A method for photoinduced N-alkylation

Abstract

The invention discloses a method for photoinduced N-alkylation, and belongs to the field of pharmaceutical compound synthesis. The method provided by the invention uses ferric chloride as a catalyst for a main reaction, performs a reaction under the condition of air or nitrogen, and obtains a dealkylation product under light irradiation at room temperature. The catalyst has high catalytic efficiency, and the yield of the product obtained by dealkylation is also high, which greatly reduces the experimental cost and is suitable for the synthesis and amplification of later compounds. The method provided by the invention has no expensive metal catalyst and oxidant, has the characteristics of high efficiency, green environmental protection, safety, saving experimental cost, and simple operation and post-processing.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical compound synthesis, and in particular to a method for photoinduced N-alkylation. Background Art

[0002] Nitrogen heterocyclic compounds are the most common substructures in drugs, agrochemicals, and natural products. In a survey of all small molecule drugs conducted by the U.S. Food and Drug Administration between 2015 and June 2020, it was found that 88% of the drugs contained one or more N-heterocyclic subunits. Therefore, carbon-nitrogen bonds are ubiquitous in organic molecules and biomolecules. As an important chemical transformation, N-dealkylation provides a pathway for the synthesis of a wide range of drugs, agrochemicals, etc. At the same time, it is ubiquitous in various transformations in the body and is an important in vivo metabolic pathway in exogenous metabolism. The cleavage of CN bonds in in vivo metabolic reactions is catalyzed by members of the cytochrome P450 enzyme family.

[0003] The existing literature reports that the dealkylation of nitrogen heterocycles has the disadvantages of requiring the use of expensive metal catalysts, oxidants and complex operations. A large number of studies have been conducted on the mechanism of enzyme-catalyzed N-dealkylation reactions. There are two possible mechanisms for the N-dealkylation of amines, namely hydrogen atom transfer (HAT) and single electron transfer. The methods of N-dealkylation mainly include chemical methods, transition metal catalysis, electrochemistry and photochemistry. Among them, chemical methods often use toxic reagents such as cyanogen bromide and chloroformate to react, and harsh conditions are required to hydrolyze the intermediates. Transition metal catalysis generally involves iron, palladium, gold, platinum, etc. Many catalysts are composed of metal complexes, which are expensive and complex in structure, or some catalysts need to be heated at high temperatures. Iron catalysts imitate cytochrome P450 enzymes and require the participation of oxidants. Photocatalysis is an emerging reaction, which is generally catalyzed in combination with precious metal complexes such as iridium and ruthenium.

[0004] Patent CN117024295A discloses a method for photoinduced dealkylation of amides and its application. The substrate disclosed in the invention mainly includes compounds with alkyl groups connected to amides. The reaction conditions introduce oxidants and bases, and the reaction system is complicated. There are few methods for dealkylation of five-membered nitrogen heterocycles in the prior art. Therefore, a convenient, environmentally friendly and safe method is urgently needed to achieve de-N-alkylation of five-membered nitrogen heterocycles. Summary of the invention

[0005] In order to overcome the above shortcomings, the purpose of the present invention is to provide a method for photoinduced dealkylation of N-alkyl groups to solve the technical problems of expensive metal catalysts, oxidants and complex operations required for dealkylation of nitrogen heterocycles.

[0006] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0007] A method for photoinduced N-alkylation, comprising the following steps: dissolving a compound represented by formula (1) in a solvent under a nitrogen or air atmosphere, adding a catalyst, and reacting under light to obtain a dealkylation product represented by formula (2);

[0008] ;

[0009] Wherein, R1-R3 are hydrogen, alkyl or halogen;

[0010] R4 is an alkyl group or a benzyl group.

[0011] Furthermore, the halogen is one of fluorine and chlorine.

[0012] Furthermore, the alkyl group in R4 is methyl or ethyl, and the alkyl group in R1-R3 is methyl or trifluoromethyl.

[0013] Furthermore, the catalyst is one of ferric sulfate, ferric nitrate or ferric chloride.

[0014] The catalyst is preferably ferric chloride.

[0015] Furthermore, the solvents are methanol-water or acetonitrile-water in a volume ratio of 5:1.

[0016] Furthermore, the wavelength range of light used in the illumination reaction is 245-525 nm.

[0017] The wavelength of light used in the light irradiation reaction is preferably 395 nm.

[0018] Furthermore, the reaction time of the illumination is 12-48 hours.

[0019] Furthermore, the molar ratio of the compound of formula (1) to the catalyst is 5:1.

[0020] Furthermore, the temperature of the light irradiation reaction is 0 to 45° C., preferably room temperature; the reaction time is 12 to 48 hours, preferably 48 hours.

[0021] Furthermore, the molar ratio of the compound of formula (1) to the catalyst is 5:1.

[0022] By adopting the above technical solution, the beneficial technical effects obtained by the present invention are:

[0023] (1) The method of the present invention is green, environmentally friendly, safe, and does not involve oxidants or toxic reagents;

[0024] (2) The method of the present invention is simple to operate. No expensive metal catalyst or oxidant is required in the dealkylation reaction of the nitrogen heterocycle. The subsequent dealkylation reaction is simple to operate and the method cost is low.

