A novel process for the preparation of tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate

Abstract

The application discloses a new process for synthesizing 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester and 4'-methyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester, which comprises the following steps: taking 4'-methyl-2-cyanobiphenyl as raw material, and reacting with isobutene under the catalysis of a cation exchange resin. The application effectively solves the problem of acid wastewater generated in the existing esterification process, has high reaction yield, good purity and simple post-treatment.

Description

Technical Field

[0001] This invention relates to a method for preparing tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate, belonging to the field of organic synthesis. Background Technology

[0002] 4'-Bromomethyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester is a synthetic intermediate for telmisartan. It is typically produced by hydrolyzing 4'-methyl-2-cyanobenzylbiphenyl to 4'-methylbiphenyl-2-carboxylic acid, followed by esterification to obtain 4'-methylbiphenyl-2-carboxylic acid tert-butyl ester, and then bromination to yield 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester. The structural formula of 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester is shown below:

[0003]

[0004] US6369266B1 reports the use of isobutylene and 4'-methylbiphenyl-2-carboxylic acid in the presence of phosphorus oxychloride for esterification, followed by bromination to obtain the product. The synthetic route is shown below:

[0005]

[0006] The above process generates a large amount of acidic phosphorus-containing wastewater, which places strict requirements on equipment and waste treatment. In addition, the product purity is low and further crystallization is required to improve the product purity in order to meet the needs of the next step of bromination reaction. Summary of the Invention

[0007] This invention provides a clean and efficient method for preparing tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylate and tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate.

[0008] The first aspect of the present invention is to provide a method for producing tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylate, comprising the following steps:

[0009] a) 4'-Methylbiphenyl-2-carboxylic acid reacts with isobutylene in a solvent under the catalysis of a cation exchange resin;

[0010] b) After the reaction is complete, filter to remove the resin and obtain a filtrate containing the target product;

[0011] c) The filtrate is separated to obtain 4'-methylbiphenyl-2-carboxylic acid tert-butyl ester; or the filtrate is used directly in the next reaction without treatment.

[0012] A second aspect of the present invention is to provide a method for producing tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate, comprising the following steps:

[0013] a) 4'-Methylbiphenyl-2-carboxylic acid reacts with isobutylene in a solvent under the catalysis of a cation exchange resin;

[0014] b) After the reaction was completed, the resin was removed by filtration to obtain a filtrate containing tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylate;

[0015] c) The filtrate was not treated and a brominating reagent was directly added to react and 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid tert-butyl ester was obtained.

[0016] As a preferred embodiment of the present invention:

[0017] The cation exchange resin is a strong acid type cation exchange resin, preferably a sulfonated polystyrene type cation exchange resin, and particularly preferably Amberlyst 15 ion exchange resin.

[0018] The amount of cation exchange resin used is 0.01 to 10 times the weight of 4'-methylbiphenyl-2-carboxylic acid, more preferably 0.1 to 0.3 times.

[0019] The solvent is selected from halogenated hydrocarbons such as dichloromethane, ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as petroleum ether and n-hexane; and ketones such as acetone and methyl isobutyl ketone.

[0020] The solvent dosage is 0.1 to 100 ml / g relative to the dosage of 4'-methylbiphenyl-2-carboxylic acid, and is more preferably 4 to 10 ml / g.

[0021] The reaction temperature is preferably between -20 and 50°C, more preferably between -10 and 30°C, and even more preferably between -5°C and 30°C.

[0022] Isobutylene can be a liquid or a gas; when a gas is used, the reaction pressure is preferably between atmospheric pressure and 3 MPa, and atmospheric pressure is even more preferred.

[0023] The advantages of the technical solution provided by this invention are as follows:

[0024] 1. The original reaction system has been changed, and phosphorus- and hydrochloric acid-containing wastewater is no longer generated; the only product is the finished product.

[0025] 2. The new process has a high yield and high product purity, with a yield of over 99% and a product purity of over 99%, eliminating the need for further purification before the next reaction step.

[0026] 3. After the reaction is complete, filter to remove the resin, and it can be directly used for the next reaction. The filtered resin can be reused without generating any more waste or requiring complicated post-treatment. Detailed Implementation

[0027] Example 1:

[0028] 10.0 g of 4'-methylbiphenyl-2-carboxylic acid was added to 80 ml of toluene and 1 g of Amberlyst 15 ion exchange resin. After vacuuming at room temperature, the air was replaced with isobutylene, and the reaction was started. After 6 h, the resin was removed by filtration. The resin was washed with 10 ml of toluene, and the toluene was distilled off under reduced pressure to obtain 12.6 g of tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylic acid (HPLC purity > 99%).

