A method for synthesizing phenylhydrazine hydrochloride
By using the coupling reaction of halogenated aromatic compounds with hydrazine hydrate and the salt formation method with hydrochloric acid, the problems of multiple steps, high cost and low purity in the synthesis of phenylhydrazine hydrochloride in the prior art have been solved, and efficient and low-cost synthesis of phenylhydrazine hydrochloride has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI SENRISE TECH CO LTD
- Filing Date
- 2026-03-20
- Publication Date
- 2026-07-03
AI Technical Summary
The synthesis of phenylhydrazine hydrochloride in the existing technology involves many steps, which increases production time and cost. In addition, the multi-step reaction may introduce impurities, affecting the purity of the product.
A method is used to generate phenylhydrazine hydrochloride by coupling a halogenated aromatic compound with hydrazine hydrate and then adding hydrochloric acid to form a salt. Palladium chloride is used as a catalyst and sodium ethoxide is used as a basic agent. The coupling reaction is carried out at 50-55℃.
It reduces reaction steps, lowers economic costs, and improves product purity and yield. The catalyst can be reused, and the reaction conditions are mild.
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Figure CN122325348A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology and relates to a method for synthesizing phenylhydrazine hydrochloride. Background Technology
[0002] Phenylated hydrazine hydrochloride, as an important organic synthesis intermediate and pharmaceutical raw material, possesses both nucleophilic reactivity and water solubility due to the presence of a hydrazine group (-NH-NH2) and a hydrochloride group in its molecular structure. It is widely used in pharmaceuticals, dyes, pesticides, and materials science. For example, in the pharmaceutical field, it is a key precursor for the synthesis of the anti-tuberculosis drug isoniazid and the antihypertensive drug hydralazine. From a synthetic principle perspective, the core of phenylhydrazine hydrochloride preparation involves introducing a hydrazine group through nucleophilic substitution or reduction reactions of aromatic compounds, followed by salt formation with hydrochloric acid to obtain the target product. The mature industrial route primarily uses aniline as a raw material, prepared via a diazotization-reduction reaction: aniline reacts with sodium nitrite and hydrochloric acid at low temperatures (0-5℃) to generate a diazonium salt, which is then reduced to a hydrazine group using reducing agents such as sodium sulfite, zinc powder, or hydrazine hydrate, ultimately forming a salt with hydrochloric acid.
[0003] Many existing technologies use fluorobromobenzene and benzophenone hydrazone as starting materials to directly obtain phenylhydrazine hydrochloride through one or more steps of reaction. Alternatively, they start with aniline compounds and proceed through four steps of fluorination, nitration, reduction, and salt formation to gradually construct and transform the molecule, ultimately obtaining phenylhydrazine hydrochloride. The existing technologies involve many reaction steps, which not only increases production time and cost but may also lead to a decrease in overall yield due to product separation at each step. In addition, the probability of introducing impurities through multiple steps increases, affecting product purity. Summary of the Invention
[0004] The purpose of this invention is to provide a method for synthesizing phenylhydrazine hydrochloride, which involves coupling a haloaromatic compound with hydrazine hydrate to form a salt, thereby reducing the number of reaction steps, providing mild reaction conditions, and achieving high product purity.
[0005] The objective of this invention can be achieved through the following technical solutions:
[0006] A method for synthesizing phenylhydrazine hydrochloride involves adding a haloaromatic compound with a bromine atom at the para position, ethanol, sodium ethoxide, palladium chloride, and hydrazine hydrate to a reaction vessel, followed by a coupling reaction, salt formation with hydrochloric acid, and rinsing to obtain phenylhydrazine hydrochloride.
[0007] The halogenated aromatic compounds with a bromine atom at the para position are one of 4-fluoro-3,5-dimethyl-1-bromobenzene and p-dibromobenzene.
[0008] Furthermore, the ratio of the amount of the halogenated aromatic compound with bromine atom at the para position, ethanol, palladium chloride, sodium ethoxide, and hydrazine hydrate is 203-260g: 1000-1200mL: 10-12g: 100-120g: 80-120g.
[0009] Furthermore, the halogenated aromatic compound with a bromine atom at the para position is 4-fluoro-3,5-dimethyl-1-bromobenzene, and the resulting phenylhydrazine hydrochloride is 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The purity of the product is 99.69%, and the yield is 92.28%.
[0010] Furthermore, the halogenated aromatic compound with a bromine atom at the para position is p-dibromobenzene, and the resulting phenylhydrazine hydrochloride is 4-bromophenylhydrazine hydrochloride, with a purity of 99.18% and a yield of 88.59%.
