JP6235932B2 - Method for producing 2-cyanophenylboronic acid derivative - Google Patents

Description

  The present invention relates to a method for producing a 2-cyanophenylboronic acid derivative that can be a raw material for pharmaceuticals and electronic materials.

  2-Cyanophenylboronic acid and its derivatives are useful as raw materials for electronic materials such as pharmaceuticals and liquid crystals used in the Suzuki coupling reaction.

  Common boronic acid production methods include (1) hydrolysis after transmetalation reaction of arylsilane or arylstannane compound and boron tribromide, and (2) aryl halide or aryl triflate and pinacol. A method of coupling borane or bispinacol diborate with a transition metal catalyst, (3) A method of reacting aryl halide with an organometallic compound such as arylmagnesium halide or aryllithium and then reacting with trialkoxyborane Etc. are known.

  The method of (3) is generally used as an industrial production method. Among boronic acids, boronic acids containing a nitrile group react with n-butyllithium because an organic magnesium compound reacts with a nitrile group. A method of reacting with a halogenated benzonitrile at a low temperature is generally used. However, it is also known that 2-cyanophenylboronic acid can be obtained only in a low yield even when n-butyllithium is used.

  Patent Document 1 describes a method in which 2-bromobenzonitrile is reacted with t-butyllithium to obtain 2-cyanophenylboronic acid as a target product in a high yield (Preparative Example 1). Patent Document 1 also includes a method in which a halogenated benzonitrile is coupled with pinacol borane or bispinacol diborane using a noble metal catalyst to obtain a target pinacol ester of 2-cyanophenylboronic acid (Preparative Example). 2).

  Non-Patent Document 1 discloses that an organic phase obtained by esterification with neopentyl glycol is further solidified via an ortho-trithiolation reaction with lithium 2,2,6,6-tetramethylpiperidide using benzonitrile as a raw material. It is reported that neopentyl glycol ester of 2-cyanophenylboronic acid can be obtained.

  In Patent Document 2, when the reaction solution is treated with an acidic aqueous solution, the pH of the aqueous phase is set to less than 7, so that N-benzoyl-2,2,6,6-tetramethylpiperidine is present even in a system in which water is present. To 1-phenyl-1- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine is stably present, followed by extraction with an organic solvent to produce a by-product 1-phenyl-1- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine is stably and selectively extracted into an acidic aqueous phase to obtain 2-cyanophenylboronic acid with high purity. There are also reports on how to obtain

  Patent Document 3 reports a method using lithium magnesium di-2,2,6,6-tetramethylpiperidide as a method for suppressing the addition reaction to nitrile in the orthotritation reaction of benzonitrile.

  In Non-Patent Document 2, a method for carrying out an ortho-tritation reaction of benzonitrile by suppressing addition reaction to the nitrile position using lithium 2,2,6,6-tetramethylpiperidide and triisobutylaluminum. Has been reported.

European Patent EP-0675118A Specification Japanese Patent 5209183 Special table 2010-516649

Organic Lett. 3 (10), 1435-1437 (2001) J.Am.Chem.Soc. 2004, 126, 10526-10527

  However, in the method described in Patent Document 1, the raw materials 2-bromobenzonitrile and t-butyllithium are expensive, and 2-cyano-3-bromophenylboronic acid, which is difficult to separate, is produced as a by-product. There were problems such as not improving. In another method described in Patent Document 1, since the raw material halogenated benzonitrile and the pinacolborane raw material are expensive, and an expensive catalyst is required for coupling, there is a problem as an industrial production method.

  In the method described in Non-Patent Document 1, the addition reaction of lithium 2,2,6,6-tetramethylpiperidide proceeds to the nitrile group of benzonitrile, and N-benzoyl-2,2,6,6-tetra There is a problem that methylpiperidine is by-produced by about 20 to 25% and the yield and purity of 2-cyanophenylboronic acid are lowered.

  The method described in Patent Document 2 also had a low yield of 57.4% due to side reactions.

