Synthesis method of 3-aminobiphenyl compounds

Abstract

The present invention provides a method for synthesizing 3-aminobiphenyl compounds, which relates to the technical field of organic synthesis. The synthesis method comprises the following steps: in acetic anhydride, under an acid promoter and a reducing agent, 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compounds generate 3-aminobiphenyl compounds at a temperature of 100-120 °C. A highly selective acid rearrangement and reduction reaction occur in the mixed system of acetic anhydride / acid promoter / reducing agent, and thus 3-aminobiphenyl compounds can be successfully prepared. The selected 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compounds are easily obtained. The acetic anhydride / acid promoter / reducing agent system used does not contain metal reagents, and the reaction conditions are compatible with a variety of functional groups. The method is simple and easy to operate, has a short reaction time, low cost, and simple post-treatment, and has little impact on environmental pollution.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for synthesizing 3-aminobiphenyl compounds. Background Art

[0002] Aromatic amines are a class of nitrogen-containing organic functional molecules with unique properties. Their structural fragments exist in many natural products, and the aromatic amine compounds themselves have very broad pharmacological activities. For example, benzocaine, procaine hydrochloride, etc. can be used for local anesthesia, bupivacaine hydrochloride can be used for postoperative analgesia, phenacetin can be used for antipyretic and analgesic, etc., while biaryl compounds, such as boscalid, have high-efficiency and low-toxicity bactericidal properties.

[0003] Meanwhile, aromatic amines have very broad and important application values in the synthesis of drugs, organic materials, and agrochemicals. They can generate diazonium salts through diazotization reactions and then be transformed into various different types of compounds through a series of conversions. For example, they can be transformed into haloarenes, aromatic nitriles, aryl phenols, and biaryl compounds, etc. These compounds are all widely used pharmaceutical and chemical raw materials and important organic intermediates.

[0004] In the prior art, the synthesis of aromatic amines mainly includes: one, after carrying out an electrophilic substitution type nitration reaction of aromatic hydrocarbons with nitric acid, then using a reducing agent to reduce the nitro group to an amino group, thus obtaining aromatic amine compounds; two, carrying out an S N Ar reaction of haloaromatic hydrocarbons and ammonia water / organic amines under a metal catalyst to generate aromatic amine compounds; three, the neopentanoyl oxime ester of tetralone and cyclohexenone can be transformed into the corresponding naphthylamine and aniline derivatives under the catalysis of a palladium reagent. Meanwhile, there are also Hofmann degradation reactions of arylamides, reduction reactions of azidoarenes, and reactions of aromatic phenol compounds and amines, etc., all of which can synthesize aromatic amine compounds.

[0005] However, although the prior art provides various methods for synthesizing aromatic amine compounds, there are still many deficiencies. For example, the nitration reaction has an explosion risk, the synthesis of haloaromatic hydrocarbons requires the use of halogenated reagents and Lewis acids that cause relatively large environmental pollution, while the S N Ar reaction requires the use of copper reagents or other precious metal reagents, with high costs and difficulty in complete separation from the products. Therefore, it is necessary to provide a solution to improve the above problems. Summary of the Invention

[0006] The object of the present invention is to provide a method for synthesizing 3-aminobiphenyl compounds. The reaction system does not contain metal reagents, has good compatibility with a variety of functional groups, is simple and easy to operate, has a short reaction time, low costs, and simple post-treatment, with little impact on environmental pollution.

[0007] A method for synthesizing 3-aminobiphenyl compounds provided by the present invention comprises the following steps:

[0008] In acetic anhydride, in the presence of an acid promoter and a reducing agent, the first raw material undergoes the following reaction at a temperature of 100-120 °C to form a compound represented by Formula I; the first raw material is a 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound;

[0009]

[0010] wherein, R 1 is hydrogen, cyano, nitroso, halogen, C1-C 30 alkoxy, C1-C 30 alkyl or C6-C 30 aryl, and R 2 is hydrogen, C1-C 30 alkyl or C6-C 30 aryl.

[0011] A method for synthesizing 3-aminobiphenyl compounds provided by the present invention uses a 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound as the first raw material, and the hydroxyl group in the oxime reacts in acetic anhydride to form an oxime ester, thereby avoiding the Beckmann rearrangement of the oxime in an acidic environment. And after the first raw material undergoes acid rearrangement to form an aromatic amine, acetic anhydride can react with the amino group in the aromatic amine to form acetamide, thereby enabling the product to be stabilized, and a 3-aminobiphenyl compound is prepared.