[0011] Furthermore, the coupling reaction is carried out at a temperature of 50-55℃ for 6-10 hours.
[0012] Furthermore, the concentration of hydrazine hydrate is 40 wt%.
[0013] Furthermore, when adding hydrochloric acid to form salt, a hydrochloric acid concentration of 30-35 wt% is used.
[0014] Furthermore, the temperature for salt formation by adding hydrochloric acid is 0-5℃, and the time is 3-4 hours.
[0015] Furthermore, the rinsing solution is icy ethanol.
[0016] The beneficial effects of this invention are:
[0017] This invention uses palladium chloride as a catalyst and sodium ethoxide as a basic agent. Under conditions of 50-55°C, an oxidative addition reaction first occurs with the bromine atom on a haloaromatic compound with a bromine atom at the para position, increasing the oxidation state of palladium and forming a highly reactive palladium intermediate. Sodium ethoxide, as a basic agent, neutralizes the hydrogen bromide generated in this process, driving the reaction forward. The lone pair electrons on the nitrogen atom in hydrazine hydrate attack the palladium intermediate, undergoing a nucleophilic substitution reaction, attaching the nitrogen atom to the carbon atom bonded to the bromine atom. The palladium intermediate then undergoes a reduction reaction, restoring the oxidation state of palladium to phenylhydrazine compounds. Simultaneously, palladium chloride is regenerated and can be used for further processing. The catalyst continues to participate in the catalytic cycle. In this process, ethanol, as a reaction solvent, provides a homogeneous environment for the reaction, promotes effective collisions between reactant molecules, and plays a role in promoting the reaction. Then, hydrochloric acid is added to the reaction system. The hydrogen ions in the hydrochloric acid combine with the nitrogen atoms in the phenylhydrazine molecules to form a stable salt, converting phenylhydrazine into a more stable and easier-to-separate and store hydrochloride form. This method has simple steps, relatively mild reaction conditions, and the product has excellent yield and purity. Moreover, the catalyst can be separated and recovered by hot filtration after the reaction and reused. This not only meets the quality requirements of phenylhydrazine hydrochloride in the pharmaceutical and other fields, but also reduces economic costs. Attached Figure Description
[0018] Figure 1 This is the organic synthesis route diagram for the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride of the present invention;
[0019] Figure 2 This is a schematic diagram of the organic synthesis route of 4-bromophenylhydrazine hydrochloride of the present invention;
[0020] Figure 3 This is the liquid chromatography detection chromatogram of Example 1 of the present invention;
[0021] Figure 4 This is the proton nuclear magnetic resonance spectrum of Example 1 of the present invention;
[0022] Figure 5 This is the liquid chromatography detection chromatogram of Example 3 of the present invention;
[0023] Figure 6 This is the liquid chromatography detection chromatogram of Example 4 of the present invention;
[0024] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of Example 3 of the present invention. Detailed Implementation
[0025] To further illustrate the technical means and effects of the present invention in achieving the intended purpose, the following detailed description of the specific implementation methods, features and effects of the present invention, in conjunction with preferred embodiments, is provided below.
[0026] Example 1: This example provides a method for synthesizing phenylhydrazine hydrochloride, comprising the following steps:
[0027] 203 g of the compound (i.e., a halogenated aromatic hydrocarbon with a bromine atom at the para position), 1000 mL of ethanol, 10 g of palladium chloride, 100 g of sodium ethoxide, and 100 g of 40 wt% hydrazine hydrate were added to a reaction vessel. The mixture was heated to 50 °C and stirred for 8 h. After the reaction was completed as detected by HPLC, the mixture was hot-filtered to separate the palladium chloride. The filtrate was cooled to 20 °C, and 200 mL of 30 wt% hydrochloric acid solution was added. The mixture was stirred for 30 min and then cooled to 0 °C. A solid precipitated out. The mixture was stirred for another 3 h, filtered, and the filter cake was washed with 190 mL of ice-cold ethanol. The filter cake was collected and dried at 60 °C to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The product yield was 90.26%, and the purity was 99.69% (e.g., ...). Figure 3 As shown), the specific reaction principle is as follows: Figure 1 As shown.
[0028] The nuclear magnetic resonance (NMR) data are as follows:
[0029] H NMR (300MHz, DMSO), 2.21 (s, 6H), 6.67-6.68 (d, 2H), such as Figure 4 As shown, based on the nuclear magnetic resonance data, the product was confirmed to be 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.
