Aromatic compound nitration method, nitrobenzene compound and method for preparing nitroaniline compound

Abstract

The present invention relates to the field of organic synthesis, and in particular to a method for nitrating aromatic compounds, nitrobenzene compounds, and a method for preparing nitroaniline compounds. In the method for nitrating aromatic compounds, the reaction formula is as follows: wherein R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3, R2 is selected from any one of C1-C4 haloalkyl, -H, and C1-C4 alkyl, or two R2s are bonded to form a five-membered or six-membered anhydride ring, X is selected from a halogen, and R3 is selected from a C1-C6 alkyl. The preparation method comprises: mixing compound 1, compound 2, and a first solvent, adding fuming nitric acid, and post-treating to obtain compound 3; or mixing compound 1 and compound 2 having a melting point of less than or equal to 20°C, adding fuming nitric acid, and post-treating to obtain compound 3. In the method for nitrating aromatic compounds of the present application, anhydride is used as a reaction reagent, an acyl group is introduced to protect the amino group, and then nitrification is performed. The reaction process is mild, and the target product can be obtained in a one-pot process, thereby improving the reaction yield.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for nitrating aromatic compounds, nitrobenzene compounds and a method for preparing nitroaniline compounds. Background Art

[0002] Chinese patent CN 115087655A discloses a benzimidazole derivative that can be used as an inhibitor of interleukin-2-inducible T-cell kinase (ITK) for treating diseases mediated by ITK, particularly skin diseases such as dermatitis (e.g., atopic dermatitis). 4-Fluoro-2-methoxy-5-nitroaniline is an important intermediate in the synthesis of the above-mentioned compound.

[0003] In the prior art, there are a variety of methods for introducing nitro groups into aromatic compounds, but these methods have violent reaction processes and are somewhat dangerous in industrial production.

[0004] For example, Chinese patent CN 110078732A discloses a method for preparing 4-fluoro-2-methoxy-5-nitroaniline using concentrated sulfuric acid as a solvent and potassium nitrate as a nitrating agent. The above method is a conventional method for introducing a nitro group, and the reaction yield is 83.7%.

[0005] For example, patent WO 2018207120A1 discloses a method for preparing 4-fluoro-2-methoxy-5-nitroaniline by protecting the amino group with an acetyl group, followed by nitration and deprotection. The method uses concentrated sulfuric acid as a solvent and reacts with fuming nitric acid to introduce a nitro group. The total yield of the two-step reaction of acetyl protection and nitro introduction is 65.1%, which is relatively low.

[0006] In summary, existing methods for preparing 4-fluoro-2-methoxy-5-nitroaniline all require strong acids as solvents, which place high demands on reaction equipment, cause significant pollution, and require the use of large amounts of base for neutralization in post-treatment. Summary of the Invention

[0007] The present invention is made to solve the above problems and aims to provide a method for nitrating aromatic compounds with mild reaction conditions and relatively good yield, as well as a method for preparing nitroaniline compounds using nitrobenzene compounds.

[0008] The first aspect of the present invention provides a method for nitrating an aromatic compound, and the reaction formula is as follows:

[0009]

[0010] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3,

[0011] R2 is selected from any one of C1-C4 haloalkyl, -H, C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring,

[0012] The haloalkyl group is an alkyl group in which one or more hydrogen atoms are replaced by halogen.

[0013] X is selected from halogen,

[0014] R3 is selected from C1-C6 alkyl,

[0015] The preparation method comprises the following steps:

[0016] Compound 1, compound 2 and the first solvent are mixed, fuming nitric acid is added, and post-processed to obtain compound 3.

[0017] The first solvent is a non-protonic acid solvent.

[0018] The second aspect of the present invention provides another method for nitrating an aromatic compound, and the reaction formula is as follows:

[0019]

[0020] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3,

[0021] R2 is selected from any one of C1-C4 haloalkyl, -H, C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring,

[0022] The haloalkyl group is an alkyl group in which one or more hydrogen atoms are replaced by halogen.

[0023] X is selected from halogen,

[0024] R3 is selected from C1-C6 alkyl,

[0025] The preparation method comprises the following steps:

[0026] Compound 1 and compound 2 having a melting point of less than or equal to 20° C. are mixed, fuming nitric acid is added, and post-treatment is performed to obtain compound 3.