  The production method described in Patent Document 3 was not satisfactory because the yield was as low as 66%.

  In the production method described in Non-Patent Document 2, the active species hardly reacts with trialkoxyborane. Therefore, the present inventors have confirmed that it cannot be applied to boronic acid synthesis (see Comparative Example). The methods described in Patent Document 3 and Non-Patent Document 2 also have a problem in that it is necessary to use an excessive amount (2 equivalents) of 2,2,6,6-tetramethylpiperidine that is both expensive.

Therefore, the problem to be solved by the present invention is to provide a lithium 2,2,6,6-tetramethyl in a method for producing a 2-cyanophenylboronic acid derivative using lithium 2,2,6,6-tetramethylpiperidide. An object of the present invention is to provide a method capable of producing a 2-cyanophenylboronic acid derivative at a high yield and at a low cost without using an excessive amount of piperidide and suppressing side reactions of nitrile group addition.

  The present inventor has intensively studied in view of the above problems. As a result, by reacting an aromatic nitrile and trialkoxyborane in the presence of an alkali metal and lithium 2,2,6,6-tetramethylpiperidide, lithium 2,2,6,6-tetramethylpiperide was reacted. 2-Cyanophenylboronic acid and its derivatives in high yield without using an excessive amount of perizide and suppressing the addition reaction of lithium 2,2,6,6-tetramethylpiperidide to the nitrile group As a result, the present invention has been completed.

That is, the present invention relates to a process for producing 2-cyanophenylboronic acid and derivatives thereof having the following description,
Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different from each other from hydrogen, a C1-C12 alkyl group, a C6- C12 aryl group and a C7- C12 aralkyl group. An aromatic nitrile represented by a hydrocarbon group or halogen atom selected from the group consisting of trialkoxyborane (in the presence of an alkali metal salt and lithium 2,2,6,6-tetramethylpiperidide) However, the alkoxy group has 1 to 6 carbon atoms), and the reaction with the general formula (2):
(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above)
The manufacturing method of 2-cyanophenyl boronic acid derivative shown by these.

(2) The production according to (1), wherein the lithium 2,2,6,6-tetramethylpiperidide is prepared from 2,2,6,6-tetramethylpiperidine and a C1-C6 alkyllithium. Law.
(3) The production method according to (2), wherein the alkyllithium of C1 to C6 is n-butyllithium.

(4) The C1-C6 alkyl lithium is used in an amount of 0.8 to 1.1 mol with respect to 2,2,6,6-tetramethylpiperidine, according to (2) or (3) Manufacturing method.
(5) The production method according to any one of (2) to (4), wherein the alkali metal salt is an alkali metal halide.
(6) The alkali metal salt according to any one of (1) to (5), wherein the alkali metal salt is used in an amount of 0.5 equivalent or more with respect to lithium 2,2,6,6-tetramethylpiperidide. Manufacturing method.

(7) A step of obtaining a 2-cyanophenylboronic acid derivative represented by the general formula (2) by carrying out the method according to any one of (1) to (6), and the step obtained A step of reacting a 2-cyanophenylboronic acid derivative represented by the general formula (2) with a C1-C8 monoalcohol or diol for esterification, the general formula (3):
(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, R ⁵ is an alkyl group having 1 to 8 carbon atoms, and may be bonded to each other to form a ring)
The manufacturing method of 2-cyanophenyl boronic acid ester derivative shown by these.

(8) The production method according to (7), wherein the diol is 1,3-propanediol.

According to the method of the present invention, a 2-cyanophenylboronic acid derivative can be obtained at a higher yield and lower cost than the conventional production method.

<Production method of general formula (2)>
The present invention is described in detail below.
A method for producing a 2-cyanophenylboronic acid derivative represented by the general formula (2) is obtained by converting an aromatic nitrile represented by the general formula (1) into an alkali metal salt and lithium 2,2,6,6-tetramethylpiperidi. And a trialkoxyborane (wherein the alkoxy group is from 1 to 6 carbon atoms) in the presence of a hydrogen atom. The production method of the present invention is characterized in that the above reaction is carried out in the presence of an alkali metal salt and lithium 2,2,6,6-tetramethylpiperidide.