[0030] Example 2: This example provides a method for synthesizing phenylhydrazine hydrochloride, including the following steps:
[0031] 250 g of 4-fluoro-3,5-dimethyl-1-bromobenzene, 1200 mL of ethanol, 12 g of palladium chloride, 120 g of sodium ethoxide, and 120 g of 40 wt% hydrazine hydrate were added to a reaction vessel. The mixture was heated to 55 °C and stirred for 10 h. After the reaction was completed as detected by HPLC, the mixture was hot-filtered to separate palladium chloride. The filtrate was cooled to 25 °C, and 220 mL of 35 wt% hydrochloric acid solution was added. The mixture was stirred for 40 min, then cooled to 5 °C, resulting in the precipitation of a solid. The mixture was stirred for another 4 h, filtered, and the filter cake was washed with 250 mL of ice-cold ethanol. The filter cake was collected and dried at 80 °C to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The product yield was 92.28%, and the purity was 98.54%.
[0032] At 50-55℃, using sodium ethoxide as a basic agent and palladium chloride as a catalyst, an oxidative addition reaction occurs between palladium and the bromine atom on 4-fluoro-3,5-dimethyl-1-bromobenzene, increasing the oxidation state of palladium and forming a highly reactive palladium intermediate. Sodium ethoxide, as a basic agent, neutralizes the hydrogen bromide generated in this process, driving the reaction forward. In this process, the lone pair of electrons on the nitrogen atom in hydrazine hydrate attacks the palladium intermediate, undergoing a nucleophilic substitution reaction, attaching the nitrogen atom to the carbon atom bonded to the bromine atom. Then, the palladium intermediate undergoes a reduction reaction, restoring the oxidation state of palladium to 4-fluoro-3,5-dimethyl-1-bromobenzene. 3,5-Dimethylphenylhydrazine (FPH) is generated, and palladium chloride is regenerated and can continue to participate in the catalytic cycle. In this process, ethanol not only serves as a reaction solvent, providing a homogeneous environment for the reaction and promoting effective collisions between reactant molecules, but may also participate in the formation of some transition states, thus promoting the reaction. After the palladium chloride catalytic coupling reaction generates 4-fluoro-3,5-dimethylphenylhydrazine, hydrochloric acid is added to the reaction system. The hydrogen ions in the hydrochloric acid combine with the nitrogen atoms in 4-fluoro-3,5-dimethylphenylhydrazine to form a stable ammonium salt structure, i.e., 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is generated.
[0033] Example 3: This example provides a method for synthesizing phenylhydrazine hydrochloride, comprising the following steps:
[0034] 236 g of compound p-dibromobenzene, 1000 mL of ethanol, 10 g of palladium chloride, and 100 g of sodium ethoxide were added to a reaction vessel. The mixture was heated to 50 °C and stirred. 80 g of 40 wt% hydrazine hydrate was added dropwise. After the addition was complete, stirring continued for 6 h. After the reaction was confirmed by HPLC, the mixture was hot-filtered to separate palladium chloride. The filtrate was cooled to 20 °C, and 200 mL of 30 wt% hydrochloric acid solution was added. The mixture was stirred for 30 min and then cooled to 0 °C. A solid precipitated. Stirring continued for 3 h, followed by filtration. The filter cake was washed with 200 mL of ice-cold ethanol, collected, and dried at 60 °C to obtain 4-bromophenylhydrazine hydrochloride. The product yield was 88.59%, and the purity was 98.98% (e.g., ...). Figure 5 As shown), the specific reaction principle is as follows: Figure 2 As shown.
[0035] The nuclear magnetic resonance (NMR) data are as follows:
[0036] H NMR (300MHz, DMSO): 6.86–6.90 (d, 2H), 7.41–7.45 (d, 2H), 8.37 (s, 1H), 10.17 (s, 3H), as shown. Figure 7 As shown, based on the nuclear magnetic resonance data, the product was confirmed to be 4-bromophenylhydrazine hydrochloride.
[0037] Example 4: This example provides a method for synthesizing phenylhydrazine hydrochloride, comprising the following steps:
[0038] 260g of compound p-dibromobenzene, 1200mL of ethanol, 12g of palladium chloride, and 120g of sodium ethoxide were added to a reaction vessel. The mixture was heated to 55℃ and stirred. 90g of 40wt% hydrazine hydrate was added dropwise. After the addition was complete, stirring continued for 8 hours. After the reaction was confirmed by HPLC, the mixture was hot-filtered to separate palladium chloride. The filtrate was cooled to 25℃, and 220mL of 35wt% hydrochloric acid solution was added. The mixture was stirred for 40 minutes, then cooled to 5℃, resulting in the precipitation of a solid. Stirring continued for 4 hours, followed by filtration. The filter cake was washed with 250mL of ice-cold ethanol, collected, and dried at 80℃ to obtain 4-bromophenylhydrazine hydrochloride. The product yield was 83.35%, and the purity was 99.18% (e.g., ...). Figure 6 (As shown).
