A method for preparing telmisartan key intermediate 4'-bromomethylbiphenyl-2-carboxylate

Abstract

The invention discloses a preparation method of a telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate, including: 2-cyano-4'-methylbiphenyl is heated and hydrolyzed under alcohol compounds and acidic conditions, and esterification "one-pot method" is used to prepare 4'-methylbiphenyl-2-carboxylate; with an organic solvent as a reaction solvent, 4'-methylbiphenyl-2-carboxylate is subjected to bromination reaction with hydrogen peroxide and a bromine source under the action of a catalyst to prepare 4'-bromomethylbiphenyl-2-carboxylate. The inventive method is simple to operate, has high specificity, and has few by-products, and can control the residual 4'-methylbiphenyl-2-carboxylate to less than 0.1%, and 4',4'-dibromomethylbiphenyl-2-carboxylate is controlled to less than 0.1%, and finally, a target product with a purity of more than 99.3% can be obtained without refining, and the total molar yield reaches more than 90%, which is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation and relates to a method for preparing 4'-bromomethylbiphenyl-2-carboxylate, a key intermediate of telmisartan. Background Art

[0002] Telmisartan is a new type of long-acting, highly effective and low-toxic AT antagonist developed by the German pharmaceutical company Bellinger-Ingelheim and launched on the market in 1997. It is also a non-peptide angiotensin II receptor antagonist that selectively and irreversibly blocks AT1 receptors, while having no effect on other receptor systems, especially those involved in the cardiovascular system.

[0003] The chemical name of Telmisartan is: 4′-[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, and its chemical structure is as follows:

[0004]

[0005] 4'-Methylbiphenyl-2-carboxylate is a key intermediate of telmisartan. At present, the preparation methods of 4'-methylbiphenyl-2-carboxylate mainly include the following: Figure 1 ):

[0006] Method 1: Chinese patent CN101172953A uses 4′-bromomethyl-2-cyanobiphenyl as the starting material, and the product is prepared by esterification, hydrolysis, re-esterification and finally bromination.

[0007] Method 2: Chinese patent application CN113105327A and Chinese patent application CN105399627A both use 2-cyano-4'-methylbiphenyl as a starting material, and prepare 4'-bromomethyl-2-biphenylcarboxylic acid methyl ester through hydrolysis, esterification and bromination.

[0008] Method 1 has a long route, and the starting material uses bromomethyl cyanobiphenyl, which is first debrominated and then brominated, which increases the production steps and produces more three wastes. Method 2 uses a method of first hydrolysis and then esterification and then esterification. Although the route is shorter than that of method 1, hydrolysis and esterification are carried out separately, and the actual operation is also more cumbersome. In addition, whether it is method 1 or method 2, the final bromination reaction uses low-boiling dichloromethane as the reaction solvent, and NBS or hydrogen bromide is used to catalyze the free radical reaction under light conditions. Since the free radical reaction is difficult to control and the reaction system is two-phase, there are more dibrominated by-products (compound 1') in the reaction, and the polarity of the target product (compound 1) and the by-product (compound 1') is very similar, which is difficult to purify and remove, resulting in a target product purity of ≤98.5%, a refining loss of ≥10%, a bromination step yield of ≤85%, a low total molar yield of ≤70%, a relatively high cost, and more three wastes.

[0009] Therefore, there is an urgent need in the art for a preparation method of a telmisartan intermediate with high yield, few by-products, low cost and more suitable for industrial production. Summary of the invention

[0010] The purpose of the present invention is to solve the defects of the existing preparation method, such as low yield of 4'-methylbiphenyl-2-carboxylate, low raw material conversion rate or high by-products, complicated operation, high cost, unsuitability for industrial production, etc., and provide a preparation method of telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate. The preparation method is simple to operate, has high raw material conversion rate, few by-products, high yield, low cost, and is more suitable for industrial production.

