A method for preparing olefin-substituted aromatic boronic acid

Abstract

The invention discloses a method for preparing an olefin-substituted aromatic boronic acid, and belongs to the technical field of pharmaceutical intermediates. Chloroacetophenone is used as a raw material, and chloro-1-phenylethanol is obtained by reduction with a reducing agent, and then a chlorostyrene solution is obtained by dehydration with an acid catalyst in a high boiling point solvent, and finally a chlorostyrene solution is reacted with a strong base reagent and a borate ester in a continuous flow, and acid hydrolysis is performed to obtain vinylbenzene boronic acid. The present invention adopts a high-temperature negative pressure dehydration method to prepare a key intermediate of chlorostyrene, with high conversion rate, few polymerization by-products, and rapid reaction; the boration reaction of chlorostyrene adopts a continuous flow method to improve reaction specificity, reduce reaction safety, and can efficiently and safely prepare high-quality vinylbenzene boronic acid.

Description

Technical Field

[0001] The invention relates to a method for preparing an olefin-substituted aromatic boric acid, belonging to the technical field of pharmaceutical intermediate synthesis. Technical Background

[0002] Aromatic boric acids, such as vinyl-substituted phenylboronic acid, are a class of fine chemicals with a wide range of uses. They can be used as pharmaceutical intermediates or reaction building blocks, or as monomers for functional materials. However, the product contains unstable olefin bonds, and polymerization or addition byproducts are easily generated during production and storage, resulting in a decrease in product quality and failure to meet the requirements of high-specification usage scenarios. The process for preparing high-purity vinyl-substituted phenylboronic acid products is very difficult.

[0003] The usual synthesis strategy is to use R-substituted halogen benzene 1 as raw material, prepare halogenated styrene intermediate 2 through different transformation strategies, then use butyl lithium, Grignard reagent or catalyst to react with borate ester for addition reaction, and then hydrolyze to prepare ethylene-substituted phenylboronic acid 3; the reaction equation is as follows:

[0004]

[0005] Among them: R substituents are acetyl, allyl acid, ethanol, ethane halides, etc.; X substituents are chlorine, bromine, iodine, etc.; the substitution positions are ortho, meta or para. But they all face the same technical difficulties:

[0006] A. During the preparation process of halogenated styrene, double bond polymerization occurs, resulting in low product yield and quality, which affects subsequent use.

[0007] B. The intermediate 2 and the Grignard reagent initiate or exchange at high temperatures, resulting in polymerization. If low-temperature butyl lithium is used to replace the halogen, side reactions also occur. Summary of the invention

[0008] In order to overcome the above technical defects, the present invention provides an economical and efficient method for preparing olefin-substituted aromatic boric acid. The technical features of this method include: 1. The key intermediate of chlorostyrene is prepared by high-temperature negative pressure dehydration, with high conversion rate, few polymerization by-products, rapid reaction, and can be prepared on a large scale by fluid chemistry. 2. The borylation reaction of chlorostyrene adopts a continuous flow method to improve the reaction specificity, reduce the reaction safety, and can efficiently and safely prepare high-quality vinylbenzene boronic acid; 3. The solvents of the two-step reaction can be universal, making the two-step reaction a one-pot process, and the overall production efficiency is more than doubled.

[0009] The invention discloses a method for preparing an olefin-substituted aromatic boronic acid, comprising the following steps: using chloroacetophenone as a raw material, reducing it with a reducing agent to obtain chloro-1-phenylethanol, then dehydrating it with an acid catalyst in a high boiling point solvent to obtain a chlorostyrene solution, and finally reacting it with a strong base reagent and a boric acid ester in a continuous flow, and acid hydrolyzing it to obtain alkenylphenylboronic acid.

[0010] Furthermore, in the above technical solution, the reducing agent in the first step is selected from sodium borohydride, potassium borohydride or lithium borohydride.

[0011] Furthermore, in the above technical solution, the molar ratio of the chloroacetophenone to the reducing agent in the first step is 1:0.35-1.2.

[0012] Furthermore, in the above technical scheme, the high boiling point solvent in the second step is selected from decahydronaphthalene, DMSO, DMF, DMA, cyclopentane, polysubstituted benzene solvents (chlorobenzene, xylene, trimethylol, anisole, etc.), and high boiling point ether solvents (n-butyl ether, etc.).

[0013] Furthermore, in the above technical solution, the acid catalyst in the second step is selected from immobilized Lewis acid or organic acid.

[0014] Furthermore, in the above technical solution, after the second step reaction is completed, conventional post-treatment is performed: washing to remove the small molecule Lewis acid or filtering to remove the immobilized catalyst, and the obtained product solution can be directly subjected to the next step of borate esterification reaction.

