Synthesis method of a meta-nitrodiphenylamine compound

Abstract

The application provides a synthesis method of m-nitro diphenylamine compounds, which comprises the following steps: carrying out an electrophilic substitution reaction on m-nitro halogenated benzene and aniline or halogenated benzene and m-nitro aniline under the condition of a sulfonic acid compound catalyst and an ionic liquid solvent to obtain the m-nitro diphenylamine compounds. The synthesis method of the m-nitro diphenylamine compounds is simple in method steps, stable in process and high in yield.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, and more particularly to a method for synthesizing m-nitrodiphenylamine compounds. Background Technology

[0002] 3-Nitrodiphenylamine, a compound of m-nitrodiphenylamines, is an important pharmaceutical intermediate, serving as a precursor in the synthesis of moricizine hydrochloride. Moricizine hydrochloride, chemically named [10-(3-morpholino)propionyl-10H-phenthiazin-2-yl]carbamate hydrochloride, has the following chemical structural formula:

[0003]

[0004] It has a significant antiarrhythmic effect and is widely used in clinical practice.

[0005] Compared to nitrodiphenylamines with other site substitutions, such as ortho- and para-substituted nitrodiphenylamines, meta-substituted nitrodiphenylamines are significantly more difficult to synthesize. Currently, the reported synthetic methods for meta-nitrodiphenylamines, such as 3-nitrodiphenylamine, mainly fall into two categories:

[0006] 1. Indirect synthesis of 3-nitrodiphenylamine, using acetanilide or N-acetyl-m-nitroaniline as starting materials, the specific synthetic route is shown below:

[0007]

[0008] Chinese Journal of New Drugs, 2006, Vol. 15, No. 14, p. 1188

[0009]

[0010] Pharmaceutical Industry, 1982(07):1-3.DOI:10.16522 / j.cnki.cjph.1982.07.001.

[0011] 2. Direct synthesis of 3-nitrodiphenylamine, using phenylboronic acid or m-nitrophenylboronic acid as starting materials, the specific synthetic route is shown below:

[0012]

[0013] Res Chem Intermed 45,2727–2747(2019); Green Chem.,23,1041-1049(2021)

[0014]

[0015] J.Org.Chem.,71,9522–9524(2006); Catal Lett 141,1171–1181(2011)

[0016] Of the methods described above, Method 1, the indirect synthesis method, requires the amino group to be acetylated first, increasing the number of reaction steps and waste. Furthermore, the indirect synthesis method requires prolonged high-temperature reactions, resulting in severe tar formation of the reaction solution and making purification difficult. Method 2 uses phenylboronic acid compounds, which are far more expensive than acetanilide, thus significantly increasing the synthesis cost of 3-nitrodiphenylamine. Summary of the Invention

[0017] Based on the technical problems existing in the background art, the present invention proposes a method for synthesizing m-nitrodiphenylamine compounds. This method is not only simple in steps, but also stable in process and has a high yield.

[0018] The present invention proposes a method for synthesizing m-nitrodiphenylamine compounds, comprising: carrying out an electrophilic substitution reaction of m-nitrohalobenzene and aniline, or of halobenzene and m-nitroaniline, under the conditions of a sulfonic acid catalyst and an ionic liquid solvent, to obtain m-nitrodiphenylamine compounds.

[0019] Preferably, the structural formula of the m-nitrohalobenzene is shown below:

[0020]

[0021] Wherein, R1 is at least one of hydrogen, alkyl, alkoxy, alkylthio, nitro or alkylcarbonyl, preferably, R1 is hydrogen; X is any one of fluorine, chlorine, bromine or iodine, preferably, X is bromine;

[0022] The structural formula of aniline is shown below:

[0023]

[0024] Wherein, R2 is at least one of hydrogen, alkyl, alkoxy, alkylthio, nitro or alkylcarbonyl, preferably, R2 is hydrogen.

[0025] Preferably, the structural formula of the m-nitroaniline is shown below:

[0026]

[0027] Wherein, R3 is at least one of hydrogen, alkyl, alkoxy, alkylthio, nitro or alkylcarbonyl, preferably, R3 is hydrogen;

[0028] The structural formula of the halobenzene is shown below:

[0029]

[0030] Wherein, R4 is at least one of hydrogen, alkyl, alkoxy, alkylthio, nitro or alkylcarbonyl, preferably, R4 is hydrogen; X is any one of fluorine, chlorine, bromine or iodine, preferably, X is bromine.

[0031] Preferably, the molar ratio of the m-nitrohalobenzene to aniline is 1:1.5-3; and the molar ratio of the halobenzene to m-nitroaniline is 1:1-3.

[0032] Preferably, the sulfonic acid compound is at least one of p-toluenesulfonic acid, aminosulfonic acid, trifluoromethanesulfonic acid, or methanesulfonic acid;

[0033] Preferably, the amount of the sulfonic acid compound is 10-40 mol of m-nitrohalobenzene or halobenzene.

[0034] Preferably, the ionic liquid is at least one of 1-butyl-2,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium chloride, 1-hexyl-3-methylimidazolium chloride, 1-octyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium tetrafluoroborate, or 1-benzyl-3-methylimidazolium chloride.

[0035] Preferably, the amount of the ionic liquid used is 10-100 wt% of m-nitrohalobenzene or halobenzene.

[0036] Preferably, the electrophilic substitution reaction is carried out under microwave heating conditions;

[0037] Preferably, the microwave power is 50-200W and the reaction time is 10-50min.