[0012] The beneficial effects are as follows: the selected 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound is easy to obtain, the used acetic anhydride / acid promoter / reducing agent system does not contain metal reagents, and the reaction conditions are compatible with a variety of functional groups, the method is simple and easy to operate, the reaction time is short, the cost is low, the post-treatment is simple, and the environmental pollution impact is small.

[0013] Optionally, when the first raw material reacts in the presence of an acid promoter and a reducing agent, the molar ratio of the first raw material to the reducing agent is 1:(0.5-2).

[0014] Optionally, the reducing agent includes one of iodine, cuprous chloride, and ferrous chloride.

[0015] Optionally, the acid promoter includes one of concentrated hydrochloric acid and sulfuric acid.

[0016] Optionally, during the reaction of the first raw material in the presence of an acid promoter and a reducing agent, the molar ratio of the first raw material to the acid promoter is 1:(1-20).

[0017] Optionally, after the compound represented by Formula I is formed, separation and purification are carried out to obtain a pure 3-aminobiphenyl compound.

[0018] Optionally, before separation and purification, a quenching solution is added to the reaction system for quenching treatment.

[0019] Optionally, during the separation and purification process, after adding an extractant, the organic phase is separated and purified by column chromatography. Detailed implementation manners

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein shall have the ordinary meanings understood by those of ordinary skill in the art in the field to which the present invention belongs. The words such as "including" used herein are intended to mean that the elements or items appearing before the word cover the elements or items listed after the word and their equivalents, without excluding other elements or items.

[0021] The embodiments of the present invention provide a method for synthesizing 3-aminobiphenyl compounds, including the following steps:

[0022] In acetic anhydride, in the presence of an acid promoter and a reducing agent, raw material one reacts at a temperature of 100-120 °C to form a compound shown in Formula I, where raw material one is a 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound;

[0023]

[0024] Wherein, R 1 is hydrogen, cyano, nitroso, halogen, C1-C 30 alkoxy, C1-C 30 alkyl or C6-C 30 aryl, and R 2 is hydrogen, C1-C 30 alkyl or C6-C 30 aryl.

[0025] Actually, when using raw material one to synthesize 3-aminobiphenyl compounds, there is no obvious reaction when the temperature is lower than 100 °C.

[0026] Actually, it is easy to obtain the 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound as raw material one, which helps to reduce the reaction cost.

[0027] In fact, in the synthesis reaction, acetic anhydride can not only act as a reactant, but also act as a solvent to dissolve raw material I, acid promoter and reducing agent. Therefore, in fact, the amount of acetic anhydride used is necessary to completely dissolve raw material I, acid promoter and reducing agent.

[0028] Specifically, the chemical structural formula of raw material I is shown in the following formula II, which has the meaning commonly understood by those skilled in the art, that is, it can have multiple substituents on the benzene ring, and at the same time has different substituents at the C-2, C-3 and C-5 positions of cyclohexadienone;

[0029]

[0030] In some embodiments, the acid promoter includes concentrated hydrochloric acid and concentrated sulfuric acid. Under the action of the acetic anhydride / acid promoter / reducing agent system, raw material I can undergo highly selective rearrangement and reduction reactions to prepare 3-aminobiphenyl compounds.

[0031] In some embodiments, during the reaction of raw material I under the acid promoter and reducing agent, the molar ratio of raw material I to the acid promoter is 1:(1-20).

[0032] In some embodiments, before the reaction of raw material I under the acid promoter and reducing agent, a reducing agent is added to the system, and the molar ratio of raw material I to the reducing agent is 1:(0.5-2).

[0033] In some embodiments, the reducing agent includes one of elemental iodine, cuprous chloride and ferrous chloride. In fact, the reducing agent can promote the reduction cleavage of the N-O bond in cyclohexadienone oxime in raw material I, thereby promoting the formation of aromatic amines.

[0034] In fact, in the acetic anhydride / acid promoter / reducing agent system, when reacting raw material I, the reaction conditions are mild, without metal reagents, have good compatibility with a variety of functional groups, the method is simple and easy to operate, the reaction time is short, and the cost is low.