[0027] The third aspect of the present invention provides a nitrobenzene compound, the structural formula of which is as follows:

[0028]

[0029] In formula 3a, X is selected from halogen.

[0030] A fourth aspect of the present invention provides a method for preparing nitroaniline compounds, and the reaction formula is as follows:

[0031]

[0032] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3,

[0033] R2 is selected from any one of C1-C4 haloalkyl, -H, C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring,

[0034] The haloalkyl group is an alkyl group in which one or more hydrogen atoms are replaced by halogen.

[0035] X is selected from halogen,

[0036] R3 is selected from C1-C6 alkyl,

[0037] The method comprises any one of the following two preparation methods:

[0038] Method 1: Step A1: Compound 1, compound 2 and a first solvent are mixed, fuming nitric acid is added, and post-treated to obtain compound 3.

[0039] Step B: Compound 3, alkali or hydrochloric acid and a second solvent are mixed and reacted to obtain compound 4.

[0040] Method 2: Step A2: Compound 1 and compound 2 having a melting point of less than or equal to 20°C are mixed, fuming nitric acid is added, and post-treated to obtain compound 3.

[0041] Step B: Compound 3, a base or hydrochloric acid and a second solvent are mixed, and after the reaction is complete, compound 4 is obtained.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] The method for nitrating aromatic compounds disclosed herein uses an acid anhydride as the reaction reagent, introduces an acyl group to protect the amino group, and then performs the nitration. This results in a mild reaction process and the target product can be obtained in a single pot, improving the reaction yield to as high as 92.2%.

[0044] According to the method for preparing nitroaniline compounds involved in the present application, the target product can be obtained with a high yield due to the selection of base or hydrochloric acid. The reaction yield can reach up to 91.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The product of Example 1 of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION

[0046] Hereinafter, embodiments of the disclosed method for nitrating aromatic compounds, nitrobenzene compounds, and method for preparing nitroaniline compounds will be described in detail.

[0047] Definition of terms

[0048] Unless otherwise specified, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0049] In general, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including for cell culture, organic chemistry, analytical chemistry, and pharmacology, etc.) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the present disclosure described herein have the same meaning as commonly understood by those skilled in the art. Additionally, in the claims and / or the specification, when the term "one" or "an" is used in conjunction with the term "comprising" or a noun, its meaning may be "one", but is also consistent with the meaning of "one or more", "at least one", and "one or more than one". Similarly, the term "another" or "other" may mean at least a second or more.

[0050] It should be understood that whenever various aspects are described herein using the terms "including" or "comprising," other similar aspects described by "consisting of" and / or "consisting essentially of" are also provided.

[0051] As used herein, the term "alkyl" used alone or in combination may be straight-chain or branched, and the number of carbon atoms may be, for example, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like.

[0052] As used herein, the term "haloalkyl" alone or in combination refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen. The number of carbon atoms may be, for example, C1-C4, C1-C3, or C1-C2. For example, haloalkyl includes, but is not limited to, -CF3, -CHF2, -CH2F, and -CH2CF3.

[0053] In this context, bonding to form a ring refers to forming an acid anhydride ring, especially forming a five-membered or six-membered acid anhydride ring.

[0054] As used herein, the term "halogen," alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0055] Method for nitration of aromatic compounds

[0056] The first aspect of the present invention provides a method for nitrating an aromatic compound, which has the following characteristics:

[0057]

[0058] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3, R2 is selected from any one of C1-C4 haloalkyl, -H, and C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring, wherein the haloalkyl is an alkyl group in which one or more hydrogen atoms are replaced by halogen, X is selected from halogen, and R3 is selected from C1-C6 alkyl.

[0059] The preparation method comprises the following steps:

[0060] Compound 1, compound 2 and a first solvent are mixed, fuming nitric acid is added, and post-processed to obtain compound 3, wherein the first solvent is a non-protonic acid solvent.

[0061] In the method for nitrating an aromatic compound provided by the present invention, the following characteristics may be further possessed: R1 is selected from -OR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0062] The method for nitrating an aromatic compound provided by the present invention may also have the following feature: R1 is selected from -OH.

