A method for preparing deuterated phenylboronic acid using Grignard reagent

Abstract

The invention provides a preparation method for deuterated phenylboronic acid which uses 2-methyltetrahydrofuran as a solvent and can efficiently synthesize high-conversion rate deuterated phenylboronic acid. The preparation method can not only greatly improve the conversion rate of high-priced deuterated bromobenzene and shorten the reaction time, but also prevent the deuterium in the deuterated phenylboronic acid from being lost into the reaction system by deuterium-hydrogen exchange during the preparation reaction, and the deuteration rate of the product can be substantially the same as that of the deuterated bromobenzene as a raw material.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing deuterated phenylboronic acid. Background Art

[0002] Deuterated phenylboronic acid is an important organic synthesis intermediate, commonly used in Suzuki coupling reaction, phthalamide reaction catalyst, 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, synthesis of OLED materials, and drug controlled release systems. The structure of deuterated phenylboronic acid is as follows:

[0003]

[0004] Deuterated chemicals refer to a class of chemicals with unique physical and chemical properties in which the hydrogen (H) atom in the compound molecule is replaced by its isotope deuterium (D) atom. Deuterated drugs can improve drug safety and have pharmacokinetic advantages (extending drug efficacy, etc.). Deuterated OLED materials can effectively improve the luminous efficiency of the device and increase the stability and life of the device.

[0005] Although there are methods for synthesizing phenylboronic acid in the prior art, there is no discussion on an efficient method for synthesizing deuterated phenylboronic acid. For example, in the prior art method for synthesizing phenylboronic acid, ether is often used as a reaction solvent, but due to the low boiling point and high volatility of ether, it is very easy to generate peroxides and cause explosions, which poses a serious safety hazard, and is therefore not suitable for large-scale preparation of deuterated phenylboronic acid. There is also a method of using tetrahydrofuran instead of ether as a reaction solvent, but in this case, the conversion rate of bromobenzene is low, and due to the high economic value of deuterated bromobenzene, it is also not suitable for large-scale preparation of deuterated phenylboronic acid. Summary of the invention

[0006] The synthesis process of deuterated phenylboronic acid of the present invention uses 2-methyltetrahydrofuran as an organic solvent, reacts deuterated bromobenzene with a magnesium strip to synthesize deuterated phenylmagnesium bromide, and then reacts the above solution with an esterifying agent and acidifies to generate a phenylboronic acid product. The details are as follows:

[0007] 1. A method for preparing deuterated phenylboronic acid using a Grignard reagent, comprising the following steps:

[0008] The first step is to prepare the Grignard reagent;

[0009] The second step is to use Grignard reagent to prepare deuterated phenylboronic acid, wherein:

[0010] The solvent used in the first step, ie, the first solvent, comprises 2-methyltetrahydrofuran.

[0011] 2. The method of claim 1, wherein the solvent used in the second step, i.e. the second solvent, comprises 2-methyltetrahydrofuran.

[0012] 3. The method according to item 1 or 2, wherein the content of 2-methyltetrahydrofuran in the first solvent is 80% or more, preferably 90%, more preferably 99% or more, and most preferably 100%.

[0013] 4. The method according to any one of items 1 to 3, wherein the content of 2-methyltetrahydrofuran in the first solvent is 80% or more, preferably 90%, most preferably 99% or more, and most preferably 100%.

[0014] 5. The method described in any one of items 1 to 4, wherein the specific steps of the first step are as follows: adding a first solvent, a magnesium bar, and deuterated bromobenzene to a reaction container, adding iodine particles to initiate the reaction, after the reaction is initiated, raising the reaction temperature to the first reaction temperature of 50-85°C, and dripping a mixed solution of deuterated bromobenzene and the first solvent into the above solution, after the mixed solution is dripped, keeping the temperature for reaction, and then returning to room temperature to obtain a Grignard reagent reaction solution.

