CN108947870B - Preparation method of bromosartanbiphenyl - Google Patents
Preparation method of bromosartanbiphenyl Download PDFInfo
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- CN108947870B CN108947870B CN201810813436.0A CN201810813436A CN108947870B CN 108947870 B CN108947870 B CN 108947870B CN 201810813436 A CN201810813436 A CN 201810813436A CN 108947870 B CN108947870 B CN 108947870B
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Abstract
The invention provides a preparation method of bromosartanbiphenyl, which comprises the following steps: adding a catalyst sodium bromate into a reaction kettle, adding an organic solvent dichloromethane into the reaction kettle, adding sartanbiphenyl, and after the materials are dissolved, adding bromine to perform bromination reaction; the molar ratio of the components is as follows: bromine: sodium bromate 1: 0.4-0.6: 0.1-0.3; layering, collecting an organic layer, and transferring the collected organic layer to a desolventizing crystallization kettle; removing dichloromethane in the organic layer; adding toluene for crystallization to obtain bromosartanbiphenyl. The invention takes sodium bromate as a catalyst, adopts sartanbiphenyl and bromine as raw materials, and can effectively improve the whole reaction conversion rate to 92.1 percent by further controlling the reaction temperature and the material ratio, and the process is stable.
Description
Technical Field
The invention relates to the technical field of substance synthesis, in particular to a preparation method of bromosartanbiphenyl.
Background
2-cyano-4' -bromomethylbiphenyl (namely bromosartan biphenyl) is a main intermediate for synthesizing sartan medicaments. The traditional synthetic method of the 2-cyano-4' -bromomethyl biphenyl mainly comprises the following steps: NBS bromination and bromine bromination. NBS bromination also suffers from the following disadvantages: (1) carbon tetrachloride and dichloroethane are generally used as solvents, and the carbon tetrachloride and the dichloroethane are forbidden to be used in medical synthesis and are not suitable for production; (2) AIBN or BPO is usually used as an initiator, the reaction mechanism is similar to a free radical reaction, and the process stability and controllability are poor in the amplification production process; (3) the cost of the production raw materials is higher. Bromine bromination uses bromine in production and requires a catalyst, and the catalysts used mainly include: cuprous bromide, nickel triphenylphosphine oxide, zinc chloride, etc., but the catalytic efficiency is not high by using these catalysts, resulting in a low yield of 2-cyano-4' -bromomethylbiphenyl.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of bromosartanbiphenyl, which adopts sodium bromate as a catalyst for bromination reaction, can effectively improve the conversion rate of the whole reaction to 92.1 percent and has stable process.
The invention is realized by the following steps:
the invention provides a preparation method of bromosartanbiphenyl, which comprises the following steps:
step 1, putting a catalyst sodium bromate into a reaction kettle, adding an organic solvent dichloromethane into the reaction kettle, adding sartanbiphenyl, and after materials are dissolved, adding bromine to perform bromination reaction; the molar ratio of the components is as follows: bromine: sodium bromate 1: 0.4-0.6: 0.1-0.3; the reaction scheme is as follows:
step 2, layering, collecting an organic layer, and transferring the collected organic layer to a desolventizing crystallization kettle;
step 3, removing the organic solvent dichloromethane in the organic layer;
and 4, adding toluene for crystallization to obtain bromosartanbiphenyl.
Preferably, the specific operation in the step 1 is that water is directly added into a reaction kettle, sodium bromate is added under stirring, dichloromethane is added into the reaction kettle, sartanbiphenyl is added into the reaction kettle after the dichloromethane is added, and bromine is added after the materials are dissolved.
Preferably, in the step 1, the temperature of the bromination reaction is controlled to be 38-45 ℃, and then the temperature is controlled to be 38-45 ℃ for heat preservation for 4-6 hours.
Preferably, the specific operation in the step 2 is that the layering temperature is controlled to be 25-35 ℃, the organic layer is collected, the water layer is barreled and recycled, the organic layer is washed twice by adding water and anhydrous sodium sulfite mixed solution, and then the organic layer is collected in a layering way; and then washing the mixture once by adding water, transferring the collected organic layer to a desolventizing crystallization kettle, standing for layering, and collecting the organic layer.