R ¹ , R ² , R ³ and R ⁴ in the general formula (1) or (2) may be the same or different from each other, hydrogen, C1 to C12 alkyl, C6 to C12 aryl and C7 to C12. A hydrocarbon group selected from the group consisting of aralkyl groups, or a halogen atom. Specifically, R ¹ , R ² , R ³ and R ⁴ represent, for example, a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cycloalkyl group, an aryl group, fluorine, chlorine, bromine, iodine or the like. Of these, alkyl groups such as a methyl group, an ethyl group, and an isopropyl group, and a hydrogen atom are preferable.

Specific compounds represented by the general formula (1) include benzonitrile (R ¹ , R ² , R ³ and R ⁴ are all hydrogen atoms), 1-cyano-4-methylbenzene (R ¹ , R ³ and R ⁴ are hydrogen atoms, R ² is a methyl group), and 1-cyano-4-fluorobenzene (R ¹ , R ³ and R ⁴ are hydrogen atoms, R ² is a fluorine atom) And the like. These compounds are all known compounds. Specific compounds represented by the general formula (2) include 2-cyanophenylboronic acid (R ¹ , R ² , R ³ and R ⁴ ) using the specific compound represented by the general formula (1) as a raw material. Are all hydrogen atoms), 2-cyano-5-methylphenylboronic acid (R ¹ , R ³ and R ⁴ are hydrogen atoms, R ² is a methyl group), and 2-cyano-5- And fluorophenylboronic acid (R ¹ , R ³ and R ⁴ are hydrogen atoms, and R ² is a fluorine atom).

  For alkali metal salts, specifically, lithium chloride, lithium bromide, lithium fluoride, lithium iodide, lithium nitrate, lithium sulfate, lithium carbonate, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, Examples thereof include sodium nitrate, potassium chloride, potassium bromide, potassium fluoride, potassium iodide, potassium nitrate, cesium chloride, cesium bromide, cesium iodide, etc., preferably lithium chloride, lithium bromide, potassium chloride, bromide Sodium is mentioned.

  As lithium 2,2,6,6-tetramethylpiperidide, those obtained by a known synthesis method can be used without particular limitation. For example, it is prepared by reaction of 2,2,6,6-tetramethylpiperidine and C1-C6 alkyllithium. 2,2,6,6-tetramethylpiperidine is a known compound and is commercially available. The C1-C6 alkyllithium is preferably C4 n-butyllithium from the viewpoint that the above reaction can be easily carried out. In consideration of operational safety, n-butyllithium is suitably used, for example, as a solution in an organic solvent such as hexane. Examples of the C1-C6 alkyl lithium other than n-butyl lithium include s-butyl lithium, t-butyl lithium, methyl lithium, ethyl lithium, n-propyl lithium, 2,2-dimethylpropyl lithium, and hexyl lithium. be able to.

  In the lithium 2,2,6,6-tetramethylpiperidide formation, the C1-C6 alkyllithium is 0.8 or more and 1.1 mol relative to 2,2,6,6-tetramethylpiperidine. It is used in the following, preferably in the range of 0.8 to 1.05 mol with respect to 2,2,6,6-tetramethylpiperidine. By making the amount of C1-C6 alkyl lithium used in this range, it is possible to suppress generation of by-products by reacting C1-C6 alkyl lithium with a nitrile group even when an excess amount is present. There is.

  When lithium 2,2,6,6-tetramethylpiperidide is prepared from 2,2,6,6-tetramethylpiperidine and n-butyllithium, 2,2,6,6-tetramethylpiperidine On the other hand, it is appropriate to use 0.8 to 1.1 mol of n-butyllithium. When n-butyllithium is excessive with respect to 2,2,6,6-tetramethylpiperidine, n-butyllithium itself reacts with the nitrile group to produce a by-product, which is not preferable. Preferably, 6,6-tetramethylpiperidine is used in slight excess. The amount of n-butyllithium used is more preferably 0.8 or more and 1.05 mol or less.