[0015] 6. The method described in any one of items 1 to 5, wherein the specific steps of the second step are as follows: add a second solvent and a borate ester esterifying agent into a reaction container, control the temperature to cool the reactant temperature to a second reaction temperature of -40°C to 80°C, dropwise add the Grignard reagent reaction solution prepared in the first step, and after the dropwise addition is completed, keep the temperature for reaction, then naturally raise the temperature to room temperature, add acid to the product for acidification, and obtain deuterated phenylboronic acid.

[0016] 7. The method according to any one of items 1 to 6, wherein the acid is a hydrochloric acid solution.

[0017] 8. The method according to any one of items 1 to 7, wherein the hydrochloric acid solution is a 1% to 20% hydrochloric acid solution, preferably a 10% hydrochloric acid solution.

[0018] 9. The method according to any one of items 1 to 8, wherein the first reaction temperature is 55°C to 85°C, preferably 65°C to 80°C.

[0019] 10. The method according to any one of items 1 to 9, wherein the second reaction temperature is -40°C to -70°C, more preferably -40°C to -60°C.

[0020] 11. The method according to any one of items 1 to 10, wherein the dripping time of the mixed solution of deuterated bromobenzene and the first solvent in the first step is controlled to be 0.1 to 10 hours, more preferably 0.5 to 5 hours, and most preferably 1.5 to 3 hours.

[0021] 12. The method according to any one of items 1 to 11, wherein the dripping time of the Grignard reagent reaction solution in the second step is controlled to be 0.1 to 10 hours, more preferably 0.5 to 5 hours, and most preferably 2 to 4 hours.

[0022] 13. The method according to any one of items 1 to 12, wherein the time for the reaction under heat preservation in the first step is 0.1 to 10 hours, more preferably 0.3 to 5 hours, and most preferably 0.5 to 1.5 hours.

[0023] 14. The method according to any one of items 1 to 13, wherein the time for the reaction under heat preservation in the second step is 0.1 to 10 hours, more preferably 0.3 to 5 hours, and most preferably 0.5 to 1 hour.

[0024] 15. The method according to any one of items 1 to 14, wherein the time for the reaction during heat preservation in the second step is 0.1 to 10 hours, more preferably 0.2 to 5 hours, and most preferably 0.4 to 0.6 hours.

[0025] 16. The method according to any one of items 1 to 15, wherein the borate ester esterifying agent is triisopropyl borate.

[0026] 17. The method according to any one of items 1 to 16, further comprising the following steps:

[0027] The third step is to purify the reaction product.

[0028] 18. The method according to any one of items 1 to 17, wherein the specific steps of the third step are as follows:

[0029] The mixture was allowed to stand for stratification, and the organic phase was collected. The solvent was evaporated by distillation under reduced pressure, and the mixture was purified by recrystallization.

[0030] 19. The method according to any one of items 1 to 18, wherein the temperature during evaporation of the solvent by reduced pressure distillation is controlled to 60° C. or lower, more preferably 55° C. or lower. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 .A flow chart illustrating an example of the preparation process of the present invention. DETAILED DESCRIPTION

[0032] Each step will be described in detail below. It should be noted that the following description is not limiting, and those skilled in the art can make any modifications and substitutions based on the following description and the technical common sense in the art without significantly hindering the technical effect of the present invention.

[0033] 1. Preparation of Grignard Reagent

[0034] First, a first solvent, a magnesium bar, and deuterated bromobenzene are added to a reaction vessel such as a three-necked flask, and iodine particles are added to initiate the reaction. The first solvent contains 2-methyltetrahydrofuran, and its content is 80% or more, preferably 90%, more preferably 99% or more, and most preferably 100%. In addition to 2-methyltetrahydrofuran, the first solvent may also contain other commonly used solvents such as water, other components such as antioxidants, and inevitable impurities.

[0035] After the reaction is initiated, the reaction temperature is raised to the first reaction temperature, and a mixed solution of deuterated bromobenzene and the first solvent is added dropwise to the above solution. After the addition of the mixed solution is completed, the temperature is kept to react.

