CN115806564A - Method for preparing deuterated phenylboronic acid by using organic lithium method - Google Patents

Abstract

The invention provides a preparation method for efficiently synthesizing deuterated phenylboronic acid with high conversion rate by using an organic lithium method. The preparation method can not only greatly increase the conversion rate of high-priced deuterated bromobenzene, shorten the reaction time, and improve the purity, but also The deuterium in the deuterated phenylboronic acid does not lose deuterium hydrogen to the reaction system during the preparation reaction, and the deuterated rate of the product can be basically kept the same as that of the raw material deuterated bromobenzene.

Description

A kind of method using organolithium method to prepare deuterated phenylboronic acid

technical field

The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of deuterated phenylboronic acid.

Background technique

Deuterated phenylboronic acid is an important intermediate in organic synthesis, which is often used in Suzuki coupling reaction, catalyst for phthalamination reaction, Diels-Alder reaction and other fields. Deuterated phenylboronic acid has good stability and high reactivity, and has very important applications in the synthesis of drugs, the synthesis of OLED materials, and drug controlled release systems. The structure of deuterated phenylboronic acid is as follows:

Deuterated chemicals refer to a class of chemicals in which the hydrogen (H) atom in the compound molecule is replaced by its isotope deuterium (D) atom, and has unique physical and chemical properties. Deuterated drugs can improve drug safety and have pharmacokinetic advantages (prolonged drug efficacy, etc.). The deuterated OLED material can effectively improve the luminous efficiency of the device and increase the stability and life of the device.

Although there is a synthetic method for phenylboronic acid in the prior art, there is no discussion on an efficient synthetic method suitable for deuterated phenylboronic acid. For example, the common phenylboronic acid process preparation method at this stage is mostly the Grignard reagent method, but the Grignard reagent method needs to use a large amount of magnesium chips, there are many by-products that are difficult to separate and purify, and the yield of the product (bromobenzene utilization rate ) is lower, for example, when using the Grignard reagent method, the yield is about 50-70%. But as far as deuterated phenylboronic acid is concerned, because the price of deuterated bromobenzene as a raw material is relatively high, therefore, the above-mentioned Grignard reagent whose utilization rate of deuterated bromobenzene is not high is not suitable for the industrial manufacture of deuterated phenylboronic acid.

Contents of the invention

The inventors of the present invention explored a new method for preparing deuterated phenylboronic acid by using the organolithium reagent method. This method can greatly increase the yield of deuterated phenylboronic acid and simplify the purification process, so it is suitable for the industrial production of deuterated phenylboronic acid.

This patent adopts organolithium reagent method to prepare deuterated phenylboronic acid, by adding the organolithium reagent dropwise to the solution containing deuterated bromobenzene, then adding esterification agent to the above solution to continue the reaction, and then acidifying and purifying to generate deuterated benzene boric acid products. details as follows:

1. A method for preparing deuterated phenylboronic acid, which uses organolithium reagent method to prepare deuterated phenylboronic acid.

2. the method described in item 1, described organolithium reagent method comprises the following steps:

Deuterobromobenzene is reacted with organolithium reagents to synthesize deuterated phenyllithium, then an esterifying agent is added to the above solution to continue the reaction, and acid is added to it for acidification to generate deuterated phenylboronic acid.

3. The method according to any one of Items 1 to 2, wherein the reaction for synthesizing deuterated phenyl lithium by reacting deuterated bromobenzene with an organolithium reagent is carried out at -40°C to -80°C, preferably at -40°C to -80°C Performed at -60°C.

4. The method according to any one of items 1 to 3, wherein the reaction time for the reaction of deuterated bromobenzene and organolithium reagent to synthesize deuterated phenyllithium is 0.1 to 10 hours, more preferably 0.3 to 6 hours. hours, more preferably 2.5 to 5.5 hours, most preferably 5 hours.

5. The method according to any one of items 1 to 4, wherein the reaction time for adding an esterifying agent to the above-mentioned solution to continue the reaction is 0.1 to 10 hours, more preferably 0.3 to 5 hours, more preferably 2.5 hours ~4.5 hours, most preferably 4 hours

6. The method according to any one of items 1 to 5, wherein the organolithium reagent is n-butyllithium.

7. The method according to any one of items 1 to 6, wherein the deuterated bromobenzene is dissolved in a solvent containing 2-methyltetrahydrofuran.

