WO2022126388A1

WO2022126388A1 - Method for synthesizing 5-bromo-1h-3-amino-1,2,4-triazole

Info

Publication number: WO2022126388A1
Application number: PCT/CN2020/136575
Authority: WO
Inventors: 叶伟平; 费安杰; 周章涛; 谢阳银; 习林刚; 向卫
Original assignee: 深圳市华先医药科技有限公司
Priority date: 2020-12-15
Filing date: 2020-12-15
Publication date: 2022-06-23

Abstract

A method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole. The method has a route as (aa), in which a mixture of sodium bromate and sodium bromide is employed to serve as a brominated reagent; and a reaction route as (bb). The synthesis of 5-bromo-1H-3-amino-1,2,4-triazole per the method has a novel process route and a total molar yield of greater than 50%. The reaction is highly safe and easy to industrialize, and has a high yield, inexpensive costs, and relatively mild reaction conditions.

Description

A kind of method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole

technical field

The invention belongs to the field of organic chemical synthesis, in particular to a new method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole.

Background technique

5-Bromo-1H-3-amino-1,2,4-triazole (structure shown below) is widely used as electroluminescent material, KDM5 inhibitor, PDE2 inhibitor, PIK3/AKt inhibitor and anti-tumor key intermediates of medicines.

At present, only patent WO2017188596 has reported the synthesis method of 5-bromo-1H-3-amino-1,2,4-triazole, and the synthesis route is shown in the following figure (for the specific operation, see Comparative Example 1). There are a lot of deficiencies in this route, resulting in difficult industrialization and high production costs. The main defects include high safety risk of diazotization reaction, low production capacity (60kg/5000L), low yield (25.5%), and extremely large amount of waste water (a large amount of high-salt waste water is formed by the neutralization of strong acid and alkali).

In summary, the development of pharmaceutical, materials and other industries urgently needs to develop a low-cost, industrializable process route for the synthesis of key intermediates 5-bromo-1H-3-amino-1,2,4-triazine azoles.

SUMMARY OF THE INVENTION

Aiming at the serious deficiency of the process route involved in the patent document WO2017188596, the present invention has developed a process route suitable for industrial production, wherein the raw material 3-amino-1,2,4-triazole is cheaper, and the reaction does not require an organic solvent , the yield is greatly improved, and the production cost is significantly reduced.

The inventor of the present invention needs to prepare 5-bromo-1H-3-amino-1,2,4-triazole in the research and development process. In the early stage of research and development, the inventor tried to repeat the synthetic route disclosed in the patent document WO2017188596, but encountered many difficulties.

First of all, this route includes the step of diazotization reaction, which makes this route have potential safety risks, especially when the scale of the reaction is expanded, the safety risks are even more uncontrollable.

Secondly, this synthetic route has many side reactions, and when the scale of the reaction is enlarged, the reproducibility of the reaction becomes poor. The inventor used 0.6Kg feed amount, under the same experimental conditions, the highest yield was only 25.5%, and the lowest yield was only 12%.

Under the circumstance that the synthetic route disclosed in the patent document WO2017188596 cannot meet the requirements, the inventors of the present invention have tried various other routes. These routes do not include the step of diazotization reaction, the safety problem has been solved, and the reproducibility of the reaction is also good. However, there are many reaction steps, complicated operation and high cost, which are still unsatisfactory. Therefore, the inventors considered returning to the synthetic route disclosed in the patent document WO2017188596, and replaced the diazotization reaction step without extending the reaction route. Under this circumstance, the inventors of the present invention thought of replacing the reaction starting material in the route disclosed in the patent document WO2017188596 with 3-amino-1,2,4-triazole, so that the product can be obtained through a one-step bromination reaction 5-Bromo-1H-3-amino-1,2,4-triazole. The reaction route is as follows:

The above reaction can be carried out smoothly in an aqueous sodium hydroxide solution, with low safety risk and low cost. However, higher reaction temperature is required, large-scale production is likely to cause leakage of bromine, and the yield is only about 15%. So continue to make improvements, try to change the bromination reagent from bromine to N-bromosuccinimide (NBS), the reaction formula is as follows:

The above reaction was carried out in trifluoroacetic acid and acetonitrile (ACN), but the yield of this route is still low. In this process, the inventors of the present invention realized that the conversion rate of the above-mentioned synthetic route is low, and the reason may be that the concentration of the bromination reagent is uneven, and the local concentration is too high, which leads to an increase in side reactions and a decrease in the conversion rate of the bromination reaction. Therefore, the inventor tried to add bromine reagents in batches and slowly during the reaction process (bromine was added dropwise in liquid, and the drop was completed in about 10-15 hours; NBS was solid, and was added in batches many times), and the conversion rate was improved to a certain extent. , but still unsatisfactory. This phenomenon caught the inventor's attention. The slow addition of the brominated reagent in batches can improve the conversion rate, indicating that the too fast addition of the brominated reagent is one of the main factors leading to the low conversion rate. But adding bromine to the reaction system dropwise is the limit of slow addition of the brominating reagent. However, every drop of bromine droplet dropped into the reaction system will create a high-concentration bromine area around the bromine droplet, resulting in the occurrence of side reactions. Based on this knowledge, the inventors considered the use of brominated reagents that release slow-release bromine sources. In the specific embodiment, the inventors tried to use sodium bromate and sodium bromide as bromination reagents, and sodium bromate and sodium bromide reacted under acidic conditions to produce bromine, so the release rate of bromine was slow enough, and the When it comes out, it is uniformly dispersed into the reaction system at the molecular level, and the reaction yield has indeed been greatly improved. Both examples in the detailed description section achieved overall yields above 50%, and the conversions were also sufficiently high. This yield is more than twice the yield of the previous route disclosed in the patent document WO2017188596, and there is no safety risk brought by the diazotization reaction, and the raw materials are cheap and the synthesis cost is low.

As described above, the inventors of the present invention have found that in the above-mentioned route proposed by the present invention, as long as the brominating reagent can release bromine sufficiently uniformly and slowly enough in the reaction system, the yield of the reaction can be significantly improved. Therefore, the slow-release bromine reagent is not limited to the few examples presented in the Examples section, and it can be expected that any system that can slowly release bromine through a chemical reaction can achieve similar effects. For example, the mixture of potassium bromate and potassium bromide, these systems can slowly release bromine under acidic conditions, so they can be used as the bromination reagent of the present invention.

An embodiment of the present invention provides a method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole, and the method route is as follows:

According to one embodiment of the present invention, for example, the brominating agent is bromine, or N-bromosuccinimide (NBS), or a slow-release brominating agent;

Preferably, when the bromination reagent is bromine, the reaction scheme is as follows:

Preferably, when the bromination reagent is N-bromosuccinimide (NBS), the reaction scheme is as follows:

According to one embodiment of the present invention, for example, the slow-release brominating agent comprises a mixture of sodium bromate and sodium bromide, or the slow-release brominating agent comprises a mixture of potassium bromate and potassium bromide.

According to an embodiment of the present invention, for example, the reaction temperature is controlled at 40°C-70°C, preferably 55°C-60°C. The purpose of controlling the temperature is, on the one hand, to control the generation speed of bromine;

According to an embodiment of the present invention, for example, the solvent includes water or acetonitrile;

Preferably, the solvent includes water. The reasons for choosing water as the solvent are: on the one hand, the cost of water is low; on the other hand, the specific heat capacity of water is high, which is beneficial to control the temperature of the system.

According to an embodiment of the present invention, for example, the slow-release bromination reagent includes a mixture of sodium bromate and sodium bromide, and the reaction scheme is as follows:

According to an embodiment of the present invention, for example, the molar ratio of the sodium bromate and the sodium bromide is 1:3-8, preferably 1:4-6, more preferably 1:5;

Preferably, the raw material 3-amino-1,2,4-triazole is 1 equivalent, the amount of sodium bromate is 0.5-0.8 equivalent, and the amount of sodium bromide is 2.5-4.0 equivalent;

Further preferably, with raw material 3-amino-1,2,4-triazole as 1 equivalent, the sodium bromate consumption is 0.6 equivalent, and the consumption of sodium bromide is 3.0 equivalent;

Preferably, the raw material 3-amino-1,2,4-triazole is 1 equivalent, and the amount of concentrated sulfuric acid is 2.5-3.5 equivalents, preferably 3.0 equivalents.

According to one embodiment of the present invention, for example, the method includes:

Water, sulfuric acid, 3-amino-1,2,4-triazole and sodium bromide were added to the reactor, and the reaction system was heated to 55°C-60°C;

Dissolve sodium bromate in water, add dropwise to the reactor under temperature control at 55°C-60°C, keep the reaction for a period of time after the dropwise addition, cool down to 20°C-30°C after the reaction, and quench the reaction;

Adjust the pH of the system to weak acidity, then filter, extract and purify to obtain a white solid product.

According to an embodiment of the present invention, for example, the holding time for the reaction is: holding the reaction for 10-40 hours, preferably 15-25 hours;

Preferably, the quenching of the reaction is: quenching the reaction with saturated sodium sulfite;

Preferably, adjusting the pH of the system to a weak acid is as follows: adjusting the pH to 5.5-6.5 with 20% sodium hydroxide solution;

Preferably, the extraction and purification include: adding an extractant to the filtrate for extraction, and concentrating at 55°C-60°C until there is no fraction; adding ethyl acetate to dissolve, filtering, concentrating the ethyl acetate until there is no fraction, adding 1,4- Dioxane was heated to 80°C for beating, cooled to 20°C-30°C for filtration, and the filter cake was vacuum-dried at 50°C-60°C for 12 hours to obtain a white solid.