[0036] The first reaction temperature is not particularly limited as long as the Grignard reagent reaction can proceed normally. For example, it can be 10°C to 85°C, preferably 50-85°C, more preferably 75°C to 85°C, further preferably 75°C to 80°C, and most preferably 80°C.

[0037] It is preferred to control the solution dropping speed. The control method is not particularly limited. For example, constant pressure dripping and other methods can be used. As for the speed, it can be adjusted according to conditions such as the reaction scale. For example, the dropping time can be 0.1 to 10 hours, more preferably 0.5 to 5 hours, further preferably 1.5 to 3 hours, and most preferably 2 hours.

[0038] As for the time of heat preservation and reaction, there is no particular restriction as long as the reaction is fully carried out, but it should be noted that if the reaction time is too long at high temperature, it is possible to cause deuterium hydrogen exchange, so that the deuteration rate of the product decreases. Specifically, the time of heat preservation and reaction can be 0.1 to 10 hours, more preferably 0.3 to 5 hours, further preferably 0.5 to 1.5 hours, and most preferably 1 hour.

[0039] Finally, the room temperature is restored to obtain the Grignard reagent reaction solution.

[0040] 2. Preparation of deuterated phenylboronic acid using Grignard reagent

[0041] First, the second solvent and the borate ester esterifying agent are added to a reaction container.

[0042] The second solvent contains 2-methyltetrahydrofuran, and its content is 80% or more, preferably 90%, more preferably 99% or more, and most preferably 100%. In addition to 2-methyltetrahydrofuran, the first solvent may also contain other commonly used solvents such as water, other ingredients such as antioxidants, and inevitable impurities.

[0043] As for the borate ester esterifying agent, the borate ester esterifying agents commonly used in the art can be used, such as trimethyl borate, triethyl borate, tributyl borate, triisopropyl borate, etc. From the perspective of reducing side reactions and improving the utilization rate of deuterated bromobenzene, triisopropyl borate is preferably used.

[0044] The temperature of the reactants is controlled to be cooled to the second reaction temperature, and the Grignard reagent reaction solution prepared in the first step is added dropwise thereto. After the addition is completed, the temperature is kept to react, and then the temperature is naturally raised to room temperature to obtain deuterated phenyl borate.

[0045] As for the second reaction temperature, there is no particular limitation as long as the reaction can proceed normally, and for example, it can be -40°C to -80°C. From the perspective of reducing side reactions and improving the utilization rate of deuterated bromobenzene, the second reaction temperature is preferably -40°C to -70°C, and more preferably -40°C to -60°C. The method for adjusting the temperature can be carried out by any method known to those skilled in the art, for example, a liquid nitrogen-ethanol reaction bath can be used.

[0046] It is preferred to control the solution dropping speed. The control method is not particularly limited. For example, constant pressure dripping and other methods can be used. As for the speed, it can be adjusted according to conditions such as the reaction scale. For example, the dropping time can be 0.1 to 10 hours, more preferably 0.5 to 5 hours, further preferably 2 to 4 hours, and most preferably 3 hours.

[0047] The time for the reaction under heat preservation is not particularly limited as long as the reaction proceeds sufficiently. Specifically, the time for the reaction under heat preservation may be 0.1 to 10 hours, more preferably 0.3 to 5 hours, further preferably 0.5 to 1 hour, and most preferably 0.5 hour.

[0048] Finally, a proper amount of acid is added to the reaction solution to acidify the reaction solution to about pH=2 to obtain the product deuterated phenylboronic acid.

[0049] The type of acid required for acidification is not particularly limited as long as it can acidify deuterated phenyl borate to deuterated phenylboronic acid, and can be common acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc. From the perspective of ease of subsequent purification, hydrochloric acid is preferably used. The concentration of hydrochloric acid is not particularly limited, for example, it can be 1% to 20%, preferably a 10% dilute hydrochloric acid solution. As for the amount to be added, there is no particular limitation as long as it can acidify deuterated phenyl borate to deuterated phenylboronic acid, for example, it can be 2-4 times the molar amount of deuterated phenyl borate, and from the perspective of ease of purification, it is preferably 2 times the molar amount.