8. The method according to any one of items 1 to 7, wherein the esterification agent is triisopropyl borate.

9. The method according to any one of items 1 to 8, wherein the ratio of the amount of deuterated bromobenzene to the organolithium reagent is 1:1-1.5, preferably 1:1.1

10. The method according to any one of items 1 to 9, wherein the acid is a hydrochloric acid solution.

11. The method according to any one of Items 1 to 10, wherein the hydrochloric acid solution is a 1% to 20% hydrochloric acid solution, preferably a 10% hydrochloric acid solution.

12. The method according to any one of items 1 to 11, further comprising the following steps:

Purification procedure for purifying deuterated phenylboronic acid.

13. The method according to any one of items 1 to 12, wherein the purification step is carried out as follows:

The reactants were separated and separated, the organic phase was collected, the solvent was evaporated by distillation under reduced pressure, and purified by recrystallization.

The method according to any one of Items 1 to 13, wherein the temperature for evaporating the solvent by distillation under reduced pressure is controlled to be 60°C or lower, more preferably 55°C or lower.

Detailed ways

Various aspects of the invention are described in detail below. It should be noted that the following descriptions are not limiting, and those skilled in the art can make arbitrary modifications and replacements according to the following descriptions based on common technical knowledge in the field without significantly hindering the technical effect of the present invention.

This patent adopts organolithium reagent method to prepare deuterated phenylboronic acid. The organolithium reagent is added dropwise into the solution containing deuterated bromobenzene, then an esterifying agent is added to the above solution to continue the reaction, and then acid is added to acidify and purify to generate deuterated boronic acid. Phenylboronic acid products. Specifically, the following steps can be followed:

1. First, add the deuterated bromobenzene solution to a container such as a three-necked flask, lower the temperature of the material to the reaction temperature of -40°C to -80°C, slowly add the organic lithium reagent to it, and keep it warm for the reaction after the addition is completed. Thereby deuterated phenyllithium is obtained.

In the method of the present invention, the organolithium reagent has the meaning understood by those skilled in the art. That is, a class of organometallic compounds in which carbon atoms and lithium ions are directly bonded. Specifically, the organolithium reagent may be n-butyllithium, tert-butyllithium, lithium diisopropylamide, or the like. From the viewpoint of reaction stability and ease of controllability, n-butyllithium is preferred.

As for the solvent of the solution containing deuterated bromobenzene, it can be arbitrarily selected according to needs, specifically, the solvent can be: 2-methyltetrahydrofuran, tetrahydrofuran. From the viewpoint of the freezing point of the material and the reaction temperature, 2-methyltetrahydrofuran is preferred.

As far as the ratio of organolithium reagent and deuterated bromobenzene is concerned, as long as the reaction can proceed, there is no particular limitation. From the viewpoint of suppressing side reactions, it is preferably 1:1-1.5, more preferably 1:1-1.2, most preferably 1 :1-1.1.

The reaction temperature is preferably -40°C to -80°C, more preferably -60°C to -70°C, and most preferably -60°C from the viewpoint of maintaining the activity of deuterated phenyllithium and suppressing side reactions. There is no particular limitation on the method of controlling the reaction temperature, and a control method known to those skilled in the art can be used, for example, a liquid nitrogen-ethanol reaction bath can be used to lower the reaction temperature to the reaction temperature.

As for the reaction time for the reaction of deuterated bromobenzene and organolithium reagent to synthesize deuterated phenyllithium, as long as the reaction is fully carried out, there is no special limitation, specifically, it can be 0.1 to 10 hours, more preferably 0.1 to 10 hours. 0.3 to 6 hours, more preferably 2.5 to 5.5 hours, most preferably 5 hours.

It should be noted that the reaction time for the reaction of deuterated bromobenzene and organolithium reagent to synthesize deuterated phenyllithium includes the time of adding organolithium reagent to deuterobromobenzene and keeping the temperature between the two after adding the organolithium reagent. response time.

It is preferred to control the addition speed of the organolithium reagent. The control method is not particularly limited. For example, methods such as constant pressure drop can be used. As far as the addition speed is concerned, it can be adjusted according to conditions such as the reaction scale. For example, the dropping time can be 0.1 ~10 hours, more preferably 2-6 hours, even more preferably 3-5 hours, most preferably 4 hours.

There is no particular limitation on the time for carrying out the reaction while maintaining the temperature, as long as the reaction is sufficiently advanced. Specifically, the time for heat preservation to perform the reaction may be 0 to 10 hours, more preferably 0.3 to 5 hours, even more preferably 0.5 to 1.5 hours, and most preferably 1 hour.

2. Next, add an esterifying agent to the above reaction solution, raise the temperature to room temperature for reaction, and obtain deuterated phenyl borate.

