A method for synthesizing high purity fumaran bisphenol
By employing a method of chlorination followed by fluorination, using sartan biphenyl as a raw material, and employing NCS or CBMG and hydrogen fluoride or potassium fluoride as reagents, combined with ether solvents and toluene crystallization, the complex synthesis process and low yield of 2-cyano-4'-fluoromethyl biphenyl in existing technologies have been solved. This method achieves the synthesis of fluorosartan biphenyl with high purity and high yield, making it suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- DO FLUORIDE CHEM CO LTD
- Filing Date
- 2023-09-13
- Publication Date
- 2026-06-23
AI Technical Summary
In the existing technology, the synthesis methods of 2-cyano-4'-bromomethylbiphenyl and 2-cyano-4'-fluoromethylbiphenyl have problems such as complex processes, low yield and low purity. In particular, there are few reports on the synthesis of 2-cyano-4'-fluoromethylbiphenyl, which needs to be improved.
A method of chlorination followed by fluorination was adopted, using sartan biphenyl as raw material, with NCS or CBMG as chlorinating reagent, hydrogen fluoride or potassium fluoride as fluorinating agent, and ether solvent and toluene as crystallization solvent to synthesize high-purity fluorinated sartan biphenyl. Concentration crystallization was used to improve purity and yield.
The synthesis of high-purity fluorosartan biphenyl was achieved with a yield of over 83%. The process is simple, suitable for industrial production, and reduces production costs.
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing high-purity fluorosartan biphenyl. Background Technology
[0002] Angiotensin II receptor blockers (ARBs) have advantages such as stable blood pressure reduction, good efficacy, long duration of action, and good patient tolerance, and have become one of the most commonly used antihypertensive drugs in clinical practice. In addition, ARBs also show broad application prospects in the prevention and treatment of heart failure, myocardial infarction, kidney disease, diabetes, and other cardiovascular and cerebrovascular diseases.
[0003] Currently, the most important intermediate in the synthetic route of sartan active pharmaceutical ingredients is 2-cyano-4'-bromomethylbiphenyl (i.e., brominated sartan biphenyl). As the core structure of most sartan drugs, its synthesis methods mainly include bromination with bromine and NBS bromination. However, both methods have different problems. Chinese patent CN102746193A discloses a method for preparing 2-cyano-4'-bromomethylbiphenyl, which reacts 2-cyano-4'-methylbiphenyl, dibromohydantoin, and tetrachloroethylene under the action of a catalyst to generate the final product. Although this method is simple and has a high yield, it does not consider the influence of byproducts, nor does it improve product selectivity, and therefore cannot obtain a product with high purity.
[0004] 2-Cyano-4'-fluoromethylbiphenyl, also known as fluorosartan biphenyl, has few reported synthesis techniques. One of the most efficient methods is to use 2-cyano-4'-bromomethylbiphenyl as a starting material for its synthesis. However, due to the shortcomings of existing techniques, the synthesis method for 2-cyano-4'-fluoromethylbiphenyl needs to be improved to simplify the process and increase synthesis efficiency. Summary of the Invention
[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for synthesizing high-purity fluorosartan biphenyl. This invention utilizes a common pharmaceutical intermediate (sartan biphenyl) through a process of chlorination followed by fluorination to obtain fluorosartan biphenyl in large quantities. It features a simple process, high synthesis efficiency, and a yield exceeding 83%.
[0006] To achieve the above objectives, the present invention adopts the following technical solution:
[0007] A method for synthesizing high-purity fluorosartan biphenyl includes the following steps:
[0008] 1) Dissolve sartan biphenyl in solvent I, add chlorination reagent, heat to 30-50℃ for reaction, monitor the reaction progress by HPLC, stop the reaction when 0.3-0.5% of sartan biphenyl remains, cool to 10-20℃, filter to obtain chlorosartan biphenyl filtrate;
[0009] 2) Heat the filtrate from step 1) to 30-50°C and react it with the fluorinating agent. Monitor the reaction progress by HPLC. Stop the reaction when the chlorsartan-biphenyl content in the reaction solution is 0.2-0.5% to obtain the reaction solution.