[0035] In some embodiments, after the compound shown in formula I is generated, separation and purification are carried out to obtain pure 3-aminobiphenyl compounds. In fact, during the separation and purification process, the operations commonly used by those skilled in the art for the separation and purification of organic substances can be adopted, such as rotary evaporation concentration, filtration and drying, and column chromatography separation, etc. Specifically, when column chromatography separation method is used for its separation, the eluent used is an ethyl acetate / petroleum ether system.

[0036] In some embodiments, before separating and purifying the compound shown in Formula I, a quenching solution is added to the reaction system for quenching treatment to avoid the occurrence of side reactions. Specifically, the quenching solution can be a mixed solution obtained by mixing an aqueous solution of saturated sodium bisulfite and an aqueous solution of saturated sodium carbonate in any ratio.

[0037] In some embodiments, when separating and purifying the compound shown in Formula I, an extractant is added to the reaction mixture and stirred and shaken, so that the 3-aminobiphenyl compound enters the organic phase, and the organic phase is separated, and anhydrous sodium sulfate is used to dry and remove water from the organic phase. Specifically, ethyl acetate can be used as the extractant.

[0038] Example 1:

[0039] Embodiment 1 of the present invention provides a method for synthesizing a 2-methyl-5-acetamidobiphenyl compound, comprising the following steps:

[0040] S1. Add 5 mL of acetic anhydride, 100 mg (0.5 mmol) of starting material 1 and 190 mg (0.75 mmol) of I2 to a sealed tube with a volume of 25 mL in sequence, stir and dissolve them uniformly under magnetic stirring to obtain a precursor solution; wherein, the name of starting material 1 under the systematic nomenclature is 4-methyl-4-phenyl-2,5-cyclohexadienone oxime;

[0041] S2. In a room temperature environment of 25 °C, slowly and uniformly drip concentrated hydrochloric acid with a concentration of 36% - 38% into the precursor solution, control the titration time to 5 min, control the total volume of concentrated hydrochloric acid titration to 155 μL (HCl is about 5 mmol), after the titration is completed, transfer it to an oil bath and stir and react at 110 °C for 4 h to obtain a mixed solution;

[0042] S3. Add 10 mL of ethyl acetate to the mixed solution and extract it three times repeatedly (a total of 30 mL of ethyl acetate is added), wash it successively with an aqueous solution of saturated ammonium bisulfite and an aqueous solution of saturated sodium carbonate, separate the organic phase, dry and remove water with anhydrous sodium sulfate, filter, concentrate the organic phase, and perform column chromatography to obtain 66 mg of a 2-methyl-5-acetamidobiphenyl compound in the form of a white solid, and calculate the yield to be 66%; wherein, the eluent used during column chromatography is an ethyl acetate / petroleum ether system.

[0043] Specifically, the synthesis reaction formula of the 2-methyl-5-acetamidobiphenyl compound in Embodiment 1 of the present invention is as follows:

[0044]

[0045] Specifically, the characterization data of the 2-methyl-5-acetamidobiphenyl compound prepared in Embodiment 1 of the present invention in 1H NMR and 13C NMR are:

[0046] 1 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.34 - 7.31 (m, 1H), 7.29 (d, J = 5.4 Hz, 2H), 7.27 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 2.20 (s, 3H), 2.12 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 168.62, 142.34, 141.46, 135.66, 131.39, 130.75, 129.07, 128.06, 126.89, 121.46, 119.19, 24.40, 19.86.

[0047] Example 2:

[0048] Example 2 of the present invention provides a method for synthesizing a 2-methyl-5-acetamidobiphenyl compound. The difference from Example 1 is that in step S2, concentrated sulfuric acid with a concentration of 98% is slowly and evenly dropped into the precursor solution, controlling the titration time to be 7 min and the total volume of concentrated sulfuric acid titration to be 265 μL (about 5 mmol of H2SO4). Thus, in step S3, 51 mg of a 2-methyl-5-acetamidobiphenyl compound in the form of a white solid is obtained, and the calculated yield is 51%.

