A kind of electrochemical catalytic synthesis method of phenidone

Abstract

The present invention provides an electrochemical catalytic synthesis method for phenidone, comprising the following steps: step (1), adding an electrolyte, phenylhydrazine, and acrylate to an organic solvent, then placing an anode electrode and a cathode electrode, and passing a direct current to perform an electrochemical catalytic reaction to obtain an intermediate 1; step (2), dissolving the intermediate 1 in an organic solvent, heating and refluxing under light-proof conditions to obtain a crude phenidone product; and step (3), recrystallizing the crude phenidone product to obtain a compound phenidone. The present invention utilizes an electrochemical method to study the reaction of phenylhydrazine and methyl acrylate. The reaction conditions are mild, the reaction occurs at room temperature, and the selectivity, yield, and safety are high. The method is a new method for synthesizing phenidone with high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for electrochemical catalytic synthesis of phenidone. Background Art

[0002] Phenidone is the transliteration of the trade name Pheaidone, and its chemical name is 1-phenyl-3-pyrazolidinone (CAS: 92-43-3). It is used as a developer for black photosensitive materials, with greater developing activity than metol. It is typically used in combination with hydroquinone to form PQ developer. Phenidone is also a commonly used pharmaceutical synthesis intermediate. It is an orally active dual inhibitor of cyclooxygenase (COX) and esteroxidase (LOX).

[0003] The current main synthesis method is to directly synthesize phenidone from phenylhydrazine hydrochloride and methyl acrylate or ethyl acrylate. The synthesis yield reported in CN108503587 is 60%, and the yield reported in Journal of Chemical Research, 42(1), 24-27, 2018 (Liu Jingjing, et al) is 75%. The yield is generally low, which may be mainly due to the low site selectivity of the reaction.

[0004]

[0005] In view of the important significance of phenidone in drug synthesis and development, a high-yield synthesis method is needed. Summary of the Invention

[0006] In view of the defects in the prior art, the object of the present invention is to provide a method for the electrochemical catalytic synthesis of phenidone, which has a high yield of phenidone and an environmentally friendly preparation process.

[0007] The object of the present invention is achieved through the following solutions:

[0008] A method for electrochemically catalyzing the synthesis of phenidone comprises the following steps:

[0009] Step (1), adding electrolyte, phenylhydrazine and acrylate to an organic solvent, then placing an anode electrode and a cathode electrode, and passing direct current to perform an electrochemical catalytic reaction to obtain intermediate 1;

[0010] Step (2), dissolving the intermediate 1 in an organic solvent, heating under reflux to obtain a crude phenidone product;

[0011] Step (3), recrystallizing the crude phenidone product to obtain the compound phenidone.

[0012] Preferably, the electrolyte is tetra-n-butylammonium perchlorate, n-Bu4NPF6, or n-Bu4NBF4. The electrolyte selection criteria are good solubility in organic solvents, strong ionicity, readily dissociated salts, and stability under electrolysis conditions. Quaternary ammonium salts with relatively long carbon chains ensure solubility in organic solvents; and highly ionic anions such as perchlorate, hexafluorophosphate, tetrafluoroborate, trifluoromethanesulfonate, sulfate, or bisulfate are preferred.

[0013] Preferably, the anode electrode is a graphite felt electrode, and the cathode electrode is a platinum sheet electrode. Graphite and platinum are two common materials used as electrodes.

[0014] Preferably, the current of the direct current is 5-20 mA, more preferably 15 mA. The optimal current selection is related to the voltage. In an electrolytic cell, the current intensity is generally relatively small (usually tens of mA). If the current is too large, more side reactions will occur.

[0015] Preferably, the direct current is applied for 3-5 hours, with the end of the reaction as the standard. After the raw materials are completely converted, continuing to apply power will only increase side reactions and reduce the yield.

[0016] Preferably, the acrylic acid ester is methyl acrylate or ethyl acrylate, because these two esters are cheap and have relatively small steric hindrance, which is conducive to ring closure and helps to improve the yield.

[0017] Preferably, the molar ratio of phenylhydrazine to acrylate is 1:1-1:5. When the ratio reaches 1:3, further increasing the amount of acrylate does not improve the reaction results. The molar ratio of phenylhydrazine to electrolyte is 30:1-50:1.