Preferably, the operation in the step 3 is to open and stir in a desolventizing crystallization kettle, control the temperature to be 40-50 ℃, firstly distill the dichloromethane under normal pressure until the temperature is 50 ℃, and then distill under reduced pressure until the dichloromethane is dried.
Preferably, the specific operation in the step 4 is to place toluene into the desolventizing crystallization kettle, stir, open steam, heat to 60-65 ℃, after the materials are dissolved, keep the temperature for half an hour, cool to 0-5 ℃, keep the temperature for 1 hour, crystallize, centrifuge after keeping the temperature, and finally, until no continuous filtrate flows out from the liquid outlet.
The invention has the beneficial effects that:
the method takes sodium bromate as a catalyst, adopts sartanbiphenyl and bromine as raw materials, and further controls the reaction temperature and the material ratio, so that the reaction yield is not reduced, but is greatly improved; meanwhile, the side reaction participating in the reaction is less, and the obtained product has less impurities. The bromosartanbiphenyl with higher yield and purity is obtained, the conversion rate of the whole reaction can be effectively improved to 92.1 percent, and the process is stable.
Detailed Description
Example 1
1. Directly adding water into a reaction kettle, stirring and adding 0.1 mol of sodium bromate, then adding dichloromethane into the reaction kettle from a metering tank, and adding 1 mol of sartanbiphenyl into the reaction kettle after adding. After the materials are dissolved, adding 0.4 mol of bromine, and controlling the temperature to be 38-45 ℃ for micro-reflux. Controlling the temperature at 38-45 ℃ and preserving the heat for 4-6 hours, and finishing the heat preservation. And (3) layering, collecting an organic layer, barreling and recovering a water layer, and then respectively adding a water and anhydrous sodium sulfite mixed solution to wash twice. And (4) layering, collecting an organic layer, and discharging a water layer into a wastewater system. Then washing with water once again, and transferring the collected organic layer to a desolventizing crystallization kettle. Standing, layering, collecting organic layer, and discharging water layer into waste water system. The layering temperature is controlled at 25-35 ℃. Stirring in a desolventizing crystallization kettle, controlling the internal temperature to be 40-50 ℃, distilling dichloromethane at normal pressure to 50 ℃, then distilling under reduced pressure to dryness, and putting toluene in a high-level tank into the desolventizing kettle. Stirring, heating to 60-65 deg.C with steam, dissolving, maintaining the temperature for half an hour, cooling to 0-5 deg.C, and maintaining the temperature for 1 hour for crystallization. And (4) after the heat preservation is finished, centrifuging until no continuous filtrate flows out from the liquid outlet. The molar ratio of the components is as follows: bromine: sodium bromate 1: 0.4: 0.1;
2. the finally obtained bromosartanbiphenyl has the molar yield of 90.7 percent and the HPLC purity of 98.4 percent.
Example 2
1. Directly adding water into a reaction kettle, stirring and adding 0.3 mol of sodium bromate, then adding dichloromethane into the reaction kettle from a metering tank, and adding 1 mol of sartanbiphenyl into the reaction kettle after adding. After the materials are dissolved, 0.6 mol of bromine is added, and the temperature is controlled to be 38-45 ℃ for micro-reflux. Controlling the temperature at 38-45 ℃ and preserving the heat for 4-6 hours, and finishing the heat preservation. And (3) layering, collecting an organic layer, barreling and recovering a water layer, and then respectively adding a water and anhydrous sodium sulfite mixed solution to wash twice. And (4) layering, collecting an organic layer, and discharging a water layer into a wastewater system. Then washing with water once again, and transferring the collected organic layer to a desolventizing crystallization kettle. Standing, layering, collecting organic layer, and discharging water layer into waste water system. The layering temperature is controlled at 25-35 ℃. Stirring in a desolventizing crystallization kettle, controlling the internal temperature to be 40-50 ℃, distilling dichloromethane at normal pressure to 50 ℃, then distilling under reduced pressure to dryness, and putting toluene in a high-level tank into the desolventizing kettle. Stirring, heating to 60-65 deg.C with steam, dissolving, maintaining the temperature for half an hour, cooling to 0-5 deg.C, and maintaining the temperature for 1 hour for crystallization. And (4) after the heat preservation is finished, centrifuging until no continuous filtrate flows out from the liquid outlet. The molar ratio of the components is as follows: bromine: sodium bromate 1: 0.6: 0.3;
2. the finally obtained bromosartanbiphenyl has the molar yield of 91.5 percent and the HPLC purity of 98.8 percent.
