KR20110045490A - Method for producing aromatic boric acid compound - Google Patents

Abstract

The present invention is a method for producing an aromatic boric acid by reacting an aryl magnesium halide and an alkyl boronate at a constant temperature in the presence of a co-solvent, aromatic in high yield and high purity under industrially applicable conditions The boric acid compound can be prepared, and the organoboron compound synthesized can be used as a key intermediate of electronic materials and pharmaceuticals.

Description

Process For Preparing Aromatic boronic Acid

The present invention relates to a method for producing an aromatic boronic acid compound, and more specifically, to an aromatic boronic acid (or aryl boronic acid, aryl) by reacting an aryl magnesium halide and an alkyl boronate at a constant temperature in the presence of a co-solvent Boronic acid).

Representative among aromatic boronic acid compounds are phenyl boronic acid (PBA), naphthalene boronic acid (NBA), fluorobenzene boronic acid (FBA), toluene boronic acid (TBA). The basic synthesis scheme of the aromatic boronic acid compound is as shown in the following figure to activate the aryl halide with a metal (Mg, Li), react with a boron compound such as trialkyl borate and boron, and then aryl boronic acid by quenching (Synthesis Organic Synthesis, Coll. Vol. IV, p68, John Wiley & Sons (1963)).

Scheme 1 Synthesis Scheme of Representative Aryl Boronic Acid

(OTF: trifluoromethanesulfonyloxy)

This method uses tetrahydrofuran (THF), which is expensive and dangerous to handle, and requires a reaction at cryogenic temperatures of -78 ° C as a reaction temperature condition to obtain an appropriate yield, and also to obtain magnesium (Mg) metal, Hazardous reagents such as lithium (Li) metals are used and therefore are not suitable for industrial methods due to the risk of fire and explosion due to hydrogen generation.

As a second synthesis method, a synthesis method using a noble metal catalyst such as palladium and a diborane compound such as bis (pinacolato) diborane, as shown in Scheme 2, has been reported to be developed in a laboratory (Ref. J). Org.Chem. 60, 7508-7510 (1995)).

Scheme 2

However, the above method is also a low-temperature reaction, but difficult to recover expensive noble metal catalyst, and the reaction proceeds only by using a ligand such as phosphorus (P) -based dichlorobis (diphenylphosphino perusenir) (DPPF) It is still difficult to apply industrially.

Therefore, in order to develop a synthetic method that can be economically and industrially applied, the conditions of the reaction solvent, reaction temperature, and acid treatment method through preliminary experiments of phenylboronic acid are changed to find the optimum operating conditions and industrial use. The possible methods were found and the following invention was completed.

In the conventional method, that is, the conventional classical Grignard method, a high yield is obtained only by synthesizing at a very low temperature, for example, a temperature of about -70 ° C. Therefore, the operating conditions of about -70 ° C are industrially applied. There was a problem that this was difficult. In order to industrially manufacture by such a conventional method, it is preferable to manufacture at least at -20 ° C to around 0 ° C to room temperature. However, there have been disadvantages in that the yield is low and many impurities are generated in this temperature range.

Accordingly, the present invention is to provide a method for producing an aromatic boronic acid by using a specific co-solvent to obtain a result of improved yield in the industrially applicable temperature range (-40 ~ 0 ℃ range) .

First, the present inventors synthesized Ph-MgBr by adding Mg, Et ₂ O (diethyl ether) or THF to reflux to bromobenzene to react with trimethyl boride, and then reacted with 10% H ₂ SO ₄ or saturated NH _4. In the process of quenching with Cl or 2N HCl to obtain the desired phenylboronic acid, it is experimentally synthesized and analyzed by TLC, HPLC, ¹³ C NMR, ¹ H NMR, IR, etc. It was intended to invent the method. In addition, the possibility of producing by-products other than the product in the process of synthesizing the possibility was examined through the following mechanism.

1) Mechanism

The present inventors believe that the reaction factors that can affect the yield of the product (phenylboronic acid) through the above mechanism are (1) solvent, (2) reaction temperature, (3) quenching method, (4) crystallization temperature. In consideration of each of these effects through various experiments.

(1) Influence of solvent

Using the same solvent, acid treatment method, and crystallization temperature and lowering the reaction temperature from room temperature to -70 ° C, the experiment showed that the lower the reaction temperature, the better the yield. Based on these results, experiments were carried out to investigate the effect of solvent on the reaction at low temperatures. The solvent was changed from THF to Et ₂ O, the reaction temperature was −60 ° C., the crystallization temperature was room temperature, and the acid treatment method was the same as 10% H ₂ SO ₄ . As a result, it was found that the solvent was Et ₂ O and the reaction temperature was -60 ° C. to -70 ° C., whereby the product was obtained with better yield. However, the above experiments did not yield high yields.

