexahydropyridine to 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid is 10:1.

[0031] Preferably, the molar ratio of 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid to photocatalyst is 100:0.2-1; the molar ratio of 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid to base is 1:1-1:10.

[0032] Preferably, the molar ratio of 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid to base is 1:5.

[0033] Preferably, the molar ratio of the 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid and the photocatalyst is 100:0.5.

[0034] Preferably, during the irradiation, a blue light of 15 W, 450-480 nm is used as the light source.

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

[0036] Preferably, during the reaction, the SF6 gas has a pressure of 1 atm, the reaction temperature is 0-50 DEG C, and the time is 5-48 h.

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

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

[0039] Preferably, the amount ratio of the 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid and the organic solvent is 0.5-0.1 mmol:1 mL.

[0040] Preferably, the amount ratio of the 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid and the organic solvent is 0.17 mmol:1 mL; and the product has the highest yield.

[0041] Preferably, during the reaction, the decomposition product of SF6 is used as the condensation reagent.

[0042] The present application has the following advantages:

[0043] In the present application, the simple and readily available hexahydropyridine and 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid are used as the reaction substrates, the commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like are used as the photocatalyst, the cheap and readily available N,N-diisopropylethylamine and the like are used as the base, and the amide compound CX546 is simply and efficiently synthesized under SF6 gas. The present application has the characteristics of mild reaction conditions, cheap and readily available reaction raw materials, cost saving, environmental friendliness, and industrial promotion. The method effectively activates and utilizes the greenhouse gas SF6, fully utilizes the decomposition product of SF6 to realize the amidation reaction of the carboxylic acid to prepare the CX546, changes the waste SF6 into treasure, the raw materials are simple and readily available, the reaction conditions are simple, green, and energy-saving, and the method has high application value. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 NMR spectrum of the benzodioxane-6-(1-piperidinyl)methylamide described in the present application example 1;

[0045] Figure 2The carbon spectrum of the benzodioxane-6-(1-piperidinyl)formamide described in Example 1 of the present application. DETAILED DESCRIPTION

[0046] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present application.

[0047] In the following examples, the test materials and reagents used, unless otherwise specified, can be obtained commercially.

[0048] In the embodiments, if the specific techniques or conditions are not specified, the techniques or conditions described in the literature in the art or according to the product instructions can be used.

[0049] In the following specific embodiments, the raw materials used are commercially available, and the reagents are purified by means known in the art if necessary before use.

[0050] 1 H NMR and 13 Both H NMR and C NMR were measured by using a Bruker Avance 400 spectrometer instrument. The test temperature was room temperature, the solvent was deuterated chloroform, and the reference was selected as: 1 H NMR: 7.260 ppm in CHCl3; 13 C NMR: 77.000 ppm in CHCl3.

[0051] Example 1

[0052] Synthesis of benzodioxane-6-(1-piperidinyl)formamide (CX546)

[0053] 2,3-dihydro-1,4-benzodioxin-6-carboxylic acid (90.1 mg), Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.8 mg) were added into a 12 mL headspace glass vial with PTFE liner, which was vacuumed and inserted with SF6 balloon, then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 min. Subsequently, hexahydropyridine (493.9 μL), N,N-diisopropylethylamine (434.6 μL) were added, the reaction system was placed under a 15 W, 465 nm blue LED light source, irradiated and stirred at room temperature for 20 h; wherein the reaction was carried out under one atmosphere of SF6 gas, after the reaction was completed, the organic solvent was removed under vacuum, and benzodioxan-6-(1-piperidinyl)formamide was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 by volume) i.e. CX546 42.0 mg, yield 34%.

[0054] The nuclear magnetic spectrum of the product benzodioxan-6-(1-piperidinyl)formamide is shown in Figure 1 and 2 The nuclear magnetic data are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.92-6.83 (m, 3H), 4.26 (s, 4H), 3.63-3.39 (m, 4H), 1.65-1.57 (m, 6H) ppm. 13 C NMR (101 MHz, CDCl3) δ 169.7, 144.6, 143.2, 129.5, 120.4, 117.1, 116.4, 64.4, 64.2, 24.6 ppm.

