Synthetic method of p-chlorophenylboronic acid

Abstract

The invention relates to a synthetic method of p-chlorophenylboronic acid, which belongs to the technical field of organic synthesis, and comprises the following steps: S1, synthesis of p-chlorophenylboronic acid: adding magnesium chips and anhydrous tetrahydrofuran into a reaction container, adding p-bromochlorobenzene in batches while stirring, automatically initiating a reaction liquid, heating and blackening, stopping adding p-bromochlorobenzene, and cooling to room temperature to obtain p-chlorophenylboronic acid; adding p-bromochlorobenzene when the temperature is reduced to 60 DEG C, repeating the operation, adding p-bromochlorobenzene until all p-bromochlorobenzene is added, carrying out cold bath when the temperature is reduced to 40 DEG C, adding trimethyl borate at 10-15 DEG C, and continuing stirring when the reaction system becomes viscous; and S2, purification of p-chlorophenylboronic acid: adding a hydrochloric acid aqueous solution, stirring, standing to separate out organic phases, extracting a water layer with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, reducing pressure to remove the solvent to obtain white solids, and drying overnight to obtain gray solids, namely p-chlorophenylboronic acid. The method is simple in process step, safe and environmentally friendly, and the chromatographic purity of the prepared p-chlorophenylboronic acid can reach 99.0% or above.

Description

Technical Field

[0001] The invention relates to a method for synthesizing p-chlorophenylboronic acid, and belongs to the technical field of organic synthesis. Background Art

[0002] p-Chlorophenylboronic acid is a boronic acid derivative used as a pharmaceutical and material intermediate. It can be used in double Suzuki coupling reactions to synthesize substituted diarylmethylenefluorenes and in Suzuki coupling reactions with pyrroline tosylate, followed by hydrogenation to synthesize baclofen lactam.

[0003] Reagents in organic synthesis: Chlorophenylboronic acid is often used as an important arylboronic acid reagent in the organic synthesis of aromatic compounds, for example, as a precursor for arylboronic acid esters. Chemical catalysts: Chlorophenylboronic acid can also be used as a ligand or catalyst in certain transition metal-catalyzed reactions, enjoying a wide range of applications. Therefore, the synthesis of this class of compounds has attracted considerable attention. Numerous methods exist for synthesizing this compound, and several patents disclose methods for synthesizing p-chlorophenylboronic acid. These are briefly described below.

[0004] (1) CN201911297925 discloses a method for synthesizing p-chlorophenylboronic acid, wherein chlorobenzene is used as a raw material and reacted with boron trichloride gas in the presence of a catalyst to obtain dichloro(4-chlorophenyl)borane, which is then subjected to acidic hydrolysis to obtain p-chlorophenylboronic acid. The reaction process is as follows:

[0005]

[0006] CN201510052383 Preparation of aryl boronic acid compounds: sodium borohydride is added, and boron trifluoride ether is slowly added dropwise, and the reaction temperature is controlled between -5 and 10°C until the addition is completed.

[0007] (2) In addition, CN201910333205 discloses a method for preparing p-chlorophenylboronic acid, which uses a mixed solvent of toluene and tetrahydrofuran to replace the single tetrahydrofuran solvent, and uses p-dichlorobenzene to replace p-chlorobromobenzene as the main raw material for the Grignard reaction, and then undergoes a condensation reaction with trimethyl borate or tributyl borate. CN201810797300 discloses a method for preparing p-chlorophenylboronic acid, which uses p-chlorobromobenzene as a mixed solvent. CN201310561231 discloses a method for preparing an aryl boronic acid compound, which uses xylene / anhydrous methyltetrahydrofuran. Methyltetrahydrofuran is expensive.

[0008] (3) CN201710157151 discloses a method for preparing p-chlorophenylboronic acid with high purity and high yield. The reaction of p-dichlorobenzene with boric acid ester requires a low temperature of -70°C.

[0009] It can be seen that although the existing technology can synthesize p-chlorophenylboronic acid, these reactions still have some limitations. Synthesis method (1) Boron trichloride is a dangerous gas, and the ether solution is highly volatile, posing a major safety hazard. Synthesis method (2) Mixed solvents increase the number of solvents, increase costs, and make recycling difficult. For example, toluene is regulated and has a high boiling point, and methyltetrahydrofuran is expensive. Synthesis method (3) The second step reaction is low-temperature, which increases energy consumption. Therefore, it is urgent to develop a process method that can synthesize p-chlorophenylboronic acid in a practical and efficient manner. Summary of the Invention

[0010] The present invention aims to provide a method for synthesizing p-chlorophenylboronic acid. The method uses p-bromochlorobenzene and trimethyl borate as basic reaction raw materials, wherein p-bromochlorobenzene is firstly initiated under magnesium chips to obtain a Grignard reagent p-chlorophenylmagnesium bromide, and trimethyl borate is dropwise added at 10-15° C. to carry out a coupling reaction to obtain a crude p-chlorophenylboronic acid product. The crude product is purified through post-treatment such as acidification to obtain high-purity p-chlorophenylboronic acid. The reaction conditions are mild and the energy consumption is low.