As far as the borate esterification agent is concerned, the borate esterification agent commonly used in this field can be used, such as: trimethyl borate, triethyl borate, tributyl borate, triisopropyl borate, etc., from reducing side effects From the viewpoint of reaction and improvement of the utilization rate of deuterated bromobenzene, it is preferable to use triisopropyl borate.

In terms of the reaction time for the deuterated phenyllithium to react with a borate esterification agent to obtain a deuterated phenyl borate, as long as the reaction is fully carried out, there is no special limitation. Specifically, the reaction time can be 0.1 to 10 hours, more preferably 0.3 to 5 hours, still more preferably 2 to 5 hours, most preferably 4 hours. The method of raising the temperature to room temperature is not particularly limited, and methods known to those skilled in the art can be used, for example, natural heating can be used. It should be noted that the reaction time referred to here starts to be calculated from the time when the boric acid ester esterification agent is added.

Preferably, the adding speed of the esterifying agent is controlled, and the control method is not particularly limited. For example, methods such as constant pressure drop can be used. As for the adding speed, it can be adjusted according to conditions such as the scale of the reaction. For example, the dropping time can be 0.1- 10 hours, more preferably 0.5 to 5 hours, still more preferably 2 to 4 hours, most preferably 3 hours. It should be noted that the time for adding the esterifying agent is also included in the reaction time for reacting the deuterated phenyllithium with the borate esterifying agent to obtain the deuterated phenyl borate.

3. Finally, add an appropriate amount of acid to the reaction solution to acidify the reaction solution to about PH=2 to obtain the product deuterated phenylboronic acid.

As far as the type of acid required for acidification is concerned, as long as the deuterated phenylboronic acid ester can be acidified into deuterated phenylboronic acid, there is no special limitation, and it can be commonly used acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc. From the viewpoint of purification, hydrochloric acid is preferably used. The concentration of hydrochloric acid is not particularly limited, for example, it may be 1% to 20%, preferably 10% dilute hydrochloric acid solution. As far as the amount added is concerned, there is no particular limitation as long as the deuterated phenylboronic acid ester can be acidified into deuterated phenylboronic acid, for example, it can be 2-4 times the molar amount of deuterated phenylboronic acid ester, from the perspective of easy purification The angle of , preferably 2 times the molar amount.

The method of the present invention may further comprise the step of purifying deuterated phenylboronic acid.

The method for purifying deuterated phenylboronic acid is not particularly limited, and any method conventionally used by those skilled in the art can be used, for example, it can be carried out as follows:

The reactants were separated and separated, the organic phase was collected, and finally the solvent was removed, and purified by recrystallization.

The method for removing the solvent is not particularly limited, and for example, distillation can be used, preferably vacuum distillation. With regard to the temperature of distillation and vacuum distillation, the inventors of the present invention have found that if deuterated phenylboronic acid dissolved in a solvent containing 2-methyltetrahydrofuran is distilled at a temperature above 60° C., deuterium hydrogen exchange will occur, resulting in The rate of deuteration decreases, so the temperature of distillation and vacuum distillation is preferably 60°C or lower, more preferably 55°C or lower.

The present invention provides a method for efficiently synthesizing deuterated phenylboronic acid with high conversion rate by applying the organolithium method to the preparation of deuterated phenylboronic acid and optimizing it. The preparation method can not only make high-priced deuterium The conversion rate of bromobenzene is greatly improved, the reaction time is shortened, and the deuterium in deuterated phenylboronic acid can be lost to the reaction system without deuterium-hydrogen exchange in the process of preparation reaction. Bromobenzene can remain essentially the same.

Example

The present invention will be further described by the following examples, but it should be noted that the following examples and comparative examples are only used to illustrate the technical effects of the present invention, and do not have any limiting effect on the present invention.

Example 1

Preparation of deuterated phenylboronic acid: In a 250mL three-necked flask, add 60mL of 2-methyltetrahydrofuran and 10 grams of deuterated bromobenzene (deuterated rate is 98%), and use a liquid nitrogen-ethanol reaction bath to cool the material temperature To -60 ℃, slowly add 20 grams of n-butyllithium, the time of dropwise addition is 4 hours, the ratio of the mass of deuterated bromobenzene to n-butyllithium is 1:1.1, keep warm for one hour after the dropwise addition is completed, and add to 30 grams of triisopropyl borate was added to the above reaction solution, and the temperature was raised to room temperature within 4 hours. Add 10 mL of 10% dilute hydrochloric acid solution to the above solution for acidification, let stand to separate layers, collect the organic phase, evaporate the organic solvent by distillation under reduced pressure, recrystallize and purify to obtain 6.5 grams of deuterated phenylboronic acid. The product deuterated phenylboronic acid is analyzed by liquid phase, the purity can reach 98%, the deuterated rate is 98%, and the yield is 85%. The raw material deuterated bromobenzene was produced by the company itself, and the rest of the reagents were purchased from Anaiji.