[0050] 3. Purification

[0051] The method for purifying the 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:

[0052] The reactants of the second step were allowed to stand for stratification, and the organic phase was collected. Finally, the solvent was removed and the mixture was purified by recrystallization.

[0053] The method for removing the solvent is not particularly limited, and for example, distillation can be used, preferably vacuum distillation. As for 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 60° C. or above, deuterium-hydrogen exchange occurs, resulting in a decrease in the deuteration rate. Therefore, the temperature of distillation and vacuum distillation is preferably 60° C. or less, more preferably 55° C. or less.

[0054] The invention uses 2-methyltetrahydrofuran as a solvent and optimizes an esterifying agent, a reaction temperature and a reaction time, thereby providing a preparation method capable of efficiently synthesizing deuterated phenylboronic acid with a high conversion rate. The preparation method can not only greatly improve the conversion rate of high-priced deuterated bromobenzene and shorten the reaction time, but also prevent the deuterium in the deuterated phenylboronic acid from being lost into the reaction system by deuterium-hydrogen exchange during the preparation reaction, and the deuteration rate of the product can be substantially the same as that of the deuterated bromobenzene as a raw material.

[0055] Example

[0056] The present invention will be further described below through examples. However, it should be noted that the following examples and comparative examples are only used to illustrate the technical effects of the present invention and have no limiting effect on the present invention.

[0057] Example 1

[0058] 1.1 Preparation of Grignard reagent reaction solution

[0059] In a 250mL three-necked flask, add 40mL of anhydrous 2-methyltetrahydrofuran, 12g of magnesium stick, 1g of deuterated bromobenzene (deuterated rate 98.5%), add iodine particles to initiate the reaction. After the reaction is initiated, the reaction temperature is raised to the first reaction temperature of 75°C, and then 26g of deuterated bromobenzene and 30mL of a mixed solution of 2-methyltetrahydrofuran are added dropwise to the above solution using a constant pressure dropper. The dropping speed is controlled and the dropping time is about 2 hours. After the mixed liquid is added dropwise, the reaction is continued to be kept warm for 1 hour, and the room temperature is restored to obtain a Grignard reagent reaction solution.

[0060] 1.2 Preparation of deuterated phenylboronic acid

[0061] In a 500mL three-necked flask, add 60mL of 2-methyltetrahydrofuran and 60g of triisopropyl borate, use liquid nitrogen-ethanol reaction bath, cool the material temperature to the second reaction temperature -60°C, use constant pressure dropper to drop the prepared Grignard reagent reaction solution, the drop time is 3 hours, after the dropwise addition is completed, keep warm for half an hour, and naturally warm to room temperature. Add 10mL of 10% dilute hydrochloric acid solution to the above acidification, let stand for stratification, collect the organic phase, evaporate the organic solvent by vacuum distillation at 55°C, and recrystallize and purify to obtain 14g of the product deuterated phenylboronic acid.

[0062] 1.3 Results Evaluation

[0063] The purity of the product deuterated phenylboronic acid can reach 90% through liquid phase analysis, and the deuterated rate is 98.5% and the yield is 70% through nuclear magnetic resonance calculation.

[0064] It should be noted that the yield is calculated by the following formula: Yield = the amount of deuterated phenylboronic acid in the product / the amount of deuterated bromobenzene fed.

[0065] In this example, the raw material deuterated bromobenzene (deuteration rate 98.5%, purity 99%) was prepared in the laboratory, and 2-methyltetrahydrofuran, magnesium bar, triisopropyl borate, and hydrochloric acid were purchased from Anergy.

[0066] Comparative Example 1

[0067] Except that tetrahydrofuran was used as the organic solvent, the reaction temperature for preparing the Grignard reagent was 60° C., and trimethyl borate was used as the esterification agent, the other steps were carried out in the same manner as in Example 1. The product deuterated phenylboronic acid was subjected to liquid phase analysis, and the yield obtained was 40%.

