CN114478313A - Method for synthesizing high-purity bromosartanbiphenyl - Google Patents
Method for synthesizing high-purity bromosartanbiphenyl Download PDFInfo
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- CN114478313A CN114478313A CN202111596320.4A CN202111596320A CN114478313A CN 114478313 A CN114478313 A CN 114478313A CN 202111596320 A CN202111596320 A CN 202111596320A CN 114478313 A CN114478313 A CN 114478313A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
Abstract
The application relates to the field of synthesis of drug intermediates, and particularly discloses a method for synthesizing high-purity bromosartanbiphenyl. The method for synthesizing the high-purity bromosartanbiphenyl comprises the following steps: dropwise adding bromine into dichloromethane solution of sartanbiphenyl, reacting for 2 hours after dropwise adding, sampling and detecting the content of dibromo compound, dropwise adding equimolar diethyl phosphite according to a detection result, reducing dibromo compound to monobromo for substitution, recovering dichloromethane after reaction, adding 50% (v/v) methanol aqueous solution, cooling and crystallizing, carrying out suction filtration, and drying to obtain the bromo sartanbiphenyl. The method has the advantages of easily controlled reaction conditions and simple operation, the prepared bromosartanbiphenyl has high yield and purity, the yield can reach more than 85 percent, the purity can reach more than 99.5 percent, the loss caused by subsequent refining is reduced, no water is consumed in the reaction process, no waste water is generated, water resources are saved, the environmental pollution is less, the method has the effects of energy conservation and environmental protection, and is suitable for industrial production.
Description
Technical Field
The application relates to the field of synthesis of drug intermediates, in particular to a method for synthesizing high-purity bromosartanbiphenyl.
Background
The sartan drug is an antihypertensive treatment drug, and has the characteristics of stable blood pressure reduction, good curative effect, long action time and good tolerance of patients. Bromo-sartan biphenyl is a basic raw material for synthesizing sartan drugs.
The conventional method for synthesizing bromosartanbiphenyl is to carry out bromination reaction on sartanbiphenyl and bromine in dichloromethane under illumination to prepare a crude product, the crude product needs to be refined for two to three times to prepare a qualified finished product with the purity meeting the requirement, and the loss in the refining process is large.
Disclosure of Invention
In order to solve the problem of large refining loss in the process of synthesizing bromosartan biphenyl, the application provides a method for synthesizing high-purity bromosartan biphenyl.
The method for synthesizing the high-purity bromosartanbiphenyl adopts the following technical scheme:
a method for synthesizing high-purity bromosartanbiphenyl comprises the following steps of refluxing at 30-40 ℃ under the illumination condition, reacting dichloromethane and sartanbiphenyl with bromine to generate monobromo and dibromo, and adding diethyl phosphite to reduce the dibromo to obtain the bromosartanbiphenyl, wherein the specific operation steps are as follows:
(1) mixing and stirring dichloromethane and sartanbiphenyl, starting illumination, and heating to 30-40 ℃ for reflux;
(2) dropwise adding bromine, and continuously stirring and reacting for a period of time;
(3) sampling to detect the content of the dibromide, adding equimolar diethyl phosphite according to the detection result, and continuously performing reflux reaction for 2 hours;
(4) vacuum distilling to recover dichloromethane;
(5) adding methanol water into the product, cooling, crystallizing, filtering, and drying to obtain bromosartanbiphenyl;
the chemical reaction equation is as follows:
by adopting the technical scheme, dichloromethane and sartanbiphenyl react with bromine to generate about 90% of monobromide and about 10% of dibromide, the dibromide is reduced by diethyl phosphite to obtain the monobromide, and then methanol water is utilized for crystallization, so that the yield of the monobromide is improved, the purity of the prepared brominated sartanbiphenyl can meet the production requirement, the subsequent refining is not needed, the loss caused by refining is reduced, water is not consumed in the synthesis process, no wastewater is generated, the production water is reduced, the environmental pollution caused by wastewater discharge is reduced, the environment is friendly, and the whole production process is more energy-saving.
Preferably, the mass ratio of sartanbiphenyl to dichloromethane is 1: 3-6.
By adopting the technical scheme, when the mass ratio of sartanbiphenyl to dichloromethane is 1:3-6, the excessive addition of dichloromethane is reduced while sartanbiphenyl is fully dissolved, the reagent waste is reduced, and the energy-saving effect is achieved.
Preferably, the molar ratio of sartanbiphenyl to bromine is 1: 1-1.1.
By adopting the technical scheme, when the molar ratio of sartanbiphenyl to bromine is 1:1-1.1, sartanbiphenyl and bromine can be fully reacted, the proportion of the obtained monobromide is large, the waste caused by excessive addition of bromine is reduced, the production cost is saved while the production requirement is met, and the energy-saving effect is better.