Example 3
1. Directly adding water into a reaction kettle, stirring and adding 0.2 mol of sodium bromate, then adding dichloromethane into the reaction kettle from a metering tank, and adding 1 mol of sartanbiphenyl into the reaction kettle after adding. After the materials are dissolved, 0.5 mol of bromine is added, and the temperature is controlled to be 38-45 ℃ for micro-reflux. Controlling the temperature at 38-45 ℃ and preserving the heat for 4-6 hours, and finishing the heat preservation. And (3) layering, collecting an organic layer, barreling and recovering a water layer, and then respectively adding a water and anhydrous sodium sulfite mixed solution to wash twice. And (4) layering, collecting an organic layer, and discharging a water layer into a wastewater system. Then washing with water once again, and transferring the collected organic layer to a desolventizing crystallization kettle. Standing, layering, collecting organic layer, and discharging water layer into waste water system. The layering temperature is controlled at 25-35 ℃. Stirring in a desolventizing crystallization kettle, controlling the internal temperature to be 40-50 ℃, distilling dichloromethane at normal pressure to 50 ℃, then distilling under reduced pressure to dryness, and putting toluene in a high-level tank into the desolventizing kettle. Stirring, heating to 60-65 deg.C with steam, dissolving, maintaining the temperature for half an hour, cooling to 0-5 deg.C, and maintaining the temperature for 1 hour for crystallization. And (4) after the heat preservation is finished, centrifuging until no continuous filtrate flows out from the liquid outlet. The molar ratio of the components is as follows: bromine: sodium bromate 1: 0.5: 0.2;
2. the finally obtained bromosartanbiphenyl has the molar yield of 91.8 percent and the HPLC purity of 98.6 percent.
Example 4
1. Directly adding water into a reaction kettle, adding 0.19 mol of sodium bromate while stirring, adding dichloromethane into the reaction kettle from a metering tank, and adding 1 mol of sartanbiphenyl into the reaction kettle after adding dichloromethane. After the materials are dissolved, 0.51 mol of bromine is added, and the temperature is controlled to be 38-45 ℃ for micro-reflux. Controlling the temperature at 38-45 ℃ and preserving the heat for 4-6 hours, and finishing the heat preservation. And (3) layering, collecting an organic layer, barreling and recovering a water layer, and then respectively adding a water and anhydrous sodium sulfite mixed solution to wash twice. And (4) layering, collecting an organic layer, and discharging a water layer into a wastewater system. Then washing with water once again, and transferring the collected organic layer to a desolventizing crystallization kettle. Standing, layering, collecting organic layer, and discharging water layer into waste water system. The layering temperature is controlled at 25-35 ℃. Stirring in a desolventizing crystallization kettle, controlling the internal temperature to be 40-50 ℃, distilling dichloromethane at normal pressure to 50 ℃, then distilling under reduced pressure to dryness, and putting toluene in a high-level tank into the desolventizing kettle. Stirring, heating to 60-65 deg.C with steam, dissolving, maintaining the temperature for half an hour, cooling to 0-5 deg.C, and maintaining the temperature for 1 hour for crystallization. And (4) after the heat preservation is finished, centrifuging until no continuous filtrate flows out from the liquid outlet. The molar ratio of the components is as follows: bromine: sodium bromate 1: 0.51: 0.19;
2. the finally obtained bromosartanbiphenyl has the molar yield of 92.1 percent and the HPLC purity of 99.8 percent.
Comparative example 1
The procedure is as in example 4 except that the sodium bromate is replaced by cuprous bromide, a conventional catalyst.