(2) influence of crystallization temperature

Subsequently, other factors as shown in Robert M. Washburn; Ernest Levenes; Charles F. Albright; Franklin A. Billig. Org.Synth . Coll., 1963, 4, 68 ; 1959, 39, 3; Among them, the lower the crystallization temperature was expected to obtain a higher yield was tested by changing the crystallization temperature.

Et ₂ O is used as the solvent, the reaction temperature is -60 ° C., and the acid treatment method is the same as that of 10% H ₂ SO ₄ , and the crystallization temperature is lowered from room temperature to 0 ° C .. It can be synthesized in a higher yield than the literature 1, the lower the crystallization temperature was synthesized in a higher yield.

(3) Effect of acid quenching method

After obtaining the above results, it will be described how the acid treatment method may affect the yield of the reaction. THF was used as the solvent, the reaction temperature and the crystallization temperature were the same at room temperature, and the acid treatment method was changed from 10% H ₂ SO ₄ to saturated NH ₄ Cl.

Higher yields were obtained when saturated NH ₄ Cl was used than when quenching was used with 10% H ₂ SO ₄ . Better yields were obtained than the yields of prior art 2 (Kazuaki Ishihara; Suguru Ohara; Hisashi Yamamoto, Org. Synth. Coll., 2004 , 10 , 80; 2002, 79, 176), tested under the same conditions. This shows that it is better to use saturated NH ₄ Cl than to use 10% H ₂ SO ₄ in the acid quenching method.

In addition, as the solvent, THF was used, the reaction temperature and the crystallization temperature were kept at room temperature, and the acid treatment method was changed to 2N HCl. This experiment yielded better yields than that of saturated NH ₄ Cl. In other words, it was found that the acid treatment method is better to use saturated NH ₄ Cl than 10% H ₂ SO ₄ and 2N HCl rather than saturated NH ₄ Cl.

(4) Influence of use of cosolvent

On the other hand, the inventors of the present invention using Et ₂ O as the solvent, the reaction temperature is 0 ℃ ~ room temperature, the acid treatment using 2N HCl, the crystallization temperature of the reaction at room temperature as a result, the product of about 78% It was possible to synthesize in a yield, when using a co-solvent in the same conditions was able to obtain a yield of 84% at room temperature, 90% yield at -40 ℃.

Based on the results of the above various experiments, the present invention was selected as the optimum conditions that can be used industrially in the present invention by using a solvent as a co-solvent, a reaction temperature of -40 ° C. to room temperature, and an acid treatment solution as 2N HCl. As in the example, the synthesis process of PBA, NBA, FBA, TBA of a certain scale was carried out.

The present invention can synthesize an aromatic boron compound useful as a base material such as electronic materials or pharmaceuticals through an optimal synthesis method within the range of -40 ℃ to room temperature using a cosolvent.

As a first embodiment of the present invention, an aromatic boronic acid is reacted by reacting an aryl magnesium halide (Formula 1) and an alkyl boronate (Formula 2) in the presence of a co-solvent at a constant temperature, as shown in the following scheme. To prepare the formula (3):

Ar-MgX (Formula 1) + B (OR) ₃ (Formula 2) → Ar-B (OH) ₂ (Formula 3)

In this formula,

Ar is an aromatic phenyl group, naphthyl group, fluorobenzyl group or toluene group,

X is a halogen group such as chlorine or bromine,

In a second aspect of the invention, the cosolvent of the invention is based on any one of THF (tetrahydrofuran), methyl tetrahydrofuran and ether, with toluene, xylene, monochlorobenzene (MCB) and ortho-dichloro It is preferable that any one of benzene (ODCB) is selected and used jointly as a cosolvent.

Moreover, this invention is 3rd aspect, It is preferable to select the temperature of this invention in the range of -40-0 degreeC. If the reaction temperature is lower than -40 ℃ is not industrially preferable, if it exceeds 0 ℃ there is a problem that the yield and the like falls.

The reagents used in the synthesis of the present invention may be used as long as the reagents do not depart from the object of the present invention. Reagent phenylmagnesium bromide (Aldrich, 1.0 M solution in tetrahydrofuran) used in the synthesis of the present invention, trimethyl borate (TCI), 1-bromo-3-fluorobenzene (Aldrich, 99 +%), 2-bro Monaphthalene (Aldrich, 97%), bromobenzene (Sigma-Aldrich, 99%), 3-bromotoluene (Aldrich, 98%) were mainly purchased from Aldrich and used without purification. All solvents used were distilled off by the usual purification methods. Thin-Layer Chromatography (TLC) used silica gel 60 F254 (Merck 25). Ethyl acetate and hexane (manufactured by Daejung Chemical Co., Ltd.) were used as the eluent for TLC.