Preferably, the method further comprises a step (6), wherein the step (6) is as follows: the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
Through adopting above-mentioned technical scheme, carry out reuse to the dichloromethane that retrieves in step (4), improved the utilization ratio of dichloromethane, be favorable to reduction in production cost to a certain extent, have certain energy-conserving effect.
Preferably, the temperature in step (2) is 40 ℃.
By adopting the technical scheme, the prepared bromosartanbiphenyl has better purity and yield at the temperature.
Preferably, the hydrogen bromide gas produced by the reaction is absorbed by water.
By adopting the technical scheme, the hydrobromic acid is generated after the water absorbs the hydrogen bromide, and the hydrobromic acid can be used for synthesis and reaction of other compounds, so that the utilization of bromine is improved, the discharge of the hydrogen bromide is reduced, the influence of the discharge of the hydrogen bromide gas on the body health of surrounding workers is reduced, and the pollution to the surrounding environment and the harm to the surrounding environment are reduced.
In summary, the present application has the following beneficial effects:
the method has the advantages of easily controlled reaction conditions and simple operation, the prepared bromosartanbiphenyl has high yield and purity, the yield can reach more than 85 percent, the purity can reach more than 99.5 percent, the loss caused by subsequent refining is reduced, no water is consumed in the reaction process, no waste water is generated, water resources are saved, the environmental pollution is less, the method has the effects of energy conservation and environmental protection, and is suitable for industrial production.
Detailed Description
The present application will be described in further detail with reference to examples.
Methanol Water 50% (v/v) methanol water was used,% (v/v) being referred to as volume percent.
The raw materials used in the following embodiments may be those conventionally commercially available unless otherwise specified.
Examples
Example 1
A method for synthesizing high-purity bromosartan biphenyl comprises the following steps of refluxing under the illumination condition at 40 ℃, reacting dichloromethane, sartan biphenyl and bromine to generate monobromo and dibromo, and adding diethyl phosphite to reduce dibromo to obtain bromosartan biphenyl, wherein the chemical reaction equation is as follows:
the method comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 10kg of dichloromethane into a 20L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 40 ℃ for reflux, and controlling the temperature fluctuation to be 40 +/-2 ℃;
(2) dropwise adding 1.75kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours when the addition amount of the diethyl phosphite is 150 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.5kg of bromosartanbiphenyl, wherein the yield is 88.7%, and the HPLC purity is 99.73%;
(6) the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
The hydrogen bromide gas produced by the reaction is absorbed by water.
Example 2
The difference from example 1 is that the reaction temperature was set differently.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 10kg of dichloromethane into a 20L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 30 ℃ for reflux, and controlling the temperature fluctuation to be 30 +/-2 ℃;
(2) dropwise adding 1.75kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours, wherein the addition amount of the diethyl phosphite is 160 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.45kg of bromosartanbiphenyl, wherein the yield is 86.9%, and the HPLC purity is 99.65%;
(6) the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
Example 3
The difference from example 1 is that the reaction temperature was set differently.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 10kg of dichloromethane into a 20L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 35 ℃ for reflux, and controlling the temperature fluctuation to be 35 +/-2 ℃;
(2) dropwise adding 1.75kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours, wherein the addition amount of the diethyl phosphite is 160 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.48kg of bromosartanbiphenyl, wherein the yield is 87.9%, and the HPLC purity is 99.71%;
(6) the dichloromethane obtained in the step (4) is used as a reaction raw material in the step (1)
Example 4
The difference from example 1 is that the amount of raw materials is different.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 6kg of dichloromethane into a 20L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 40 ℃ for reflux, and controlling the temperature fluctuation to be 40 +/-2 ℃;
(2) dropwise adding 1.65kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours, wherein the addition amount of the diethyl phosphite is 160 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.44kg of bromosartanbiphenyl, wherein the yield is 86.5%, and the HPLC purity is 99.67%;
(6) the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
Example 5
The difference from example 1 is that the amount of raw materials is different.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 12kg of dichloromethane into a 50L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 40 ℃ for reflux, and controlling the temperature fluctuation to be 40 +/-2 ℃;
(2) dropwise adding 1.82kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours when the addition amount of the diethyl phosphite is 170 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.57kg of bromosartanbiphenyl, wherein the yield is 91.1%, and the HPLC purity is 99.75%;
(6) the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
Example 6
The difference from example 1 is that the amount of raw materials is different.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 3kg of sartanbiphenyl and 15kg of dichloromethane into a 50L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 40 ℃ for refluxing, and controlling the temperature fluctuation to be 40 +/-2 ℃;
(2) dropwise adding 1.75kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) sampling and detecting the content of the dibromide, dripping equimolar diethyl phosphite according to the detection result, keeping the temperature for 2 hours, wherein the addition amount of the diethyl phosphite is 230 g.
(4) Reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(5) adding 18kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 3.8kg of bromosartanbiphenyl, wherein the yield is 90%, and the HPLC purity is 99.78%;
(6) the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
Comparative example
Comparative example 1
The difference from example 1 is that the reaction was carried out without adding diethyl phosphite.