  The alkali metal salt can be used at 0.5 equivalent or more with respect to lithium 2,2,6,6-tetramethylpiperidide. Preferably it is 0.8-1.5 equivalent with respect to lithium 2,2,6,6-tetramethylpiperidide. By setting it within this range, there is an advantage that the addition reaction of lithium 2,2,6,6-tetramethylpiperidide to the nitrile group can be remarkably suppressed.

  The lithium 2,2,6,6-tetramethylpiperidide is, for example, an organic solvent containing 2,2,6,6-tetramethylpiperidine (for example, THF, diethyl ether, methyl-t-butyl ether, cyclopentyl). It can be formed by adding C1-C6 alkyl lithium to methyl ether, toluene, etc.). C1-C6 alkyl lithium is preferably added dropwise as a solution of an organic solvent such as hexane. Further, the addition of the C1-C6 alkyl lithium is more preferably performed under cooling. More specifically, a method of preparing by lithiation by adding n-butyllithium to a THF solution of 2,2,6,6-tetramethylpiperidine is exemplified. The prepared lithium 2,2,6,6-piperidide does not need to be completely dissolved in the solution, but is used in the reaction as a slurry solution containing lithium 2,2,6,6-tetramethylpiperidide crystals. You can also In the case of preparing lithium 2,2,6,6-tetramethylpiperidide by adding C1-C6 alkyllithium to an organic solvent containing 2,2,6,6-tetramethylpiperidine, An alkali metal salt can be allowed to coexist in an organic solvent containing 6,6-tetramethylpiperidine. Lithium 2,2,6,6-tetramethylpiperidide prepared in the presence of an alkali metal salt can be directly subjected to the reaction with the next trialkoxyborane.

  Examples of the trialkoxyborane (wherein the alkoxy group has 1 to 6 carbon atoms) include, for example, trimethoxyborane, triethoxyborane, and triisopropoxyborane that are generally used in boronic acid synthesis. A particularly preferred example is triisopropoxyborane.

  An aromatic nitrile represented by the general formula (1) is mixed with trialkoxyborane in the presence of an alkali metal salt and lithium 2,2,6,6-tetramethylpiperidide, and represented by the general formula (2). 2-cyanophenylboronic acid is obtained.

  Lithium 2,2,6,6-tetramethylpiperidide can be used, for example, in a molar ratio of 0.9 to 2 with respect to the aromatic nitrile represented by the general formula (1). By using this range, there is an advantage that the amount of expensive 2,2,6,6-tetramethylpiperidine used can be reduced.

  The trialkoxyborane can be used at a molar ratio of 0.9 to 5 with respect to the aromatic nitrile represented by the general formula (1). By setting it within this range, there is an advantage that the conversion rate from the nitrile compound to the boronic acid can be improved.

  The order of addition of the substrate in the synthesis of the 2-cyanophenylboronic acid derivative is not particularly limited, but considering the thermal stability of lithium 2,2,6,6-tetramethylpiperidide and orthotrithio, the prepared lithium 2 A method in which trialkoxyborane and an aromatic nitrile are sequentially or simultaneously added to a 2,2,6,6-tetramethylpiperidide solution is preferred.

  The solvent used for the reaction can be appropriately selected from solvents having no active protons. In addition to the reaction without solvent, examples include aromatic hydrocarbons such as toluene, ethers such as diethyl ether, t-butyl methyl ether, diisopropyl ether, and THF. A particularly preferred example is THF.