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

[0012] A method for preparing 4'-bromomethylbiphenyl-2-carboxylate, a key intermediate of telmisartan, wherein the synthetic route is as follows:

[0013]

[0014] Wherein, R is selected from C1-C4 alkyl.

[0015] The steps include:

[0016] Step (1), heating 2-cyano-4'-methylbiphenyl in an alcohol compound under acidic conditions to hydrolyze and esterify to obtain 4'-methylbiphenyl-2-carboxylate of formula I in a one-pot method;

[0017] Step (2), using an organic solvent as a reaction solvent, 4'-methylbiphenyl-2-carboxylate is subjected to a bromination reaction with hydrogen peroxide and a bromine source in the presence of a catalyst to obtain 4'-bromomethylbiphenyl-2-carboxylate shown in formula II.

[0018] In step (1), the alcohol compound is a C1-C4 alcohol compound having a boiling point of more than 100°C under normal pressure or pressure; specifically, the alcohol compound is n-butanol or isobutanol having a boiling point of more than 100°C under normal pressure, or methanol or ethanol having a boiling point of more than 100°C under pressure.

[0019] The alcohol compound is used as both a reaction solvent and a reaction reagent, and there is no special requirement for the amount of the alcohol compound, as long as the system is easy to stir. Generally, the weight ratio of the alcohol compound to 2-cyano-4′-methylbiphenyl is ≥3:1.

[0020] The acidic condition is formed by adding an acid, which is sulfuric acid, hydrochloric acid or hydrogen chloride, hydrobromic acid or hydrogen bromide, preferably sulfuric acid.

[0021] The molar ratio of the acid to 2-cyano-4′-methylbiphenyl is 1.5:1.0 to 4.0:1.0.

[0022] The reaction temperature is 100-150°C.

[0023] In step (2), the molar ratio of the hydrogen peroxide to 4′-methyl-2-biphenylcarboxylate is 1.0:1.0 to 5.0:1.0, preferably 1.0:2.0, calculated as hydrogen peroxide.

[0024] The bromine source is one of bromine, hydrobromic acid or hydrogen bromide, and N-bromosuccinimide (NBS).

[0025] When the bromine source is bromine, the molar ratio of the bromine source to 4′-methyl-2-biphenylcarboxylate is 0.5:1.0 to 0.7:1.0; when the bromine source is one of hydrobromic acid, hydrogen bromide, and N-bromosuccinimide (NBS), the molar ratio of the bromine source to 4′-methyl-2-biphenylcarboxylate is 1.0:1.0 to 1.4:1.0.

[0026] The catalyst is a phase transfer catalyst or an initiating catalyst; the phase transfer catalyst is one of benzyltriethylammonium chloride (TEBA), tetrabutylammonium chloride (TBAC) and tetrabutylammonium bromide (TBAB); the initiating catalyst is azobisisobutyronitrile (AIBN).

[0027] The molar ratio of the catalyst to 4'-methylbiphenyl-2-carboxylate is 0.1:100 to 5:100.

[0028] The organic solvent is one of ethyl acetate, n-hexane, cyclohexane and petroleum ether, which have relatively low polarity and relatively high boiling point.

[0029] The bromination reaction is carried out under reflux conditions.

[0030] The 4'-methylbiphenyl-2-carboxylate is 4'-bromomethyl-2-biphenylcarboxylic acid methyl ester, 4'-bromomethyl-2-biphenylcarboxylic acid ethyl ester, 4'-bromomethyl-2-biphenylcarboxylic acid n-propyl ester, 4'-bromomethyl-2-biphenylcarboxylic acid isopropyl ester, 4'-bromomethyl-2-biphenylcarboxylic acid n-butyl ester, and 4'-bromomethyl-2-biphenylcarboxylic acid isobutyl ester.

