A method for synthesizing N-alkylazole compounds

Abstract

This invention discloses a method for synthesizing N-alkylazole compounds, relating to the field of photochemical synthesis technology. The synthetic method provided by this invention includes utilizing photocatalysis at room temperature to break down the N-H bonds of azoles and the α-C(sp) bonds of amines. 3 The N-alkylazole compounds are synthesized through cross-coupling of H-bonds. The reaction does not require pre-activated substrates, metal catalysts, photocatalysts, or oxidants. It is mild, simple to operate, and has both step economy and atom economy.

Description

Technical Field

[0001] This invention relates to the field of photochemical synthesis technology, specifically to a method for synthesizing N-alkylazole compounds. Background Technology

[0002] N-alkylazole compounds are widely present as pharmacophores in active drug molecules due to their unique structure and properties. For example, bifonazole, which contains an N-benzylimidazole skeleton, is a broad-spectrum antifungal drug used to treat various tinea infections; vorozole, which contains an N-alkyltriazole skeleton, is a non-steroidal aromatase inhibitor with antitumor activity and shows significant potential for application in breast cancer research.

[0003] The strategy of combining transition metal catalysts with oxidants is currently the most effective way to achieve the bonding of NH bonds and alkyl C(sp) bonds in azole compounds. 3 The cross-coupling reaction of H-bonds is one of the effective ways to synthesize N-alkylazole compounds. However, such catalytic systems generally require stoichiometric organic / inorganic peroxides, high reaction temperatures, and metal catalysts, especially expensive metal photocatalysts. Reactions involving metals have potential problems such as metal residues, environmental pollution, high toxicity, and high costs; the addition of stoichiometric oxidants often leads to cumbersome post-processing, or generates waste and triggers unnecessary side reactions, while also posing challenges to the operability and safety of the reaction. Therefore, there is an urgent need to provide a solution to improve these problems. Summary of the Invention

[0004] This invention aims to provide a method for synthesizing N-alkylazole compounds, utilizing photocatalysis of the NH bond of azoles and the α-C(sp) bond of amines. 3 The N-alkylazole compounds are synthesized by cross-coupling of H-bonds. The reaction does not require the participation of metal catalysts, photocatalysts and oxidants. The conditions are mild and the operation is simple, with both step economy and atom economy.

[0005] This invention provides a method for synthesizing N-alkylazole compounds, comprising irradiating an azole compound and an amine compound with visible light in a solvent environment to react and generate N-alkylazole compounds.

[0006] The synthesis method provided by this invention does not require activation of the reaction substrate. Under normal temperature and visible light irradiation, it utilizes photocatalysis of the NH bond of azoles and the α-C(sp) bond of amines. 3 N-alkylazole compounds are synthesized via cross-coupling of H-bonds. This method is characterized by mild reaction conditions, simple operation, safety, and environmental friendliness. It requires no metal catalysts, photocatalysts, or oxidants and exhibits atom economy and step economy, aligning with the principles of green development.

[0007] Optionally, the solvent includes an organic solvent, specifically, at least one selected from acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, dichloromethane, 1,2-dichloroethane, methanol, ethanol, and isopropanol.

[0008] Optionally, the reaction conditions are at room temperature.

[0009] Optionally, the visible light wavelength range is 300nm-800nm.

[0010] Optionally, the visible light source includes any one of LED, xenon lamp, mercury lamp and sun lamp, and the irradiation time is 0.5h-24h.

[0011] Optionally, the structure of the azole compound is shown in formula (I) or (II):

[0012]

[0013] R1, R2, and R3 are independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0014] R4, R5, R6, R7, and R8 are each independently one of H, OCH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0015] Optionally, the structure of the amine compound is as shown in formula (III) or (IV):

[0016]

[0017] R9 is aryl, R 10 R 11 R 12 and R 13 The elements are independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0018] R 14R is any one of CH3, CH3CH2, (CH3)2CH, (CH3)3C, and Ph. 15 R 16 R 17 R 18 and R 19 The elements are independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0019] Optionally, the concentration of the azole compound in the solvent environment is 1 / 30 mol / L to 1 / 3 mmol / L.

[0020] Optionally, the amine compound is provided in excess of the azole compound in a solvent environment.

[0021] Optionally, the method includes the following steps: adding azole compounds and amine compounds to a solvent to obtain a mixed solution; irradiating the mixed solution with visible light at room temperature to react and generate N-alkylazole compounds. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments are briefly introduced below.