[0025] (3) The method of the present invention is highly efficient. Under a nitrogen-containing atmosphere, the catalytic efficiency of the catalyst and the yield of the dealkylation product are relatively high (up to 97.49%), which is suitable for the synthesis and amplification of subsequent compounds and greatly reduces the experimental cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The product prepared in Example 6 of the present invention 1 H NMR spectra;

[0027] Figure 2 The product prepared in Example 4 of the present invention 1 H NMR spectra;

[0028] Figure 3 The product prepared in Example 11 of the present invention 1 H NMR spectra;

[0029] Figure 4 The product prepared in Example 8 of the present invention 1 H NMR spectra;

[0030] Figure 5 The product prepared in Example 12 of the present invention 1 H NMR spectra. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings. It should be understood that these descriptions are only exemplary and are not intended to limit the scope of the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0032] Example 1

[0033] ;

[0034] In air atmosphere and room temperature, 1-methyl-3-phenyl-1 H -Pyrazole (31.64 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 15 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (25.23 mg, yield 87.50%). 1H NMR (800 MHz, CDCl3) δ 12.38 (s,1H), 7.67 (d, J = 7.3 Hz, 2H), 7.50 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 10.5,4.8 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.51 (d, J = 2.2 Hz, 1H).

[0035] Example 2

[0036] ;

[0037] In air atmosphere and room temperature, 1-ethyl-3-phenyl-1 H -Pyrazole (34.45 mg, 0.2 mmol, 1 eq), methanol: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (20.45 mg, yield 70.90%). 1 H NMR (800 MHz, CDCl3) δ 10.91 (s,1H), 7.80 (d, J = 8.1 Hz, 3H), 7.56 (d, J = 2.3 Hz, 3H), 6.60 (d, J = 2.3 Hz,1H).

[0038] Example 3

[0039] ;

[0040] Under nitrogen atmosphere at room temperature, 1-benzyl-3-phenyl-1 H -Pyrazole (46.86 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric sulfate (16.02 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (18.80 mg, yield 65.18%). 1 H NMR (800 MHz, CDCl3) δ 10.87 (s,1H), 7.80 (d, J = 8.1 Hz, 3H), 7.56 (d, J= 2.3 Hz, 3H), 6.60 (d, J = 2.3 Hz,1H).

[0041] Example 4

[0042] ;

[0043] 3-(2-fluorophenyl)-1-methyl-1 H -Pyrazole (35.24 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 12 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (29.46 mg, yield 90.82%). 1 H NMR (800 MHz, CDCl3)δ 10.57 (s, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.25 –7.23 (m, 1H), 7.15 – 7.13 (m, 1H), 7.10 (ddd, J = 11.5, 8.3, 0.9 Hz, 1H),6.67 (t, J = 2.0 Hz, 1H), spectrum as shown. Figure 2 shown.

[0044] Example 5

[0045] ;

[0046] Under nitrogen atmosphere at room temperature, 3-(2-fluorophenyl)-1-ethyl-1 H -Pyrazole (38.04 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 255 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (22.89 mg, yield 70.58%). 1H NMR (800 MHz, CDCl3)δ 12.79 (s, 1H), 7.48 – 7.44 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (d, J =7.6 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H).

[0047] Example 6

[0048] ;

[0049] In air atmosphere and room temperature, 1-ethyl-3-(4-fluorophenyl)-1 H -Pyrazole (38.04 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (22.41 mg, yield 69.10%). 1 H NMR (800 MHz, CDCl3)δ 12.24 (s, 1H), 7.63 (dd, J = 8.1, 5.6 Hz, 2H), 7.49 (d, J = 2.2 Hz, 1H),6.98 (t, J = 8.7 Hz, 2H), 6.47 (d, J = 2.2 Hz, 1H). The spectrum is shown in Figure 1 shown.

[0050] Example 7

[0051] ;

[0052] Under nitrogen atmosphere at room temperature, 1-benzyl-3-(4-fluorophenyl)-1 H -Pyrazole (50.46 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 455 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (25.06 mg, yield 77.25%). 1H NMR (800 MHz, CDCl3) δ12.24 (s, 1H), 7.63 (dd, J = 8.1, 5.6 Hz, 2H), 7.49 (d, J = 2.2 Hz, 1H), 7.00– 6.97 (m, 2H), 6.47 (d, J = 2.2 Hz, 1H).

[0053] Example 8

[0054] ;

[0055] 3-(4-chlorophenyl)-1-methyl-1 H -Pyrazole (38.53 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 24 hours under 520 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (30.00 mg, yield 83.98%). 1 H NMR (800 MHz, CDCl3)δ 10.69 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1H), 7.32 –7.30 (m, 2H), 6.54 (d, J = 2.3 Hz, 1H), spectrum as shown. Figure 4 shown.