According to an embodiment of the present invention, for example, the extractant includes n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, and more preferably 2-methyltetrahydrofuran.

The excellent technical effects brought by the present invention include: using the synthesis method of the present invention to synthesize 5-bromo-1H-3-amino-1,2,4-triazole, the process route is novel, and the total molar yield is greater than 50%. The reaction has high safety, easy industrialization, high yield, low cost and relatively mild reaction conditions.

Detailed ways

The preferred embodiments of the present invention are described in detail below, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the protection scope of the present invention can be more clearly defined.

Example 1 Synthesis of 5-bromo-1H-3-amino-1,2,4-triazole

Water (30L), sulfuric acid (15kg), 3-amino-1,2,4-triazole (5kg) and sodium bromide (15kg) were added to the reaction kettle, and the system was heated to 55°C-60°C. Dissolve sodium bromate (4.5kg) in water (15L), add dropwise to the reaction kettle at a temperature of 55°C-60°C, complete the dropwise addition, keep the reaction for 20h, and finish the reaction, cool down to 20°C-30°C, use saturated Quenched with sodium sulfite, adjusted to pH 5.5-6.5 with 20% sodium hydroxide solution, and filtered. Add n-butanol to the filtrate for extraction three times, and concentrate at 55℃-60℃ until there is no fraction. Add ethyl acetate to dissolve, filter through silica gel, and concentrate ethyl acetate until there is no fraction. 1,4-dioxane was added, heated to 80°C for beating, cooled to 20°C-30°C for filtration, and the filter cake was vacuum-dried at 50°C-60°C for 12 hours to obtain 5.4kg of white solid with a purity of 97.28% and a yield of 55.8%.

Example 2 Synthesis of 5-bromo-1H-3-amino-1,2,4-triazole

Acetonitrile (30L), sulfuric acid (18kg), 3-amino-1,2,4-triazole (5kg) and sodium bromide (21kg) were added to the reaction kettle, and the system was heated to 55°C-60°C. Dissolve sodium bromate (6.2kg) in water (15L), add dropwise to the reaction kettle with temperature control at 55°C-60°C, complete the dropwise addition, keep the reaction for 20h, the reaction is over, cool down to 20°C-30°C, add saturated sodium sulfite Quenched, concentrated acetonitrile to no fractions at 50°C-55°C, adjusted pH to 5.5-6.5 with 20% sodium hydroxide solution, and filtered. The filtrate was added with 2-methyltetrahydrofuran, extracted three times, dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated to no fractions with 2-methyltetrahydrofuran. 1,4-dioxane was added and heated to 80°C for beating, cooled to 20°C-30°C for filtration, and vacuum dried at 50°C-60°C for 12 hours to obtain 4.99kg of white solid with a purity of 97.36% and a yield of 51.5%.

Example 3 Synthesis of 5-bromo-1H-3-amino-1,2,4-triazole

Water (20 L) was added to the reaction flask, stirring was started, sodium hydroxide (1.08 kg) was added, 3,5-diamino-1,2,4-triazole (3 kg) was added, and the mixture was stirred for half an hour. The temperature was raised to 95°C-100°C, and bromine (11.4kg) was added dropwise, and the dropping time was controlled to be 10h-15h, and the temperature was controlled to 95°C-100°C. After dripping, keep the temperature for 5h-6h, and the reaction ends. Cool to 20°C-30°C, quench with aqueous sodium sulfite solution, adjust pH to 6, concentrate off half of the water, extract with tetrahydrofuran (100L), dry the filtrate with anhydrous sodium sulfate, and concentrate to no fractions. Dioxane (2.0 vol.) was added and the temperature was raised to 80°C for 1 hour, then cooled to 20°C-30°C for filtration. The filter cake was vacuum-dried at 50°C-60°C for 8 hours to obtain 901 g of white solid with a purity of 94.64% and a yield of 15.5%. Compared with the route disclosed in the patent document WO2017188596 (see Comparative Example 1), although the method of Example 3 has a decrease in purity and yield, the cost of raw materials is lower, and the potential safety hazard is eliminated due to avoiding the diazotization reaction, It also has certain practical value.

Example 4 Synthesis of 5-bromo-1H-3-amino-1,2,4-triazole

Acetonitrile (1 L) was added to the reaction flask, stirring was started, trifluoroacetic acid (100 mL) was added, 3,5-diamino-1,2,4-triazole (100 g) was added, and the mixture was stirred for half an hour. 10 times, once every half an hour, add NBS (423 g), and control the temperature to 25°C-35°C. After the addition was completed, the temperature was raised to 60° C., and the temperature was maintained for 15h-16h. The reaction solution was sampled, and HPLC detected that the product had a low purity (15.17%). As can be seen from the results of Example 4, even if the brominated reagent is added in batches, the reaction yield is still not high enough.