[0038] Preferably, the synthetic method comprises: reacting 3-nitrobromobenzene with aniline, or bromobenzene with 3-nitroaniline, under the conditions of a sulfonic acid catalyst and an ionic liquid solvent to undergo an electrophilic substitution reaction, yielding a m-nitrodiphenylamine compound, the synthetic route of which is shown below:

[0039]

[0040] Preferably, the m-nitrodiphenylamine compound is 3-nitrodiphenylamine, and its structural formula is shown below:

[0041]

[0042] The present invention proposes a method for synthesizing m-nitrodiphenylamine compounds, which involves carrying out an electrophilic substitution reaction between m-nitrohalobenzene and aniline, or between halobenzene and m-nitroaniline, under the catalysis of sulfonic acid compounds and the solvent conditions of ionic liquids, to obtain the m-nitrodiphenylamine compounds. This method has the advantages of simple reaction steps, mild synthesis conditions, good reproducibility, convenient processing, and high yield. Furthermore, the use of m-nitrohalobenzene and aniline, or halobenzene and m-nitroaniline, as reactants is inexpensive and widely available, which is conducive to large-scale production. Attached Figure Description

[0043] Figure 1 The image shows the 1H NMR spectrum of 3-nitrodiphenylamine synthesized in Example 1 of this invention. Detailed Implementation

[0044] The present invention will now be described in detail through specific embodiments. However, these embodiments are clearly provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0045] Example 1

[0046] A method for synthesizing 3-nitrodiphenylamine, comprising:

[0047] Aniline (0.1 mol), m-bromonitrobenzene (0.05 mol), p-toluenesulfonic acid (0.01 mol), and 1-butyl-2,3-dimethylimidazolium chloride (1.0 g) were added to a tetrafluoroethylene reactor equipped with a stirrer. The reactor was then placed in a microwave reactor and reacted for 15 min at a microwave power of 100 W. After the reaction was completed, the resulting reaction solution was poured into 20 mL of rapidly stirred water. The solid product was separated by filtration and dried to obtain 10 g of iron-red solid, which was the 3-nitrodiphenylamine, with a yield of 93% and a liquid phase purity of 99.2%.

[0048] Reference Figure 1 , Figure 1 The image shows the 1H NMR spectrum of the 3-nitrodiphenylamine synthesized in this example, which demonstrates that aniline and m-bromonitrobenzene reacted effectively to obtain 3-nitrodiphenylamine.

[0049] Example 2

[0050] A method for synthesizing 3-nitrodiphenylamine, comprising:

[0051] 0.1 mol of m-nitroaniline, 0.05 mol of bromobenzene, 0.02 mol of p-toluenesulfonic acid, and 1.5 g of 1-ethyl-3-methylimidazolium chloride were added to a tetrafluoroethylene reactor equipped with a stirrer. The reactor was then placed in a microwave reactor and reacted for 25 min at a microwave power of 100 W. After the reaction was completed, the resulting reaction solution was poured into 25 mL of rapidly stirred water. The solid product was separated by filtration and dried to obtain 10.2 g of iron-red solid, which was the 3-nitrodiphenylamine, with a yield of 95% and a liquid phase purity of 99.4%.

[0052] Example 3

[0053] A method for synthesizing 3-nitrodiphenylamine, comprising:

[0054] 0.1 mol of m-nitroaniline, 0.05 mol of bromobenzene, 0.015 mol of trifluoromethanesulfonic acid, and 2.0 g of 1-hexyl-3-methylimidazolium chloride were added to a tetrafluoroelastomer reactor equipped with a stirrer. The reactor was then placed in a microwave reactor and reacted for 50 min at a microwave power of 50 W. After the reaction was completed, the resulting reaction solution was poured into 20 mL of rapidly stirred water. The solid product was separated by filtration and dried to obtain 9.8 g of iron-red solid, which was the 3-nitrodiphenylamine, with a yield of 92% and a liquid phase purity of 99.6%.

[0055] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a m-nitrodiphenylamine compound, characterized in that, include: The m-nitro halobenzene and aniline, or the halobenzene and m-nitroaniline, are subjected to an electrophilic substitution reaction under the conditions of a sulfonic acid catalyst and an ionic liquid solvent to obtain the m-nitrodiphenylamine compound. The sulfonic acid compound is at least one of p-toluenesulfonic acid or trifluoromethanesulfonic acid; the ionic liquid is at least one of 1-butyl-2,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride or 1-hexyl-3-methylimidazolium chloride.

2. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1, characterized in that, The structural formula of the m-nitrohalobenzene is shown below: Wherein, R1 is hydrogen; X is any one of fluorine, chlorine, bromine or iodine; The structural formula of aniline is shown below: R2 is hydrogen.

3. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, The structural formula of the m-nitroaniline is shown below: Wherein, R3 is hydrogen; The structural formula of the halobenzene is shown below: Wherein, R4 is hydrogen; X is any one of fluorine, chlorine, bromine or iodine.

4. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, The molar ratio of the m-nitrohalobenzene to aniline is 1:1.5-3; the molar ratio of the halobenzene to m-nitroaniline is 1:1-3.

5. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, The amount of the sulfonic acid compound used is 10-40 mol of m-nitrohalobenzene or halobenzene.

6. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, The amount of the ionic liquid used is 10-100 wt% of m-nitrohalobenzene or halobenzene.

7. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, The electrophilic substitution reaction was carried out under microwave heating conditions; The microwave power is 50-200W, and the reaction time is 10-50min.

8. The method for synthesizing the m-nitrodiphenylamine compound according to claim 1 or 2, characterized in that, include: The m-nitrodiphenylamine compound is obtained by electrophilic substitution reaction of 3-nitrobromobenzene and aniline, or bromobenzene and 3-nitroaniline, under the conditions of sulfonic acid catalyst and ionic liquid solvent.

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