[0031] Specifically, a method for preparing 4′-bromomethyl-2-biphenylcarboxylate, a key intermediate of telmisartan, comprises the following steps:

[0032] Step (1), mixing 4′-methyl-2-cyanobiphenyl and an alcohol compound, heating to 80° C., adding an acid, and performing hydrolysis and esterification reactions at 100-150° C. under normal pressure or pressure until the reaction rate of 2-cyano-4′-methylbiphenyl is ≤0.1%; concentrating under reduced pressure until the alcohol compound is 8%-35%wt of the initial amount of the alcohol compound, avoiding caking at the bottom of the kettle caused by the complete evaporation of the solvent, and retaining part of the solvent to ensure easy stirring during production, cooling to ≤15° C., adding water in an amount equal to the initial amount of the alcohol compound, stirring at room temperature for 1-2 hours, filtering, and drying to constant weight to obtain a pure product of 4′-methyl-2-biphenyl carboxylate;

[0033] Step (2), using an organic solvent as a reaction solvent, 4′-methyl-2-biphenylcarboxylate is subjected to a bromination reaction with hydrogen peroxide and a bromine source in the presence of a phase transfer catalyst under reflux conditions; after the reaction is completed, the temperature is lowered to ≤30° C., a 10% sodium bisulfite solution is added to quench the reaction, the reaction is stirred, filtered, and the filter cake is rinsed with an organic solvent that is the same as the reaction solvent, and dried to obtain 4′-bromomethyl-2-biphenylcarboxylate.

[0034] Beneficial effects of the present invention:

[0035] (1) Compared with the existing process in which hydrolysis and esterification are performed in two or more steps, the "one-pot" hydrolysis and esterification reaction of the present invention has the advantages of simple operation, less waste, less waste and environmental protection.

[0036] (2) The bromination reaction of the present invention uses a solvent with a relatively low polarity and a relatively high boiling point, and the free radical reaction is made easier to proceed by controlling the reaction temperature; by adding a catalyst, more raw materials participate in the bromination reaction, and further bromination of the target 4'-methylbiphenyl-2-carboxylate to produce a dibrominated by-product (compound 1') is avoided, thereby effectively improving the conversion rate of the raw materials while reducing the generation of dibrominated by-products; the method of the present invention is simple to operate, has high specificity, and produces few by-products, and can control the residual 4'-methylbiphenyl-2-carboxylate to less than 0.1%, and the 4',4'-dibromomethylbiphenyl-2-carboxylate to less than 0.1%. Finally, the target product with a purity of more than 99.3% can be obtained without refining, and the total molar yield is more than 90%, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The following is a reaction scheme for the existing 4'-methylbiphenyl-2-carboxylate. DETAILED DESCRIPTION

[0038] The technical scheme of the present invention is further described below by way of examples, but the present invention should not be limited to the scope of the examples. If the specific implementation conditions are not specified in the following examples, conventional methods and conditions are used.

[0039] Example 1

[0040] Add 38.7 g (0.2 mol) of 2-cyano-4′-methylbiphenyl and 116 g of n-butanol to a 1L reaction bottle, raise the temperature to 80°C, and add 40.0 g (0.4 mol) of concentrated sulfuric acid (mass fraction 98%, the same below) dropwise while stirring; after the addition is completed, raise the temperature to 118°C for reflux reaction, and control it in HPLC. After 4 hours, the reaction of 2-cyano-4′-methylbiphenyl is ≤0.1%, and the reaction is stopped; concentrate under reduced pressure until the remaining n-butanol is about 38 g, cool to ≤15°C, and add 116 g of purified water to the system; after the addition is completed, stir at room temperature for 1.5 hours, filter, and dry the filter cake under reduced pressure at 50°C to constant weight to obtain 50.7 g of 4′-methyl-2-biphenylcarboxylic acid n-butyl ester (white solid) with a molar yield of 94.5%.