[0023] Figure 1 The 1H NMR spectrum of 2-phenyl-1-(1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline synthesized in Example 1 of this invention;

[0024] Figure 2 The image shows the carbon NMR spectrum of 2-phenyl-1-(1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline synthesized in Example 1 of this invention. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described below with reference to the accompanying drawings and through the following embodiments. However, the following embodiments are illustrative and are only used to specifically describe the present invention, and not to limit the present invention.

[0026] In addition, unless otherwise specified, all raw materials used in this invention can be obtained commercially available. Any range described in this invention includes the end value and any value between the end values, as well as any subrange formed by the end value or any value between the end values.

[0027] This invention provides a method for synthesizing N-alkylazole compounds, the specific synthetic route being as follows: Figure 1As shown, this involves irradiating azole compounds and amine compounds with visible light in a solvent environment to react and generate N-alkylazole compounds.

[0028] In some embodiments, the structure of azole compounds is shown in formula (I) or (II):

[0029]

[0030] Specifically, R1, R2, and R3 are each independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0031] Specifically, R4, R5, R6, R7, and R8 are each independently one of H, OCH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0032] In some embodiments, the structure of the amine compound is shown in formula (III) or (IV):

[0033]

[0034] Specifically, R9 is aryl, R 10 R 11 R 12 and R 13 The elements are independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0035] Specifically, R 14 R is any one of CH3, CH3CH2, (CH3)2CH, (CH3)3C, and Ph. 15 R 16 R 17 R 18 and R 19 The elements are independently selected from H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, CH2OH, COOCH3, COOCH2CH3, CF3, F, Cl, Br, NH2, OH, CN, NO2, OCH2Ph, and Ph.

[0036] Specifically, when an azole compound with structural formula (I) reacts with an amine compound with structural formula (III) under visible light to form an N-alkylazole compound, the reaction equation is as follows:

[0037]

[0038] Specifically, when an azole compound of formula (I) reacts with an amine compound of formula (IV) under visible light to form an N-alkylazole compound, the reaction equation is as follows:

[0039]

[0040] Specifically, when an azole compound with structural formula (II) reacts with an amine compound with structural formula (III) under visible light to form an N-alkylazole compound, the reaction equation is as follows:

[0041]

[0042] Specifically, when an azole compound of formula (II) reacts with an amine compound of formula (IV) under visible light to form an N-alkylazole compound, the reaction equation is as follows:

[0043]

[0044] In some embodiments, the solvent includes an organic solvent, specifically, at least one selected from acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, dichloromethane, 1,2-dichloroethane, methanol, ethanol, and isopropanol.

[0045] In some embodiments, when the mixed solution is irradiated with visible light, the reaction condition is room temperature.

[0046] In some embodiments, the visible light wavelength range is 300nm-800nm.

[0047] In some embodiments, the visible light source includes any one of LED, xenon lamp, mercury lamp and sun lamp, and the irradiation time is 0.5h-24h.

[0048] In some embodiments, the concentration of the azole compound in the solvent environment is 1 / 30 mol / L to 1 / 3 mol / L.

[0049] In some embodiments, the amine compound is provided in excess of the azole compound in a solvent environment.

[0050] In fact, the method for synthesizing N-alkylazole compounds provided by this invention includes the following steps:

[0051] S1. Add azole compounds and amine compounds to a solvent to obtain a mixed solution;

[0052] S2. At room temperature, the mixed solution is irradiated with visible light to react and generate N-alkylazole compounds.

[0053] Specifically, after the N-alkylazole compounds are generated in step S2, the N-alkylazole compounds can be separated using purification and separation methods commonly used in the art, including but not limited to vacuum concentration and column chromatography.

[0054] Example 1

[0055] Example 1 of this invention provides a method for synthesizing N-alkylazole compounds, specifically including the following steps:

[0056] S1. Add 3 mL of acetonitrile to a 10 mL test tube, and add 0.1 mmol of pyrazole (CAS: 288-13-1) and 0.15 mmol of 2-phenyl-1,2,3,4-tetrahydroisoquinoline (CAS: 3340-78-1) to the test tube to obtain a mixed solution;

[0057] S2. At room temperature, the mixture obtained in step S1 was irradiated with LED blue light (λ=405nm) for 1h. The solvent was evaporated and the mixture was separated by silica gel column chromatography to obtain 22.2 mg of 2-phenyl-1-(1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline. The calculated yield was 81%, as shown in Table 1.