[0049] Example 3:

[0050] Example 3 of the present invention provides a method for synthesizing a 2-methyl-5-acetamidobiphenyl compound. The difference from Example 1 is that in step S1, 5 mL of acetic anhydride, 100 mg (0.5 mmol) of the first raw material, and 74 mg (1.5 mmol) of CuCl are successively added to a sealed tube with a volume of 25 mL. Thus, in step S3, 53 mg of a 2-methyl-5-acetamidobiphenyl compound in the form of a white solid is obtained, and the calculated yield is 53%.

[0051] Example 4:

[0052] Example 4 of the present invention provides a method for synthesizing a 2-methyl-5-acetamido-4'-methoxybiphenyl compound, which is different from Example 1 in that in step S1, 5 mL of acetic anhydride, 229 mg (1 mmol) of the first raw material, and 380 mg (1.5 mmol) of I2 are successively added to a sealed tube with a volume of 25 mL, and the name of the first raw material under the systematic nomenclature is 4-methyl-4-(4-methoxyphenyl)-2,5-cyclohexadienone oxime; in step S2, the total volume of concentrated hydrochloric acid titration is controlled to be 309 μL (HCl is about 10 mmol). Thus, in step S3, 138 mg of the 2-methyl-5-acetamido-4'-methoxybiphenyl compound in the form of an orange-yellow solid is prepared, and the calculated yield is 60.3%.

[0053] Specifically, the synthesis reaction formula of the 2-methyl-5-acetamido-4'-methoxybiphenyl compound in Example 4 of the present invention is as follows:

[0054]

[0055] Specifically, the characterization data of the 2-methyl-5-acetamido-4'-methoxybiphenyl compound prepared in Example 4 of the present invention in 1H NMR and 13C NMR are as follows:

[0056] 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 168.59, 158.57, 141.95, 135.65, 133.89, 131.50, 130.73, 130.16, 121.52, 118.91, 113.48, 55.27, 24.41, 19.95.

[0057] Example 5:

[0058] In Example 5 of the present invention, a method for synthesizing a 2-methyl-5-acetamido-4'-methylbiphenyl compound is provided. The difference from Example 1 is that in step S1, 5 mL of acetic anhydride, 215 mg (1 mmol) of the first raw material, and 380 mg (1.5 mmol) of I2 are successively added to a sealed tube with a volume of 25 mL. The name of the first raw material under the systematic nomenclature is 4-methyl-4-p-methylphenyl-2,5-cyclohexadienone oxime; in step S2, the total volume of concentrated hydrochloric acid titration is controlled to be 309 μL (HCl is about 10 mmol). Thus, in step S3, 135 mg of the 2-methyl-5-acetamido-4'-methylbiphenyl compound in the form of an orange-yellow solid is prepared, and the calculated yield is 62.7%.

[0059] Specifically, the synthesis reaction formula of the 2-methyl-5-acetamido-4'-methylbiphenyl compound in Example 5 of the present invention is as follows:

[0060]

[0061] Specifically, the characterization data of the 2-methyl-5-acetamido-4'-methylbiphenyl compound prepared in Example 5 of the present invention in the 1H NMR and 13C NMR spectra are as follows:

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.28 (s, 1H), 7.18 (d, 4H), 7.15 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 168.66, 142.28, 138.53, 136.49, 135.68, 131.42, 130.72, 128.95, 128.76, 121.50, 119.06, 24.39, 21.16, 19.92.

[0063] Example 6

[0064] In Example 6 of the present invention, a method for synthesizing 2-methyl-3-phenyl-5-acetamidobiphenyl compound is provided. The difference from Example 1 is that in step S1, 5 mL of acetic anhydride, 293 mg (1 mmol) of the first raw material and 380 mg (1.5 mmol) of I2 are successively added into a sealed tube with a volume of 25 mL, and the name of the first raw material under the systematic nomenclature is 4-methyl-3,4-diphenyl-2,5-cyclohexadienone oxime; in step S2, the total volume of concentrated hydrochloric acid titration is controlled to be 309 μL (HCl is about 10 mmol). Thus, in step S3, 140 mg of 2-methyl-3-phenyl-5-acetamidobiphenyl compound in the form of an orange-yellow solid is prepared, and the calculated yield is 47.8%.