[0010] 3) Add solvent II to the reaction solution obtained in step 2), cool to allow crystallization, filter, and dry to obtain high-purity fluorosartan biphenyl.
[0011] Specifically, in step 1), solvent I is one of methyl tert-butyl ether (MTBE), diethyl ether, anisole, ethylene glycol dimethyl ether, and perfluoroether.
[0012] Specifically, in step 1), the chlorination reagent is NCS (N-chlorosuccinimide), CBMG (chlorobis(methoxycarbonyl)guanidine), or a mixture of the two, with a molar ratio of 1 to 10 in the mixture.
[0013] Furthermore, in step 1), the mass ratio of sartan biphenyl to solvent I is 1:(2.0 to 10.0), preferably 1:3.0; the molar ratio of sartan biphenyl to chlorinating reagent is 1:(1.0 to 5.0), preferably 1:1.4.
[0014] Furthermore, the reaction in step 1) is carried out in a tetrafluoroethylene reactor, under pressure of 0.5–2 kg during the reaction.
[0015] Furthermore, the fluorinating agent in step 2) is hydrogen fluoride or potassium fluoride.
[0016] Furthermore, the molar ratio of chlorosartan biphenyl to fluorinating agent in step 2) is 1:(1.2-4.0), preferably 1:1.5.
[0017] Furthermore, the reaction described in step 2) is preferably carried out at 40–50°C.
[0018] Furthermore, when the fluorinating agent is hydrogen fluoride, a tail gas is also obtained after the reaction. The tail gas obtained in step 2) is post-treated: specifically, the tail gas is first condensed at low temperature and then absorbed by alkaline solution.
[0019] More preferably, the alkaline solution used for exhaust gas aftertreatment is a sodium hydroxide aqueous solution with a mass concentration (mass fraction) of 5-20%.
[0020] Furthermore, the reaction solution obtained in step 2) is post-processed to recover solvent I: specifically, the reaction solution is cooled to -10 to 30°C (preferably 10 to 20°C), purged with nitrogen, and then concentrated under a vacuum of -0.05 to -0.1 kPa (preferably -0.08 to -0.09 kPa) to recover the separated solvent I, which is then used in the next batch of reaction.
[0021] Furthermore, in step 3), when solvent II is added, the temperature of the reaction solution is 15–30°C.
[0022] Furthermore, in step 3), solvent II is one of toluene, dichloromethane, dichloroethane, and chloroform.
[0023] Furthermore, in step 3), the mass of solvent II added is 2 to 10 times that of chlorosartan biphenyl, preferably 3 to 5 times that of chlorosartan biphenyl.
[0024] Furthermore, the cooling and crystallization temperature in step 3) is -10 to 30°C, preferably 5 to 10°C.
[0025] Compared with the prior art, the beneficial effects of the present invention are:
[0026] 1. The synthesis method of the present invention uses mixed reagents as chlorination reagents, which have high reactivity and are easy to recover. Sartan biphenyl and chlorosartan biphenyl are well separated in ether solvents, which facilitates subsequent operations.
[0027] 2. The synthesis method of the present invention uses hydrogen fluoride as the fluorinating agent, which is easy to recover, the fluorinating agent is inexpensive, the required mass is minimal, and the production cost is reduced.
[0028] 3. The product synthesized in this invention is produced by concentration and crystallization. Toluene is the unsuitable solvent. The operation is simple, safe, and inexpensive, which helps to reduce production costs.
[0029] 4. The method of the present invention can synthesize products continuously and efficiently, and the process is simple, making it suitable for industrial production and widespread application. Detailed Implementation
[0030] The technical solutions of this application will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.
[0031] Unless otherwise specified, the experimental methods in the following examples are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise specified, the raw materials and reagents used are all commercially available products.
[0032] The specifications and parameters of each raw material in the following examples are shown in Table 1.
[0033] Table 1
[0034] name index Sartan biphenyl White or off-white crystalline powder, moisture: ≤0.5%, ash content: ≤0.2%, purity (HPLC): ≥99.0%. MTBE Purity: ≥99.9%, Moisture: ≤20ppm NCS Content ≥98%, available chlorine ≥26% CBMG Purity: ≥95% hydrogen fluoride Content ≥99.9%, Moisture ≤0.05%, Fluorosilicic acid ≤0.01%, Sulfur dioxide ≤0.01% Toluene Purity: ≥99.5%, Moisture: ≤100ppm
[0035] The sartan biphenyl in the following examples needs to be crushed and re-dried before the reaction to ensure that the moisture content is ≤200ppm.