A method for synthesizing high-purity bromosartanbiphenyl comprises the following steps:
(1) adding 2kg of sartanbiphenyl and 10kg of dichloromethane into a 20L reaction bottle provided with a thermometer and a mechanical stirring device, then starting the stirring device to mix and stir the sartanbiphenyl and the dichloromethane, wherein the stirring speed is 120r/min, starting a 25W LED lamp to irradiate the reaction bottle, then heating the reaction bottle in a water bath to 40 ℃ for reflux, and controlling the temperature fluctuation to be 40 +/-2 ℃;
(2) dropwise adding 1.75kg of bromine, and continuously stirring for reaction for 2 hours after the dropwise adding is finished;
(3) reducing the pressure to-0.085 Mpa, and distilling and recovering dichloromethane;
(4) adding 15kg of 50% (v/v) methanol water into the product, cooling to 40 ℃, crystallizing, filtering, and drying to obtain 2.1kg of bromosartanbiphenyl, wherein the yield is 74%, and the HPLC purity is 99.24%;
(5) the methylene chloride obtained in step (3) was used as a reaction raw material in step (1).
Through comparison between the above examples and comparative examples, it can be seen that the dibromo compound is reduced by using diethyl phosphite, the doping of the dibromo compound can be reduced, and bromosartanbiphenyl with high yield and purity can be obtained without subsequent refining, so that the energy consumption required for refining is reduced, and the reaction conditions are easy to control, simple to operate and suitable for industrial production.
The specific embodiments are only for explaining the present application and are not limiting to the present application, and those skilled in the art can make modifications to the embodiments without inventive contribution as required after reading the present specification, but all the embodiments are protected by patent law within the scope of the claims of the present application.
Claims (6)
1. A method for synthesizing high-purity bromosartanbiphenyl is characterized by comprising the following steps: under the condition of illumination, refluxing at 30-40 ℃, reacting dichloromethane, sartanbiphenyl and bromine to generate monobromide and dibromide, and adding diethyl phosphite to reduce the dibromide to obtain bromosartanbiphenyl, wherein the specific operation steps are as follows:
(1) mixing and stirring dichloromethane and sartanbiphenyl, starting illumination, and heating to 30-40 ℃ for reflux;
(2) dropwise adding bromine, and continuously stirring and reacting for a period of time;
(3) sampling to detect the content of the dibromide, adding equimolar diethyl phosphite according to the detection result, and continuously performing reflux reaction for 2 hours;
(4) vacuum distilling to recover dichloromethane;
(5) adding methanol water into the product, cooling, crystallizing, filtering, and drying to obtain bromosartanbiphenyl;
the chemical reaction equation is as follows:
2. the method for synthesizing high-purity bromosartan biphenyl according to claim 1, wherein: the mass ratio of sartanbiphenyl to dichloromethane is 1: 3-6.
3. The method for synthesizing high-purity bromosartan biphenyl according to claim 1, wherein: the molar ratio of sartanbiphenyl to bromine is 1: 1-1.1.
4. The method for synthesizing high-purity bromosartan biphenyl according to claim 1, wherein: the method further comprises a step (6), wherein the step (6) is as follows: the methylene chloride obtained in step (4) was used as a reaction raw material in step (1).
5. The method for synthesizing high-purity bromosartan biphenyl according to claim 1, wherein: the temperature in the step (1) is 40 ℃.
6. The method for synthesizing high-purity bromosartan biphenyl according to claim 1, wherein: the hydrogen bromide gas produced by the reaction is absorbed by water.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200455A (en) * | 2007-09-29 | 2008-06-18 | 王俊华 | Method for preparing sartan drug main ring 5-(4'-formyl biphenyl-2-group)-1H-tetrazole treating hypertension |
| CN110183354A (en) * | 2019-06-06 | 2019-08-30 | 山东汉兴医药科技有限公司 | A method of 4 '-bromomethyl -2- cyanobiphenyls are prepared using the continuous bromination reaction of illumination |
| CN112441942A (en) * | 2020-12-24 | 2021-03-05 | 江苏新瑞药业有限公司 | Debromination method of sartans intermediate polybrominated substituent |
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2021
- 2021-12-24 CN CN202111596320.4A patent/CN114478313A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200455A (en) * | 2007-09-29 | 2008-06-18 | 王俊华 | Method for preparing sartan drug main ring 5-(4'-formyl biphenyl-2-group)-1H-tetrazole treating hypertension |
| CN110183354A (en) * | 2019-06-06 | 2019-08-30 | 山东汉兴医药科技有限公司 | A method of 4 '-bromomethyl -2- cyanobiphenyls are prepared using the continuous bromination reaction of illumination |
| CN112441942A (en) * | 2020-12-24 | 2021-03-05 | 江苏新瑞药业有限公司 | Debromination method of sartans intermediate polybrominated substituent |
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