[0063] In the method for nitrating an aromatic compound provided by the present invention, the following characteristics may be further possessed: R1 is selected from -NHCOR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0064] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein R1 is selected from R3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0065] The method for nitration of aromatic compounds provided by the present invention may also have the following characteristics: wherein, preferably, R1 is selected from -OCH3.

[0066] In the method for nitration of aromatic compounds provided by the present invention, it can also have the following characteristics: wherein R2 is selected from a C1-C4 halogenated alkyl group, optionally, R2 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, etc., preferably, R2 is selected from -CF3.

[0067] The method for nitration of an aromatic compound provided by the present invention may also have the following characteristics: wherein R2 is selected from -H.

[0068] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein R2 is selected from a C1-C4 alkyl group. Alternatively, R2 is selected from a C1-C3 alkyl group. Further alternatively, R2 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0069] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein two R2 are bonded to form a five-membered or six-membered anhydride ring.

[0070] The method for nitrating aromatic compounds provided by the present invention may also have the following characteristics: wherein the compound 1 is Alternatively, R3 is selected from a C1-C6 alkyl group. Further alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Preferably, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group. Alternatively, X is selected from a fluorine group, a chlorine group, a bromine group, or an iodine group. Preferably, X is fluorine.

[0071] Preferably, when R3 is methyl and X is fluorine, compound 1 is

[0072] The method for nitration of aromatic compounds provided by the present invention may also have the following characteristics: wherein the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, and methyl tert-butyl ether.

[0073] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the molar ratio of compound 1 to compound 2 is 1:(1.0-2.0). Alternatively, the molar ratio of compound 1 to compound 2 may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0074] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0075] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-5.0) mL. Alternatively, the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-4.0) mL or 1 g: (4.0-5.0) mL, etc.

[0076] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the reaction temperature is 0°C-20°C. Alternatively, the reaction temperature may be, for example, 0°C-5°C, 5°C-20°C, 5°C-10°C, 10°C-15°C, or 15°C-20°C.

[0077] Method for nitration of aromatic compounds

[0078] The second aspect of the present invention provides another method for nitrating an aromatic compound, which has the following characteristics:

[0079]

[0080] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3, R2 is selected from any one of C1-C4 haloalkyl, -H, and C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring, wherein the haloalkyl is an alkyl group in which one or more hydrogen atoms are replaced by halogen, X is selected from halogen, and R3 is selected from C1-C6 alkyl.

[0081] The preparation method comprises the following steps:

[0082] Compound 1 and compound 2 having a melting point of less than or equal to 20° C. are mixed, fuming nitric acid is added, and post-treatment is performed to obtain compound 3.

[0083] In the method for nitrating an aromatic compound provided by the present invention, the following characteristics may be further possessed: R1 is selected from -OR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0084] The method for nitrating an aromatic compound provided by the present invention may also have the following feature: R1 is selected from -OH.

[0085] In the method for nitrating an aromatic compound provided by the present invention, the following characteristics may be further possessed: R1 is selected from -NHCOR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0086] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein R1 is selected from R3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0087] The method for nitration of aromatic compounds provided by the present invention may also have the following characteristics: wherein, preferably, R1 is selected from -OCH3.

[0088] In the method for nitration of aromatic compounds provided by the present invention, it can also have the following characteristics: wherein R2 is selected from a C1-C4 halogenated alkyl group, optionally, R2 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, etc., preferably, R2 is selected from -CF3.

[0089] The method for nitration of an aromatic compound provided by the present invention may also have the following characteristics: wherein R2 is selected from -H.

[0090] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein R2 is selected from a C1-C4 alkyl group. Alternatively, R2 is selected from a C1-C3 alkyl group. Further alternatively, R2 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0091] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein two R2 are bonded to form a five-membered or six-membered anhydride ring.

[0092] The method for nitrating aromatic compounds provided by the present invention may also have the following characteristics: wherein the compound 1 is Alternatively, R3 is selected from a C1-C6 alkyl group. Further alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Preferably, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group. Alternatively, X is selected from a fluorine group, a chlorine group, a bromine group, or an iodine group. Preferably, X is fluorine.