[0036] Example 1
[0037] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0038] 1) Add 1932.4g of sartan biphenyl and 5797.2g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 50℃. Then add 2477.98g of chlorination reagent (specifically 801.18g of NCS and 1676.8g of CNMG) in batches. Monitor the reaction progress by HPLC. Stop the reaction when the sartan biphenyl content reaches 0.45% (molar percentage). Cool to 20℃ and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 2Kg through the tetrafluoroethylene reactor.
[0039] 2) Heat the filtrate obtained in step 1) to 50°C and slowly pass hydrogen fluoride through it to carry out the reaction. The entire reaction process is monitored by HPLC. When the content of chlorasartan biphenyl in the reaction solution is 0.4% (molar percentage), the reaction is stopped, and the reaction solution and tail gas are obtained. At this time, the calculated mass of hydrogen fluoride used is 300g.
[0040] The exhaust gas from the reaction was first condensed at low temperature and then absorbed by a 5% sodium hydroxide aqueous solution. At the same time, the reaction solution was cooled to 10°C, purged with nitrogen, and then concentrated under a negative pressure of -0.08 kPa to recover the separated MTBE, which was then used in the next batch of reaction. The recovery rate of MTBE was 94.2%.
[0041] 3) Under normal pressure, 816.6 g of toluene was slowly added to the remaining reaction solution after concentration. The reaction solution temperature was 20°C at the time of addition. The mixture was stirred and cooled to 5°C to crystallize. After filtration and drying, 1794.6 g of high-purity fluorosartan biphenyl was obtained, with a yield of 88.71% and a purity of 99.8%.
[0042] Example 2
[0043] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0044] 1) Add 1932.4g of sartan biphenyl and 5797.2g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 40℃. Then add 2477.98g of chlorination reagent (specifically 801.18g of NCS and 1676.8g of CNMG) in batches. Monitor the reaction progress by HPLC. Stop the reaction when the sartan biphenyl content reaches 0.5% (molar percentage). Cool to 20℃ and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 1Kg through the tetrafluoroethylene reactor.
[0045] 2) Heat the filtrate obtained in step 1) to 40°C and slowly pass hydrogen fluoride through it to carry out the reaction. The entire reaction process is monitored by HPLC. When the content of chlorasartan biphenyl in the reaction solution is 0.5% (molar percentage), the reaction is stopped, and the reaction solution and tail gas are obtained. At this time, the calculated mass of hydrogen fluoride used is 600g.
[0046] The exhaust gas from the reaction was first condensed at low temperature and then absorbed by a 5% sodium hydroxide aqueous solution. At the same time, the reaction solution was cooled to 20°C, purged with nitrogen, and then concentrated under a negative pressure of -0.08 kPa to recover the separated MTBE, which was then used in the next batch of reaction. The recovery rate of MTBE was 92.8%.
[0047] 3) Under a slight positive pressure, 2722g of toluene was slowly added to the remaining reaction solution after concentration. The temperature of the reaction solution was 15℃ at the time of addition. The mixture was stirred and cooled to -10℃ to crystallize. After filtration and drying, 1811.6g of high-purity fluorosartan biphenyl was obtained, with a yield of 89.55% and a purity of 99.7%.
[0048] Example 3
[0049] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0050] 1) Add 1932.4g of sartan biphenyl and 19324g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 30°C. Then add 7433.94g of chlorination reagent (specifically 2403.54g of NCS and 5030.4g of CNMG) in batches. Monitor the reaction progress with HPLC. Stop the reaction when the sartan biphenyl content reaches 0.5% (molar percentage). Cool to 10°C and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 2Kg through the tetrafluoroethylene reactor during the process.
[0051] 2) Heat the filtrate obtained in step 1) to 40°C and slowly pass hydrogen fluoride through it to carry out the reaction. The entire reaction process is monitored by HPLC. When the content of chlorsartan biphenyl in the reaction solution is 0.45% (molar percentage), the reaction is stopped, and the reaction solution and tail gas are obtained. At this time, the calculated mass of hydrogen fluoride used is 800g.