[0018] Preferably, in step (1), the organic solvent is acetonitrile, a mixed solvent of acetonitrile and methanol, or a mixed solvent of acetonitrile and water, preferably acetonitrile; and in step (2), the organic solvent is toluene.

[0019] Preferably, the solvent used for recrystallization is ethyl acetate.

[0020] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses an electrochemical method to study the reaction of phenylhydrazine and methyl acrylate, the reaction conditions are mild, the reaction occurs at room temperature, the selectivity is high, the yield is good, and the safety is high, and it is a new method for synthesizing phenidone with a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0022] Figure 1is the hydrogen spectrum of intermediate 1;

[0023] Figure 2 is the carbon spectrum of intermediate 1. DETAILED DESCRIPTION

[0024] The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several changes and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0025] Electrochemistry, as an efficient synthesis method, has gradually received more attention. In organic synthesis, electrons can replace stoichiometric oxidants and reducing agents as reactants that are clean and safe in nature, and different intermediates (free radicals, radical ions, cations and anions) are produced by electron transfer between substrate and electrode to react. We have studied the reaction of phenylhydrazine and methyl acrylate using an electrochemical method and obtained a new method for synthesizing phenidone in high yield. Its mechanism is that free radicals are produced by an electrochemical method at room temperature, and high selectivity is shown to the site where free radicals are produced. Michael addition reaction occurs between free radicals and methyl acrylate to generate intermediates, and the conversion rate is high. Therefore, the yield of electrochemical catalysis is higher than that of traditional synthesis methods in the prior art. Below in conjunction with specific embodiments, technical scheme of the present invention is further described.

[0026]

[0027] Example 1:

[0028] The electrochemical catalytic synthesis method of phenidone comprises the following steps:

[0029] Step (1) 200 mg of tetrabutylammonium perchlorate (0.6 mmol), 30 mL of acetonitrile, 3.24 g (30 mmol) of phenylhydrazine and 7.75 g (90 mmol) of methyl acrylate were added to a 50 mL three-necked flask equipped with a magnetic stirrer. A graphite felt electrode (15 mm × 10 mm × 0.2 mm) was used as the anode, and a platinum electrode (10 mm × 10 mm × 0.1 mm) was used as the cathode. The cathode and anode were immersed in the reaction solution respectively. The reaction solution was stirred at room temperature, and a constant current of 10 mA was supplied to the reaction solution through a DC stabilized current power supply. After about 4 hours of reaction, TLC showed that phenylhydrazine disappeared, generating intermediate 1. The electrodes were removed, and the reaction solution was evaporated to dryness under reduced pressure. The residue was dissolved in 40 mL of toluene, washed with 20 mL of water and 20 mL of 10% saline, dried over anhydrous sodium sulfate, and filtered. If the parameters of intermediate 1 are to be characterized, the reaction solution is evaporated to dryness under reduced pressure, and the residue is purified by silica gel column chromatography to separate intermediate 1 as a light yellow oil. Figure 1 As shown: 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (t, J = 7.6 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H), 3.70 (t, J = 6.8 Hz, 2H), 3.67 (s, 3H), 2.69 (t, J = 6.8 Hz, 2H). Figure 2 As shown: 13 C NMR (101MHz, Chloroform-d) δ: 173.17, 151.37, 129.22, 118.77, 113.22, 51.81, 51.27, 31.72. HRMS(ESI)m / z:[M+H] + Calcdfor C10H15N2O2 + 195.1129, found 195.1127.

[0030] Step (2): The filtrate was heated to reflux and maintained at reflux for 2 hours. TLC showed that the intermediate 1 disappeared, and the target compound phenidone was generated.

[0031] Step (3): The reaction solution of step (2) was evaporated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 4.42 g of light yellow solid phenidone, with a yield of 91%. The hydrogen spectrum data of phenidone are: 1H NMR (400 MHz, Chloroform-d): δ 8.93 (s, 1H), 7.35-7.21 (m, 2H), 7.12-6.92 (m, 3H), 3.96 (t, J = 8.0 Hz, 2H), 2.57 (t, J = 8.0 Hz, 2H). MS (ESI+): 163.0. Melting point: 118.4-120.5°C.

[0032] According to the conditions of Example 1, the usage ratio of phenylhydrazine and methyl acrylate was optimized, and the results are shown in the following table:

[0033] Table 1. Optimization of the dosage ratio of phenylhydrazine and methyl acrylate

[0034]

[0035] When the molar ratio of phenylhydrazine to methyl acrylate was 1 / 3, the yield of phenidone was 91%. When the amount of methyl acrylate was further increased to 1 / 4, the yield of phenidone did not increase.