  Examples of the reaction temperature include a range of −100 ° C. to 0 ° C. When the temperature is lower than −100 ° C., the reaction is slow, and when the temperature is higher than 0 ° C., a by-product (1-phenyl-1- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine) Is unfavorable because of the increase in A particularly preferred temperature is -80 ° C to -20 ° C. The reaction time is, for example, in the range of 2 to 5 hours. However, it is not intended to be limited to this range, and can be appropriately determined in consideration of the progress of the reaction and the like.

  The 2-cyanophenylboronic acid (reaction product) represented by the general formula (2) can be used in the next reaction (use) as it is or after being appropriately purified. For example, it can be used for the production of an ester derivative described later.

<Method for producing 2-cyanophenylboronic acid ester derivative of general formula (3)>
The present invention includes a step of carrying out the method for producing a 2-cyanophenylboronic acid derivative represented by the general formula (2) of the present invention, and a 2-cyanophenyl represented by the general formula (2) obtained in this step. It includes a method for producing an ester derivative represented by the general formula (3), which comprises a step of esterifying a boronic acid derivative with an alcohol.

R ⁵ in the general formula (3) represents a linear or branched alkyl group having 1 to 8 carbon atoms or an allyl group. Further, it may be cyclic, and specifically includes, for example, a methyl group, ethyl group, isopropyl group, oxygen, and cyclic 1,3-propanediol ester, neopentyl glycol ester, catechol ester, pinacol ester and the like. .

  The 2-cyanophenylboronic acid derivative obtained by the method for producing a 2-cyanophenylboronic acid derivative represented by the general formula (2) of the present invention is an organic compound that is immiscible with water without isolation or isolation. It can be esterified by reacting with a C1-C8 monoalcohol or diol in a state dissolved in a solvent (eg: ethyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, methylene chloride, etc.). it can. The esterification reaction can be carried out by a usual esterification method.

Examples of the monoalcohol include methanol, ethanol, and isopropanol, and examples of the diol include 1,3-propanediol, catechol, pinacol, and the like. When monoalcohol is used, R ⁵ in general formula (3) is an alkyl group or allyl group, and when diol is used, R ⁵ in general formula (3) is a cyclic ester. The usage-amount of the monoalcohol or diol with respect to the 2-cyanophenyl boronic acid derivative shown by General formula (2) can be made into the range of 0.8-2.0 equivalent, for example, Preferably it is 0.9-1 .5 equivalent range.

  Although there is no restriction | limiting in particular in reaction temperature and time, For example, the range of 50 degrees C or less, Preferably, it is 1 minute or more at 15-25 degreeC, Preferably it is the range of 1 minute-10 hours, More preferably, it is 10 minutes-5 hours It can be implemented in the range.

  The effects of the present invention will be described below with reference to examples, but the present invention is not limited to these examples.

<Analysis conditions>
Liquid Chromatographic Analysis Sample Solution: The sample was dissolved in a mixed solution of water / acetonitrile = 40: 60 (V / V) so that the concentration of 2-cyanophenylboronic acid was 1 mg / 1 ml or less.

Equipment: Tosoh High Pressure Gradient System (manufactured by Tosoh Corporation)
Detector: UV-8020 (manufactured by Tosoh Corporation)
Column: YMC-Pack Pro C18 RS (4.6 mmφ × 150 mmL)
Temperature: 40 ° C
Mobile phase: Liquid A: water / acetonitrile / 70% perchloric acid (900/100/1 V / V / V)
Liquid B: water / acetonitrile / 70% perchloric acid (100/900/1 V / V / V)
Gradient method: Liquid B 0 min / 5% → 20 min / 5% → 40 min / 100% → 50 min / 100%

Flow rate: 1.0 ml / min
Detection wavelength: UV 230nm
Injection volume: 10 μl

Quantitative analysis conditions Liquid chromatography analysis: analysis conditions are the same as above Sample solution: About 400 mg of the organic phase after acid washing was dissolved in 50 ml of acetonitrile.
Calibration curve creation: Create a calibration curve with high concentration using 2-cyanophenylboronic acid samples with known concentrations (analysis 4 points)

    Quantification method: After analyzing the sample solution, the organic phase concentration is calculated from the prepared calibration curve, and the yield of 2-cyanophenylboronic acid is calculated from the weight of the organic phase.