[0041] 40.3 g (0.15 mol) of 4′-methyl-2-biphenylcarboxylic acid n-butyl ester was added to 200 g of n-hexane and 33.4 g of 40% hydrobromic acid (0.165 mol), and then 0.05 g (0.15 mmol) of TBAB was added; after the addition, the temperature was raised to 60° C. under stirring, and 17.0 g (0.15 mol) of 30% hydrogen peroxide was added dropwise, and the addition was completed within about 2 h. The temperature was raised to reflux reaction for 30 min, and the raw material residue was controlled to ≤1.0% in HPLC; the temperature was lowered to ≤30° C., 53 g of 10% sodium bisulfite solution was added dropwise, and after the addition was completed, the mixture was stirred for 30 min, filtered, and the filter cake was rinsed with 30 g of n-hexane, and the filter cake was dried to obtain 49.8 g of 4′-bromomethyl-2-biphenylcarboxylic acid n-butyl ester (white solid), with a molar yield of 95.6%, HPLC: 99.43%, and no dibromo impurity was detected.

[0042] Example 2

[0043] Add 38.7 g (0.2 mol) of 2-cyano-4′-methylbiphenyl and 116 g of isobutanol to a 1L reaction bottle, raise the temperature to 80°C, and add 78.4 g (0.784 mol) of concentrated sulfuric acid dropwise while stirring; after the addition is completed, raise the temperature to 105°C for reflux reaction, and control it in HPLC. After 6 hours, the reaction of 2-cyano-4′-methylbiphenyl is ≤0.1%, and the reaction is stopped; concentrate under reduced pressure until the remaining isobutanol is about 38 g, cool to ≤15°C, and add 116 g of purified water to the system; after the addition is completed, stir at room temperature for 1.5 hours, filter, and dry the filter cake under reduced pressure at 50°C to constant weight to obtain 50.5 g of 4′-methyl-2-biphenylcarboxylic acid isobutyl ester (white solid) with a molar yield of 94.2%.

[0044] 40.3 g (0.15 mol) of 4′-methyl-2-biphenylcarboxylic acid isobutyl ester was added to 200 g of n-hexane and 33.4 g of 40% hydrobromic acid (0.165 mol), and then 0.15 g (0.45 mmol) of TBAB was added; after the addition, the temperature was raised to 60° C. with stirring, and 34.0 g (0.30 mol) of 30% hydrogen peroxide was added dropwise, and the addition was completed within about 2 h. The temperature was raised to reflux reaction for 30 min, and the raw material residue was controlled to ≤1.0% in HPLC; the temperature was lowered to ≤30° C., 53 g of 10% sodium bisulfite solution was added dropwise, and after the addition was completed, the mixture was stirred for 30 min, filtered, and the filter cake was rinsed with 30 g of n-hexane, and the filter cake was dried to obtain 50.6 g of 4′-bromomethyl-2-biphenylcarboxylic acid isobutyl ester (white solid), with a molar yield of 97.2%, HPLC: 99.58%, and no dibromo impurity was detected.

[0045] Example 3

[0046] 38.7 g (0.2 mol) of 2-cyano-4′-methylbiphenyl and 194 g of n-butanol were added to a 1L reaction bottle, the temperature was raised to 80°C, and 40.0 g (0.4 mol) of concentrated sulfuric acid was added dropwise while stirring; after the addition was completed, the system was controlled to react at 150°C at 5-10 MPa, and the reaction of 2-cyano-4′-methylbiphenyl was controlled by HPLC. After 1 h, the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the reaction was stopped, and the system was concentrated under reduced pressure to about 37 g of n-butanol remaining, and the temperature was lowered to ≤15°C. 116 g of purified water was added to the system; after the addition was completed, the system was stirred at room temperature for 1.5 h, filtered, and the filter cake was dried under reduced pressure at 50°C to constant weight to obtain 51.1 g of n-butyl 4′-methyl-2-biphenylcarboxylate (white solid) with a molar yield of 95.3%.

