CN115806564A - Method for preparing deuterated phenylboronic acid by using organic lithium method - Google Patents
Method for preparing deuterated phenylboronic acid by using organic lithium method Download PDFInfo
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Abstract
The invention provides a preparation method for efficiently synthesizing deuterated phenylboronic acid with high conversion rate by using an organic lithium method, which can greatly improve the conversion rate of high-valence deuterated bromobenzene, shorten reaction time and improve purity, and can ensure that deuterium in the deuterated phenylboronic acid is lost into a reaction system without deuterium-hydrogen exchange in the preparation reaction process, and the deuteration rate of a product can be basically kept the same as that of raw material deuterated bromobenzene.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of deuterated phenylboronic acid.
Background
Deuterated phenylboronic acid is an important organic synthesis intermediate, and is commonly used in fields such as Suzuki coupling reaction, a phthalein amination reaction catalyst, diels-Alder reaction and the like. The deuterated phenylboronic acid has good stability and high reaction activity, and has very important application in the aspects of drug synthesis, OLED material synthesis and drug controlled release systems. The structure of the deuterated phenylboronic acid is as follows:
deuterated chemicals refer to chemicals having unique physicochemical properties in which hydrogen (H) atoms in the molecules of the compounds are replaced by deuterium (D) atoms, which is an isotope thereof. The deuterated drugs can improve the safety of the drugs and have the pharmacokinetic advantages (prolonging the drug effect and the like). The deuterated OLED material can effectively improve the luminous efficiency of the device, and increase the stability and the service life of the device.
Although the prior art has provided methods for synthesizing phenylboronic acid, no efficient synthesis method suitable for deuterated phenylboronic acid has been discussed. For example, most of the conventional phenylboronic acid processes at present are the grignard reagent method, but the grignard reagent method requires a large amount of magnesium chips, and has the phenomena of difficult separation and purification of by-products, and low yield of the product (bromobenzene utilization), for example, about 50-70% when the grignard reagent method is used. However, since deuterated bromobenzene as a raw material is expensive, the above grignard reagent having a low deuterated bromobenzene utilization rate is not suitable for industrial production of deuterated phenylboronic acid.
Disclosure of Invention
The inventor of the invention gropes a novel preparation method of deuterated phenylboronic acid by using an organic lithium reagent method. The method can greatly improve the yield of the deuterated phenylboronic acid and simplify the purification process, and is suitable for industrial production of the deuterated phenylboronic acid.
The method adopts an organic lithium reagent method to prepare the deuterated phenylboronic acid, and comprises the steps of dropwise adding the organic lithium reagent into a solution containing deuterated bromobenzene, adding an esterifying agent into the solution to continue reaction, and then acidifying and purifying to obtain a deuterated phenylboronic acid product. The method comprises the following specific steps:
1. a method for preparing deuterated phenylboronic acid uses an organolithium reagent method.
2. The process of item 1, the organolithium reagent process comprising the steps of:
reacting deuterated bromobenzene with an organic lithium reagent to synthesize deuterated phenyl lithium, adding an esterifying agent into the solution for continuous reaction, and adding acid into the solution for acidification to generate deuterated phenylboronic acid.
3. The method according to any one of items 1 to 2, wherein the reaction of deuterated bromobenzene with organolithium reagent to synthesize deuterated phenyllithium is carried out at-40 ℃ to-80 ℃, preferably at-60 ℃.
4. The method according to any one of items 1 to 3, wherein the reaction time for synthesizing deuterated phenyl lithium by reacting deuterated bromobenzene with organolithium reagent is 0.1 to 10 hours, more preferably 0.3 to 6 hours, still more preferably 2.5 to 5.5 hours, and most preferably 5 hours.
5. The process according to any one of items 1 to 4, wherein the reaction time for continuing the reaction by adding the esterifying agent to the solution is 0.1 to 10 hours, more preferably 0.3 to 5 hours, still more preferably 2.5 to 4.5 hours, and most preferably 4 hours
6. The process of 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 deuterated bromobenzene is dissolved in a solvent containing 2-methyltetrahydrofuran.
8. The method of any one of items 1 to 7, wherein the esterifying agent is triisopropyl borate.
9. The method according to any one of items 1 to 8, wherein the amount ratio of deuterated bromobenzene to organolithium reagent is 1:1-1.5, preferably 1
10. The method of 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 of any one of items 1 to 11, further comprising the step of:
a purification step of purifying deuterated phenylboronic acid.