It should be noted that the productive rate is calculated by the following calculation formula: productive rate=the amount of substance of deuterated phenylboronic acid/deuterated bromobenzene in the product.

In this example, the raw material deuterated bromobenzene (deuterated rate 98.5%, purity 99%) was prepared by the laboratory itself, and 2-methyltetrahydrofuran, magnesium strips, triisopropyl borate, and hydrochloric acid were all purchased from Anai lucky.

Comparative example 1

Using the same starting material deuterated bromobenzene, deuterated phenylboronic acid was prepared using the Grignard reagent method.

The specific operation is as follows:

In a 250mL three-necked flask, add 60mL of anhydrous 2-methyltetrahydrofuran, 12 grams of magnesium bars, 1 gram of deuterated bromobenzene (98.5% deuteration rate), add iodine particles to initiate the reaction, and after the reaction is initiated, the reaction temperature is raised to As high as 75°C, then use constant pressure drops to add 26 grams of deuterated bromobenzene and 30 mL of 2-methyltetrahydrofuran mixed solution dropwise to the above solution, control the drop rate, the drop time is about 2 hours, and the mixed liquid is added dropwise After completion, continue to incubate for 1 hour, return to room temperature, and obtain the Grignard reagent reaction solution.

In a 500mL three-necked flask, add 60mL of 2-methyltetrahydrofuran and 60g of triisopropyl borate, use a liquid nitrogen-ethanol reaction bath, lower the temperature of the material to -60°C, and add the above-mentioned The prepared Grignard reagent reaction solution was added dropwise for 3 hours. After the dropwise addition was completed, it was incubated for half an hour and then naturally warmed up to room temperature. Add 10 mL of 10% dilute hydrochloric acid solution to the above to acidify, let stand to separate layers, collect the organic phase, conduct vacuum distillation at 55°C to evaporate the organic solvent, recrystallize and purify to obtain 14 grams of deuterated phenylboronic acid.

The product deuterated phenylboronic acid is analyzed by liquid phase, and the purity of deuterated phenylboronic acid is 90%, and the deuterated rate is 98.5% through NMR calculation, and the yield is 70%.

Comparative example 2

Preparation of deuterated phenylboronic acid: In a 250mL three-necked flask, add 60mL of 2-methyltetrahydrofuran and 10 grams of deuterated bromobenzene (deuterated rate is 98%), and use a liquid nitrogen-ethanol reaction bath to cool the material temperature To -60 ℃, slowly add 28 grams of n-butyllithium, the time of dropping is 4 hours, the ratio of the mass of deuterated bromobenzene to n-butyllithium is 1:1.5, after the dropwise addition is completed, keep warm for one hour, and then add to 30 grams of triisopropyl borate was added to the above reaction solution, and the temperature was raised to room temperature within 4 hours. Add 10 mL of 10% dilute hydrochloric acid solution to the above solution for acidification, let stand to separate layers, collect the organic phase, evaporate the organic solvent by distillation under reduced pressure, recrystallize and purify to obtain 6 grams of deuterated phenylboronic acid. The product deuterated phenylboronic acid is analyzed by liquid phase, the purity can reach 87%, the deuterated rate is 98%, and the yield is 79%.

Comparative example 3

Placed underpressure distillation evaporation organic solvent is temperature is 65 ℃, other steps are carried out in the same manner with embodiment 1, and product deuterated phenylboronic acid is carried out NMR analysis, deuteration rate is 97.2%.

Comparative example 4

Preparation of deuterated phenylboronic acid: In a 250mL three-necked flask, add 60mL of 2-methyltetrahydrofuran and 10 grams of deuterated bromobenzene (deuterated rate is 98%), and use a liquid nitrogen-ethanol reaction bath to cool the material temperature To -40 ℃, slowly add 20 grams of n-butyllithium, dropwise time is 4 hours, the ratio of the substance amount of deuterated bromobenzene and n-butyllithium is 1:1.1, keep warm for one hour after the dropwise addition is completed, and then add 30 grams of triisopropyl borate was added to the above reaction solution, and the temperature was raised to room temperature within 4 hours. Add 10 mL of 10% dilute hydrochloric acid solution to the above solution to acidify, let stand to separate layers, collect the organic phase, evaporate the organic solvent by distillation under reduced pressure, recrystallize and purify to obtain 4.5 g of deuterated phenylboronic acid. The product deuterated phenylboronic acid is analyzed by liquid phase, the purity can reach 95%, the deuterated rate is 98%, and the yield is 60%.