[0068] Comparative Example 2

[0069] 2-Methyltetrahydrofuran was used as an organic solvent, the reaction temperature for preparing the Grignard reagent was 75° C., trimethyl borate was used as an esterifying agent, and the other steps were carried out in the same manner as in Example 1. Liquid phase analysis of the product deuterated phenylboronic acid showed a yield of 53%.

[0070] Example 2

[0071] 2-Methyltetrahydrofuran was used as an organic solvent, the reaction temperature for preparing the Grignard reagent was 60° C., triisopropyl borate was used as an esterifying agent, and the other steps were carried out in the same manner as in Example 1. Liquid phase analysis of the product deuterated phenylboronic acid showed a yield of 58%.

[0072] Comparative Example 4

[0073] 2-Methyltetrahydrofuran was used as an organic solvent, the reaction temperature for preparing the Grignard reagent was 75° C., triisopropyl borate was used as an esterifying agent, the organic phase was collected, and the organic solvent was evaporated by reduced pressure distillation at a temperature of 65° C. The other steps were carried out in the same manner as in Example 1, and the product deuterated phenylboronic acid was subjected to nuclear magnetic resonance analysis, and the deuteration rate was 97.8%.

[0074] Comparative Example 5

[0075] 2-Methyltetrahydrofuran was used as the organic solvent, the second reaction temperature was -35°C, triisopropyl borate was used as the esterification agent, and the other steps were carried out in the same manner as in Example 1. Liquid phase analysis of the product deuterated phenylboronic acid showed a yield of 47%.

[0076] in conclusion

[0077] According to the above test data, when 2-methyltetrahydrofuran is used as a solvent, the reaction temperature for preparing the Grignard reagent can be increased to about 80°C, and increasing the reaction temperature means that the preparation time for preparing the Grignard reagent can also be shortened (for example, compared with Comparative Example 1, the reaction time can be shortened by about 30% in Example 1), and the conversion rate of deuterated bromobenzene is also improved. It should be noted that the inventors also found that when there is hydrochloric acid in the reaction system and the high temperature reaction occurs, the deuterium of deuterated phenylboronic acid is easily exchanged with deuterium and hydrogen and lost. For example, when the solvent is distilled, once the temperature reaches about 60°C, the deuteration rate of deuterated phenylboronic acid will decrease significantly. In contrast, if the vacuum distillation temperature is controlled below 55°C, the deuteration rate of deuterated phenylboronic acid will not decrease.

[0078] It should be understood that although the present invention has been described exemplarily according to its preferred embodiments, it should not be limited to the above embodiments. For those skilled in the art, the present invention may have various modifications and variations. For those skilled in the art, several simple substitutions can be made without departing from the concept and principle of the present invention, which should all be included in the protection scope of the present invention.

[0079] Industrial Applicability

[0080] The present invention provides a preparation method for deuterated phenylboronic acid that can safely and efficiently synthesize high-conversion rate. The preparation method can not only greatly improve the conversion rate of high-priced deuterated bromobenzene and shorten the reaction time, but also prevent the deuterium in the deuterated phenylboronic acid from being lost to the reaction system by deuterium-hydrogen exchange during the preparation reaction, and the deuteration rate of the product can be basically the same as that of the raw material deuterated bromobenzene. Due to the above characteristics, the preparation method is suitable for industrial mass production of deuterated phenylboronic acid.

