Phenylhydrazine derivative and preparation method thereof
The preparation of phenylhydrazine derivatives via the Japp-Klingemann reaction solves the problems of reducing agent toxicity and wastewater pollution in existing technologies, and provides a simple, safe and low-cost synthetic route suitable for the preparation of phenylhydrazine derivatives from a variety of substrates.
Patent Information
- Application Number
- CN202411569637.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-05
- Publication Date
- 2025-01-21
AI Technical Summary
Existing methods for synthesizing phenylhydrazine derivatives use reducing agents such as stannous chloride, which are toxic and expensive. Sulfur-containing reducing agents cause wastewater pollution, and the purity and yield of the products are low.
The Japp-Klingemann reaction was used to generate phenyl diazonium salt by diazotization of aniline, which was then reacted with β-keto ester compounds in a buffer salt system to generate phenylhydrazone, which was then hydrolyzed to obtain phenylhydrazine derivatives. This method avoids the use of toxic reducing agents and controls the reaction conditions.
It enables the preparation of phenylhydrazine derivatives that are simple to operate, safe, low in cost, and have high yield, and is suitable for the synthesis of a variety of substrates.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of compound preparation, and more specifically, relates to a phenylhydrazine derivative and a preparation method thereof. Background Art
[0002] Phenylhydrazine and its derivatives are an important class of chemical and pharmaceutical raw materials, and are important raw materials for the synthesis of pyrazolone and indole compounds.
[0003] The conventional method for synthesizing phenylhydrazine derivatives uses aniline as a starting material, performs a diazotization reaction to prepare a benzene diazonium salt, and then uses a reducing agent to reduce and synthesize phenylhydrazine or a phenylhydrazine derivative.
[0004] There are two main types of reducing agents used. One is metal reducing agents, such as stannous chloride, but tin is toxic and expensive; the other is sulfur-containing reducing agents, such as sodium sulfite, sodium bisulfite, etc. This type of reducing agent produces a large amount of sulfur-containing wastewater, and the product purity and yield are often low. Summary of the invention
[0005] After repeated studies, the inventors found that the mutual conversion between hydrazone and hydrazine can be achieved through chemical reactions. On the other hand, hydrazone can be prepared by using the Japp-Klingemann reaction, that is, β-ketoester and diazonium salt under alkali or acid catalysis, and the reaction conditions of the Japp-Klingemann reaction are mild, and the reaction solution is close to a neutral reaction. The present invention was completed on this basis.
[0006] In view of this, the present invention aims to provide a novel method for preparing phenylhydrazine derivatives which is simple to operate and has mild reaction conditions.
[0007] Another object of the present invention is to provide a phenylhydrazine derivative prepared by the above preparation method.
[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:
[0009] The method for preparing a phenylhydrazine derivative according to the first embodiment of the present invention comprises the following steps:
[0010] Step S1, subjecting aniline to a diazotization reaction to generate a benzene diazonium salt derivative;
[0011] Step S2, reacting a benzene diazonium salt derivative and a β-ketoester compound in a buffer salt system to generate a phenylhydrazone derivative;
[0012] Step S3, hydrolyzing the phenylhydrazone derivative to generate a phenylhydrazone derivative.
[0013] In some embodiments of the present invention, in step S1, the diazotization reaction is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, fluoroboric acid, acetic acid, or a mixture thereof.
[0014] Furthermore, the step S1 specifically includes:
[0015] In the presence of the acid, the aniline and the diazotizing agent undergo the diazotization reaction to generate the benzene diazonium salt derivative, and the diazotizing agent includes sodium nitrite, nitrite ester, or a mixture thereof.
[0016] Furthermore, in step S1, the molar ratio of aniline:diazotizing agent:acid is 1:(1-1.5):(3-5), the reaction temperature is -10-10°C, and the reaction time is 0-1 hour.
