Synthesis method of phenylhydrazine hydrochloride

Abstract

The invention relates to a synthetic method of phenylhydrazine hydrochloride, which belongs to the technical field of drug synthesis, and comprises the following steps: by taking palladium chloride as a catalyst, carrying out oxidative addition reaction on the palladium chloride and bromine atoms on halogenated aromatic compounds of which the para-position is bromine atoms at 50-55 DEG C to increase the oxidation state of palladium so as to form a palladium intermediate with higher activity; lone pair electrons on a nitrogen atom in hydrazine hydrate attack the palladium intermediate, a nucleophilic substitution reaction is carried out, the nitrogen atom is connected to a carbon atom connected with a bromine atom, the palladium intermediate is subjected to a reduction reaction, the oxidation state of palladium is recovered, the phenylhydrazine compound is generated, meanwhile, palladium chloride is regenerated and can continue to participate in a catalytic cycle, and in the process, the palladium intermediate is subjected to a reduction reaction. Ethanol is used as a reaction solvent to provide a homogeneous environment for the reaction, promote effective collision among reactant molecules and play a role in promoting the reaction, then hydrochloric acid is added into the reaction system, and hydrogen ions in the hydrochloric acid are combined with nitrogen atoms in phenylhydrazine molecules to form stable salts.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and relates to a synthesis method of phenylhydrazine hydrochloride. BACKGROUND

[0002] Phenylhydrazine hydrochloride is an important organic synthesis intermediate and pharmaceutical chemical raw material, and contains hydrazine groups (-NH-NH2) and hydrochloride groups in the molecular structure, so that it has nucleophilic reactivity and water solubility, and is widely used in the fields of medicine, dyes, pesticides and material science. For example, in the field of medicine, it is a key precursor for synthesizing isoniazid, an antituberculosis drug, and hydralazine, an antihypertensive drug. From the synthesis principle, the preparation core of phenylhydrazine hydrochloride is to introduce a hydrazine group through nucleophilic substitution or reduction reaction of an aromatic compound, and then to obtain the target product by salting with hydrochloric acid. The mature path of industrialization mainly takes aniline as the raw material, and is prepared through diazotization-reduction reaction: aniline reacts with sodium nitrite and hydrochloric acid at low temperature (0-5℃) to generate a diazonium salt, and then the diazonium group is reduced to a hydrazine group by a reducing agent such as sodium sulfite, zinc powder or hydrazine hydrate, and finally salting with hydrochloric acid.

[0003] There are many literatures in the prior art which directly obtain phenylhydrazine hydrochloride through one or more steps from fluorine-containing bromobenzene and benzophenone hydrazone as starting materials, or gradually construct and transform the molecules through four steps of fluorination, nitration, reduction and salting from aniline compounds as starting materials, and finally obtain phenylhydrazine hydrochloride. The reaction steps of the prior art are more, which not only increases the production time and cost, but also may cause the total yield to be reduced due to the product separation and other links of each reaction step, and the probability of impurities introduced by multi-step reaction is also increased, thereby affecting the purity of the product. SUMMARY

[0004] The purpose of the present application is to provide a synthesis method of phenylhydrazine hydrochloride, which obtains phenylhydrazine hydrochloride from halogenated aromatic compounds and hydrazine hydrate through coupling reaction and salting, so as to reduce the reaction steps, achieve mild reaction conditions and high product purity.

[0005] The purpose of the present application can be achieved by the following technical solutions. A synthesis method of phenylhydrazine hydrochloride, which comprises the following steps: adding halogenated aromatic compounds with a bromine atom at the para position, ethanol, palladium chloride and hydrazine hydrate into a reaction kettle, and then performing coupling reaction, salting with hydrochloric acid and washing to obtain phenylhydrazine hydrochloride, wherein 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.

[0006] Further, the amount ratio of the halogenated aromatic compounds with a bromine atom at the para position, ethanol, palladium chloride and hydrazine hydrate is 203-260 g: 1000-1200 mL: 10-12 g: 80-120 g.

[0007] Further, the halogenated aromatic compound with bromine atom at para position is 4-fluoro-3,5-dimethyl-1-bromobenzene, the obtained phenylhydrazine hydrochloride is 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, the purity of the product is 99.69%, and the yield is 92.28%.