[0093] Preferably, when R3 is methyl and X is fluorine, compound 1 is

[0094] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0095] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the mass volume ratio of the compound 1 to the compound 2 is 1 g: (8.0-10.0) mL. Alternatively, the mass volume ratio of the compound 1 to the compound 2 may be, for example, 1 g: (8.0-9.0) mL or 1 g: (9.0-10.0) mL.

[0096] The method for nitrating an aromatic compound provided by the present invention may also have the following characteristics: wherein the reaction temperature is 0°C-20°C. Alternatively, the reaction temperature may be, for example, 0°C-5°C, 5°C-20°C, 5°C-10°C, 10°C-15°C, or 15°C-20°C.

[0097] Nitrobenzene compounds

[0098] The third aspect of the present invention provides a nitrobenzene compound having the following characteristics:

[0099]

[0100] In formula 3a, X is selected from halogen, wherein the halogen may be, for example, fluorine, chlorine, bromine or iodine.

[0101] Among the nitrobenzene compounds provided by the present invention, the following characteristics may also be present: Preferably, Formula 3a is

[0102]

[0103] Method for preparing nitroaniline compounds

[0104] The present invention provides a method for preparing nitroaniline compounds, which has the following characteristics:

[0105]

[0106] In the formula, R1 is selected from any one of -OR3, -OH, -NHCOR3, and R3,

[0107] R2 is selected from any one of C1-C4 haloalkyl, -H, C1-C4 alkyl, or two R2 are bonded to form a five-membered or six-membered anhydride ring, wherein the haloalkyl is one or more hydrogens on the alkyl group are replaced by halogen, X is selected from halogen, R3 is selected from C1-C6 alkyl,

[0108] The method comprises any one of the following two preparation methods:

[0109] Method 1: Step A1: Compound 1, compound 2 and a first solvent are mixed, fuming nitric acid is added, and post-treated to obtain compound 3.

[0110] Step B: Compound 3, alkali or hydrochloric acid and a second solvent are mixed and reacted to obtain compound 4.

[0111] Method 2: Step A2: Compound 1 and compound 2 having a melting point of less than or equal to 20°C are mixed, fuming nitric acid is added, and post-treated to obtain compound 3.

[0112] Step B: Compound 3, a base or hydrochloric acid and a second solvent are mixed, and after the reaction is complete, compound 4 is obtained.

[0113] The method for preparing nitroanilines provided by the present invention may also have the following characteristics: wherein R1 is selected from -OR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further optionally, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0114] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: R1 is selected from -OH.

[0115] In the method for preparing nitroanilines provided by the present invention, R1 may be selected from -NHCOR3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0116] The method for preparing nitroanilines provided by the present invention may also have the following characteristics: wherein R1 is selected from R3, wherein R3 is selected from a C1-C6 alkyl group. Alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Further alternatively, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0117] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, preferably, R1 is selected from -OCH3.

[0118] In the method for preparing nitroaniline compounds provided by the present invention, it can also have the following characteristics: wherein R2 is selected from a C1-C4 halogenated alkyl group, optionally, R2 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, etc., preferably, R2 is selected from -CF3.

[0119] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein R2 is selected from -H.

[0120] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein R2 is selected from a C1-C4 alkyl group. Alternatively, R2 is selected from a C1-C3 alkyl group. Further optionally, R2 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0121] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein two R2 are bonded to form a five-membered or six-membered anhydride ring.

[0122] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein the compound 1 is Alternatively, R3 is selected from a C1-C6 alkyl group. Further alternatively, R3 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. Preferably, R3 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group. Alternatively, X is selected from a fluorine group, a chlorine group, a bromine group, or an iodine group. Preferably, X is fluorine.

[0123] Preferably, when R3 is methyl and X is fluorine, compound 1 is

[0124] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step A1, the first solvent is a non-protonic acid solvent, optionally, the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, and methyl tert-butyl ether.

[0125] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step A1, the molar ratio of compound 1 to compound 2 is 1:(1.0-2.0). Alternatively, the molar ratio of compound 1 to compound 2 may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0126] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step A1, the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0127] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step A1, the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-5.0) mL. Alternatively, the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-4.0) mL or 1 g: (4.0-5.0) mL, etc.