The finally obtained bromosartanbiphenyl has a molar yield of 71.2% and an HPLC purity of 71.6%.
Through the above examples and comparative examples, it can be seen that the invention uses sodium bromate as a catalyst, sartanbiphenyl and bromine as raw materials, and further controls the reaction temperature and the material ratio, not only does not reduce the reaction yield, but also greatly improves the reaction yield; meanwhile, the side reaction participating in the reaction is less, and the obtained product has less impurities. The bromosartanbiphenyl with higher yield and purity is obtained, the conversion rate of the whole reaction can be effectively improved to 92.1 percent, and the process is stable.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
1. The preparation method of the bromo sartan biphenyl is characterized by comprising the following steps:
step 1, putting a catalyst sodium bromate into a reaction kettle, adding an organic solvent dichloromethane into the reaction kettle, adding sartanbiphenyl, and after materials are dissolved, adding bromine to perform bromination reaction; the molar ratio of the components is as follows: bromine: sodium bromate 1: 0.4-0.6: 0.1-0.3;
step 2, layering, collecting an organic layer, and transferring the collected organic layer to a desolventizing crystallization kettle;
step 3, removing the organic solvent dichloromethane in the organic layer;
and 4, adding toluene for crystallization to obtain bromosartanbiphenyl.
2. The method for preparing bromosartanbiphenyl according to claim 1, wherein the specific operation in step 1 is that water is directly added into a reaction kettle, sodium bromate is added while stirring, dichloromethane is added into the reaction kettle, sartanbiphenyl is added into the reaction kettle after the addition, and bromine is added after the materials are dissolved.
3. The method for preparing bromosartanbiphenyl according to claim 1, wherein in the step 1, the bromination reaction temperature is controlled to be 38-45 ℃, and then the temperature is controlled to be 38-45 ℃ and the temperature is kept for 4-6 hours.
4. The method for preparing bromosartanbiphenyl according to claim 1, wherein the specific operation in step 2 is that the layering temperature is controlled to be 25-35 ℃, the organic layer is collected, the water layer is barreled and recycled, the organic layer is washed twice by adding a mixed solution of water and anhydrous sodium sulfite, and then the organic layer is collected in layers; and then washing the mixture once by adding water, transferring the collected organic layer to a desolventizing crystallization kettle, standing for layering, and collecting the organic layer.
5. The method for preparing bromosartanbiphenyl according to claim 1, wherein the specific operation in the step 3 is to open and stir in a desolventizing and crystallizing kettle, control the temperature to be 40-50 ℃, firstly distill dichloromethane under normal pressure until the temperature is 50 ℃, and then distill under reduced pressure until the dichloromethane is dried.
6. The method for preparing bromosartanbiphenyl according to claim 1, wherein the specific operation in step 4 is to place toluene into the desolventizing crystallization kettle, stir, open steam to heat to 60-65 ℃, after the materials are dissolved out, keep the temperature for half an hour, cool to 0-5 ℃, keep the temperature for 1 hour for crystallization, centrifuge after the heat preservation is finished, and finally, no continuous filtrate flows out from the liquid outlet.
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| CN112441942B (en) * | 2020-12-24 | 2024-03-26 | 江苏新瑞药业有限公司 | Debromination method of sartan intermediate polybrominated substituent |
| CN114426501A (en) * | 2021-12-23 | 2022-05-03 | 山东艾孚特科技有限公司 | Preparation method of bromosartanbiphenyl based on aqueous phase reaction |
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| JP4537678B2 (en) * | 2003-09-04 | 2010-09-01 | 住友化学株式会社 | 2 '-(1H-tetrazol-5-yl) biphenyl-4-carbaldehyde crystal and method for producing the same |
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| US5750728A (en) * | 1992-10-29 | 1998-05-12 | Clariant Gmbh | Process for the preparation of aromatic bromomethyl compounds |
| US6111114A (en) * | 1997-04-11 | 2000-08-29 | Istituto Luso Farmaco D'italia S.P.A. | Process for the preparation of 4-bromomethyl diphenyl compounds |
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