[0015] Further, in the above technical scheme, the first three steps (with p-chloroacetophenone as raw material) summarize the technical scheme as follows: select p-chloroacetophenone, which is in large supply in the market, as the starting material, use a conventional reducing agent to convert it into a chlorophenylethanol intermediate, dissolve it in a high boiling point solvent, such as decahydronaphthalene, a multi-substituted benzene solvent, a high boiling point ether solvent, add a solid-supported Lewis acid or organic acid as a catalyst, and quickly dehydrate under negative pressure and high temperature to form an olefin bond, and then quickly remove and cool to produce a high-purity p-chlorostyrene solution. The solution is subjected to conventional post-treatment, such as washing with water to remove the small molecule Lewis acid, or filtering to remove the solid-supported catalyst, and the resulting product solution can be directly subjected to the next step of borate esterification reaction.

[0016] Furthermore, in the above technical solution, the strong base reagent in the fourth step is selected from n-butyl lithium, sec-butyl lithium, lithium hexamethyldisilazide, etc.

[0017] Furthermore, in the above technical solution, the boric acid ester in the fourth step is selected from trimethyl borate, triethyl borate, triisopropyl borate, etc.

[0018] Furthermore, in the above technical solution, in the fourth step, the molar ratio of chlorostyrene, strong base reagent and borate ester is 1:0.95-1.20:1.0-1.5.

[0019] Furthermore, in the above technical solution, the continuous flow reaction in the fourth step adopts a plate-type or tube-type continuous flow reaction device. The continuous flow reaction process is shown in the attached Figure 1 .

[0020] Furthermore, in the above technical solution, the acid in the fourth step is selected from hydrochloric acid, sulfuric acid, phosphoric acid, etc. as the acidic hydrolysis agent.

[0021] Furthermore, in the above technical scheme, the basic process of the continuous flow reaction in the fourth step is to first pump in a chlorostyrene solution and a strong base solution, react in a reactor C to generate benzene anions, then pump in a borate solution, mix and react in a reactor E to generate benzene borate, and then react with an acid to hydrolyze in a reactor G to generate a crude vinylbenzene boronic acid product. The crude vinylbenzene boronic acid product is separated from the continuous flow device, and conventional post-treatment and refining and purification are performed to obtain a high-quality p-vinylbenzene boronic acid product with high yield.

[0022] Advantageous Effects of the Invention

[0023] 1. Use a pulsed high-temperature vacuum reactor to dehydrate at high temperature for a short time, then evaporate under vacuum and collect the dehydrated product. Negative pressure helps to avoid polymerization of styrene compounds. Use a high-boiling hydrocarbon solvent or ether solvent to prepare para-chlorostyrene, cool it down and treat it, remove the catalyst, and the resulting chlorostyrene solution can be used for the next reaction.

[0024] 2. Using plate-type continuous flow equipment or tubular continuous flow equipment, using refrigerant to cool, using butyl lithium to replace chloride ions to produce lithium salts; then mixing with boric acid esters to produce phenyl boric acid esters; using acid water to hydrolyze, and crystallizing and purifying the product to obtain p-chlorophenylboric acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a schematic diagram of the fourth step continuous flow reaction process of the present invention. DETAILED DESCRIPTION

[0026]

[0027] Embodiment 1:

[0028] 20 g (129.9 mmol) of p-chloroacetophenone 4 was dissolved in 100 mL of a mixed solvent of THF and methanol (volume ratio 10:1-1:1), and 2.09 g of NaBH4 (55.2 mmol) was added under ice bath. After the reaction was completed, the reaction solution was poured into 200 mL of ice water, and the pH was adjusted to 6-7 with 1N dilute hydrochloric acid, and then the layers were separated. The aqueous phase was extracted twice with 40 mL of ethyl acetate, and the organic phases were combined and desolventized to obtain 18.1 g of intermediate 5.

[0029] Weigh 10g of intermediate 5 (1.0eq, FW=182.6) and dissolve it in 80mL of trimethylbenzene, add 4.17g of p-toluenesulfonic acid (0.5eq, FW=152.24) and 0.5g of p-hydroxyanisole, and the reaction solution is sucked into a tubular reactor by negative pressure, flows through a high temperature zone of 130-140°C, pauses for 2-3 minutes, and then turns on high vacuum to evaporate the dehydrated product and part of the solvent together, quickly leaves the high temperature zone, cools down, condenses and collects. The distilled liquid is detected by TLC, and the raw material basically disappears, forming a low-polarity ultraviolet product point, and there is basically no polymer. Cool, wash, extract, and dry to obtain a high-purity 96.42% p-chlorostyrene solution with a conversion yield of 86%.