[0008] Further, the halogenated aromatic compound with bromine atom at para position is 4-fluoro-3,5-dimethyl-1-bromobenzene, the obtained phenylhydrazine hydrochloride is 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, the purity of the product is 99.69%, and the yield is 92.28%.

[0009] Further, the temperature of the coupling reaction is 50-55 DEG C, and the time is 6-10h.

[0010] Further, the concentration of the hydrazine hydrate is 40wt%.

[0011] Further, the hydrochloric acid used for salification has a concentration of 30-35wt%.

[0012] Further, the temperature for salification is 0-5 DEG C, and the time is 3-4h.

[0013] Further, the eluent for elution is ice ethanol.

[0014] The present application has the following beneficial effects: In the present application, palladium chloride is used as catalyst, and the bromine atom on the halogenated aromatic compound with bromine atom at para position is subjected to oxidative addition reaction under the condition of 50-55 DEG C, so that the oxidation state of palladium is increased, and a palladium intermediate with high activity is formed, the lone pair electron on the nitrogen atom of hydrazine hydrate attacks the palladium intermediate, and nucleophilic substitution reaction occurs, so that the nitrogen atom is connected to the carbon atom connected with the bromine atom, and then the palladium intermediate is subjected to reduction reaction, the oxidation state of palladium is restored, and phenylhydrazine compound is generated, meanwhile, the palladium chloride is regenerated, and can continue to participate in catalytic cycle, in this process, ethanol is used as reaction solvent, and provides homogeneous environment for reaction, so as to promote effective collision between reaction molecules, and plays a role in promoting reaction, then hydrochloric acid is added to the reaction system, the hydrogen ion in the hydrochloric acid is combined with the nitrogen atom in the phenylhydrazine molecule, and stable salt is formed, so that the phenylhydrazine is converted into hydrochloride form which is more stable, and is easier to separate and preserve, the present method has simple steps, relatively mild reaction condition, and the product has excellent yield and purity, and the catalyst can be separated and recovered by hot filtration after reaction, and can be reused, which not only meets the quality requirement of phenylhydrazine hydrochloride in the field of medicine and other fields, but also reduces the economic cost. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The organic synthesis route chart of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride in the present application is shown in the figure; Figure 2 The organic synthesis route chart of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride in the present application is shown in the figure; Figure 3 Liquid chromatogram of Example 1 of the present application; Figure 4 NMR spectrum of Example 1 of the present application; Figure 5 Liquid chromatogram of Example 3 of the present application; Figure 6 Liquid chromatogram of Example 4 of the present application; Figure 7 NMR spectrum of Example 3 of the present application. DETAILED DESCRIPTION

[0016] In order to further clarify the technical means and effects of the present application for achieving the predetermined object, the following will be described in detail in combination with the preferred embodiments, the specific embodiments, features and effects according to the present application.

[0017] Example 1: This embodiment provides a synthesis method of phenylhydrazine hydrochloride, which comprises the following steps: Compound (i.e. halogenated aromatic compound with bromine atom at para position) 203 g 4-fluoro-3,5-dimethyl-1-bromobenzene, 1000 mL ethanol, 10 g palladium chloride and 100 g 40 wt% concentration of hydrazine hydrate were added into a reaction kettle, and the temperature was raised to 50 °C, and stirred for 8 h. After the reaction was detected by HPLC, it was filtered hot, and the palladium chloride was separated and recovered. The filtrate was cooled to 20 °C, 200 mL of 30 wt% concentration of hydrochloric acid solution was added, and stirred for 30 min. The temperature was lowered to 0 °C, and solid was precipitated. The stirring was continued for 3 h, and then filtered. The filter cake was washed with 190 mL of ice ethanol, and the filter cake was collected and dried at 50 °C to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The yield of the product was 90.26%, and the purity was 99.69% (as shown in Figure 3 , and the specific reaction principle is shown in Figure 1 .