13. The method of any one of items 1 to 12, wherein the purification step is performed as follows:
standing and layering the reactant, collecting an organic phase, distilling under reduced pressure to evaporate the solvent, and recrystallizing and purifying.
The process according to any one of items 1 to 13, wherein the temperature at the time of evaporating the solvent by distillation under reduced pressure is controlled to 60 ℃ or lower, more preferably 55 ℃ or lower.
Detailed Description
Various aspects of the invention are described in detail below. It should be noted that the following description is not intended to be limiting, and those skilled in the art can make modifications and substitutions without significantly hindering the technical effects of the present invention, based on the common general knowledge in the art.
The method adopts an organic lithium reagent method to prepare the deuterated phenylboronic acid, the organic lithium reagent is dripped into a solution containing deuterated bromobenzene, an esterifying agent is added into the solution for continuous reaction, and then acid is added for acidification and purification to generate the deuterated phenylboronic acid product. Specifically, the following steps may be performed:
1. firstly, adding a deuterated bromobenzene solution into a container such as a three-neck flask, cooling the temperature of the material to a reaction temperature of-40 ℃ to-80 ℃, slowly adding an organic lithium reagent into the mixture, and preserving heat for reaction after the dropwise addition is finished, thereby obtaining deuterated phenyllithium.
In the process of the present invention, the organolithium reagent has the meaning understood by the person skilled in the art. I.e. a class of organometallic compounds in which carbon atoms are directly bonded to lithium ions. Specifically, the organolithium reagent may be n-butyllithium, t-butyllithium, lithium diisopropylamide, or the like. From the viewpoint of stability of the reaction and easiness of control, n-butyllithium is preferable.
The solvent for the solution containing deuterated bromobenzene can be arbitrarily selected according to the needs, and 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.
The ratio of the organolithium reagent to the deuterated bromobenzene is not particularly limited as long as the reaction proceeds, but is preferably 1:1-1.5, more preferably 1:1-1.2, and most preferably 1:1-1.1, from the viewpoint of suppressing side reactions.
From the viewpoint of maintaining the activity of deuterated phenyllithium and suppressing the occurrence of side reactions, the reaction temperature is preferably from-40 ℃ to-80 ℃, more preferably from-60 ℃ to-70 ℃, and most preferably from-60 ℃. As for the method of controlling the reaction temperature, there is no particular limitation, and a control method known to those skilled in the art may be used, and for example, the reaction temperature may be lowered to the reaction temperature using a liquid nitrogen-ethanol reaction bath.
The reaction time for synthesizing deuterated phenyllithium by reacting deuterated bromobenzene with organolithium reagent is not particularly limited as long as the reaction is sufficiently performed, and specifically may be 0.1 to 10 hours, more preferably 0.3 to 6 hours, still more preferably 2.5 to 5.5 hours, and most preferably 5 hours.
The reaction time for synthesizing deuterated phenyllithium by reacting deuterated bromobenzene with organolithium reagent includes the time for adding organolithium reagent to deuterated bromobenzene and the time for keeping the reaction between deuterated bromobenzene and organolithium reagent after the completion of the addition of organolithium reagent.
The rate of addition of the organolithium reagent is preferably controlled, and the control method is not particularly limited, and for example, a method such as dropping under constant pressure can be used, and the rate of addition can be adjusted depending on the conditions such as the scale of the reaction, and for example, the dropping time may be 0.1 to 10 hours, more preferably 2 to 6 hours, further preferably 3 to 5 hours, and most preferably 4 hours.
The time for carrying out the reaction under the heat-retention condition is not particularly limited as long as the reaction is sufficiently carried out. Specifically, the reaction time may be 0 to 10 hours, more preferably 0.3 to 5 hours, still more preferably 0.5 to 1.5 hours, and most preferably 1 hour.
2. Next, an esterifying agent is added to the reaction solution, and the temperature is raised to room temperature to carry out a reaction, thereby obtaining deuterated phenyl borate.
As the borate ester esterifying agent, there may be used a borate ester esterifying agent commonly used in the art, for example: trimethyl borate, triethyl borate, tributyl borate, triisopropyl borate, etc., triisopropyl borate is preferably used from the viewpoint of reducing side reactions and improving the utilization rate of deuterated bromobenzene.