Generally, a cosolvent is a generic term for solvents used together in a specific reaction, taking into account specific reaction steps and costs. For example, co-solvents use two or more solvents, as melting a rubber with only toluene takes 12 hours, whereas adding a small amount of hexane, ethyl acetate, etc. reduces the dissolution time. It is also used to further increase the desired performance.

In the present invention, as described above, when using a co-solvent in the process of selecting the optimum conditions that can be industrially available on the basis of various experimental results for the synthesis of aryl boronic acid, the reaction temperature by chance even at -40 to 0 ℃ The present invention has been completed based on the fact that the product can be obtained in the desired yield.

As the basic solvent used in the present invention, any one of THF (tetrahydrofuran), methyl tetrahydrofuran and ether can be used as used in the prior art. Here, as the ether solvent, THF, diethyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, di-n-pentyl ether, methylcyclopentyl ether, methylcyclohexyl ether, di-n -Butyl ether, di-sec-butyl ether, diisopentyl ether, di-sec-pentyl ether, di-t-amyl ether, di-n-hexyl ether and the like.

In addition, as an auxiliary solvent to be used with the basic solvent of the present invention, any one of toluene, xylene, monochlorobenzene (MCB) and ortho-dichlorobenzene (ODCB) may be selected and used.

Product structure analysis and purity measurement

Used for structural analysis of the product of the present invention ¹ H-NMR and ¹³ C NMR were measured using 400 MHz FT-NMR (Bruker). Chemical shifts (d) are expressed in parts per million (ppm) relative to tetramethylsilane and coupling constants ( J values) are expressed in hertz. FT-IR was measured using VERTEX 70 (Bruker) in the laboratory.

The following examples specifically illustrate the process of directly preparing the aryl magnesium halide required in each embodiment starting from Mg to activate it, but by omitting the entire process, the allyl magnesium halide reagent can be directly purchased to directly alkyl. Reaction with boronate may produce the desired aryl boronic acid. In addition, the following examples and experimental procedures are provided to better understand the present invention, and do not limit the scope of the present invention as defined in the claims.

Example 1 Synthesis of Phenyl Boronic Acid (PBA)

1) Experimental method

Mg 15.5g (0.64 mol) was added to a 1 L three-necked flask, and the internal air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C. while stirring for 1 hr using a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.64 mol) of bromo benzene is dissolved in 300 ml of THF and slowly added over 1.5 hr.

100 g (0.96 mol) of trimethyl borate was added to a separate 1 L three-necked flask, and 150 ml of THF / toluene was added and stirred at -20 to 0 ° C. Here, phenylmagnesium bromide prepared above was slowly added dropwise (maintained at -20 to 0 ° C.) and stirred at 0 ° C. for 5 h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H ₂ O, dry over MgSO ₄ , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to determine the yield, purity (by LC).

2) Experimental result

The test procedure was carried out at the reaction temperature of 0 ℃, -10 ℃, -20 ℃, respectively, the average yield was 87%, it was possible to obtain a white solid with a purity of 99.0%. ¹ H NMR (400 MHz, CDCl ₃ ); δ 8.26 (d, 1H, J = 6.7 Hz, Ar-H), 7.74 (d, 1H, J = 6.8 Hz, Ar-H), 7.61 (t, 1H, J = 6.7 Hz, Ar-H), 7.43-7.54 (m, 1H, Ar-H), 7.41 (t, 1H, J = 6.8 Hz, Ar-H) ppm.

Example 2 Synthesis of Naphthalene Boronic Acid (NBA)

1) Experimental method

Mg 12.2g (0.50 mol) was added to a 1L three-necked flask, and the inside air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C while stirring for 1hr with a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.48 mol) of 2-bromonaphthalene is dissolved in 300 ml of THF and slowly added over 1.5 hr.

Into a separate 1 L three-necked flask, 74.8 g (0.72 mol) of trimethyl borate was added, and 150 ml of THF / toluene was added and stirred at -40 to -20 ° C. Here, phenylmagnesium bromide prepared above was slowly added dropwise (internal temperature maintained at -40 to -20 ° C) and stirred at 0 ° C for 5h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H ₂ O, dry over MgSO ₄ , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).

2) Experimental results

The test procedure was carried out at the reaction temperature of -20 ℃, -20 ℃, -40 ℃, respectively, the average yield was 83%, it was able to obtain a white solid with a purity of 99.3%. ¹ H NMR (400 MHz, DMSO); δ 9.11 (d, 1H, J = 6.7 Hz, Ar-H), 8.38 (d, 1H, J = 7.0 Hz, Ar-H), 7.92 (d, 1H, J = 7.9 Hz, Ar-H), 7.90 (t, 1H, J = 7.3 Hz, Ar-H), 7.88 (t, 1H, J = 6.4 Hz, Ar-H), 7.54-7.32 (m, 1H, Ar-H), 7.30 (dt, 1H, J _HF = 8.3 Hz, J = 2.6 Hz, Ar-H) ppm.