[0128] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step A1, the reaction temperature is 0°C-20°C. Alternatively, the reaction temperature may be, for example, 0°C-5°C, 5°C-20°C, 5°C-10°C, 10°C-15°C, or 15°C-20°C.

[0129] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step A2, the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1:(1.0-1.2), 1:(1.2-2), 1:(1.0-1.5), or 1:(1.5-2).

[0130] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step A2, the mass volume ratio of compound 1 to compound 2 is 1 g: (8.0-10.0) mL. Alternatively, the mass volume ratio of compound 1 to compound 2 may be, for example, 1 g: (8.0-9.0) mL or 1 g: (9.0-10.0) mL.

[0131] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step A2, the reaction temperature is 0°C-20°C. Alternatively, the reaction temperature may be, for example, 0°C-5°C, 5°C-20°C, 5°C-10°C, 10°C-15°C, or 15°C-20°C.

[0132] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step B, the second solvent is either methanol or ethanol.

[0133] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step B, the base is either potassium carbonate or sodium carbonate.

[0134] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step B, the mass volume ratio of the compound 3 to the base is 1 g:(4-6) mL. Alternatively, the mass volume ratio of the compound 3 to the base can be 1 g:(4-5) mL or 1 g:(5-6) mL, etc.

[0135] The method for preparing nitroaniline compounds provided by the present invention may also have the following characteristics: wherein, in step B, the mass volume ratio of the compound 3 to the hydrochloric acid may be, for example, 1 g:(4-6) mL. Alternatively, the mass volume ratio of the compound 3 to the hydrochloric acid may be, for example, 1 g:(4-5) mL or 1 g:(5-6) mL.

[0136] The method for preparing nitroaniline compounds provided by the present invention may also have the following feature: wherein, in step B, the mass volume ratio of the compound 3 to the second solvent is 1 g:(4-6) mL. Alternatively, the mass volume ratio of the compound 3 to the second solvent may be, for example, 1 g:(4-5) mL or 1 g:(5-6) mL.

[0137] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to embodiments and drawings.

[0138] In the following examples, unless otherwise specified, all reaction raw materials are commercially available products.

[0139] Unless otherwise specified, the purity of each product in each embodiment of the present invention exceeds 98%.

[0140] <Example 1>

[0141] Preparation of compound 3a

[0142] This example provides a method for preparing compound 3a, and the reaction formula is as follows:

[0143]

[0144] The steps include:

[0145] Under nitrogen protection, 40 g of compound 1a (0.28 mol, 1.0 eq), 71.42 g of compound 2a (0.34 mol, 1.2 eq), and 160 mL of dichloromethane were added to a reaction vessel, stirred at 5°C for 4 h, 21.42 g of fuming nitric acid (0.34 mol, 1.2 eq) was added dropwise, stirred at 5°C for 16 h, a 20% mass fraction of sodium bicarbonate solution was added, the pH was adjusted to 7, and the mixture was filtered. The filter cake was taken, the filtrate was separated, and the organic phase was taken. The organic phase was combined with the filter cake, the solvent was distilled off under reduced pressure, and n-heptane was added for washing and drying. The yield was 92.2%.

[0146] Product 1 HNMR spectrum Figure 1 shown.

[0147] <Example 2>

[0148] Preparation of compound 3b

[0149] This example provides a method for preparing compound 3b, and the reaction formula is as follows:

[0150]

[0151] The steps include:

[0152] Under nitrogen protection, 40 g of compound 1a (0.28 mol, 1.0 eq) and 320 mL of acetic anhydride were added to a reaction vessel, stirred at 5°C for 4 h, 21.42 g of fuming nitric acid (0.34 mol, 1.2 eq) was added dropwise, stirred at 5°C for 16 h, 800 mL of water was added with stirring, filtered, and the filter cake was air-dried at 50°C to constant weight. The yield was 76.6%.

[0153] <Example 3>

[0154] Screening of the first solvent in method 1

[0155] Based on Example 1, this example screened the first solvent in Method 1. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1. Sequence number 3 corresponds to Example 1.