[0047] 40.3 g (0.15 mol) of 4′-methyl-2-biphenylcarboxylic acid n-butyl ester was added to 200 g of n-hexane and 33.4 g of 40% hydrobromic acid (0.165 mol), and then 0.125 g (0.45 mmol) of TBAC was added; after the addition, the temperature was raised to 60° C. under stirring, and 34.0 g (0.30 mol) of 30% hydrogen peroxide was added dropwise, and the addition was completed within about 2 h. The temperature was raised to reflux reaction for 30 min, and the raw material residue was controlled to ≤1.0% in HPLC; the temperature was lowered to ≤30° C., 53 g of 10% sodium bisulfite solution was added dropwise, and after the addition was completed, the mixture was stirred for 30 min, filtered, and the filter cake was rinsed with 30 g of n-hexane, and the filter cake was dried to obtain 50.5 g of 4′-bromomethyl-2-biphenylcarboxylic acid n-butyl ester (white solid), with a molar yield of 97.0%, HPLC: 99.53%, and no dibromo impurity was detected.

[0048] Example 4

[0049] 58.0 g (0.3 mol) of 2-cyano-4′-methylbiphenyl and 580 g of ethanol were added to a 1L pressure reactor, the temperature was raised to 75°C, and 45.0 g (0.45 mol) of concentrated sulfuric acid was added dropwise while stirring. After the addition was completed, the system was controlled to react at 100°C under 5-10 MPa. HPLC central control was started after 16 hours, and thereafter, central control was performed every 1 hour until the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the system was concentrated under reduced pressure to about 50 g of residual ethanol, cooled to ≤15°C, and 174 g of purified water was added to the system; after the addition was completed, the mixture was stirred at room temperature for 1.5 hours, filtered, and the filter cake was dried under reduced pressure at 45°C to constant weight to obtain 68.6 g of ethyl 4′-methyl-2-biphenylcarboxylate (white solid) with a molar yield of 95.1%.

[0050] 48g (0.2mol) of ethyl 4'-methyl-2-biphenylcarboxylate was added to 240g of ethyl acetate and 41.8g of 40% hydrobromic acid (0.2mol), and then 0.137g (0.6mmol) of TEBA was added; after the addition, the temperature was raised to 60°C with stirring, and 68.0g (0.6mol) of 30% hydrogen peroxide was added dropwise, and the addition was completed in about 4h, and the temperature was raised to reflux reaction for 30min, and the raw material residue was controlled to ≤1.0% in HPLC; the temperature was lowered to ≤30°C, 416g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30min, filtered, and the filter cake was rinsed with 30g of ethyl acetate at ≤15°C, and the filter cake was dried to obtain 62.0g of ethyl 4'-bromomethyl-2-biphenylcarboxylate (white solid), with a molar yield of 97.1%, HPLC: 99.69%, and no dibromo impurity was detected.

[0051] Example 5

[0052] 58 g (0.3 mol) of 2-cyano-4′-methylbiphenyl and 406 g of methanol were added to a 1L pressurized reaction bottle, the temperature was raised to 60°C, and 45.0 g (0.45 mol) of concentrated sulfuric acid was added dropwise while stirring; after the addition was completed, the system was controlled to react at 110°C under 5-10 MPa, and HPLC central control was started after 12 hours, and thereafter, central control was performed every 1 hour until the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the system was concentrated under reduced pressure to about 50 g of residual methanol, the temperature was lowered to ≤15°C, and 174 g of purified water was added to the system; after the addition was completed, the mixture was stirred at room temperature for 1.5 hours, filtered, and the filter cake was dried under reduced pressure at 45°C to constant weight to obtain 64.6 g of methyl 4′-methyl-2-biphenylcarboxylate (white solid) with a molar yield of 95.2%.

