Preparation method of substituted biphenyl compound

Abstract

The preparation method of the substituted biphenyl compound as shown in the formula (3) comprises the following step of enabling substituted aniline salt as shown in the formula (1) to react with a nitrite compound as shown in R1-NO2 and a benzene compound as shown in the formula (2) in the presence of a catalyst. In the formula, R1 is a C1-10 alkyl group; r2 is Cl, Br, I or NO2, R2 is located at the ortho-position, meta-position or para-position of the amino group, and the number of R2 can be one or more than two; r3 is H, Cl, Br, I or a C1-10 alkyl group; x is F, Cl, Br or I; wherein the benzene compound represented by the formula (2) also serves as a reaction solvent, and other solvents are not used additionally. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing a substituted biphenyl compound. Background Art

[0002] Chinese patent application CN110325513A discloses a method for preparing substituted biphenyls, which uses a palladium catalyst having a special phosphorus ligand and a solvent mixture containing water and an organic solvent at least partially miscible with water to prepare substituted 2-nitrobiphenyls through Suzuki coupling. In this method, expensive metal palladium is used as a catalyst, the production cost is high, and it is not conducive to large-scale industrial production.

[0003] Chinese patent application CN108069861A discloses a method for synthesizing nitrobiphenyl, which is to mix nitroaniline and benzene in a solvent containing a halogenated organic acid, a halogenated metal salt, and a nitrite and react to obtain nitrobiphenyl. In this method, nitrite is used as a raw material, so a large amount of organic ester is required to be used as a solvent to dissolve the nitrite, and the reaction is a heterogeneous reaction. Therefore, when the reaction is carried out at a low temperature, the reaction speed is too slow and the reaction time is too long. The

[0047] paragraph of the application specification also records that the reaction time is as long as 100h when the reaction temperature is 30°C. Therefore, in order to improve the reaction efficiency, it is necessary to increase the reaction temperature. However, the

[0032] paragraph of the application specification records that when the reaction temperature is too high, the reaction is too intense and dangerous.

[0004] Since substituted biphenyl compounds are important chemical intermediates used in the production of pesticides such as boscalid and flupyraclostrobin, it is urgent to develop a cost-effective and safer method for preparing such compounds. Summary of the invention

[0005] The inventors of the present application have found that in the method disclosed in Chinese patent application CN108069861A, since a large amount of solvent must be used to dissolve nitrite, the reactant concentration is low and the mass transfer is poor, which is the reason for the low reaction efficiency. At the same time, it also leads to insufficient reaction of the expensive intermediate aniline diazonium salt generated by nitroaniline and nitrite, which is also disadvantageous in terms of cost.

[0006] In view of the above problems, the present application aims to provide a new method for preparing substituted biphenyl compounds, which does not use expensive palladium catalysts and greatly reduces production costs; at the same time, the reactants in this method also serve as solvents, and there is no need to use a large amount of other solvents. It is a homogeneous reaction and can be completed in a shorter time under low temperature conditions. The reaction is sufficient and the production efficiency is high.

[0007] The preparation method of the substituted biphenyl compound of the present invention is achieved by the following route. Specifically, the present invention relates to:

[0008] (1) A method for preparing a substituted biphenyl compound represented by the following formula (3), comprising reacting a substituted aniline salt represented by the formula (1) with a nitrite compound represented by R1-NO2 and a benzene compound represented by the formula (2) in the presence of a catalyst to produce the following reaction:

[0009]

[0010] In the formula, R1 is C 1-10 alkyl;

[0011] R2 is Cl, Br, I or NO2, R2 is located at the ortho, meta or para position of the amino group, there may be 1 or more R2, and more than 2 R2 may be the same or different;

[0012] R3 is H, Cl, Br, I or C 1-10 alkyl;

[0013] X is F, Cl, Br or I;

[0014] The benzene compound represented by formula (2) also serves as the reaction solvent, and no other solvent is used separately.