[0156] The screening results are shown in Table 1.

[0157] Table 1 Screening of the first solvent

[0158] Serial number First solvent Product yield (%) 1 98wt% sulfuric acid 45.7 2 <![CDATA[Acetic acid a > NR 3 dichloromethane 92.2

[0159] a is the reaction temperature of 25°C.

[0160] As can be seen from the above table, when the first solvent is acetic acid, a large amount of raw materials remain and no product is generated. When the first solvent is sulfuric acid, the yield of the product is only 45.7%, and the reaction effect is poor. When the first solvent is dichloromethane, the product yield is higher.

[0161] <Example 4>

[0162] Screening of nitric acid concentration

[0163] This example screened the nitric acid concentration based on Example 1. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1. Sequence number 1 corresponds to Example 1.

[0164] The screening results are shown in Table 2.

[0165] Table 2 Screening of nitric acid concentration

[0166] Serial number Nitric acid concentration (%) Product yield (%) 1 98 92.2 2 68 NR 3 <![CDATA[68 b ]]> 43.2

[0167] b is the reaction temperature of 40℃

[0168] As can be seen from the above table, when the concentration of nitric acid is 68%, no product is generated at 5°C, and the reaction can occur at 40°C, but the reaction yield is only 43.2%; when the concentration of nitric acid is 98%, the product yield is higher. Therefore, this application uses fuming nitric acid as the reaction reagent.

[0169] <Example 5>

[0170] Screening of solvents and their dosage in method 2

[0171] Based on Example 2, this example screened the solvent and its amount in Method 2. Except for the parameters listed in the table below, the remaining steps are the same as those described in Example 2. Among them, sequence number 1 corresponds to Example 2.

[0172] The screening results are shown in Table 3.

[0173] Table 3 Screening of solvents and their dosage in method 2

[0174] Serial number Solvent and dosage in method 2 Product yield (%) 1 Acetic anhydride (320 mL) 76.6 2 Dichloromethane (160 mL) and acetic anhydride (80 mL) 49.7 3 Dichloromethane (160 mL) and 98 wt% sulfuric acid (80 mL) 27.9

[0175] As can be seen from the above table, when the solvent is dichloromethane and acetic anhydride, the yield of the product is low, at 49.7%. When the solvent is dichloromethane and sulfuric acid, the yield of the product is only 27.9%. Therefore, acetic anhydride is the best solvent.

[0176] <Example 6>

[0177] Preparation of compound 4a

[0178] This example provides a method for preparing compound 4a, and the reaction formula is as follows:

[0179]

[0180] The steps include:

[0181] 40 g of compound 3a (0.14 mol, 1.0 eq), 200 mL of 20% potassium carbonate aqueous solution, and 200 mL of methanol were added to a reaction vessel. The mixture was reacted at 25° C. for 20 h. Water was added, the mixture was stirred, filtered, and the filter cake was dried. The yield was 91.9%.

[0182] <Example 7>

[0183] Acid and base screening

[0184] This example screened the acid and base based on Example 6. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 6. Sequence number 1 corresponds to Example 6.

[0185] The screening results are shown in Table 4.

[0186] Table 4 Screening of acids and bases

[0187] Serial number Acids and bases Product yield (%) 1 20% potassium carbonate aqueous solution 91.9 2 20% sodium carbonate aqueous solution 86.3 3 hydrochloric acid 84.2

[0188] As can be seen from the above table, when the base is 20% potassium carbonate or sodium carbonate aqueous solution, the reaction can achieve good results, with product yields of 91.9% and 86.3% respectively; when it is hydrochloric acid, a good reaction yield can also be obtained.

[0189] Comparative Example 1

[0190] Preparation of compound 3b

[0191] This example provides a method for preparing compound 3b, and the reaction formula is as follows:

[0192]

[0193] The steps include:

[0194] 40 g of compound 1a (0.28 mol, 1.0 eq), 34.71 g of compound 2b (0.34 mol, 1.2 eq), and 160 mL of dichloromethane were added to a reaction vessel, stirred at 5°C for 4 h, 21.42 g of fuming nitric acid (0.34 mol, 1.2 eq) was added dropwise, and stirred at 5°C for 16 h. A 20% mass fraction of sodium bicarbonate solution was added, and the pH was adjusted to 7. The mixture was filtered, the filter cake was collected, the filtrate was separated, and the organic phase was collected. The organic phase was combined with the filter cake, the solvent was distilled off under reduced pressure, and the mixture was washed with n-heptane and dried. The yield was 49.7%.