[0029] Example 2

[0030] 10.0 g of 4'-methylbiphenyl-2-carboxylic acid was added to 100 ml of dichloromethane and 2 g of Amberlyst 15 ion exchange resin. After vacuuming at -5°C, the air was replaced with isobutylene, and the reaction was started. After 20 h, the resin was removed by filtration. The resin was washed with 10 ml of dichloromethane, and the dichloromethane was distilled off under reduced pressure to obtain 12.6 g of tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylic acid (HPLC purity > 99%).

[0031] Example 3

[0032] 10.0 g of 4'-methylbiphenyl-2-carboxylic acid was added to 100 ml of tetrahydrofuran and 2 g of Amberlyst 15 ion exchange resin. After vacuuming at -5°C, the air was replaced with isobutylene, and the reaction was started. After 10 h, the resin was removed by filtration. The resin was washed with 10 ml of tetrahydrofuran, and the tetrahydrofuran was distilled off under reduced pressure to obtain 12.6 g of tert-butyl 4'-methyl-[1,1'-biphenyl]-2-carboxylic acid (HPLC purity > 99%).

[0033] Example 4

[0034] 10.0 g of 4'-methylbiphenyl-2-carboxylic acid was added to 100 ml of n-hexane and 2 g of Amberlyst 15 ion exchange resin. After vacuuming at -5°C, the air was replaced with isobutylene, and the reaction was started. After the reaction solution became clear, the resin was removed by filtration. The resin was washed with 10 ml of n-hexane. 0.5 g of azobisisobutyronitrile and 10.9 g of N-bromosuccinimide were added to the filtrate. The temperature was raised to 60°C and kept until the color of the reaction solution turned pale yellow. Heating was stopped and the temperature was lowered to 20°C and kept for 1 h. The solution was filtered, and the filtrate was washed with water. The solvent was then concentrated and the solution was dissolved in isopropanol. The solution was cooled to -5°C and crystallized for 2 h. The solution was filtered and dried to obtain 14.4 g of tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid (yield 88.0%, HPLC purity 94%).

[0035] Example 5

[0036] 30g of 4'-methylbiphenyl-2-carboxylic acid was added to 120ml of n-hexane and 1g of Amberlyst 15 ion exchange resin. Sufficient isobutylene was introduced at room temperature to start the reaction. After 6 hours, the resin was removed by filtration. 0.5g of azobisisobutyronitrile and 10.9g of N-bromosuccinimide were added to the filtrate. The temperature was raised to 60℃ and maintained until the reaction solution turned pale yellow. Heating was stopped and the temperature was lowered to 20℃ and maintained for 1 hour. The filtrate was filtered, washed with water, concentrated to remove the solvent, and isopropanol was added to dissolve it. The solution was then cooled to -5℃ and crystallized for 2 hours. After filtration and drying, 15.0g of tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylic acid was obtained (yield 91.7.0%, HPLC purity 93%).

[0037] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate, comprising the following steps: a) 4'-Methylbiphenyl-2-carboxylic acid reacts with isobutylene in a solvent under the catalysis of a cation exchange resin; b) After the reaction is complete, filter to remove the resin and obtain a filtrate containing the target product; c) The filtrate was not treated before being directly reacted with a brominating reagent to yield tert-butyl 4'-bromomethyl-[1,1'-biphenyl]-2-carboxylate. The solvent mentioned therein is selected from n-hexane.

2. The method according to claim 1, wherein the cation exchange resin is a strong acid type cation exchange resin.

3. The method according to claim 2, wherein the cation exchange resin is a sulfonated polystyrene type cation exchange resin.

4. The method according to claim 3, wherein the cation exchange resin is Amberlyst 15 ion exchange resin.

5. The method according to claim 1, characterized in that, The amount of cation exchange resin used is 0.1-0.3 times the weight of 4'-methylbiphenyl-2-carboxylic acid.

6. The method according to claim 1, wherein the amount of solvent used is 4 to 10 ml / g relative to the amount of 4'-methylbiphenyl-2-carboxylic acid.

7. The method according to claim 1, characterized in that, The reaction temperature is between -5℃ and 30℃.

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