[0015] (2) The preparation method described in (1) above, wherein the catalyst comprises a combination of a metal catalyst and a phase transfer catalyst.

[0016] (3) The preparation method according to (1) or (2) above, wherein the molar ratio of the nitrite compound represented by R1-NO2 to the substituted aniline salt represented by formula (1) is (1-10):1, preferably (1-3):1.

[0017] (4) The preparation method according to (2) or (3) above, wherein the metal catalyst is cuprous fluoride, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, preferably cuprous chloride.

[0018] (5) The preparation method according to any one of (2) to (4) above, wherein the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride.

[0019] (6) The preparation method according to any one of (2) to (5) above, wherein the reaction temperature of reaction 1 is 0°C to room temperature, preferably 0 to 10°C.

[0020] (7) The preparation method according to any one of (2) to (6) above, wherein the nitrite compound represented by R1-NO2 is prepared by the following reaction 2:

[0021] R1-OH+NaNO2+HCl→R1-NO2

[0022] Reaction 2

[0023] In the formula, R1 is as defined in the above (1).

[0024] (8) The preparation method according to (7) above, wherein the reaction temperature of reaction 2 is 0°C to room temperature, preferably 0 to 10°C.

[0025] (9) The preparation method according to any one of the above (1) to (8), wherein the substituted aniline salt represented by formula (1) is prepared by the following reaction 3:

[0026]

[0027] In the formula, R2 and X are as defined in (1) above;

[0028] Here, a benzene compound represented by formula (2) is used as a reaction solvent.

[0029] (10) The preparation method according to the above (9), wherein the reaction temperature of reaction three is 0-80°C, preferably 50-70°C. DETAILED DESCRIPTION

[0030] In Chinese patent application CN108069861A, nitrite is used as a raw material, and the reaction system is a heterogeneous system, so a large amount of organic ester solvent is required to dissolve the nitrite. The present invention is obtained on the basis of improving this method.

[0031] Specifically, the present invention uses a nitrite represented by R1-NO2 instead of a nitrite (e.g., NaNO2), and the nitrite can be dissolved in the benzene compound represented by formula (2). Thus, the compound of formula (2) can be used as both a reactant and a reaction solvent, without the need to use other reaction solvents. Excess solvents are easily recovered and can be applied.

[0032] Therefore, the present invention provides a method for preparing a substituted biphenyl compound, which comprises reacting a substituted aniline salt represented by formula (1) with a nitrite compound represented by R1-NO2 and a benzene compound represented by formula (2) in the presence of a catalyst to produce the following reaction:

[0033]

[0034] In the formula,

[0035] R1 is C 1-10 Alkyl, specific examples include but are not limited to n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, etc., preferably n-butyl;

[0036] R2 is Cl, Br, I or NO2, preferably NO2, R2 can be located at the ortho, meta or para position of the amino group, there can be 1 or more R2, and more than 2 R2 can be the same or different;

[0037] R3 is H, Cl, Br, I or C 1-10 Alkyl, C 1-10 Specific examples of alkyl include, but are not limited to, methyl, ethyl, propyl, etc.; R3 is preferably H or Cl;

[0038] X is F, Cl, Br or I, preferably F.

[0039] In reaction 1, the benzene compound shown in formula (2) also serves as a reaction solvent, and no other solvent is used. The substituted aniline salt shown in formula (1) and the nitrite compound shown in R1-NO2 are both dissolved in the benzene compound shown in formula (2), so reaction 1 is a homogeneous reaction. In addition, since there is no need to use a large amount of solvent, the reactants are not excessively diluted, the mass transfer is good, and the reaction can be carried out at a low temperature. The reaction temperature of reaction 1 can be reduced to 0°C to room temperature, preferably reduced to 0 to 10°C.