[0017] In some embodiments of the present invention, in step S2, the β-ketoester compound is selected from one or more of ethyl acetoacetate and diethyl malonate.
[0018] Furthermore, the molar equivalent ratio of the benzene diazonium salt to the β-ketoester compound is 1:(1-5).
[0019] Furthermore, the buffer salt system maintains pH=7-9.
[0020] Furthermore, the buffer salt system is a sodium acetate-sodium hydroxide buffer salt system.
[0021] Furthermore, the hydrolysis reaction is a hydrazinolysis reaction or an acidic hydrolysis reaction.
[0022] According to the second aspect of the present invention, there is also provided a phenylhydrazine derivative prepared by any one of the embodiments of the first aspect.
[0023] The above technical solution of the present invention has at least one of the following beneficial effects:
[0024] According to the preparation method of the phenylhydrazine derivative of the embodiment of the present invention, benzene diazonium salt is synthesized by diazotization reaction of aniline, and then reacted with β-ketoester compound to obtain intermediate hydrazone, and the hydrazone is further reacted to be hydrolyzed to obtain phenylhydrazine. The raw and auxiliary materials involved in the preparation method of the present invention are cheap and easy to obtain, the experiment is highly safe, the operation is simple, and the conditions are easy to control. In particular, it can be used as an effective alternative when other conventional methods are not feasible. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 This is the NMR result of the product obtained in Example 1;
[0026] Figure 2 The NMR result of the product obtained in Example 2 is shown in FIG. DETAILED DESCRIPTION
[0027] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.
[0028] The following first describes in detail the preparation method of the phenylhydrazine derivative according to the embodiment of the present invention.
[0029] The method for preparing a phenylhydrazine derivative according to an embodiment of the present invention comprises the following steps:
[0030] Step S1, subjecting aniline to a diazotization reaction to generate a benzene diazonium salt derivative;
[0031] Step S2, reacting a benzene diazonium salt derivative and a β-ketoester compound in a buffer salt system to generate a phenylhydrazone derivative;
[0032] Step S3, hydrolyzing the phenylhydrazone derivative to generate a phenylhydrazone derivative.
[0033] Specifically, the preparation method of the present application has a synthetic route as shown in the following formula (1):
[0034]
[0035] That is, according to the method for preparing phenylhydrazine of the embodiment of the present invention, the key intermediate hydrazone is obtained by diazotization reaction of aniline and Japp-Klingemann reaction (i.e., the reaction of step S2), and the hydrazone is then hydrolyzed to obtain phenylhydrazine, which has a short route and low synthesis cost.
[0036] In some embodiments of the present invention, in step S1, the diazotization reaction is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, fluoroboric acid, acetic acid, or a mixture thereof. Among them, it can be appropriately selected according to the practicality and application scenarios of different substrates and environmental requirements. In the presence of an acid, the diazonium salt can dissolve, which is conducive to promoting the reaction.
[0037] Among them, if conventional hydrochloric acid, hydrobromic acid and other acids are used, the diazonium salt may not be completely dissolved in water. You can consider replacing other acids or increasing the amount of solvent water, or other co-solvents, or using fluoroboric acid to filter and separate the diazonium salt solid in the first step for feeding in the second step.
[0038] Furthermore, the step S1 specifically includes:
[0039] In the presence of the acid, the aniline and the diazotizing agent undergo the diazotization reaction to generate the benzene diazonium salt derivative, and the diazotizing agent includes sodium nitrite, nitrite ester, or a mixture thereof.
[0040] That is to say, the diazotization reaction can be achieved by using the sodium nitrite method or the nitrite ester method.
[0041] Furthermore, in step S1, the molar ratio of aniline:diazotizing agent:acid is 1:(1-1.5):(3-5), the reaction temperature is -10-10°C, and the reaction time is 0-1 hour. Aniline and the acidic solution react with sodium nitrite to generate diazonium salt, wherein the amount of sodium nitrite should not be too much, and the reaction needs to be carried out at low temperature and the reaction solution needs to be temporarily stored at low temperature.