Example 1 Synthesis Example of 2-Cyanophenylboronic Acid In a nitrogen-substituted 300 ml flask, 7.88 g (55.8 mmol) of 2,2,6,6-tetramethylpiperidine and 2.77 g (65.3 mmol) of lithium chloride: After adding 100 ml of THF to 1.17 equivalents of 2,2,6,6-tetramethylpiperidine), 24.2 g (58.2 mmol) of 15% -n-butyllithium hexane solution was added dropwise at -10 ° C. Lithium 2,2,6,6-tetramethylpiperidide solution was prepared. After cooling this solution to −50 ° C., 10.93 g (58.2 mmol) of triisopropoxyborane was added dropwise, followed by dropwise addition of 4.98 g (48.3 mmol) of benzonitrile, followed by aging at the same temperature for 3 hours. did. When the reaction solution was analyzed by HPLC, the area% of 2-cyanophenylboronic acid was 98.6%, and the area% was 1.38% 1-phenyl-1- (2,2,6,6-tetramethylpiperidine. By-product of -1-yl) methylimine was confirmed. This reaction solution was added to 38 ml of 3N HCl to conduct hydrolysis. After adding 150 ml of ethyl acetate and stirring, the acid phase was separated. The organic phase was washed with 50 ml of 0.2N HCl, and the resulting organic phase solution was quantified with 2-cyanophenylboronic acid using HPLC. As a result, the yield of 2-cyanophenylboronic acid was 95.0. % Was confirmed. Further, 1-phenyl- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine contained 0.45% by area%.

Examples 2 to 7 (Synthesis of 2-cyanophenylboronic acid)
In Example 1, the reaction was performed in the same manner as in Example 1 except that the equivalents of alkali metal salt and alkali metal salt were changed. The results are shown in Table 1. Comparative Example 1 is also shown in Table 1.

Example 8 Synthesis of 2-cyanophenylboronic acid ester To the organic phase obtained in Example 1, 3.69 g (48.5 mmol) of 1,3-propanediol was added and stirred at room temperature for 1 hour. After the separated aqueous phase was separated, the solvent was distilled off with an evaporator. To the residual oily substance, 2 ml of toluene and 120 ml of heptane were added to precipitate crystals. The obtained crystals were washed with 30 ml of heptane and then dried to obtain 1,3-propanediol ester of 2-cyanophenylboronic acid (2- (1,3,2-dioxaborin-2-yl) benzonitrile) 7 .44 g (yield: 82.4%) was obtained. This crystal contained 0.40% of 1-phenyl-1- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine.

Comparative Example 2: Lithium 2,2,6,6-tetramethylpiperidine and triisobutylaluminum (boronic acid synthesis was performed by the method of Non-Patent Document 2)
In a 300 ml flask purged with nitrogen, 7.53 g (53.3 mmol) of 2,2,6,6-tetramethylpiperidine was dissolved in 100 ml of THF, and then 20% of 15% n-butyllithium hexane solution at −78 ° C. After 8 g (48.5 mmol) was added dropwise, the mixture was aged at 0 ° C. for 30 minutes. After aging, the mixture was cooled to −78 ° C., and then 35.6 g (50.9 mmol) of a 28% triisobutylaluminum hexane solution was added dropwise, followed by aging at 0 ° C. for 30 minutes. After aging, the mixture was cooled to −78 ° C. and 2.5 g (24.2 mmol) of benzonitrile was added dropwise. After aging for 2 hours, 17.8 g (94.6 mmol) of triisopropoxyborane was added, Although it was aged at -40 ° C for 2 hours and at room temperature for 40 hours, the formation of 2-cyanophenylboronic acid was not confirmed.