[0053] 45.3 g (0.2 mol) of methyl 4′-methyl-2-biphenylcarboxylate was added to 275 g of petroleum ether, and then 0.32 g (1 mmol) of TBAB was added. The mixture was heated to 60° C. under stirring, and 22.7 g (0.2 mol) of 30% hydrogen peroxide and 16.0 g (0.1 mol) of bromine were added dropwise at the same time. The reaction was completed in about 2 h. The mixture was heated to reflux for 30 min and the residue was controlled to ≤1.0% by HPLC. The mixture was cooled to ≤30° C., 70 g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was rinsed with 150 g of petroleum ether. The filter cake was dried to obtain 58.2 g of methyl 4′-bromomethyl-2-biphenylcarboxylate (white solid). The molar yield was 95.3%, and the HPLC: 99.40%. No dibromo impurity was detected.

[0054] Example 6

[0055] 58 g (0.3 mol) of 2-cyano-4′-methylbiphenyl and 174 g of methanol were added to a 1L pressurized reaction bottle, and 16.4 g (0.45 mol) of hydrogen chloride was introduced while stirring at a temperature of 5-15°C. The system was heated to 110°C at 5-10 MPa for reaction, and HPLC central control was started after 12 hours, and then central control was performed every 1 hour until the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the system was concentrated under reduced pressure to about 50 g of residual methanol, cooled to ≤15°C, and 174 g of purified water was added to the system; after the addition, the mixture was stirred at room temperature for 1.5 hours, filtered, and the filter cake was dried under reduced pressure at 45°C to constant weight to obtain 64.4 g of methyl 4′-methyl-2-biphenylcarboxylate (white solid) with a molar yield of 94.9%.

[0056] 45.3 g (0.2 mol) of methyl 4′-methyl-2-biphenylcarboxylate was added to 275 g of n-hexane, and then 36.3 g (0.204 mol) of NBS and 0.32 g (1 mmol) of TBAB were added. The mixture was heated to 60° C. with stirring, and 22.7 g (0.2 mol) of 30% hydrogen peroxide was added dropwise. The addition was completed within about 2 h. The mixture was heated to reflux for 30 min and the raw material residue was controlled to ≤1.0% by HPLC. The mixture was cooled to ≤30° C., 70 g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was rinsed with 150 g of n-hexane. The filter cake was dried to obtain 58.0 g of methyl 4′-bromomethyl-2-biphenylcarboxylate (white solid). The molar yield was 94.9%, and the HPLC: 99.43%. No dibromo impurity was detected.

[0057] Example 7

[0058] 116 g (0.6 mol) of 2-cyano-4′-methylbiphenyl and 580 g of methanol were added to a 1L pressurized reaction bottle, the temperature was raised to 60°C, and 243.4 g (2.4 mol) of concentrated hydrochloric acid (mass fraction 36%) was added dropwise while stirring; after the addition, the system was controlled to react at 110°C under 5-10 MPa, HPLC central control was started after 12 hours, and then central control was performed every 1 hour until the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the system was concentrated under reduced pressure to about 80 g of residual methanol, the temperature was lowered to ≤15°C, the mixture was stirred at this temperature for 1.5 hours, filtered, and the filter cake was dried under reduced pressure at 45°C to constant weight to obtain 127.7 g of methyl 4′-methyl-2-biphenylcarboxylate (white solid) with a molar yield of 94.1%.

[0059] 45.3 g (0.2 mol) of methyl 4′-methyl-2-biphenylcarboxylate was added to 275 g of n-hexane, and then 36.3 g (0.204 mol) of NBS and 1.64 g (0.01 mol) of AIBN were added. The mixture was heated to 60° C. with stirring, and 45.4 g (0.4 mol) of 30% hydrogen peroxide was added dropwise. The addition was completed within about 2 h. The mixture was heated to reflux for 30 min and the raw material residue was controlled to ≤1.0% by HPLC. The mixture was cooled to ≤30° C., 70 g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was rinsed with 150 g of n-hexane. The filter cake was dried to obtain 58.8 g of ethyl 4′-bromomethyl-2-biphenylcarboxylate (white solid). The molar yield was 96.2%, and the HPLC: 99.54%. No dibromo impurity was detected.