[0052] The exhaust gas from the reaction was first condensed at low temperature and then absorbed by a 5% sodium hydroxide aqueous solution. At the same time, the reaction solution was cooled to 30°C, purged with nitrogen, and then concentrated under a negative pressure of -0.08 kPa to recover the separated MTBE, which was then used in the next batch of reaction. The recovery rate of MTBE was 93.6%.
[0053] 3) Under a slight positive pressure, 544.4 g of toluene was slowly added to the remaining reaction solution after concentration (the temperature of the reaction solution was 20°C at the time of addition). The mixture was stirred and cooled to 30°C to crystallize. After filtration and drying, 1697.6 g of high-purity fluorosartan biphenyl was obtained, with a yield of 83.89% and a purity of 99.76%.
[0054] Example 4
[0055] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0056] 1) Add 1932.4g of sartan biphenyl and 19324g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 30°C. Then add 7433.94g of chlorination reagent (specifically 2403.54g of NCS and 5030.4g of CNMG) in batches. Monitor the reaction progress with HPLC. Stop the reaction when the sartan biphenyl content reaches 0.5% (molar percentage). Cool to 10°C and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 0.5Kg through the tetrafluoroethylene reactor during the process.
[0057] 2) Heat the filtrate obtained in step 1) to 50°C and slowly pass hydrogen fluoride through it to carry out the reaction. The entire reaction process is monitored by HPLC. When the content of chlorasartan biphenyl in the reaction solution is 0.2% (molar percentage), the reaction is stopped, and the reaction solution and tail gas are obtained. At this time, the calculated mass of hydrogen fluoride used is 500g.
[0058] The exhaust gas from the reaction was first condensed at low temperature and then absorbed by a 5% sodium hydroxide aqueous solution. At the same time, the reaction solution was cooled to 10°C, purged with nitrogen, and then concentrated under a negative pressure of -0.08 kPa to recover the separated MTBE, which was then used in the next batch of reaction. The recovery rate of MTBE was 93.1%.
[0059] 3) Under slight positive pressure, 1088.8 g of toluene was slowly added to the remaining reaction solution after concentration (the temperature of the reaction solution was 15°C at the time of addition). The mixture was stirred and cooled to 5°C to crystallize. The solution was filtered and dried to obtain 1828.2 g of high-purity fluorosartan biphenyl, with a yield of 90.36% and a purity of 99.84%.
[0060] Example 5
[0061] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0062] 1) Add 1932.4g of sartan biphenyl and 19324g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 30°C. Then add 7433.94g of chlorination reagent (specifically 2403.54g of NCS and 5030.4g of CNMG) in batches. Monitor the reaction progress with HPLC. Stop the reaction when the sartan biphenyl content reaches 0.5% (molar percentage). Cool to 10°C and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 0.5Kg through the tetrafluoroethylene reactor during the process.
[0063] 2) The filtrate obtained in step 1) was heated to 50°C, and potassium fluoride was slowly added to carry out the reaction. The entire reaction process was monitored by HPLC. When the content of chlorasartan biphenyl in the reaction solution was 5% (molar percentage), the reaction was stopped, and the reaction solution was obtained. At this time, the calculated mass of potassium fluoride used was 2672.6g. The reaction solution was cooled to 10°C, purged with nitrogen, and then concentrated under negative pressure of -0.08KPa to recover the separated MTBE and use it for the next batch of reaction. The recovery rate of MTBE was 93.4%.
[0064] 3) Under a slight positive pressure, 1088.8 g of toluene was slowly added to the remaining reaction solution after concentration. The reaction solution temperature was 25 °C at the time of addition. The mixture was stirred and cooled to 5 °C to crystallize. After filtration and drying, 1796.8 g of high-purity fluorosartan biphenyl was obtained, with a yield of 88.76% and a purity of 96.66%.