[0011] The purpose of the present invention is achieved through the following technical solutions:

[0012] A method for synthesizing p-chlorophenylboronic acid comprises the following steps:

[0013] S1. Synthesis of p-chlorophenylboronic acid: magnesium chips and anhydrous tetrahydrofuran were added to a reaction vessel, and p-bromochlorobenzene was added in batches under stirring. The reaction solution was self-initiated, heated up, and turned black. The addition of p-bromochlorobenzene was stopped. When the temperature dropped to 60°C, p-bromochlorobenzene was added again. The above operation was repeated to add p-bromochlorobenzene until all p-bromochlorobenzene was added. When the temperature dropped to 40°C, a cold bath was performed. Trimethyl borate was added at 10-15°C. The reaction system became viscous and stirring was continued.

[0014] S2. Purification of p-chlorophenylboronic acid: Add aqueous hydrochloric acid solution and stir, let stand to separate the organic phase, extract the aqueous layer with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain a white solid, which is dried and allowed to stand to obtain a gray solid, which is p-chlorophenylboronic acid.

[0015] Preferably, the molar ratio of p-bromochlorobenzene to magnesium chips in S1 is 1:1.0-1.5;

[0016] The molar ratio of p-bromochlorobenzene to trimethyl borate is 1:1.1-1.5;

[0017] The volume ratio of p-bromochlorobenzene mole to tetrahydrofuran is 1 mol: 400-1000 mL;

[0018] The batches of adding 4-bromochlorobenzene are 5 to 8 batches.

[0019] Preferably, the molar ratio of p-bromochlorobenzene to magnesium chips is 1:1.2;

[0020] The molar ratio of p-bromochlorobenzene to trimethyl borate is 1:1.3;

[0021] The volume ratio of p-bromochlorobenzene to tetrahydrofuran is 1:800.

[0022] Preferably, in S1, magnesium chips and anhydrous tetrahydrofuran are added to the reaction flask under argon protection.

[0023] Preferably, the temperature of the reaction vessel is 60° C. when magnesium chips and anhydrous tetrahydrofuran are added to the container in S1;

[0024] After adding trimethyl borate to S1, stirring is continued for 6 to 24 hours.

[0025] Preferably, after adding trimethyl borate to S1, stirring is continued for 20 hours.

[0026] Preferably, after adding the hydrochloric acid aqueous solution to S2, the stirring time is 0.3 to 2 hours, and the standing time is 0.5 to 1 hour.

[0027] Preferably, the stirring time after adding the hydrochloric acid aqueous solution to S2 is 0.5 hours;

[0028] The concentration of the aqueous hydrochloric acid solution in S2 is 2M, and the volume ratio of anhydrous tetrahydrofuran, aqueous hydrochloric acid solution and ethyl acetate is 4-10:5:6;

[0029] The ethyl acetate extraction was divided into two equal volumes and extracted twice.

[0030] Preferably, the pressure of the solvent removal under reduced pressure in S2 is -0.095 to -0.1 MPa, and the temperature is 20 to 28°C.

[0031] Preferably, the drying temperature in S2 is 68-72° C., and the standing time is not less than 4 hours.

[0032] The synthetic route of the method of the present invention is as follows:

[0033]

[0034] Beneficial effects:

[0035] (1) The raw materials and catalysts of the present invention are simple and easy to obtain, and the reaction operation is simple and practical. Using p-bromochlorobenzene as the raw material, the Grignard reagent p-chlorophenylmagnesium bromide is obtained by initiation under magnesium chips, and a coupling reaction is carried out with trimethyl borate to synthesize p-chlorophenylboric acid. The method of the present invention does not use dangerous boron trichloride, but uses mild trimethyl borate. The method of the present invention uses readily available tetrahydrofuran as a single solvent, which is convenient to purchase and recycle, low in cost, safe, environmentally friendly, and easy to operate. The method of the present invention is not temperature-critical in the second step, does not require very low temperatures, and has low energy consumption.

[0036] (2) The present invention provides a method for synthesizing p-chlorophenylboronic acid. The method has a simple synthetic route and process steps, high reaction activity, mild reaction conditions, and is environmentally friendly and green. Furthermore, separation is convenient, and a high-purity product can be obtained. The method has simple process steps, is safe and environmentally friendly, and the chromatographic purity of the prepared p-chlorophenylboronic acid can reach over 99.0%. DETAILED DESCRIPTION

[0037] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. The methods described are all conventional methods unless otherwise specified, and the raw materials described can be obtained from public commercial channels unless otherwise specified.