[0040] The catalyst used in reaction 1 includes a metal catalyst selected from cuprous fluoride, cuprous chloride, cuprous bromide, cuprous iodide and copper powder, preferably cuprous chloride. The above catalyst is used instead of the expensive palladium catalyst used in the past, which greatly reduces the cost. The molar ratio of the above catalyst to the substituted aniline salt shown in formula (1) is usually (0.01-10):1, preferably (0.1-1):1.

[0041] In order to improve the reaction rate, a phase transfer catalyst can be further used. The inventors of the present application have found that, under the condition of not using a phase transfer catalyst, solids are precipitated during the reaction, and analysis confirms that the solids are aniline diazonium salt intermediates. When using a phase transfer catalyst, the reaction is accelerated, and the aniline diazonium salt intermediate will not accumulate and precipitate. The reaction time can be reduced to less than 3 hours, or even less than 2 hours.

[0042] The phase transfer catalyst is preferably tetrabutylammonium bromide or tetrabutylammonium chloride. The molar ratio of the phase transfer catalyst to the substituted aniline salt represented by formula (1) can be (0.01-10):1, preferably (0.01-0.1):1.

[0043] In reaction 1, the molar ratio of the substituted aniline salt represented by formula (1) to the benzene compound represented by formula (2) is preferably 1:(5-15). The molar ratio of the substituted aniline salt represented by formula (1) to the nitrite compound represented by R1-NO2 is preferably 1:(1-3).

[0044] The nitrite compound represented by R1-NO2 can be prepared by the following reaction 2:

[0045] R1-OH+NaNO2+HCl→R1-NO2

[0046] Reaction 2

[0047] In the formula, R1 is as defined above.

[0048] The reaction temperature of reaction 2 may be 0°C to room temperature, preferably 0 to 10°C.

[0049] The substituted aniline salt shown in formula (1) can be prepared by the following reaction:

[0050]

[0051] In the formula, R2 and X are as defined above;

[0052] Reaction 3 preferably uses the benzene compound represented by formula (2) as the reaction solvent, and the reaction temperature can be 0-80°C, preferably 50-70°C.

[0053] In reaction three, the molar ratio of the halogenated carboxylic acid to the substituted aniline is preferably (1-1.5):1.

[0054] Example

[0055] The present invention is described in more detail below through specific embodiments, but the present application is not limited to the specific embodiments, and any modification or change without departing from the gist of the present application falls within the scope of the present application.

[0056] In the following examples, the conditions for high performance liquid chromatography analysis are as follows: the instrument is Agilent 1100LC liquid chromatograph, UV detector. The chromatographic column is Kromasil 100-5-C18, 4.6×250 mm. The mobile phase is acetonitrile: water (adjusted with formic acid to pH=3.7-4.1)=80:20, the column temperature is 30°C, the flow rate is 1.0 mL / min, and the wavelength is 225 nm.

[0057] Example 1

[0058] Step 1: Synthesis of Nitrite

[0059] In a 2000mL four-necked bottle, add 222.36g n-butanol (3.00mol), 341.46g water (18.95mol) and 227.64g sodium nitrite (3.30mol), control the temperature at 0-5℃ in an ice bath, add 318.96g concentrated hydrochloric acid (3.15mol) dropwise, maintain 0-5℃ after the addition, stir and react for 1h. After the reaction is completed, separate the liquid to obtain 320g of the organic phase of n-butyl nitrite.

[0060] Step 2: Aniline salt formation

[0061] In a 500 mL four-necked bottle, 20.70 g of o-nitroaniline (0.15 mol), 22.20 g of trifluoroacetic acid (0.195 mol) and 100.00 g of benzene (1.28 mol) were added, heated to 60° C., and stirred for 1 h to form a salt solution.