[0018] The nuclear magnetic resonance data are as follows: HNMR (300 MHz, DMSO), 2.21 (s, 6H), 6.67-6.68 (d, 2H), as shown in Figure 4 , according to the nuclear magnetic resonance data, it is confirmed that the product is 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0019] Example 2: This embodiment provides a synthesis method of phenylhydrazine hydrochloride, which comprises the following steps: The reaction kettle is charged with 250 g of 4-fluoro-3,5-dimethyl-1-bromobenzene, 1200 mL of ethanol, 12 g of palladium chloride, and 120 g of 40 wt% hydrazine hydrate, heated to 55°C, stirred for 10 h, and after the reaction is completed by HPLC detection, hot filtration is performed, the palladium chloride is separated and recovered, the filtrate is cooled to 25°C, 220 mL of 35 wt% hydrochloric acid solution is added, stirred for 40 min, cooled to 5°C, and solids are precipitated, continued stirring for 4 h, filtration, the filter cake is rinsed with 250 mL of ice ethanol, the filter cake is collected, and dried at 52°C to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The product yield is 92.28%, and the purity is 98.54%.

[0020] At a temperature of 50-55°C, palladium chloride can undergo oxidative addition with the bromine atom on 4-fluoro-3,5-dimethyl-1-bromobenzene, increasing the oxidation state of palladium to form a highly active palladium intermediate. In this process, the lone pair of electrons on the nitrogen atom in the nitrogen-hydrogen bond of hydrazine hydrate attacks the palladium intermediate, and a nucleophilic substitution reaction occurs, connecting the nitrogen atom to the carbon atom connected to the bromine atom. Then, the palladium intermediate undergoes reduction, the oxidation state of palladium returns to normal, and 4-fluoro-3,5-dimethylphenylhydrazine is generated. At the same time, 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 reaction molecules, but also may participate in the formation of part of the transition state, promoting the reaction. After the palladium chloride catalyzed 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 the 4-fluoro-3,5-dimethylphenylhydrazine to form a stable ammonium salt structure, i.e., 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0021] Example 3: This example provides a method for synthesizing phenylhydrazine hydrochloride, which includes the following steps: The reaction kettle is charged with 236 g of p-dibromobenzene, 1000 mL of ethanol, and 10 g of palladium chloride, heated to 50°C, stirred, and 80 g of 40 wt% hydrazine hydrate is added dropwise. After the dropwise addition is completed, stirring is continued for 6 h, and after the reaction is completed by HPLC detection, hot filtration is performed, the palladium chloride is separated and recovered, the filtrate is cooled to 20°C, 200 mL of 30 wt% hydrochloric acid solution is added, stirred for 30 min, cooled to 0°C, and solids are precipitated, continued stirring for 3 h, filtration, the filter cake is rinsed with 200 mL of ice ethanol, the filter cake is collected, and dried at 50°C to obtain 4-bromophenylhydrazine hydrochloride. The product yield is 88.59%, and the purity is 98.98% (as shown in Figure 5 , and the specific reaction principle is shown in Figure 2 .

[0022] The nuclear magnetic resonance data are as follows: HNMR (300 MHz, DMSO): 6.86-6.90 (d, 2H), 7.41-7.45 (d, 2H), 8.37 (s, 1H), 10.17 (s, 3H), as Figure 7 indicated, according to nuclear magnetic resonance data, the product is confirmed to be 4-bromophenylhydrazine hydrochloride.

[0023] Example 4: The present embodiment provides a method for synthesizing phenylhydrazine hydrochloride, comprising the following steps: The reaction kettle was charged with 260 g of compound p-dibromobenzene, 1200 mL of ethanol and 12 g of palladium chloride, heated to 55°C, stirred, and 90 g of hydrazine hydrate with a concentration of 40 wt% was added dropwise. After the dropwise addition was completed, the stirring was continued for 8 h. After the reaction was completed as detected by HPLC, the hot filtration was performed, and the palladium chloride was separated out for recovery. The filtrate was cooled to 25°C, and 220 mL of hydrochloric acid solution with a concentration of 35 wt% was added. The stirring was continued for 40 min, and the temperature was lowered to 5°C. Solid was precipitated, and the stirring was continued for 4 h. The filtration was performed, and the filter cake was rinsed with 250 mL of ice ethanol. The filter cake was collected and dried at 52°C to obtain 4-bromophenylhydrazine hydrochloride. The product yield was 83.35%, and the purity was 99.18% (as Figure 6 indicated).