The reaction time for obtaining the deuterated phenylboronate by reacting the deuterated phenyllithium with the boronate esterifying agent is not particularly limited as long as the reaction is sufficiently performed, and specifically, the reaction time may be 0.1 to 10 hours, more preferably 0.3 to 5 hours, still more preferably 2 to 5 hours, and most preferably 4 hours. The method for raising the temperature to room temperature is not particularly limited, and a method known to those skilled in the art can be used, and for example, the temperature can be raised naturally. The reaction time referred to herein is calculated from the time when the addition of the borate ester esterifying agent is started.
The addition rate of the esterification agent is preferably controlled, and the control method is not particularly limited, and for example, a method such as dropping at a constant pressure may be used, and the addition rate may be adjusted depending on the conditions such as the scale of the reaction, and for example, the dropping time may be 0.1 to 10 hours, more preferably 0.5 to 5 hours, further preferably 2 to 4 hours, and most preferably 3 hours. The time for adding the esterifying agent is also included in the reaction time for reacting deuterated phenyl lithium with the borate esterifying agent to obtain deuterated phenyl borate.
3. And finally, adding a proper amount of acid into the reaction solution, and acidifying the reaction solution until the pH =2 to obtain the product deuterated phenylboronic acid.
The type of acid required for the acidification is not particularly limited as long as it can acidify the deuterated phenylboronic acid ester into deuterated phenylboronic acid, and may be any of the commonly used acids such as hydrochloric acid, sulfuric acid, nitric acid, and acetic acid, and hydrochloric acid is preferably used from the viewpoint of easy purification thereafter. The concentration of hydrochloric acid is not particularly limited, and may be, for example, a dilute hydrochloric acid solution of 1% to 20%, preferably 10%. The amount to be added is not particularly limited as long as the deuterated phenylboronate can be acidified to deuterated phenylboronic acid, and may be, for example, 2 to 4 times the molar amount of the deuterated phenylboronate, and is preferably 2 times the molar amount in view of easy purification.
The method of the present invention may further comprise the step of purifying the 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, and for example, the following can be performed:
standing the reaction mixture to separate layers, collecting an organic phase, removing the solvent, and recrystallizing for purification.
The method for removing the solvent is not particularly limited, and for example, a distillation method, preferably a distillation method under reduced pressure, may be used. The present inventors have found that, in terms of the temperature of distillation and reduced pressure distillation, when deuterated phenylboronic acid dissolved in a solvent containing 2-methyltetrahydrofuran is distilled at 60 ℃ or higher, deuterium hydrogen exchange occurs and the rate of deuteration decreases, and therefore, the temperature of distillation and reduced pressure distillation is preferably 60 ℃ or lower, more preferably 55 ℃ or lower.
The preparation method can greatly improve the conversion rate of high-valence deuterated bromobenzene, shorten reaction time, prevent deuterium in the deuterated phenylboronic acid from exchanging deuterium and losing to a reaction system in the preparation reaction process, and basically keep the same deuterium rate of a product as that of raw material deuterated bromobenzene.
Examples
The present invention will be further illustrated by the following examples, but it should be noted that the following examples and comparative examples are only for illustrating the technical effects of the present invention, and do not limit the present invention at all.
Example 1
Preparation of deuterated phenylboronic acid: 60mL of 2-methyltetrahydrofuran and 10 g of deuterated bromobenzene (the deuteration rate is 98%) are added into a 250mL three-neck flask, the temperature of the material is reduced to-60 ℃ by using a liquid nitrogen-ethanol reaction bath, 20 g of n-butyl lithium is slowly added, the dropping time is 4 hours, the mass ratio of the deuterated bromobenzene to the n-butyl lithium is 1.1, the temperature is kept for one hour after the dropping is finished, 30 g of triisopropyl borate is added into the reaction liquid, and the temperature is raised to the room temperature within 4 hours. And adding 10mL of 10% diluted hydrochloric acid solution into the solution, acidifying, standing for layering, collecting an organic phase, distilling under reduced pressure to evaporate the organic solvent, and recrystallizing and purifying to obtain 6.5 g of the deuterated phenylboronic acid product. The product deuterated phenylboronic acid has the purity of 98 percent, the deuteration rate of 98 percent and the yield of 85 percent through liquid phase analysis. The raw material deuterated bromobenzene is the deuterated bromobenzene produced by the company, and the rest reagents are purchased from An Naiji.