[0039] At a temperature of 50-55℃, using sodium ethoxide as a basic agent and palladium chloride as a catalyst, an oxidative addition reaction occurs between palladium and the bromine atom on p-dibromobenzene, increasing the oxidation state of palladium and forming a highly active palladium intermediate. Sodium ethoxide, as a basic agent, neutralizes the hydrogen bromide generated in this process, promoting the forward reaction. In this process, the lone pair electrons on the nitrogen atom of hydrazine hydrate attack the palladium intermediate, undergoing a nucleophilic substitution reaction, attaching the nitrogen atom to the carbon atom bonded to the bromine atom. Then, the palladium intermediate undergoes a reduction reaction, restoring the oxidation state of palladium to 4-bromophenylhydrazine. Simultaneously, palladium chloride is regenerated and can continue to participate in the catalytic cycle. In this process, ethanol not only acts as a reaction solvent, providing a homogeneous environment for the reaction and promoting effective collisions between reactant molecules, but may also participate in the formation of some transition states, playing a certain promoting role in the reaction. After the palladium chloride catalytic coupling reaction generates 4-bromophenylhydrazine, hydrochloric acid is added to the reaction system. The hydrogen ions in the hydrochloric acid combine with the nitrogen atom in 4-bromophenylhydrazine to form a stable ammonium salt structure, i.e., 4-bromophenylhydrazine hydrochloride is generated.
[0040] Table 1. Summary of Product Yield and Purity
[0041] project Example 1 Example 2 Example 3 Example 4 Yield (%) 90.26 92.28 88.59 83.35 purity(%) 99.69 98.54 98.98 99.18
[0042] As shown in Table 1, the yields and purities of Examples 1-4 are all high. This is likely because palladium chloride, as a highly efficient catalyst, can effectively catalyze the coupling reaction between hydrazine hydrate and halogenated aromatic compounds with bromine atoms at the para position, efficiently replacing the bromine atoms at the para position of the aromatic ring and providing the core catalytic role for the efficient reaction. At the same time, sodium ethoxide, as a basic agent, can neutralize the hydrogen bromide generated during the reaction and promote the reaction to proceed in the forward direction. By combining a one-step coupling reaction with the simple process of salt formation with hydrochloric acid, the product loss and impurity introduction caused by multiple reaction steps are reduced. Therefore, Examples 1-4 have good yields and purities, fewer reaction steps, mild reaction conditions, and high product purity.
[0043] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.
Claims
1. A method for synthesizing phenylhydrazine hydrochloride, characterized in that, A haloaromatic compound with a bromine atom at the para position, ethanol, sodium ethoxide, palladium chloride, and hydrazine hydrate were added to a reaction vessel, and after coupling reaction, salt formation with hydrochloric acid, and rinsing, phenylhydrazine hydrochloride was obtained. The halogenated aromatic compound with a bromine atom at the para position is one of 4-fluoro-3,5-dimethyl-1-bromobenzene and p-dibromobenzene.
2. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The ratio of the amount of the halogenated aromatic compound with bromine atom at the para position, ethanol, palladium chloride, sodium ethoxide, and hydrazine hydrate is 203-260g: 1000-1200mL: 10-12g: 100-120g: 80-120g.
3. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The halogenated aromatic compound with a bromine atom at the para position is 4-fluoro-3,5-dimethyl-1-bromobenzene, and the resulting phenylhydrazine hydrochloride is 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The purity of the product is 99.69%, and the yield is 92.28%.
4. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The halogenated aromatic compound with a bromine atom at the para position is p-dibromobenzene, and the resulting phenylhydrazine hydrochloride is 4-bromophenylhydrazine hydrochloride. The purity of the product is 99.18%, and the yield is 88.59%.
5. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of 50-55℃ for 6-10 hours.
6. The method for synthesizing phenylhydrazine hydrochloride according to claim 2, characterized in that, The concentration of the hydrated hydrazine is 40 wt%.
7. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The hydrochloric acid used in the salt formation process is a 30-35 wt% hydrochloric acid.
8. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The temperature for adding hydrochloric acid to form salt is 0-5℃, and the time is 3-4 hours.
9. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The rinsing solution is icy ethanol.