[0055] As can be known from Example 1, the present application uses simple and readily available 2,3-dihydro-1,4-benzodioxin-6-carboxylic acid and hexahydropyridine as reaction substrates, uses commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, uses inexpensive and readily available N,N-diisopropylethylamine as a base, uses 15 W of 465 nm blue light as a light source at room temperature under one atmosphere of SF6 gas, and simply and efficiently synthesizes CX564. The method is a synthesis method of CX564 which is mild in conditions, simple in operation and easy to promote in industry. Moreover, the method effectively activates and utilizes SF6, a greenhouse gas, to fully utilize the decomposition products of SF6 to prepare CX564, and turns SF6 into treasure.

[0056] Example 2

[0057] Synthesis of benzodioxan-6-(1-piperidinyl)formamide (CX546)

[0058] Into a 12 mL headspace glass vial with PTFE liner, 2,3-dihydro-1,4-benzodioxin-6- carboxylic acid (90.1 mg), Ir[dF(CF3)ppy]2(dtbbpy)PF6(1.2 mg) were added, and then the vial was evacuated and capped with a SF6 balloon. Subsequently, 5.0 mL of anhydrous tetrahydrofuran was added and bubbled for 3 minutes. Then, hexahydropyridine (49.4 μL), N,N- diisopropylethylamine (87.5 μL) were added, and the reaction system was irradiated under a 15 W, 480 nm blue LED lamp source and stirred at room temperature for 20 hours; wherein the reaction was carried out under one atmosphere of SF6 gas, and after the reaction was completed, the organic solvent was removed under vacuum, and benzodioxan-6-(1-piperidinyl)formamide was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 by volume).

[0059] Example 3

[0060] Synthesis of benzodioxan-6-(1-piperidinyl)formamide (CX546)

[0061] Into a 12 mL headspace glass vial with PTFE liner, 2,3-dihydro-1,4-benzodioxin-6- carboxylic acid (90.1 mg), Ir[dF(CF3)ppy]2(dtbbpy)PF6(1.2 mg) were added, and then the vial was evacuated and capped with a SF6 balloon. Subsequently, 5.0 mL of anhydrous tetrahydrofuran was added and bubbled for 3 minutes. Then, hexahydropyridine (49.4 μL), N,N- diisopropylethylamine (87.5 μL) were added, and the reaction system was irradiated under a 15 W, 480 nm blue LED lamp source and stirred at room temperature for 20 hours; wherein the reaction was carried out under one atmosphere of SF6 gas, and after the reaction was completed, the organic solvent was removed under vacuum, and benzodioxan-6-(1-piperidinyl)formamide was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 by volume).

[0062] The above examples are only used to illustrate the technical solutions of the present application, but not limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A process for the preparation of CX546 using sulfur hexafluoride, characterized in that: The CX546 is obtained by using hexahydropyridine and 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid as raw materials, and performing a reaction in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light irradiation.

2. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: The method comprises the following steps: 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid and a photocatalyst are added into a reaction device, an organic solvent is added after vacuumizing, sulfur hexafluoride gas is introduced, then hexahydropyridine and a base are added, and the reaction system is placed under a light source to obtain the CX546.

3. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

4. The process for the preparation of CX546 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 process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: The base is N,N-diisopropyl ethylamine.

6. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of hexahydropyridine to 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid is 1:1-20:

1.

7. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid to the photocatalyst is 100:0.2-1, and the molar ratio of 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid to the base is 1:1-1:

10.

8. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: During the light irradiation, blue light with a wavelength of 450-480 nm and a power of 15 W is used as the light source.

9. The process for the preparation of CX546 using sulfur hexafluoride according to claim 1, characterized in that: During the reaction, the pressure of the SF6 gas is 1 atm, the reaction temperature is 0-50 DEG C, and the reaction time is 5-48 h.

10. The process for the preparation of CX546 with sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The amount ratio of 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid to the organic solvent is 0.5-0.1 mmol:1 mL.

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