[0056] Example 9

[0057] ;

[0058] 3-(4-chlorophenyl)-1-ethyl-1 H -Pyrazole (41.33 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (23.49 mg, yield 65.78%). 1H NMR (800 MHz, CDCl3)δ 10.72 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1H), 7.32 –7.30 (m, 2H), 6.54 (d, J = 2.3 Hz, 1H).

[0059] Example 10

[0060] ;

[0061] Under nitrogen atmosphere at room temperature, 1-benzyl-3-(4-chlorophenyl)-1 H -Pyrazole (53.75 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), and ferric nitrate (16.20 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 20 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (22.47 mg, yield 62.95%). 1 H NMR (800 MHz, CDCl3) δ11.35 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1H), 7.32 –7.30 (m, 2H), 6.54 (d, J = 2.3 Hz, 1H).

[0062] Embodiment 11

[0063] ;

[0064] In air atmosphere and room temperature, 1-methyl-3-m-tolyl-1 H -Pyrazole (34.45 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (20.35 mg, yield 64.30%). 1H NMR (800 MHz, CDCl3) δ 12.79 (s, 1H), 7.48 – 7.44 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz,1H), 6.48 (d, J = 1.9 Hz, 1H), 2.24 (s, 3H), the spectrum is as follows Figure 3 shown.

[0065] Example 12

[0066] ;

[0067] Under nitrogen atmosphere at room temperature, 1-benzyl-3-(4-(trifluoromethyl)phenyl)-1 H -Pyrazole (60.46 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (41.37 mg, yield 97.49%). 1 H NMR (800 MHz,CDCl3) δ 10.57 (s, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H),7.25 – 7.23 (m, 1H), 7.15 – 7.13 (m, 1H), 7.10 (ddd, J = 11.5, 8.3, 0.9 Hz,1H), 6.67 (t, J = 2.0 Hz, 1H), spectrum as shown. Figure 5 shown.

[0068] Example 13

[0069] ;

[0070] 1-Ethyl-3-(4-(trifluoromethyl)phenyl)-1 H -Pyrazole (48.05 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (4 mL), ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 10 mL quartz test tube and stirred for 18 hours under 395 nm light. After the reaction was completed, it was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the dealkylation product (32.53 mg, yield 76.64%).1 H NMR (800 MHz, CDCl3) δ 12.24 (s, 1H), 7.63 (dd, J = 8.1, 5.6 Hz, 2H), 7.49 (d, J = 2.2 Hz,1H), 7.00 – 6.97 (m, 2H), 6.47 (d, J = 2.2 Hz, 1H).

[0071] It can be seen from the above examples that the preparation method provided by the present invention can prepare a dealkylation product with a high yield by using only a simple catalyst and light under a nitrogen atmosphere.

[0072] It should be understood that the above specific embodiments of the present invention are only used to illustrate or explain the principles of the present invention, and do not constitute a limitation of the present invention. Therefore, any modifications, equivalent substitutions, improvements, etc. made without departing from the spirit and scope of the present invention should be included in the protection scope of the present invention. In addition, the appended claims of the present invention are intended to cover all changes and modifications that fall within the scope and boundaries of the appended claims, or the equivalent forms of such scope and boundaries.

Claims

1. A method for photoinduced N-alkylation, characterized in that: The following steps are involved: In a nitrogen or air atmosphere, the compound represented by formula (1) is dissolved in a solvent, a catalyst is added, and a light irradiation reaction is carried out at room temperature to obtain a dealkylation product represented by formula (2); ； Wherein, R1-R3 are hydrogen, alkyl or halogen; R4 is an alkyl group or a benzyl group; The catalyst is one of ferric sulfate, ferric nitrate or ferric chloride; The solvent is methanol-water or acetonitrile-water in a volume ratio of 5:

1.

2. The method of photoinduced N-alkylation according to claim 1, characterized in that: The halogen is fluorine or chlorine.

3. The method of photoinduced N-dealkylation according to claim 1, characterized in that: The alkyl group in R4 is methyl or ethyl, and the alkyl group in R1-R3 is methyl.

4. The method of photoinduced N-dealkylation according to claim 1, characterized in that: The catalyst is ferric chloride.

5. The method of photoinduced N-dealkylation according to claim 1, characterized in that: The light wavelength used in the illumination reaction is 245-525nm.

6. The method of photoinduced N-alkylation according to claim 5, characterized in that: The wavelength of light used in the light irradiation reaction is 395 nm.

7. The method of photoinduced N-alkylation according to claim 1, characterized in that: The light reaction time is 12-48 hours.

8. The method of photoinduced N-alkylation according to claim 1, characterized in that: The molar ratio of the compound of formula (1) to the catalyst is 5:

1.

9. A method for photoinduced N-dealkylation, characterized in that: The following steps are involved: In a nitrogen or air atmosphere, the compound represented by formula (1) is dissolved in a solvent, a catalyst is added, and a light irradiation reaction is carried out at room temperature to obtain a dealkylation product represented by formula (2); ； Wherein, the catalyst is one of ferric sulfate, ferric nitrate or ferric chloride; The solvent is methanol-water or acetonitrile-water in a volume ratio of 5:1; The alkyl group in R4 is methyl or ethyl, and R1-R3 are trifluoromethyl.

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