[0038] Example 1

[0039] A method for synthesizing p-chlorophenylboronic acid, comprising the following steps:

[0040] (1) Synthesis of p-chlorophenylboronic acid: Under argon, magnesium chips (2.43 g, 0.10 mol) and anhydrous tetrahydrofuran (100 ml) were added to the reaction flask. p-Bromochlorobenzene (19.15 g, 0.10 mol) was added in 6 batches while stirring. The reaction solution was self-initiated, heated up and turned black. When the temperature dropped to 60°C, p-Bromochlorobenzene was added. After the addition was completed, the temperature dropped to 40°C and a cold bath was placed. Trimethyl borate (11.43 g, 0.11 mmol) was added at 13°C. The reaction system became viscous and stirred for 6 hours.

[0041] (2) Purification of p-chlorophenylboronic acid: Add 2M HCl (50 ml) and stir for 0.3 h. Let stand for 30 minutes to separate the organic phase. Extract the aqueous layer twice with ethyl acetate (30 ml x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure at -0.1 MPa and 28°C to obtain a white solid. Dry at 68°C overnight to obtain a gray solid.

[0042] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this example is 67%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 99.2%.

[0043] Example 2

[0044] A method for synthesizing high-purity p-terphenyl, comprising the following steps:

[0045] (1) Synthesis of p-chlorophenylboronic acid: Under argon, magnesium chips (2.92 g, 0.12 mol) and anhydrous tetrahydrofuran (80 ml) were added to the reaction flask. p-Bromochlorobenzene (19.15 g, 0.10 mol) was added in 8 batches while stirring. The reaction solution was self-initiated, heated up and turned black. When the temperature dropped to 60°C, p-Bromochlorobenzene was added. After the addition was completed, the temperature dropped to 40°C and a cold bath was placed. Trimethyl borate (13.50 g, 0.13 mmol) was added at 10°C. The reaction system became viscous and stirred for 20 h.

[0046] (2) Purification of p-chlorophenylboronic acid: Add 2M HCl (50 ml) and stir for 0.5 h. Let stand for 40 minutes to separate the organic phase. Extract the aqueous layer twice with ethyl acetate (30 ml x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure at -0.098 MPa and 25°C to obtain a white solid. Dry at 70°C overnight to obtain a gray solid.

[0047] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this embodiment is 73%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 99.3%.

[0048] Example 3

[0049] A method for synthesizing high-purity p-terphenyl, comprising the following steps:

[0050] (1) Synthesis of p-chlorophenylboronic acid: Under argon, magnesium chips (3.65 g, 0.15 mol) and anhydrous tetrahydrofuran (40 ml) were added to the reaction flask. p-Bromochlorobenzene (19.15 g, 0.10 mol) was added in 5 batches while stirring. The reaction solution was self-initiated, heated up and turned black. When the temperature dropped to 60°C, p-Bromochlorobenzene was added. After the addition was completed, the temperature dropped to 40°C and a cold bath was placed. Trimethyl borate (15.59 g, 0.15 mmol) was added at 15°C. The reaction system became viscous and stirred for 24 hours.

[0051] (2) Purification of p-chlorophenylboronic acid: Add 2M HCl (50 ml) and stir for 2 h. Let stand for 60 min to separate the organic phase. Extract the aqueous layer twice with ethyl acetate (30 ml x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure at -0.095 MPa and 20°C to obtain a white solid. Dry at 72°C overnight to obtain a gray solid.

[0052] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this embodiment is 70%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 99.0%.

[0053] Comparative Example 1

[0054] The difference between this comparative example and Example 2 is that the molar ratio of magnesium chips to p-bromochlorobenzene is 2.5; otherwise, the same as Example 2.

[0055] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this comparative example is 73%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 98.6%.

[0056] Comparative Example 2

[0057] The difference between this comparative example and Example 2 is that the molar ratio of magnesium chips to p-bromochlorobenzene is 1.0; otherwise, the same as Example 2.

[0058] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this comparative example is 64.2%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 99.25%.

[0059] As can be seen from Comparative Examples 1 and 2: the molar ratio of magnesium chips to p-bromochlorobenzene increased from 1.2 to 2.5, which had little effect on the yield of p-chlorophenylboric acid, but affected the purity of p-chlorophenylboric acid, which was significantly reduced; the molar ratio of magnesium chips to p-bromochlorobenzene decreased from 1.2 to 1.0, which had little effect on the purity of p-chlorophenylboric acid, but affected the yield of p-chlorophenylboric acid, which was significantly reduced. Therefore, the molar ratio of magnesium chips to p-bromochlorobenzene is most preferably 1.2.