[0024] At a temperature of 50-55°C, palladium chloride can undergo oxidative addition reaction with the bromine atom on p-dibromobenzene as a catalyst, so that the oxidation state of palladium is increased, and a palladium intermediate with high activity is formed. In this process, the lone pair of electrons on the nitrogen atom in the nitrogen-hydrogen bond in hydrazine hydrate attacks the palladium intermediate, and a nucleophilic substitution reaction occurs, so that the nitrogen atom is connected to the carbon atom connected to the bromine atom. Then, the palladium intermediate undergoes reduction reaction, and the oxidation state of palladium is restored, so that 4-bromophenylhydrazine is generated, and the palladium chloride is regenerated and can continue to participate in the catalytic cycle. In this process, ethanol not only serves as a reaction solvent to provide a homogeneous environment for the reaction and promote the effective collision between the reaction molecules, but also may participate in the formation of part of the transition state, and plays 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 ion in the hydrochloric acid combines with the nitrogen atom in the 4-bromophenylhydrazine to form a stable ammonium salt structure, i.e., 4-bromophenylhydrazine hydrochloride is generated.

[0025] Table 1: Product yield and purity table Item 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 As can be seen from Table 1, the yield and purity of Examples 1-4 are relatively high, which may be because the high-efficiency catalysis of the catalyst palladium chloride enables the hydrazine hydrate to quickly react with the halogenated aromatic compound with bromine at the para position, replace the bromine atom at the para position, and be converted into stable phenylhydrazine hydrochloride after the salt formation reaction, so that the reaction has good yield and purity, the reaction steps are few, the reaction conditions are mild, and the product purity is high.

[0026] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form. Although the present application has been described above with reference to preferred embodiments, the present application is not intended to be limited to the above-described embodiments, and any person skilled in the art, without departing from the technical solution of the present application, can make some changes or modifications to the above-described disclosed technical content to obtain equivalent embodiments with equivalent changes. However, as long as it does not deviate from the technical solution of the present application, any modification, equivalent change and modification of the above embodiments according to the technical essence of the present application are still within the scope of the technical solution of the present application.

Claims

1. A process for the synthesis of phenylhydrazine hydrochloride, characterized in that, A halogenated aromatic compound with bromine atom at para position, ethanol, palladium chloride and hydrazine hydrate are added into a reaction kettle, and a coupling reaction, salification with hydrochloric acid and elution are carried out to obtain phenylhydrazine hydrochloride. The halogenated aromatic compound with bromine atom at para position is one of 4-fluoro-3, 5-dimethyl-1-bromobenzene and p-dibromobenzene.

2. The process for the synthesis of phenylhydrazine hydrochloride according to claim 1, characterized in that, The halogenated aromatic compound with bromine atom at para position, ethanol, palladium chloride and hydrazine hydrate are used in a ratio of 203-260g: 1000-1200mL: 10-12g: 80-120g.

3. The process for the synthesis of phenylhydrazine hydrochloride according to claim 1, characterized in that, The halogenated aromatic compound with bromine atom at para position is 4-fluoro-3, 5-dimethyl-1-bromobenzene, and the obtained phenylhydrazine hydrochloride is 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride, with a purity of 99.69% and a yield of 92.28%.

4. The process for the synthesis of phenylhydrazine hydrochloride according to claim 1, characterized in that, The halogenated aromatic compound with bromine atom at para position is p-dibromobenzene, and the obtained phenylhydrazine hydrochloride is 4-bromophenylhydrazine hydrochloride, with a purity of 99.18% and a yield of 88.59%.

5. The process for synthesis of phenylhydrazine hydrochloride according to claim 1, wherein, The coupling reaction is carried out at a temperature of 50-55℃ for 6-10h.

6. The method for synthesizing phenylhydrazine hydrochloride according to claim 2, characterized in that, The concentration of hydrazine hydrate is 40wt%.

7. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The salification with hydrochloric acid is carried out using hydrochloric acid with a concentration of 30-35wt%.

8. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The salification with hydrochloric acid is carried out at a temperature of 0-5℃ for 3-4h.

9. The method for synthesizing phenylhydrazine hydrochloride according to claim 1, characterized in that, The elution is carried out using ice ethanol.

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