Example 3 Synthesis of Fluorobenzene Boronic Acid (FBA)

1) Experimental method

Mg 14.1 g (0.58 mol) was added to a 1 L three-necked flask, and the internal air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C. while stirring for 1 hr using a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.57 mol) of 3-fluorobenzene was dissolved in 300 ml of THF, and then slowly added over 1.5 hours.

88.3 g (0.85 mol) of trimethyl borate was added to a separate 1 L three-neck flask, and 150 ml of THF / toluene was added and stirred at -30 to -40 ° C. The phenylmagnesium bromide prepared above is slowly added dropwise (maintained at -30 ~ -40 ℃) and stirred for 5 h at 0 ℃. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H ₂ O, dry over MgSO ₄ , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).

2) Experimental results

The test procedure was carried out at the reaction temperature of -30 ℃, -30 ℃, -40 ℃ respectively, the average yield was 81.3%, it was able to obtain a white solid of 99.0% purity. ¹ H NMR (400 MHz, CDCl ₃ ); δ 7.99 (d, 1H, J _HF = 7.3 Hz, Ar-H), 7.86 (dd, 1H, J _HF = 8.9 Hz, J = 2.6 Hz, Ar-H), 7.48-7.53 (m, 1H, Ar -H), 7.30 (dt, 1H, J _HF = 8.3 Hz, J = 2.6 Hz, Ar-H) ppm.

Example 4 Synthesis of Toluene Boronic Acid (TBA)

1) Experiment Method

Mg 14.3g (0.59 mol) was added to a 1L three-necked flask, and the internal air was removed by vacuum. After washing three times with nitrogen, the temperature was raised to 200 ° C. while stirring for 1hr with a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.58 mol) of 3-methylbenzene bromide is dissolved in 300 ml of THF, and slowly added over 1.5 hr.

90.4 g (0.87 mol) of trimethyl borate was added to a separate 1 L three-necked flask, and 150 ml of THF / toluene was added and stirred at -40 to -20 ° C. The Grignard reagent (magnesium organometallic) prepared above was slowly added dropwise (maintained at -40 to -20 ° C) and stirred at 0 ° C for 5 h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H ₂ O, dry over MgSO ₄ , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).

2) Experiment result

The test procedure was carried out at the reaction temperature of -20 ℃, -20 ℃, -40 ℃ respectively, the average yield was 82%, it was able to obtain a white solid of 99.0% purity. ¹ H NMR (400 MHz, CDCl ₃ ); δ 8.05 (t, 1H, J = 5.6 Hz, Ar-H), 8.05 (s, 1H, Ar-H), 7.41 (t, 2H, J = 5.6 Hz, Ar-H), 2.47 (s, 3H , toluene CH ₃ ) ppm.

In consideration of the above Examples 1 to 4 as a whole, as a result of each performed at -40 to 0 ℃, the aromatic boronic acid to be synthesized in the present invention was each obtained an average yield of 81.3% to 87%. Through these examples, the present invention confirms that the desired aryl boronic acid PBA, NBA, FBA, TBA can be synthesized in a desired yield by using a cosolvent in an industrially available temperature range, that is, -40 to 0 ° C. Could.

The aromatic boronic acid compound obtained in the present invention will be usefully used as a base material for electronic materials or pharmaceuticals.

Those skilled in the art will appreciate that various changes and / or modifications may be made through the above detailed description and examples, and that such changes and / or modifications may be made without departing from the spirit of the invention. something to do. Accordingly, the appended claims should be construed as including all changes and / or modifications within the spirit and scope of the invention.

Claims (3)

A method of preparing an aromatic boronic acid (Chemical Formula 3) by reacting an aryl magnesium halide (Chemical Formula 1) and an alkyl boronate (Chemical Formula 2) at a predetermined temperature in the presence of a co-solvent as shown in the following scheme. : Ar-MgX (Formula 1) + B (OR) ₃ (Formula 2) → Ar-B (OH) ₂ (Formula 3) In this formula, Ar is an aromatic phenyl group, naphthyl group, fluorobenzyl group or toluene group, X is a halogen group such as chlorine or bromine, R is an alkyl group. The method of claim 1, wherein the cosolvent is based on any one of THF (tetrahydrofuran), methyl tetrahydrofuran and ether, toluene, xylene, monochlorobenzene (MCB) and ortho-dichlorobenzene ( ODCB) is selected and used jointly as a co-solvent. The method according to claim 1 or 2, wherein the temperature is -20 to 0 ° C.