[0195] The above method for preparing compounds 3a and 3b uses equivalent amounts of acetic anhydride and fuming nitric acid as reaction reagents and dichloromethane as solvent, but the yield of the product is only 49.7%. Therefore, using trifluoroacetic anhydride as the reaction reagent can achieve a high yield of over 90%.

[0196] Functions and Effects of the Embodiments

[0197] According to the methods for nitrating aromatic compounds described in the above embodiments, since dichloromethane is selected as the solvent in the first method (eg, Example 1), a higher reaction yield can be achieved compared to acetic acid and sulfuric acid.

[0198] Because fuming nitric acid is selected as the reaction reagent, the target product can be obtained in a higher yield.

[0199] Because acetic anhydride is selected as the solvent in the second method, a higher reaction yield can be achieved.

[0200] According to the method for preparing nitroaniline compounds involved in the above embodiment, since 20% potassium carbonate or sodium carbonate aqueous solution is selected as the base, or hydrochloric acid is selected as the acid, the target product can be obtained with a higher yield.

[0201] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

[0202] The applicant states that while the present invention uses the aforementioned embodiments to illustrate the methods for nitrating aromatic compounds, nitrobenzene compounds, and methods for preparing nitroanilines, the present invention is not limited to these embodiments, nor does it necessarily rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0203] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple variations of the technical solution of the present invention can be made, and these simple variations all fall within the scope of protection of the present invention.

[0204] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for nitrating an aromatic compound, characterized in that: The reaction formula is as follows: In the formula, R1 is selected from -OR3, R2 is -CF3, X is selected from halogen, R3 is selected from C1-C6 alkyl, The preparation method comprises the following steps: Compound 1, compound 2 and the first solvent are mixed, fuming nitric acid is added, and post-processed to obtain compound 3. The first solvent is selected from dichloromethane.

2. The method for nitrating an aromatic compound according to claim 1, wherein: The molar ratio of the compound 1 to the compound 2 is 1:(1.0-2.0); and / or, the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0); and / or, the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-5.0) mL; And / or, the reaction temperature is 0°C-20°C.

3. A nitrobenzene compound, characterized in that: The structural formula is as follows: In formula 3a, X is selected from halogen.

4. The nitrobenzene compound according to claim 3, wherein: Formula 3a is 5. A method for preparing nitroaniline compounds, characterized in that: The reaction formula is as follows: Wherein, R1 is selected from -OR3 R2 is -CF3, X is selected from halogen, R3 is selected from C1-C6 alkyl, Step A1: Compound 1, compound 2 and a first solvent are mixed, fuming nitric acid is added, and post-processed to obtain compound 3. Step B: Compound 3, a base or hydrochloric acid and a second solvent are mixed, and after the reaction is complete, compound 4 is obtained; The first solvent is selected from dichloromethane.

6. The method for preparing nitroaniline compounds according to claim 5, characterized in that: In step A1, the molar ratio of compound 1 to compound 2 is 1:(1.0-2.0); And / or, in step A1, the molar ratio of the compound 1 to the fuming nitric acid is 1:(1.0-2.0); And / or, in step A1, the mass volume ratio of the compound 1 to the first solvent is 1 g: (3.0-5.0) mL; And / or, in step A1, the reaction temperature is 0°C-20°C; And / or, in step B, the second solvent is any one of methanol or ethanol; And / or, in step B, the base is any one of potassium carbonate or sodium carbonate; And / or, in step B, the mass volume ratio of the compound 3 to the base is 1 g: (4-6) mL; And / or, in step B, the mass volume ratio of the compound 3 to the hydrochloric acid is 1 g: (4-6) mL; And / or, in step B, the mass volume ratio of the compound 3 to the second solvent is 1 g: (4-6) mL.

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