[0042] In addition, if the reaction volume is large enough, it can be considered to develop a continuous flow reaction.
[0043] In some embodiments of the present invention, in step S2, the β-ketoester compound is selected from one or more of ethyl acetoacetate and diethyl malonate.
[0044] That is to say,
[0045] Furthermore, the molar equivalent ratio of the benzene diazonium salt to the β-ketoester compound is 1:(1-5).
[0046] Furthermore, the buffer salt system maintains a pH of 7 to 9. That is, the buffer salt system is preferably a neutral or weakly alkaline system.
[0047] Furthermore, the buffer salt system is a sodium acetate-sodium hydroxide buffer salt system.
[0048] Since the β-ketoester equivalent is in excess in step S2, the use of a sodium acetate-sodium hydroxide buffer system and maintaining the pH of the reaction solution between 7 and 9 are crucial to the success of the reaction, preferably around 8.
[0049] Furthermore, the hydrolysis reaction is a hydrazinolysis reaction or an acidic hydrolysis reaction.
[0050] That is, in the reaction of the intermediate hydrazone to hydrazine in step S3, the hydrazine hydrolysis reaction under the condition of hydrazine hydrate is generally preferred. If the substrate is sensitive to alkalinity or insensitive to acid, hydrolysis under acidic conditions can also be selected.
[0051] According to the second aspect of the present invention, there is also provided a phenylhydrazine derivative prepared by any one of the embodiments of the first aspect.
[0052] The preparation method of the phenylhydrazine derivatives of the present invention is further described in detail below through specific examples.
[0053] Example 1
[0054] (I) Synthesis of hydrazone intermediates:
[0055] Concentrated hydrochloric acid (250 g, 3.0 eq) was diluted with water (250 mL), and AcOH (140 g) was added. p-Anisidine (100 g, 1.0 eq) was added to completely dissolve to form a brown-black solution. The temperature was lowered to 0°C, and an aqueous solution of sodium nitrite (57.2 g, 1.02 eq) was slowly added dropwise to the reaction solution. After the addition was completed, it was temporarily stored at 0-5°C to obtain a benzene diazonium salt solution.
[0056] In another reaction bottle, add ethyl acetoacetate (126.8 g, 1.2 eq) and ethanol (400 mL) to dissolve, add water (400 mL), add sodium acetate (200 g, 3.0 eq) in batches, cool to 10° C. in an ice-water bath, dropwise add the benzene diazonium salt solution prepared above, and simultaneously dropwise add NaOH aqueous solution to control the pH of the reaction solution to 8-10. After the addition is complete, stir for 30 minutes and filter to obtain an intermediate wet solid;
[0057] Add NaOH (65 g) to water (900 mL) to dissolve, add the intermediate wet solid, heat to 70°C, stir for 3 h, slowly cool to room temperature, filter, and vacuum dry to obtain 138 g of a yellow solid, yield: 88%.
[0058] (II) Synthesis of phenylhydrazine (hydrazine solution method):
[0059] The obtained hydrazone intermediate (21g) was dissolved in ethanol (200mL), and hydrazine hydrate (40mL) diluted to 40% was added and heated to 50°C. The reaction was controlled by TLC. If the reaction was not complete, hydrazine hydrate was added appropriately. The reaction was completed. Water and ethyl acetate were added and stirred for extraction. The obtained ethyl acetate was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, desolventized to dryness, acetonitrile was added to dissolve, hydrochloric acid gas was introduced until the reaction turned purple, filtered, acetonitrile was rinsed to white, and dried to obtain 13.1g of p-methoxyphenylhydrazine hydrochloride, with a yield of 68.7%. Among them, the yield was calculated based on the theoretical value of the obtained solid p-methoxyphenylhydrazine hydrochloride.