[0065] Specifically, the synthesis reaction formula of the 2-methyl-3-phenyl-5-acetamidobiphenyl compound in Example 6 of the present invention is as follows:

[0066]

[0067] Specifically, the characterization data of the 2-methyl-3-phenyl-5-acetamidobiphenyl compound prepared in Example 6 of the present invention in 1H NMR and 13C NMR are as follows:

[0068] 1 H NMR(400 MHz, CDCl3) δ 7.88(s, 1H), 7.43 - 7.35(m, 6H), 7.32(d, J = 7.5 Hz, 6H), 2.07(s, 3H), 2.06(s, 3H). 13 C NMR(101 MHz, CDCl3) δ 168.80, 143.41, 142.04, 135.22, 129.27, 128.08, 126.92, 120.77, 24.35, 18.20.

[0069] Example 7

[0070] In Example 7 of the present invention, a method for synthesizing 2,3-dimethyl-5-acetamidobiphenyl compound is provided. The difference from Example 1 is that in step S1, 5 mL of acetic anhydride, 213 mg (1 mmol) of the first raw material and 380 mg (1.5 mmol) of I2 are successively added into a sealed tube with a volume of 25 mL, and the name of the first raw material under the systematic nomenclature is 3,4-dimethyl-4-phenyl-2,5-cyclohexadienone oxime; in step S2, the total volume of concentrated hydrochloric acid titration is controlled to be 309 μL (HCl is about 10 mmol). Thus, in step S3, 115 mg of 2,3-dimethyl-5-acetamidobiphenyl compound in the form of an orange-yellow solid is prepared, and the calculated yield is 54%.

[0071] Specifically, the synthesis reaction formula of the 2,3-dimethyl-5-acetamidobiphenyl compound in Example 7 of the present invention is as follows:

[0072]

[0073] Specifically, the characterization data of a 2,3-dimethyl-5-acetamidobiphenyl compound prepared in Example 7 of the present invention in 1H NMR and 13C NMR are as follows:

[0074] 1 H NMR(400 MHz, CDCl3) δ7.82(s, 1H), 7.46(td, J = 7.0, 1.4 Hz, 2H), 7.41 - 7.33(m, 3H), 6.97(s, 1H), 6.91(s, 1H), 2.40(s, 3H), 2.32(s, 3H), 2.10(s, 3H). 13 C NMR(101 MHz, CDCl3) δ168.73, 147.27, 143.52, 141.77, 136.60, 131.72, 129.93, 128.12, 126.99, 121.60, 120.39, 21.08, 20.87, 18.61.

[0075] Although the embodiments of the present invention have been described in detail above, it is obvious to those skilled in the art that various modifications and changes can be made to these embodiments. However, it should be understood that such modifications and changes are all within the scope and spirit of the present invention described in the claims. Moreover, the present invention described herein can have other embodiments and can be implemented or realized in various ways.

Claims

1. A method for synthesizing 3 - aminobiphenyl compounds, characterized in that, Comprising the following steps: In acetic anhydride, in the presence of an acid promoter and a reducing agent, a first raw material undergoes the following reaction at a temperature of 100 - 120 °C to form a compound represented by Formula I; the first raw material is a 4-methyl-4-phenyl-2,5-cyclohexadienone oxime compound; ； Among them, R 1 is hydrogen, halogen, C1-C 30 alkoxy, C1-C 30 alkyl or C6-C 30 aryl, R 2 is hydrogen, C1-C 30 alkyl or C6-C 30 aryl; the reducing agent is at least one of iodine, cuprous chloride and ferrous chloride; the acid promoter is at least one of concentrated hydrochloric acid and sulfuric acid.

2. The synthesis method according to claim 1, characterized in that, When the first raw material reacts in the presence of an acid promoter and a reducing agent, the molar ratio of the first raw material to the reducing agent is 1:(0.5 - 2).

3. The synthesis method according to claim 1, characterized in that, During the reaction of the first raw material in the presence of an acid promoter and a reducing agent, the molar ratio of the first raw material to the acid promoter is 1:(1 - 20).

4. The synthesis method according to claim 1, characterized in that, After forming the compound represented by Formula I, separation and purification are carried out to obtain a pure 3-aminobiphenyl compound.

5. The synthesis method according to claim 4, characterized in that, Before separation and purification, a quenching solution is added to the reaction system for quenching treatment.

6. The synthesis method according to claim 4, wherein, During the separation and purification process, after adding an extraction agent, the organic phase is separated and purified by column chromatography.

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