[0065] Example 6
[0066] A method for synthesizing high-purity fluorosartan biphenyl, the specific steps of which are as follows:
[0067] 1) Add 1932.4g of sartan biphenyl and 19324g of MTBE (methyl tert-butyl ether) to a tetrafluoroethylene reactor equipped with a thermometer, stirrer, and heating device. Stir to dissolve and heat to 30°C. Then add 10680g of chlorination reagent (specifically 7476g of NCS and 3204g of CNMG) in batches. Monitor the reaction progress by HPLC. Stop the reaction when the sartan biphenyl content reaches 1.8% (molar percentage). Cool to 10°C and filter to obtain chlorosartan biphenyl filtrate. The reaction is pressurized by 0.5Kg through the tetrafluoroethylene reactor during the process.
[0068] 2) Heat the filtrate obtained in step 1) to 50°C and slowly pass hydrogen fluoride through it to carry out the reaction. The entire reaction process is monitored by HPLC. When the content of chlorasartan biphenyl in the reaction solution is 0.5% (molar percentage), the reaction is stopped, and the reaction solution and tail gas are obtained. At this time, the calculated mass of hydrogen fluoride used is 530g.
[0069] The exhaust gas from the reaction was first condensed at low temperature and then absorbed by a 5% sodium hydroxide aqueous solution. At the same time, the reaction solution was cooled to 10°C, purged with nitrogen, and then concentrated under a negative pressure of -0.08 kPa to recover the separated MTBE, which was then used in the next batch of reaction. The recovery rate of MTBE was 92.9%.
[0070] 3) Under a slight positive pressure, 1088.8 g of toluene was slowly added to the remaining reaction solution after concentration. The reaction solution temperature was 15 °C at the time of addition. The mixture was stirred and cooled to 5 °C to crystallize. After filtration and drying, 1806.7 g of high-purity fluorosartan biphenyl was obtained, with a yield of 89.25% and a purity of 99.58%.
[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for synthesizing 2-cyano-4'-fluoromethylbiphenyl, characterized in that, Includes the following steps: 1) Dissolve sartan biphenyl in solvent I, add chlorination reagent, heat to 30-50℃ for reaction, monitor the reaction progress by HPLC, stop the reaction when 0.3-0.5% of sartan biphenyl remains, cool to 10-20℃, filter to obtain chlorosartan biphenyl filtrate; 2) Heat the filtrate from step 1) to 30-50°C and react it with the fluorinating agent. Monitor the reaction progress by HPLC. Stop the reaction when the chlorsartan-biphenyl content in the reaction solution is 0.2-0.5% to obtain the reaction solution. The reaction solution was cooled to -10 to 30°C, purged with nitrogen, and then concentrated under a vacuum of -0.05 to -0.1 kPa. Solvent I was recovered and used in the next batch of reaction. 3) Add solvent II to the remaining reaction solution after concentration in step 2), cool to allow crystallization, filter, and dry to obtain 2-cyano-4'-fluoromethylbiphenyl; In step 1), solvent I is one of methyl tert-butyl ether, diethyl ether, anisole, and ethylene glycol dimethyl ether; In step 1), the chlorination reagent is a mixture of N-chlorosuccinimide and chlorobis(methoxycarbonyl)guanidine, with a molar ratio of 1 to 10. The fluorinating agent in step 2) is hydrogen fluoride or potassium fluoride; In step 3), solvent II is toluene.
2. The method as described in claim 1, characterized in that, The mass ratio of sartan biphenyl to solvent I in step 1) is 1:(2.0 to 10.0); the molar ratio of sartan biphenyl to chlorination reagent is 1:(1.0 to 5.0).
3. The method as described in claim 1, characterized in that, The reaction in step 1) is carried out in a tetrafluoroethylene reactor, and the reactor is pressurized by 0.5 to 2 kg during the reaction.
4. The method as described in claim 1, characterized in that, The molar ratio of chlorosartan biphenyl to fluorinating agent in step 2) is 1:(1.2 to 4.0).
5. The method as described in claim 1, characterized in that, In step 3), when solvent II is added, the temperature of the reaction solution is 15–30°C.
6. The method as described in claim 1, characterized in that, In step 3), the mass of solvent II added is 2 to 10 times that of chlorosartan biphenyl.
7. The method as described in claim 1, characterized in that, The cooling and crystallization temperature mentioned in step 3) is -10 to 30°C.