[0036] According to the conditions of Example 1, the magnitude of the constant current is optimized, and the results are shown in the following table:

[0037] Table 2. Optimization of constant current

[0038]

[0039] When no current was applied, the reaction did not occur, indicating that the reaction between phenylhydrazine and methyl acrylate under these reaction conditions did not proceed via the conventional Michael addition mechanism. When the current was 15 mA, the reaction achieved the best yield of 92%.

[0040] Example 8

[0041] The difference from Example 1 is that ethyl acrylate is used instead of methyl acrylate. The other reaction conditions are the same as those in Example 1. The final yield of phenidone is 78%.

[0042] Characterization data of intermediate 1 (R=Et)

[0043] 1 H NMR(400MHz,Chloroform-d)δ7.18(t,J=7.6Hz,2H),6.89(d,J=8.0Hz,2H),6.72(t,J=7.2Hz,1 H), 4.05 (q, J = 7.2Hz, 2H), 3.62 (t, J = 6.8Hz, 2H), 2.59 (t, J = 6.8Hz, 2H), 1.16 (t, J = 7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ171.62,150.32,128.11,117.62,112.16,59.55,50.26,30.89,13.16.

[0044] Example 9

[0045] The difference from Example 1 is that n-Bu4NPF6 is used instead of tetrabutylammonium perchlorate. The other reaction conditions are the same as those in Example 1. The yield of phenidone obtained by silica gel column chromatography is 77%.

[0046] Comparative Examples 2-5

[0047] The difference from Example 1 is that tetrabutylammonium perchlorate is replaced with a different supporting electrolyte. The other reaction conditions are the same as in Example 1. The results are shown in Table 1:

[0048] Table 3. Experimental data of different supporting electrolytes

[0049]

[0050] a The product was separated by silica gel column chromatography and the separation yield was

[0051] The experimental results in combination with Example 1 and Table 3 show that the yield of phenidone obtained by using tetrabutylammonium perchlorate is the highest.

[0052] Comparative Examples 6-8

[0053] Table 4. Experimental data of different electrodes

[0054]

[0055] a The size of the graphite rod electrode is Φ6mm, and the solution immersion depth is about 10.0mm.

[0056] b The product was separated by silica gel column chromatography and the separation yield was

[0057] Combining the experimental results of Example 1 and Table 4, it is shown that the results of using the graphite felt (+) / platinum (-) electrode combination in Example 1 are better than those of the above electrodes.

[0058] In summary, the present invention uses an electrochemical method to study the reaction of phenylhydrazine and methyl acrylate, and provides an electrochemical catalytic synthesis method for phenidone. The yield of the obtained phenidone is high, and the preparation process is environmentally friendly, the reaction conditions are mild, the reaction occurs at room temperature, the selectivity is high, and the safety is high. This is a new method for synthesizing phenidone with high yield.

[0059] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. The embodiments of this application and the features in the embodiments may be combined with each other in any manner unless there is a conflict.

Claims

1. A method for electrochemically catalyzing the synthesis of phenidone, characterized in that: The following steps are involved: Step (1): adding electrolyte, phenylhydrazine and acrylate to an organic solvent, then placing an anode electrode and a cathode electrode, and passing a direct current to perform an electrochemical catalytic reaction to obtain an intermediate 1. Wherein, R=Me or Et, the electrolyte is tetrabutylammonium perchlorate, the anode electrode is a graphite felt electrode, and the cathode electrode is a platinum sheet electrode; the direct current current is 10 mA or 15 mA; and the molar ratio of phenylhydrazine to acrylate is 1:3; Step (2), dissolving the intermediate 1 in an organic solvent, heating under reflux to obtain a crude phenidone product; Step (3), recrystallizing the crude phenidone product to obtain the compound phenidone.

2. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The direct current is supplied for 3-5 hours.

3. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The molar ratio of the phenylhydrazine to the electrolyte is 30:1-50:

1.

4. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: In the step (1), the organic solvent is acetonitrile, a mixed solvent of acetonitrile and methanol, or a mixed solvent of acetonitrile and water; and in the step (2), the organic solvent is toluene.

5. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The solvent used for recrystallization was ethyl acetate.

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