The yield was calculated by the following calculation formula: yield = amount of material of deuterated phenylboronic acid in product/amount of material of deuterated bromobenzene charged.
In this example, deuterated bromobenzene (deuteration rate 98.5%, purity 99%) was prepared by laboratory, and 2-methyltetrahydrofuran, magnesium strips, triisopropyl borate, and hydrochloric acid were purchased from An Naiji.
Comparative example 1
Deuterated bromobenzene as the same raw material is used to prepare deuterated phenylboronic acid by a Grignard reagent method.
The specific operation is as follows:
adding 60mL of anhydrous 2-methyltetrahydrofuran, 12 g of magnesium strips and 1 g of deuterated bromobenzene (with the deuteration rate of 98.5%) into a 250mL three-neck flask, adding iodine particles to initiate reaction, raising the reaction temperature to 75 ℃ after the reaction is initiated, then dropwise adding a mixed solution of 26 g of deuterated bromobenzene and 30mL of 2-methyltetrahydrofuran into the solution by using constant pressure dropping, controlling the dropping speed, keeping the dropping time for about 2 hours, continuing the heat preservation reaction for 1 hour after the dropwise addition of the mixed solution is finished, and recovering the room temperature to obtain the Grignard reagent reaction solution.
Adding 60mL of 2-methyltetrahydrofuran and 60 g of triisopropyl borate into a 500mL three-neck flask, cooling the temperature of the materials to-60 ℃ by using a liquid nitrogen-ethanol reaction bath, dropwise adding the prepared Grignard reagent reaction solution by using constant-pressure dropping liquid for 3 hours, preserving heat for reacting for half an hour after the dropwise adding is finished, and naturally heating to room temperature. And adding 10mL of 10% diluted hydrochloric acid solution into the mixture, acidifying, standing, layering, collecting an organic phase, distilling under reduced pressure at 55 ℃ to evaporate the organic solvent, and recrystallizing and purifying to obtain 14 g of the product deuterated phenylboronic acid.
Through liquid phase analysis, the product deuterated phenylboronic acid has the purity of 90%, the deuteration rate of 98.5% through nuclear magnetic calculation, and the yield of 70%.
Comparative example 2
Preparation of deuterated phenylboronic acid: 60mL of 2-methyltetrahydrofuran and 10 g of deuterated bromobenzene (the deuteration rate is 98%) are added into a 250mL three-neck flask, the temperature of the material is reduced to-60 ℃ by using a liquid nitrogen-ethanol reaction bath, 28 g of n-butyl lithium is slowly added, the dropping time is 4 hours, the mass ratio of the deuterated bromobenzene to the n-butyl lithium is 1.5, the temperature is kept for one hour after the dropping is finished, 30 g of triisopropyl borate is added into the reaction liquid, and the temperature is raised to the room temperature within 4 hours. And adding 10mL of 10% diluted hydrochloric acid solution into the solution, acidifying, standing for layering, collecting an organic phase, distilling under reduced pressure to evaporate the organic solvent, and recrystallizing and purifying to obtain 6 g of the product deuterated phenylboronic acid. The product deuterated phenylboronic acid has the purity of 87 percent, the deuteration rate of 98 percent and the yield of 79 percent through liquid phase analysis.
Comparative example 3
The nuclear magnetic analysis of the product deuterated phenylboronic acid was carried out in the same manner as in example 1 except that the temperature of the organic solvent evaporated by distillation under reduced pressure was 65 ℃, and the deuteration rate was 97.2%.
Comparative example 4
Preparation of deuterated phenylboronic acid: 60mL of 2-methyltetrahydrofuran and 10 g of deuterated bromobenzene (the deuteration rate is 98%) are added into a 250mL three-neck flask, the temperature of the material is reduced to-40 ℃ by using a liquid nitrogen-ethanol reaction bath, 20 g of n-butyl lithium is slowly added, the dropping time is 4 hours, the mass ratio of the deuterated bromobenzene to the n-butyl lithium is 1.1, the temperature is kept for one hour after the dropping is finished, 30 g of triisopropyl borate is added into the reaction liquid, and the temperature is raised to the room temperature within 4 hours. And adding 10mL of 10% dilute hydrochloric acid solution into the solution, acidifying, standing for layering, collecting an organic phase, distilling under reduced pressure to evaporate the organic solvent, and recrystallizing and purifying to obtain 4.5 g of the deuterated phenylboronic acid product. The product deuterated phenylboronic acid has the purity of 95 percent, the deuteration rate of 98 percent and the yield of 60 percent through liquid phase analysis.
