Electrochemical catalytic synthesis method of phenidone

Abstract

The invention provides an electrochemical catalytic synthesis method of phenidone, which comprises the following steps: step (1), adding electrolyte, phenylhydrazine and acrylate into an organic solvent, then putting into an anode electrode and a cathode electrode, and electrifying direct current to carry out electrochemical catalytic reaction to obtain an intermediate 1; (2) dissolving the intermediate 1 in an organic solvent, and heating and refluxing under a dark condition to obtain a phenidone crude product; and (3) recrystallizing the phenidone crude product to obtain the compound phenidone. The reaction of phenylhydrazine and methyl acrylate is researched by utilizing an electrochemical method, the reaction condition is mild, the reaction is performed at room temperature, the selectivity is high, the yield is good, the safety is high, and the method is a novel method capable of synthesizing the phenidone at high yield.

Description

Technical Field

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

[0002] Pheidone 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, and its developing activity is greater than that of metol, and it is usually used in combination with hydroquinone to form PQ developer. At the same time, phenidone is also a commonly used drug synthesis intermediate. It is an orally active dual inhibitor of cyclooxygenase (COX) and esteroxidase (LOX).

[0003] The main synthesis method at present 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 not high, 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, it is necessary to study a synthesis method with high yield. 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 electrochemically catalyzing the synthesis of phenidone, the yield of the obtained phenidone is high, and the preparation process is environmentally friendly.

[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 into an organic solvent, then placing an anode electrode and a cathode electrode, and passing direct current to perform an electrochemical catalytic reaction to obtain an 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 selection criteria of the electrolyte are good solubility in organic solvents, strong ionicity, easy dissociation of salts, and self-stability under electrolysis conditions. Quaternary ammonium salts have a relatively long carbon chain length to ensure solubility in organic solvents; anions are highly ionic, such as perchlorate, hexafluorophosphate, tetrafluoroborate, trifluoromethanesulfonate, and sulfate or hydrogen sulfate.

[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 small (usually tens of mA). If the current is too large, there will be more side reactions.

[0015] Preferably, the direct current is supplied for 3-5 hours, with the end of the reaction as the standard. After the raw material is completely converted, continuing to supply 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 result. 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 is carried out at room temperature, the selectivity is high, the yield is good, and the safety is high. 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 from the detailed description of non-limiting embodiments made with reference to the following drawings:

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

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

[0024] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments 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 of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0025] As an efficient synthesis method, electrochemistry has gradually received more attention. In organic synthesis, electrons can replace stoichiometric oxidants and reductants as essentially clean and safe reactants, 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 of free radicals and methyl acrylate generates 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. The technical scheme of the present invention is further described below in conjunction with specific embodiments.

[0026]

[0027] Embodiment 1:

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

[0029] Step (1), add 200mg tetrabutylammonium perchlorate (0.6mmol), 30mL acetonitrile, 3.24g (30mmol) phenylhydrazine and 7.75g (90mmol) methyl acrylate in a 50mL three-necked bottle equipped with a magnetic stirrer. A graphite felt electrode (15mm×10mm×0.2mm) is used as the anode, and a platinum sheet electrode (10mm×10mm×0.1mm) is used as the cathode, and the cathode and the anode are immersed in the reaction solution respectively. The reaction solution is stirred at room temperature, and a 10mA constant current is passed into the reaction solution through a DC current-stabilized power supply. After about 4 hours of reaction, TLC shows that phenylhydrazine disappears and intermediate 1 is generated. The electrode is removed, and the reaction solution is evaporated to dryness under reduced pressure. The residue is dissolved in 40mL toluene, washed with 20mL water and 20mL 10% brine, 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 (400MHz, Chloroform-d) δ7.26 (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). Carbon spectrum data are as follows 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), heating the filtrate to reflux and maintaining reflux for 2 hours, TLC shows that the intermediate 1 disappears, and the target compound phenidone is 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 is: 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 dosage 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 phenylhydrazine to methyl acrylate (molar ratio) of 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 the present reaction conditions was not through the usual Michael addition mechanism. When the current was 15 mA, the reaction achieved the best yield of 92%.

[0040] Embodiment 8,

[0041] The difference from Example 1 is that ethyl acrylate is used instead of methyl acrylate, and 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, and the other reaction conditions are the same as those in Example 1. The yield of phenidone finally 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, and the other reaction conditions are the same as those 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: Φ6mm, 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 result of using the graphite felt (+) / platinum (-) electrode combination in Example 1 is better than the results 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 of phenidone. The yield of the obtained phenidone is high, and the preparation process is environmentally friendly, the reaction conditions are mild, the reaction is carried out at room temperature, the selectivity is high, and the safety is high. The present invention is a new method for synthesizing phenidone with high yield.

[0059] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various changes or modifications within the scope of the claims, which does not affect the essence of the present invention. In the absence of conflict, the embodiments of the present application and the features in the embodiments can be combined with each other arbitrarily.

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 into an organic solvent, then placing an anode electrode and a cathode electrode, and passing direct current to perform an electrochemical catalytic reaction to obtain an intermediate 1; 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 electrolyte is tetrabutylammonium perchlorate, n-Bu4NPF6 or n-Bu4NBF4.

3. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The anode electrode is a graphite felt electrode, and the cathode electrode is a platinum sheet electrode.

4. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The current of the direct current is 5-20 mA.

5. The electrochemical catalytic synthesis method of phenidone according to claim 1 or 4, characterized in that: The direct current is switched on for 3-5 hours.

6. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The acrylate is methyl acrylate or ethyl acrylate.

7. The electrochemical catalytic synthesis method of phenidone according to claim 1, characterized in that: The molar ratio of the phenylhydrazine to the acrylate is 1:1-1:5, and the molar ratio of the phenylhydrazine to the electrolyte is 30:1-50:

1.

8. 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.

9. 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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