[0030] Embodiment 2:

[0031] Weigh 10g of intermediate 5 (1.0eq, FW=182.6) and dissolve it in 100mL of n-butyl ether, add 4.17g of p-toluenesulfonic acid (0.5eq, FW=152.24) and 0.5g of p-hydroxyanisole. The reaction solution is sucked into a tubular reactor by negative pressure, flows through a high temperature zone of 140-150°C, pauses for 2-3 minutes, and then turns on high vacuum to evaporate the dehydrated product and part of the solvent together, quickly leaves the high temperature zone, cools down, condenses and collects. The distilled liquid is detected by TLC, and the raw material basically disappears, forming a low-polarity ultraviolet product point, and there is basically no polymer. Wash, extract, and dry to obtain a high-purity p-chlorostyrene solution with a conversion yield of 80%.

[0032] Embodiment 3:

[0033] Weigh 10g of intermediate 5 (1.0eq, FW=182.6) and dissolve it in 100mL DMSO, add 2.0g solid acid catalyst HND-8 and 0.5g p-hydroxyanisole. The reaction solution is sucked into a tubular reactor by negative pressure, flows through a high temperature zone of 140-150°C, pauses for 2-3 minutes, and then turns on high vacuum to evaporate the dehydrated product and part of the solvent together, quickly leaves the high temperature zone, cools down, condenses and collects. The distillate is detected by TLC, and the raw material basically disappears, forming a low-polarity ultraviolet product point, and there is basically no polymer. Dissolve in n-butyl ether, wash with water, extract, and dry to obtain a high-purity n-butyl ether solution of p-chlorostyrene.

[0034] Example 4

[0035] The concentration of the p-chlorostyrene solution is adjusted to 1.25M, and the concentration of the butyl lithium solution is 2.5M; they are pumped into the reactor C at a speed of 2.0mL / min and 1.0mL / min respectively, and the temperature is controlled below -60°C with a refrigerant to carry out a mixed reaction. The thermal effect of the reaction is obvious, and the pumping speed of the material can be adjusted according to the refrigeration effect of the refrigerant. The reaction liquid is pushed along the pipeline to the second reactor E, maintained at a low temperature of -60°C, where a tetrahydrofuran solution of trimethyl borate (concentration of 1.25M, pumping speed of 2.0mL / min) is pumped in, and the two are mixed to undergo a substitution reaction to generate phenyl borate online.

[0036] The reaction solution is continuously pushed into the reactor G along the pipeline, and acid water is pumped in for mixing and quenching. The quenching solution flows out and is directly collected in a large volume container and stirred at room temperature. The phenylboronic acid ester is completely hydrolyzed into phenylboric acid by TLC or HPLC control. The collection container is replaced regularly, and the hydrolyzed p-vinylbenzene boronic acid solution is phase-separated, washed with water, dried, and concentrated to obtain a crude product, which is then refined and purified to obtain 9.0 g of p-vinylbenzene boronic acid, a qualified product, with a yield of 85% and a purity of more than 99%.

[0037] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing olefin-substituted aromatic boronic acid, characterized in that: The method comprises the following steps: using chloroacetophenone as a raw material, reducing it with a reducing agent to obtain chloro-1-phenylethanol, then dehydrating it with an acid catalyst in a high boiling point solvent to obtain a chlorostyrene solution, and finally reacting it with a strong base reagent and a boric acid ester in a continuous flow to obtain alkenylphenylboronic acid by acid hydrolysis.

2. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the first step, the reducing agent is selected from sodium borohydride, potassium borohydride or lithium borohydride.

3. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the first step, the molar ratio of chloroacetophenone to reducing agent is 1:0.35-1.

2.

4. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the second step, the high boiling point solvent is selected from decahydronaphthalene, DMSO, DMF, DMA, sulfolane, multi-substituted benzene solvents, and high boiling point ether solvents.

5. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the second step, the acid catalyst is selected from immobilized Lewis acid or organic acid.

6. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: After the second step reaction is completed, conventional post-treatment is performed: washing with water to remove the small molecule Lewis acid or filtering to remove the immobilized catalyst, and the obtained product solution can be directly subjected to the next step of borate esterification reaction.

7. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the fourth step, the strong base reagent is selected from n-butyl lithium, sec-butyl lithium, and lithium hexamethyldisilazide; and the boric acid ester is selected from trimethyl borate, triethyl borate, and triisopropyl borate.

8. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the fourth step, the molar ratio of chlorostyrene, strong base reagent and borate ester is 1:0.95-1.20:1.0-1.

5.

9. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: The continuous flow reaction in the fourth step adopts a plate-type or tubular continuous flow reaction device.

10. The method for preparing olefin-substituted aromatic boric acid according to claim 1, characterized in that: In the fourth step, the acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.

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