Comparative Example 1 Synthesis of 5-bromo-1H-3-amino-1,2,4-triazole

5-Bromo-1H-3-amino-1,2,4-triazole was synthesized according to the route disclosed in the patent document WO2017188596. A 48% HBr aqueous solution (9.0 L) was added to the reaction flask, stirring was started, and 3,5-diamino-1,2,4-triazole (600 g) was added and stirred for half an hour. The temperature was lowered to 20°C-30°C, an aqueous solution of sodium nitrite (501.3 g) was added dropwise, and the temperature was controlled at 20°C-30°C. After the dropwise addition, the temperature was kept for 1 hour, the temperature was raised to 40° C. and stirred for 1 hour, and the temperature was raised to 60° C. and stirred for 1 hour, and the reaction was completed. Cool to below 0°C, adjust pH to 6.5-7.5 with 50wt% sodium hydroxide solution, extract with tetrahydrofuran, concentrate, dry, filter, add ethyl acetate (20vol.) and stir to dissolve, filter ethyl acetate (10vol. ) to elute, concentrate ethyl acetate until there is no fraction, add dioxane (2.0 vol.), raise the temperature to 80°C for 1 hour, and then cool to 20°C-30°C for filtration. The filter cake was vacuum-dried at 50°C-60°C for 8 hours to obtain 245 g of white solid with a purity of 97.02% and a yield of 25.5%. Compared with Example 1 and Example 2, the yield of the product obtained by the route disclosed in the patent document WO2017188596 is significantly reduced.

Claims

The method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole is characterized in that the method route is as follows:
The method according to claim 1, wherein the brominated reagent is bromine, or N-bromosuccinimide (NBS), or a sustained-release brominated reagent;

Preferably, when the bromination reagent is bromine, the reaction scheme is as follows:

Preferably, when the bromination reagent is N-bromosuccinimide (NBS), the reaction scheme is as follows:
The method according to claim 1, wherein the slow-release brominated reagent comprises a mixture of sodium bromate and sodium bromide, or the slow-release brominated reagent comprises a mixture of potassium bromate and potassium bromide.
The method according to claim 3, wherein the reaction temperature is controlled at 40°C-70°C, preferably 55°C-60°C.
The method according to claim 3 or 4, wherein the solvent comprises water or acetonitrile;

Preferably, the solvent includes water.
method according to claim 5, is characterized in that, described slow-release bromination reagent comprises the mixture of sodium bromate and sodium bromide, and reaction scheme is as follows:
The method according to claim 6, wherein the mol ratio of the sodium bromate and the sodium bromide is 1:3-8, preferably 1:4-6, more preferably 1:5;

Preferably, the raw material 3-amino-1,2,4-triazole is 1 equivalent, the amount of sodium bromate is 0.5-0.8 equivalent, and the amount of sodium bromide is 2.5-4.0 equivalent;

Further preferably, the raw material 3-amino-1,2,4-triazole is 1 equivalent, the consumption of sodium bromate is 0.6 equivalent, and the consumption of sodium bromide is 3.0 equivalent;

Preferably, the raw material 3-amino-1,2,4-triazole is 1 equivalent, and the amount of concentrated sulfuric acid is 2.5-3.5 equivalents, preferably 3.0 equivalents.
The method of claim 6, wherein the method comprises:

Water, sulfuric acid, 3-amino-1,2,4-triazole and sodium bromide were added to the reactor, and the reaction system was heated to 55°C-60°C;

Dissolve sodium bromate in water, add dropwise to the reactor under temperature control at 55°C-60°C, keep the reaction for a period of time after the dropwise addition, cool down to 20°C-30°C after the reaction, and quench the reaction;

Adjust the pH of the system to weak acidity, then filter, extract and purify to obtain a white solid product.
method according to claim 8, is characterized in that, described heat preservation reaction period of time is: heat preservation reaction 10-40 hours, preferably 15-25 hours;

Preferably, the quenching of the reaction is: quenching the reaction with saturated sodium sulfite;

Preferably, adjusting the pH of the system to a weak acid is as follows: adjusting the pH to 5.5-6.5 with 20% sodium hydroxide solution;

Preferably, the extraction and purification include: adding an extractant to the filtrate for extraction, and concentrating at 55°C-60°C until there is no fraction; adding ethyl acetate to dissolve, filtering, concentrating the ethyl acetate until there is no fraction, adding 1,4- Dioxane was heated to 80°C for beating, cooled to 20°C-30°C for filtration, and the filter cake was vacuum-dried at 50°C-60°C for 12 hours to obtain a white solid.
The method according to claim 9, wherein the extractant comprises n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, and more preferably 2-methyltetrahydrofuran.