[0058] Table 1. Synthesis results in Example 1

[0059]

[0060] The 2-phenyl-1-(1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline prepared in Example 1 was characterized by 1H NMR spectroscopy as follows: Figure 1 As shown, the carbon NMR characterization is as follows: Figure 2 As shown.

[0061] Examples 2 to 4

[0062] Examples 2 to 4 of this invention provide a method for synthesizing N-alkylazole compounds. The difference from Example 1 is that the solvent used in step S1 is as shown in Table 2.

[0063] Table 2. Yields of different solvents and products in Examples 2 to 4

[0064] serial number Solvent types Product yield (%) Example 2 acetone 74 Example 3 dichloroethane 52 Example 4 N,N-Dimethylformamide 64

[0065] According to the results shown in Tables 1 and 2, the product yield was relatively the highest when acetonitrile was used as the solvent in step S1.

[0066] Examples 5 to 7

[0067] Examples 5 to 7 of this invention provide a method for synthesizing N-alkylazole compounds. The difference from Example 1 is that the wavelength of the light source used in step S2 is as shown in Table 3.

[0068] Table 3. Light source wavelengths and product yields in Examples 5 to 7.

[0069] serial number Light source wavelength (nm) Product yield (%) Example 5 365 64 Example 6 445 21 Example 7 505 10

[0070] According to the results shown in Tables 1 and 3, the product yield was the highest when a light source with a wavelength of 405 nm was used in step S2.

[0071] Examples 8 to 20

[0072] Examples 8 to 20 of the present invention provide a method for synthesizing N-alkylazole compounds. The difference from Example 1 is that the types of amine compounds used in step S1 are shown in Table 4.

[0073] Table 4. Different amine compounds and synthesis results in Examples 8 to 20

[0074]

[0075]

[0076]

[0077]

[0078] Examples 21 to 53

[0079] Examples 21 to 53 of this invention provide methods for synthesizing N-alkylazole compounds, which differ from Example 1 in that the types of azole compounds used in step S1 are different. The results are shown in Table 5.

[0080] Table 5. Different azole compounds and synthesis results in Examples 21 to 53

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.

Claims

1. A kind N A method for synthesizing alkylazole compounds, characterized in that, In an organic solvent environment, irradiation of azole and amine compounds with visible light in the wavelength range of 365 nm-405 nm produces a reaction that generates... N -alkylazole compounds; The organic solvent is selected from acetonitrile, acetone, etc. N , N -Dimethylformamide, N , N -At least one of dimethylacetamide, ethyl acetate, dichloromethane, 1,2-dichloroethane, methanol, ethanol and isopropanol; The structures of the azole compounds are shown in Formula I or II: or ; R1, R2, and R3 are each independently one of H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, COOCH3, COOCH2CH3, CF3, F, Cl, Br, CN, NO2, OCH2Ph, and Ph; R4, R5, R6, R7, and R8 are each independently one of H, OCH3, CH3CH2, (CH3)2CH, (CH3)3C, COOCH3, COOCH2CH3, CF3, F, Cl, Br, CN, NO2, OCH2Ph, and Ph; The structure of the amine compound is shown in Formula III: ； R9 is aryl, R 10 R 11 R 12 and R 13 The components are independently H, OCH3, CH3, CH3CH2, (CH3)2CH, (CH3)3C, COOCH3, COOCH2CH3, CF3, F, Cl, Br, CN, NO2, OCH2Ph, and Ph. The N The structure of alkylazole compounds is shown in the following formula: or .

2. The synthesis method according to claim 1, characterized in that, When the visible light is irradiated: the reaction condition is room temperature; and / or the light source of the visible light includes any one of LED, xenon lamp, mercury lamp and sun lamp; and / or the irradiation time is 0.5 h to 24 h.

3. The synthesis method according to claim 1, characterized in that, The concentration of the azole compound in the solvent environment is 1 / 30 mol / L to 1 / 3 mol / L; and / or, the amine compound is set in excess of the azole compound in the solvent environment.

4. The synthesis method according to any one of claims 1 to 3, characterized in that, Includes the following steps: A azole compound and an amine compound were added to an organic solvent to obtain a mixed solution; the mixed solution was then irradiated with visible light at room temperature, and the reaction produced... N - Alkylazole compounds.

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