[0060] Comparative Example 3

[0061] The difference between this comparative example and Example 2 is that p-bromochlorobenzene is added once with stirring; other parts are the same as Example 2.

[0062] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this comparative example is 58.7%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 90.11%.

[0063] From this comparative example, it can be seen that the addition of p-bromochlorobenzene once in comparative example 3 has a huge impact on the purity and yield of p-chlorophenylboric acid, both of which are significantly reduced.

[0064] Comparative Example 4

[0065] The difference between this comparative example and Example 2 is that p-bromochlorobenzene is added once with stirring; other parts are the same as Example 2.

[0066] The yield of high-purity p-chlorophenylboronic acid synthesized by the method described in this comparative example is 58.7%. The purity of p-chlorophenylboronic acid was tested by liquid chromatography, and it was found that the purity of p-chlorophenylboronic acid synthesized by the method reached 90.11%.

[0067] From this comparative example, it can be seen that the addition of p-bromochlorobenzene once in comparative example 3 has a huge impact on the purity and yield of p-chlorophenylboric acid, both of which are significantly reduced.

[0068] In summary, the above are only preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing p-chlorophenylboronic acid, characterized in that: The steps include: S1. Synthesis of p-chlorophenylboronic acid: magnesium chips and anhydrous tetrahydrofuran were added to a reaction vessel, and p-bromochlorobenzene was added in batches under stirring. The reaction solution was self-initiated, heated up, and turned black. The addition of p-bromochlorobenzene was stopped. When the temperature dropped to 60°C, p-bromochlorobenzene was added again. The above operation was repeated to add p-bromochlorobenzene until all p-bromochlorobenzene was added. When the temperature dropped to 40°C, a cold bath was performed. Trimethyl borate was added at 10-15°C. The reaction system became viscous and stirring was continued. S2. Purification of p-chlorophenylboronic acid: Add aqueous hydrochloric acid solution and stir, let stand to separate the organic phase, extract the aqueous layer with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain a white solid, which is dried and allowed to stand to obtain a gray solid, which is p-chlorophenylboronic acid.

2. A method for synthesizing p-chlorophenylboronic acid according to claim 1, characterized in that, The molar ratio of p-bromochlorobenzene to magnesium chips in S1 is 1:1.0-1.5; The molar ratio of p-bromochlorobenzene to trimethyl borate is 1:1.1-1.5; The volume ratio of p-bromochlorobenzene mole to tetrahydrofuran is 1 mol: 400-1000 mL; The batches of adding 4-bromochlorobenzene are 5 to 8 batches.

3. A method for synthesizing p-chlorophenylboronic acid according to claim 2, characterized in that, The molar ratio of p-bromochlorobenzene to magnesium chips is 1:1.2; The molar ratio of p-bromochlorobenzene to trimethyl borate is 1:1.3; The volume ratio of p-bromochlorobenzene to tetrahydrofuran is 1:

800.

4. The method for synthesizing p-chlorophenylboronic acid according to claim 1, wherein In S1, magnesium chips and anhydrous tetrahydrofuran were added to the reaction flask under argon protection.

5. The method for synthesizing p-chlorophenylboronic acid according to claim 1, wherein When magnesium chips and anhydrous tetrahydrofuran are added to the container in S1, the temperature of the reaction container is 60°C; After adding trimethyl borate to S1, stirring is continued for 6 to 24 hours.

6. The method for synthesizing p-chlorophenylboronic acid according to claim 5, wherein After adding trimethyl borate to S1, stirring was continued for 20 hours.

7. The method for synthesizing p-chlorophenylboronic acid according to claim 1, wherein After adding the hydrochloric acid aqueous solution to S2, the stirring time is 0.3 to 2 hours and the standing time is 0.5 to 1 hour.

8. The method for synthesizing p-chlorophenylboronic acid according to claim 7, wherein: After adding the hydrochloric acid aqueous solution to S2, the stirring time was 0.5 hours; The concentration of the aqueous hydrochloric acid solution in S2 is 2M, and the volume ratio of anhydrous tetrahydrofuran, aqueous hydrochloric acid solution and ethyl acetate is 4-10:5:6; The ethyl acetate extraction was divided into two equal volumes and the extraction was performed twice.

9. The method for synthesizing p-chlorophenylboronic acid according to claim 1, wherein The solvent is removed under reduced pressure in S2 at a pressure of -0.095 to -0.1 MPa and a temperature of 20 to 28°C.

10. The method for synthesizing p-chlorophenylboronic acid according to claim 1, wherein The drying temperature in S2 is 68-72°C, and the storage time is not less than 4 hours.

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