Conclusion
According to the test data, the highest yield of the deuterated phenylboronic acid prepared by the Grignard reagent method in the prior art can reach 70%, two byproducts exist, the purification process is complex, the synthesis steps are divided into two steps, the process route is complex, and the purity is low. The deuterated phenylboronic acid is prepared by adopting an n-butyl lithium method, the feeding ratio is controlled in a preferable range, the purity of a crude product can reach over 90 percent, and the purity can reach 95 percent after recrystallization and purification. The present inventors have also found that deuterium in deuterated phenylboronic acid is easily lost by deuterium hydrogen exchange when hydrochloric acid is present in the reaction system and the reaction is carried out at a high temperature, and that, for example, when the solvent is distilled, the deuterium ratio of deuterated phenylboronic acid is greatly reduced when the temperature reaches about 60 ℃. On the other hand, if the reduced pressure distillation temperature is controlled to 55 ℃ or lower, the deuteration ratio of the deuterated phenylboronic acid will not decrease.
It should be understood that although the present invention has been described by way of example in terms of the preferred embodiments thereof, it should not be limited to the embodiments described above, but various modifications and changes will become apparent to those skilled in the art. It will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims.
Industrial applicability
The preparation method can greatly improve the conversion rate of high-valence deuterated bromobenzene, shorten reaction time and improve purity, can ensure that deuterium in the deuterated phenylboronic acid is lost into a reaction system without deuterium-hydrogen exchange in the preparation reaction process, and ensures that the deuterated rate of a product is basically the same as that of raw material deuterated bromobenzene. The preparation method has the characteristics, so that the preparation method is suitable for industrial mass production of the deuterated phenylboronic acid.
Claims (14)
1. A method for preparing deuterated phenylboronic acid uses an organolithium reagent method to prepare deuterated phenylboronic acid.
2. The process of claim 1, the organolithium reagent process comprising the steps of:
reacting deuterated bromobenzene with an organic lithium reagent to synthesize deuterated phenyl lithium, adding an esterifying agent into the solution for continuous reaction, and adding acid into the solution for acidification to generate deuterated phenylboronic acid.
3. The process of any one of claims 1-2, wherein the reaction of deuterated bromobenzene with organolithium reagent to synthesize deuterated phenyllithium is carried out at-40 ℃ to-80 ℃, preferably at-60 ℃.
4. The method of any one of claims 1-3, wherein the deuterated bromobenzene is reacted with organolithium reagent to synthesize deuterated phenyl lithium in a reaction time of 0.1 to 10 hours, more preferably 0.3 to 6 hours, even more preferably 2.5 to 5.5 hours, and most preferably 5 hours.
5. The process according to any one of claims 1 to 4, wherein the addition of the esterifying agent to the solution is continued for a reaction time of 0.1 to 10 hours, more preferably 0.3 to 5 hours, still more preferably 2.5 to 4.5 hours, and most preferably 4 hours.
6. The process of any one of claims 1 to 5, wherein the organolithium reagent is n-butyllithium.
7. The method of any one of claims 1-6, wherein deuterated bromobenzene is dissolved in a solvent comprising 2-methyltetrahydrofuran.
8. The process of any one of claims 1 to 7, wherein the esterifying agent is triisopropyl borate.
9. The method of any one of claims 1-8, wherein the amount of deuterated bromobenzene to organolithium reagent is 1:1-1.5, preferably 1.
10. The method of any one of claims 1-9, wherein the acid is a hydrochloric acid solution.
11. The method according to any one of claims 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 of any one of claims 1-11, further comprising the step of:
a purification step of purifying the deuterated phenylboronic acid.
13. The method of any one of claims 1-12, wherein the purification step is performed as follows:
standing and layering the reactant, collecting an organic phase, distilling under reduced pressure to evaporate the solvent, and recrystallizing and purifying.
14. The process according to any one of claims 1 to 13, wherein the temperature at which the solvent is evaporated by distillation under reduced pressure is controlled to 60 ℃ or lower, more preferably 55 ℃ or lower.
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