in conclusion

According to the above test data, it can be seen that the yield of deuterated phenylboronic acid prepared by the Grignard reagent method in the prior art can reach up to 70%, there are two kinds of by-products, the purification process is complicated, and the synthesis steps are divided into two steps, the process route is complicated, and The purity is lower. And by adopting n-butyllithium method to prepare deuterated phenylboronic acid, the feeding ratio is controlled in the preferred range, the purity of the crude product can reach more than 90%, and the purity after recrystallization and purification can reach 95%. It should be noted that the present inventors also found that when there is hydrochloric acid in the reaction system and the deuterium in deuterated phenylboronic acid is prone to deuterium hydrogen exchange and loss, for example, when the solvent is distilled, once the temperature reaches about 60 ° C, the deuterium The deuteration rate of phenylboronic acid will drop greatly. In contrast, if the vacuum distillation temperature is controlled below 55°C, the deuteration rate of deuterated phenylboronic acid will not decrease.

It should be understood that although the present invention has been exemplarily described according to its preferred embodiments, it should not be limited to the above-mentioned embodiments, and various modifications and changes may be made to the present invention by those skilled in the art. For those skilled in the art, without departing from the idea and principle of the present invention, some simple substitutions can also be made, and these should be included in the protection scope of the present invention.

Industrial Applicability

The invention provides a method for safely and efficiently synthesizing deuterated phenylboronic acid with high conversion rate. The preparation method can not only greatly increase the conversion rate of high-priced deuterated bromobenzene, shorten the reaction time, and increase the purity, but also can The deuterium in the deuterated phenylboronic acid does not lose deuterium hydrogen to the reaction system during the preparation reaction, and the deuterated rate of the product can be basically kept the same as that of the raw material deuterated bromobenzene. The preparation method is suitable for industrial mass production of deuterated phenylboronic acid due to the above-mentioned characteristics.

Claims (14)

1. A method for preparing deuterated phenylboronic acid, which uses organolithium reagent method to prepare deuterated phenylboronic acid. 2. the described method of claim 1, described organolithium reagent method comprises the following steps: Deuterobromobenzene is reacted with organolithium reagents to synthesize deuterated phenyllithium, then an esterifying agent is added to the above solution to continue the reaction, and acid is added to it for acidification to generate deuterated phenylboronic acid. 3. The method according to any one of claims 1 to 2, wherein the reaction of deuterated bromobenzene and organolithium reagents to synthesize deuterated phenyllithium is carried out at -40°C to -80°C, preferably Performed at -60°C. 4. The method according to any one of claims 1 to 3, wherein the reaction time for the synthesis of deuterated phenyl lithium by the reaction of deuterated bromobenzene and organolithium reagent is 0.1 to 10 hours, more preferably 0.3 to 10 hours. 6 hours, more preferably 2.5 to 5.5 hours, most preferably 5 hours. 5. The method according to any one of claims 1 to 4, wherein the reaction time for adding an esterifying agent to the above-mentioned solution to continue the reaction is 0.1 to 10 hours, more preferably 0.3 to 5 hours, more preferably 2.5 to 4.5 hours, most preferably 4 hours. 6. The method according to any one of claims 1 to 5, wherein the organolithium reagent is n-butyllithium. 7. The method according to any one of claims 1 to 6, wherein deuterated bromobenzene is dissolved in a solvent containing 2-methyltetrahydrofuran. 8. The method according to any one of claims 1 to 7, wherein the esterification agent is triisopropyl borate. 9. The method according to any one of claims 1 to 8, wherein the ratio of the amount of deuterated bromobenzene to the organolithium reagent is 1:1-1.5, preferably 1:1.1. 10. The method according to any one of claims 1 to 9, wherein the acid is a hydrochloric acid solution. 11. The method according to any one of claims 1-10, wherein the hydrochloric acid solution is a 1%-20% hydrochloric acid solution, preferably a 10% hydrochloric acid solution. 12. The method according to any one of claims 1 to 11, further comprising the steps of: Purification procedure for purifying deuterated phenylboronic acid. 13. The method of any one of claims 1 to 12, wherein the purification step is performed as follows: The reactants were separated and separated, the organic phase was collected, the solvent was evaporated by distillation under reduced pressure, and purified by recrystallization. 14. The method according to any one of claims 1 to 13, wherein the temperature when the solvent is evaporated by distillation under reduced pressure is controlled to be 60°C or lower, more preferably 55°C or lower.