[0060] The NMR results of the product are as follows Figure 1 As shown, the results show that the structure is consistent with that of the target product p-methoxyphenylhydrazine hydrochloride.
[0061] In addition, the results of HPLC showed that the purity of the product obtained by drying was 99.9% and the melting point was 165.2° C.-165.5° C. (dec.).
[0062] Example 2
[0063] The steps for synthesizing the hydrazone intermediate are the same as those in Example 1, and the detailed description thereof is omitted here.
[0064] (II) Synthesis of phenylhydrazine (acid hydrolysis method):
[0065] The hydrazone intermediate (21 g) obtained in Example 1 (I) was dissolved in acetonitrile (500 mL), and concentrated hydrochloric acid (50 mL) was added dropwise in batches. The temperature was controlled at 15° C. for 2 h, and a brown solid was gradually precipitated. The reaction was controlled to be complete by TLC. The crude product was filtered to obtain a crude product of p-methoxyphenylhydrazine hydrochloride. The obtained crude product was added to 98% acetonitrile (50 mL) and heated to 50° C. Most of it was dissolved. The product was filtered while hot and cooled to 10° C. A white solid was precipitated. The solid was filtered, washed with acetonitrile until white, and dried to obtain 9.2 g of p-methoxyphenylhydrazine hydrochloride, with a yield of 48.2%.
[0066] The NMR results of the product are as follows Figure 2 As shown, the results show that the structure is consistent with that of the target product p-methoxyphenylhydrazine hydrochloride.
[0067] In addition, the results of HPLC showed that the purity of the product obtained by drying was 99.9% and the melting point was 165.3° C.-165.5° C. (dec.).
[0068] In addition, the inventors have verified through a large number of experiments that the above reaction conditions in each step are applicable to different aniline substrates, and the detailed description thereof is omitted here.
[0069] It can be seen from the above examples that the method for preparing phenylhydrazine derivatives by using the Japp-Klingemann reaction of the present invention has the advantages of simple operation, short route, low cost and high yield.
[0070] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing a phenylhydrazine derivative, characterized in that: The steps include: Step S1, subjecting aniline to a diazotization reaction to generate a benzene diazonium salt derivative; Step S2, reacting a benzene diazonium salt derivative and a β-ketoester compound in a buffer salt system to generate a phenylhydrazone derivative; Step S3, hydrolyzing the phenylhydrazone derivative to generate a phenylhydrazone derivative.
2. The preparation method according to claim 1, characterized in that: In the step S1, the diazotization reaction is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, fluoroboric acid, acetic acid, or a mixture thereof.
3. The preparation method according to claim 2, characterized in that: The step S1 specifically includes: In the presence of the acid, the aniline and the diazotizing agent undergo the diazotization reaction to generate the benzene diazonium salt derivative, and the diazotizing agent includes sodium nitrite, nitrite ester, or a mixture thereof.
4. The preparation method according to claim 3, characterized in that: In the step S1, the molar ratio of aniline:diazotizing agent:acid is 1:(1-1.5):(3-5), the reaction temperature is -10-10°C, and the reaction time is 0-1 hour.
5. The preparation method according to claim 1, characterized in that: In the step S2, the β-ketoester compound is selected from one or more of ethyl acetoacetate and diethyl malonate.
6. The preparation method according to claim 5, characterized in that: The molar equivalent ratio of the benzene diazonium salt and the β-ketoester compound is 1:1-5.
7. The preparation method according to claim 5, characterized in that: The buffer salt system maintains pH=7-9.
8. The preparation method according to claim 7, characterized in that: The buffer salt system is a sodium acetate-sodium hydroxide buffer salt system.
9. The preparation method according to claim 1, characterized in that: The hydrolysis reaction is a hydrazinolysis reaction or an acidic hydrolysis reaction.
10. A phenylhydrazine derivative prepared according to the preparation method according to any one of claims 1 to 9.