Claims

1. A method for preparing deuterated phenylboronic acid using a Grignard reagent, comprising the following steps: The first step is to prepare the Grignard reagent; The second step is to use Grignard reagent to prepare deuterated phenylboronic acid, wherein: The solvent used in the first step, i.e. the first solvent, is 2-methyltetrahydrofuran, The solvent used in the second step, i.e. the second solvent, is 2-methyltetrahydrofuran, The specific steps of the first step are as follows: adding a first solvent, a magnesium bar, and deuterated bromobenzene to a reaction container, adding iodine particles to initiate a reaction, after the reaction is initiated, raising the reaction temperature to a first reaction temperature of 50-85° C., dripping a mixed solution of deuterated bromobenzene and the first solvent into the above solution, after the mixed solution is dripped, keeping the temperature to react, and then returning to room temperature to obtain a Grignard reagent reaction solution, The specific steps of the second step are as follows: add a second solvent and a borate ester esterifying agent to a reaction container, control the temperature to cool the reactant to a second reaction temperature of -40°C to 80°C, dropwise add the Grignard reagent reaction solution prepared in the first step, after the dropwise addition is completed, keep the temperature to react, then naturally raise the temperature to room temperature, add acid to the product for acidification, and obtain deuterated phenylboronic acid. The borate ester esterifying agent is triisopropyl borate.

2. The method of claim 1, wherein: The acid is hydrochloric acid solution.

3. The method of claim 2, wherein: The hydrochloric acid solution is a 1% to 20% hydrochloric acid solution.

4. The method of claim 3, wherein: The hydrochloric acid solution is a 10% hydrochloric acid solution.

5. The method of claim 1, wherein: The first reaction temperature is 55°C to 85°C.

6. The method of claim 1, wherein: The first reaction temperature is 65°C to 80°C.

7. The method of claim 1, wherein: The second reaction temperature is -40°C to -70°C.

8. The method of claim 1, wherein: The second reaction temperature is -40°C to -60°C.

9. The method of claim 1, wherein: In the first step, the dripping time of the mixed solution of deuterated bromobenzene and the first solvent is controlled to be 0.1 to 10 hours.

10. The method of claim 1, wherein: In the first step, the dripping time of the mixed solution of deuterated bromobenzene and the first solvent is controlled to be 0.5 to 5 hours.

11. The method of claim 1, wherein: In the first step, the dripping time of the mixed solution of deuterated bromobenzene and the first solvent is controlled to be 1.5 to 3 hours.

12. The method of claim 1, wherein: In the second step, the dropwise addition time of the Grignard reagent reaction solution is controlled to be 0.1 to 10 hours.

13. The method of claim 1, wherein: In the second step, the dropwise addition time of the Grignard reagent reaction solution is controlled to be 0.5 to 5 hours.

14. The method of claim 1, wherein: In the second step, the dropwise addition time of the Grignard reagent reaction solution is controlled to be 2 to 4 hours.

15. The method of claim 1, wherein: The time for the reaction under heat preservation in the first step is 0.1 to 10 hours.

16. The method of claim 1, wherein: The time for the reaction under heat preservation in the first step is 0.3 to 5 hours.

17. The method of claim 1, wherein: The first step is to keep the temperature for the reaction for 0.5 to 1.5 hours.

18. The method of claim 1, wherein: In the second step, the reaction time is 0.1 to 10 hours.

19. The method of claim 1, wherein: In the second step, the reaction time is 0.3 to 5 hours.

20. The method of claim 1, wherein: In the second step, the reaction time is 0.5 to 1 hour.

21. The method of claim 1, wherein: In the second step, the reaction time is 0.1 to 10 hours.

22. The method of claim 1, wherein: In the second step, the reaction time is 0.2 to 5 hours.

23. The method of claim 1, wherein: In the second step, the reaction time is 0.4 to 0.6 hours.

24. The method of claim 1, further comprising the steps of: The third step is to purify the reaction product.

25. The method of claim 24, wherein: The specific steps of the third step are as follows: The reactants of the second step were allowed to stand for stratification, and the organic phase was collected. The solvent was evaporated by distillation under reduced pressure, and the phase was purified by recrystallization.

26. The method of claim 25, wherein: The temperature during the evaporation of the solvent by reduced pressure distillation was controlled to be 60° C. or less.

27. The method of claim 25, wherein: The temperature during the evaporation of the solvent by reduced pressure distillation was controlled to be 55° C. or less.

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