Comparative Example 3: Lithium magnesium di-2,2,6,6-tetramethylpiperidide (boronic acid synthesis by the method of Patent Document 3)
In a 200 ml flask purged with nitrogen, 0.77 g (31.7 mmol) of ground magnesium and 65 ml of THF were added. 3.17 g (32.0 mmol) of 1,2-dichloroethane was added dropwise and the reaction was stirred for about 3 hours until all the magnesium was consumed. In another 300 ml flask purged with nitrogen, 9.04 g (64.0 mmol) of 2,2,6,6-tetramethylpiperidine and THF (30 ml) were placed. The solution was cooled to −40 ° C. and 27.3 g (63.9 mmol) of 15% -n-butyllithium hexane solution was added dropwise. After the addition, the reaction was warmed to 0 ° C. and stirred at the same temperature for 30 minutes. The MgCl ₂ solution was added dropwise to the lithium-2,2,6,6-tetramethylpiperidide solution at 0 ° C. and the reaction mixture was stirred at 0 ° C. for 30 minutes, then warmed to room temperature and stirred for an additional hour. . The solution was removed under reduced pressure, and then 100 ml of THF was added with stirring until the salts were completely dissolved.

The prepared lithium magnesium di-2,2,6,6-tetramethylpiperidide-THF solution was added dropwise with 3.0 g (29.1 mmol) of benzonitrile at −20 ° C. and aged at −20 ° C. for 3 hours. , 4.54 g (43.7 mmol) of trimethoxyborane was added dropwise at the same temperature. After dropping, the mixture was aged at -20 ° C for 1 hour and then aged at room temperature for 3 hours. This reaction solution was added to 50 ml of 3N HCl to conduct hydrolysis. The organic phase solution obtained by extracting three times with 50 ml of ethyl acetate was subjected to quantification of 2-cyanophenylboronic acid using HPLC. As a result, it was found that 2-cyanophenylboronic acid was obtained at 66.0%. confirmed. Moreover, it contained 0.27% of 1-phenyl- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine.

  Since the nitrile group-containing aromatic boronic acid can be obtained at low cost according to the present invention, it is useful as a raw material for pharmaceuticals and electronic materials.

Claims (8)

Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different from each other from hydrogen, a C1-C12 alkyl group, a C6- C12 aryl group and a C7- C12 aralkyl group. An aromatic nitrile represented by a hydrocarbon group or halogen atom selected from the group consisting of trialkoxyborane (in the presence of an alkali metal salt and lithium 2,2,6,6-tetramethylpiperidide) However, the alkoxy group has 1 to 6 carbon atoms), and the reaction with the general formula (2):
(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above)
The manufacturing method of 2-cyanophenyl boronic acid derivative shown by these. The process according to claim 1, wherein the lithium 2,2,6,6-tetramethylpiperidide is prepared from 2,2,6,6-tetramethylpiperidine and a C1-C6 alkyllithium. The manufacturing method of Claim 2 whose said C1-C6 alkyl lithium is n-butyllithium. The production method according to claim 2 or 3, wherein the C1-C6 alkyl lithium is used in an amount of 0.8 to 1.1 mol with respect to 2,2,6,6-tetramethylpiperidine. The manufacturing method of any one of Claims 1-4 whose said alkali metal salt is a halide of an alkali metal. The method according to any one of claims 2 to 5, wherein the alkali metal salt is used in an amount of 0.5 equivalent or more based on lithium 2,2,6,6-tetramethylpiperidide. The process of obtaining the 2-cyanophenyl boronic acid derivative shown by the said General formula (2) by implementing the method of any one of Claims 1-6, and the general formula (2) obtained at the said process A step of reacting a C1-C8 monoalcohol or diol with a 2-cyanophenylboronic acid derivative represented by the general formula (3):
(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, R ⁵ is an alkyl group having 1 to 8 carbon atoms, and may be bonded to each other to form a ring)
The manufacturing method of 2-cyanophenyl boronic acid ester derivative shown by these.
  The process according to claim 7, wherein the diol is 1,3-propanediol.