[0060] Comparative Example 1

[0061] 45.3 g (0.2 mol, Example 7) of methyl 4′-methyl-2-biphenylcarboxylate was added to 275 g of n-hexane, and then 36.3 g (0.204 mol) of NBS was added, the temperature was raised to 60° C., 45.4 g (0.4 mol) of 30% hydrogen peroxide was added dropwise, and the addition was completed within about 2 h. The temperature was raised to reflux reaction for 30 min, and the raw material residue was controlled to be 14.09% in HPLC (reaction time was the same as in Example 7); the temperature was lowered to ≤30° C., 70 g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30 min, filtered, and the filter cake was rinsed with 150 g of n-hexane. The filter cake was dried to obtain 51.5 g of ethyl 4′-bromomethyl-2-biphenylcarboxylate (white solid), with a molar yield of 84.2%, HPLC: 96.05%, a raw material residue of 1.42%, and a dibromo impurity of 1.34%.

[0062] Comparative Example 2

[0063] 4′-methyl-2-formate biphenyl (i.e. 4′-methyl-2-biphenylcarboxylic acid methyl ester, the same below) prepared by the method of Example 1 of patent CN105399627A was used as a raw material to carry out a bromination reaction:

[0064] Add 27.7g (0.12mol) of 4′-methyl-2-formate biphenyl, 138.5g of dichloromethane, and 24g (0.13mol) of NBS to the reaction bottle, react at 25°C for 5h under 18000lx light conditions, and control by HPLC. At this time, the raw material residue is 9.4% and dibromide is generated by 5.0%; add 100g of 10% sodium bisulfite solution to wash the organic layer, and then wash the organic layer with 100g of saturated brine and 100g of purified water respectively, and finally add anhydrous sodium sulfate to dry the organic layer; filter after drying, and concentrate to dryness under reduced pressure; add 22g of methanol, quickly cool to 0°C, stir and crystallize for 5h, and only a small amount of solid precipitates; filter, and dry the filter cake in vacuum at 35°C for 8h to obtain 31.2g of white crystals, with a molar yield of 83.6%, HPLC: 97.75%, and dibromide residue: 1.78%.

[0065] Comparative Example 3

[0066] Using 4′-methyl-2-formate biphenyl prepared by the method of Example 1 of patent CN113105327A as raw material, bromination reaction was carried out:

[0067] 25 g (0.094 mol) of 4′-methyl-2-formate biphenyl, 120 g of dichloromethane and 64 g of water were added to the reaction flask and stirred evenly. Under irradiation with an 80 W LED light source and keeping the system temperature at 25° C., 12 g of bromine (0.075 mol) and 22.4 g of hydrogen peroxide (mass fraction 30%) were added dropwise simultaneously. After the addition was completed, the reaction was kept at 25° C. for 5 min. According to HPLC control, the raw material residue was 1.9% and the dibromoacetate was 14.2 %; stop the reaction, let stand for 30 minutes to separate the layers, wash the organic layer twice with 100 g of saturated anhydrous sodium sulfate aqueous solution; concentrate the organic layer under reduced pressure at 40°C (avoid excessive reduced pressure at 70°C, which may cause safety hazards) to dryness; add it to 50 mL of ethanol, heat it to 50°C and keep it warm for 30 minutes, then cool it down by 0-5°C and keep it warm for 1 hour, filter it, and dry the filter cake to obtain 27.5 g of white crystals, with a molar yield of 81.6%, HPLC: 97.3%, and dibromo residue: 1.9%.