[0062] Step 3: Synthesis of 2-nitrobiphenyl

[0063] Add 3.75g CuCl (0.038mol) and 2.41g tetrabutylammonium bromide (0.0075mol) to the salt solution in the second step, control the temperature at 0-5°C in an ice bath, and dropwise add 47.25g (0.46mol) of the organic phase of n-butyl nitrite in the first step. After the dropwise addition is completed, maintain the temperature at 0-5°C, stir and react for 1h, and use liquid phase detection to track the reaction process to confirm that the purity of o-nitroaniline is less than 1%, terminate the reaction, and obtain 180g of the reaction solution. Wash with 2×150g water to remove CuCl, and evaporate benzene under reduced pressure to obtain a dark brown oily substance, which is separated by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain 2-nitrobiphenyl.

[0064] Example 2

[0065] Step 1: Synthesis of Nitrite

[0066] The n-butyl nitrite prepared in Example 1 was used.

[0067] Step 2: Aniline salt formation

[0068] In a 500mL four-necked bottle, add 20.70g o-nitroaniline (0.15mol), 22.20g trifluoroacetic acid (0.195mol) and 150.00g chlorobenzene (1.33mol), heat to 60°C, and stir for 1h to form a salt solution. Step 3: Synthesis of 4'-chloro-2-nitrobiphenyl

[0069] Add 3.75g CuCl (0.038mol) and 2.41g tetrabutylammonium bromide (0.0075mol) to the salt solution in the second step, control the temperature at 0-5°C in an ice bath, and dropwise add 47.25g (0.46mol) of the organic phase of n-butyl nitrite in the first step. After the dropwise addition is completed, maintain the temperature at 0-5°C, stir and react for 1h, and then detect the progress of the reaction by liquid phase detection to confirm that the purity of o-nitroaniline is less than 1%, terminate the reaction, and obtain 230g of the reaction solution. Wash with 2×150g water to remove CuCl, and evaporate chlorobenzene under reduced pressure to obtain a dark brown oily substance, which is separated by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain 4'-chloro-2-nitrobiphenyl.

Claims

1. A method for preparing a substituted biphenyl compound represented by the following formula (3), comprising reacting a substituted aniline salt represented by the formula (1), a nitrite compound represented by R1-NO2 and a benzene compound represented by the formula (2) in the presence of a catalyst to perform the following reaction: In the formula, R1 is C 1-10 alkyl; R2 is Cl, Br, I or NO2, R2 is located at the ortho, meta or para position of the amino group, there may be 1 or more R2, and more than 2 R2 may be the same or different; R3 is H, Cl, Br, I or C 1-10 alkyl; X is F, Cl, Br or I; in, The benzene compound represented by formula (2) also serves as the reaction solvent, and no other solvent is used separately.

2. The preparation method according to claim 1, wherein the catalyst comprises a combination of a metal catalyst and a phase transfer catalyst.

3. The preparation method according to claim 1 or 2, wherein the molar ratio of the nitrite compound represented by R1-NO2 to the substituted aniline salt represented by formula (1) is (1-10):1, preferably (1-3):

1.

4. The preparation method according to claim 2 or 3, wherein the metal catalyst is cuprous fluoride, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, preferably cuprous chloride.

5. The preparation method according to any one of claims 2 to 4, wherein the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride.

6. The preparation method according to any one of claims 2 to 5, wherein the reaction temperature of reaction 1 is 0°C to room temperature, preferably 0 to 10°C.

7. The preparation method according to any one of claims 2 to 6, wherein the nitrite compound represented by R1-NO2 is prepared by the following reaction 2: R1-OH+NaNO2+HCl→R1-NO2 Reaction 2 In the formula, R1 is as defined in claim 1.

8. The preparation method according to claim 7, wherein the reaction temperature of reaction 2 is 0°C to room temperature, preferably 0 to 10°C.

9. The preparation method according to any one of claims 1 to 8, wherein the substituted aniline salt represented by formula (1) is prepared by the following reaction 3: In the formula, R2 and X are as defined in claim 1; in, A benzene compound represented by formula (2) is used as a reaction solvent.

10. The preparation method according to claim 9, wherein the reaction temperature of reaction three is 0-80°C, preferably 50-70°C.

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