[0068] Comparative Example 4

[0069] 45.3 g (0.2 mol, Example 7) of methyl 4′-methyl-2-biphenylcarboxylate was added to 275 g of dichloromethane, and then 36.3 g (0.204 mol) of NBS and 1.64 g (0.01 mol) of AIBN were added. The temperature was raised to 40° C. (already refluxed), and 45.4 g (0.4 mol) of 30% hydrogen peroxide was added dropwise. The addition was completed within about 2 hours, and the reflux reaction was continued for 30 minutes. The raw material residue was controlled at 10.49% by HPLC. The temperature was lowered to ≤30° C., 70 g of 10% sodium bisulfite solution was added dropwise, and the mixture was stirred for 30 minutes after the addition was completed. The mixture was allowed to stand for stratification, and the organic layer was washed with 200 g of saturated brine. After stratification, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. 30 g of methanol was added, the temperature was lowered by 0 to 5°C, and the mixture was stirred for 5 h. The filter cake was rinsed with 150 g of n-hexane and dried to obtain 49.3 g of ethyl 4′-bromomethyl-2-biphenylcarboxylate (white solid), with a molar yield of 80.6%, HPLC: 96.83%, 1.15% of raw material residue, and 1.30% of dibromo impurity.

Claims

1. A method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate, characterized in that: The synthetic route is as follows: Wherein, R is selected from C1-C4 alkyl; The steps include: Step (1), heating 2-cyano-4′-methylbiphenyl in an alcohol compound under acidic conditions for hydrolysis and esterification to obtain 4′-methylbiphenyl-2-carboxylate in a one-pot method; Step (2), using an organic solvent as a reaction solvent, 4'-methylbiphenyl-2-carboxylate is subjected to a bromination reaction with hydrogen peroxide and a bromine source in the presence of a catalyst to obtain 4'-bromomethylbiphenyl-2-carboxylate; wherein the organic solvent is one of ethyl acetate, n-hexane, cyclohexane, and petroleum ether; the bromine source is one of bromine, hydrobromic acid or hydrogen bromide, and N-bromosuccinimide; the catalyst is a phase transfer catalyst or an initiating catalyst; the phase transfer catalyst is one of benzyltriethylammonium chloride, tetrabutylammonium chloride, and tetrabutylammonium bromide; the initiating catalyst is azobisisobutyronitrile; and the bromination reaction is carried out under reflux conditions.

2. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 1, characterized in that: In step (1), the alcohol compound is a C1-C4 alcohol compound with a boiling point above 100° C. under normal pressure or pressure.

3. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 1, characterized in that: In step (1), the acidic condition is formed by adding an acid; the acid is sulfuric acid, hydrochloric acid or hydrogen chloride, hydrobromic acid or hydrogen bromide.

4. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 3, characterized in that: In step (1), the acid is sulfuric acid.

5. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 3, characterized in that: The molar ratio of the acid to 2-cyano-4′-methylbiphenyl is 1.5:1.0 to 4.0:1.

0.

6. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 1, characterized in that: In step (1), the reaction temperature is 100-150°C.

7. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 1, characterized in that: In step (2), the molar ratio of the hydrogen peroxide to 4′-methyl-2-biphenylcarboxylate is 1.0:1.0 to 5.0:1.0, calculated as hydrogen peroxide.

8. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 7, characterized in that: In step (2), the molar ratio of hydrogen peroxide to 4′-methyl-2-biphenylcarboxylate is 1.0:2.0, calculated as hydrogen peroxide.

9. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 2, characterized in that: When the bromine source is bromine, the molar ratio of the bromine source to 4′-methyl-2-biphenylcarboxylate is 0.5:1.0 to 0.7:1.0; when the bromine source is one of hydrobromic acid, hydrogen bromide and N-bromosuccinimide, the molar ratio of the bromine source to 4′-methyl-2-biphenylcarboxylate is 1.0:1.0 to 1.4:1.

0.

10. The method for preparing telmisartan intermediate 4'-bromomethylbiphenyl-2-carboxylate according to claim 1, characterized in that: The molar ratio of the catalyst to 4'-methylbiphenyl-2-carboxylate is 0.1:100 to 5:100.

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