Method for producing (2-methylpyrimidin-5-yl)boronic acid derivatives

Abstract

The method according to the present invention for producing (2-methylpyrimidin-5-yl)boronic acid derivatives (3) characteristically comprises a step for synthesizing 5-bromo-2-methylpyrimidine (2) by the decarboxylation of the carboxyl group from a 5-bromopyrimidine derivative (1). This enables the efficient production of 5-bromo-2-methylpyrimidine (2) by a method that has a low environmental load and thereby enables the efficient production of (2-methylpyrimidin-5-yl)boronic acid derivatives (3), which are useful as pharmaceutical intermediates.

Description

[Technical Field]

[0001] The present invention relates to a method for producing (2-methylpyrimidin-5-yl)boronic acid derivatives that are useful as pharmaceutical intermediates. [Background technology]

[0002] As a method for producing a (2-methylpyrimidin-5-yl)boronic acid derivative, the following method is known, in which 5-bromo-2-methylpyrimidine is used as a synthetic intermediate.

[0003] 1) 5-Bromo-2-iodopyrimidine is reacted with dimethylzinc in the presence of a palladium catalyst to produce 5-bromo-2-methylpyrimidine, which is then converted to 2-methyl-5-lithiopyrimidine by reaction with n-butyllithium at −78° C., and then reacted with triisopropoxyborane to produce (2-methylpyrimidin-5-yl)boronic acid through hydrolysis (Patent Document 1).

[0004] 2) Acetamidine hydrochloride and mucobromic acid are reacted in the presence of sodium ethoxide to give 5-bromo-2-methylpyrimidine-4-carboxylic acid, which is then converted to 5-bromo-2-methylpyrimidine. Subsequently, a mixture of 5-bromo-2-methylpyrimidine, bis(pinacolato)diboron, PdCl2(dppf)2, and potassium acetate is reacted at 85°C to produce 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Patent Document 2). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2015-537010 [Patent Document 2] Special Publication No. 2012-514650 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the method described in Patent Document 1 has a problem in that it uses a heavy metal reagent that places a heavy burden on the environment in the process of producing 5-bromo-2-methylpyrimidine.Furthermore, although the process of producing 5-bromo-2-methylpyrimidine described in Patent Document 2 does not use a heavy metal reagent, the yield in the step of synthesizing 5-bromo-2-methylpyrimidine-4-carboxylic acid is 42%, and the yield in the subsequent step of synthesizing 5-bromo-2-methylpyrimidine is 61%, so improvement in terms of yield is necessary. [Means for solving the problem]

[0007] As a result of extensive investigations, the present inventors have developed a method for producing (2-methylpyrimidin-5-yl)boronic acid derivatives that can be carried out on an industrial scale, thereby completing the present invention. That is, the present invention relates to the following [1] to [8]. [1] The following formula (1); [ka] (In the formula, R 1 represents a hydrogen atom or COH.) to obtain a 5-bromopyrimidine derivative represented by the following formula (2); [ka] The method includes a step of synthesizing 5-bromo-2-methylpyrimidine represented by the following formula (3): [ka] (In the formula, R 2 , R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent. 2 and R 3may be taken together to form a ring. [2] The method according to [1], wherein the decarboxylation step is carried out at a temperature of 150°C or less. [3] The method according to [1] or [2], wherein the decarboxylation step is carried out in at least one solvent selected from the group consisting of alcohols having 1 to 5 carbon atoms and water. [4] The production method according to any one of [1] to [3], comprising a step of contacting the 5-bromo-2-methylpyrimidine, a trialkoxyboron compound, and an organolithium reagent in a flow reactor to produce the (2-methylpyrimidin-5-yl)boronic acid derivative. [5] The production method according to [4], wherein the 5-bromo-2-methylpyrimidine, the trialkoxyboron compound, and the organolithium reagent are contacted at a temperature of −50° C. or higher. [6] The method according to [4] or [5], wherein a solution containing the 5-bromo-2-methylpyrimidine and the trialkoxyboron compound is contacted with the organolithium reagent. [7] The method according to any one of [4] to [6], wherein the trialkoxy boron compound is triisopropoxyborane. [8] The method according to any one of [4] to [7], wherein the organolithium reagent is n-butyllithium. [Effects of the Invention]

[0008] According to the present invention, (2-methylpyrimidin-5-yl)boronic acid derivatives useful as pharmaceutical intermediates can be efficiently produced by a method with little environmental impact. More specifically, according to the present invention, 5-bromo-2-methylpyrimidine, a synthetic intermediate for (2-methylpyrimidin-5-yl)boronic acid derivatives, can be efficiently produced without using heavy metal reagents. [Brief explanation of the drawings]

[0009] [Figure 1]FIG. 1 is a schematic diagram showing an example of the configuration of a flow reactor employed in the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] The method for producing a (2-methylpyrimidin-5-yl)boronic acid derivative according to the present invention will be described in detail below.

[0011] The 5-bromopyrimidine derivative, which is the starting material of the present invention, is represented by the following formula (1): [ka] (In the formula, R 1 represents a hydrogen atom or CO2H.

[0012] 5-Bromo-2-methylpyrimidine, an intermediate of the present invention, can be represented by the following formula (2): [ka] It is expressed as:

[0013] The (2-methylpyrimidin-5-yl)boronic acid derivative, which is the product of the present invention, is represented by the following formula (3): [ka] (In the formula, R 2 , R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent. 2 and R 3 may be joined together to form a ring.

[0014] where R 2 , R 3Examples of the alkyl group having 1 to 6 carbon atoms represented by the formula (I) include chain alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, and a neopentyl group; and cycloalkyl groups such as a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

[0015] R 2 and R 3 together form a ring, R 2 and R 3 are bonded together to form a ring consisting of the boron atom and the oxygen atom. 2 and R 3 The group formed by bonding together is *-R 2a -R 3a -* (* indicates the bond to the oxygen atom; R 2a is R 2 is a divalent group obtained by removing one hydrogen atom from 3a is R 3 R is a divalent group represented by the formula (a divalent group in which one hydrogen atom has been removed from R), and examples thereof include an ethylene group, a 1,1,2,2-tetramethylethylene group, a 1,1'-bicyclohexane-1,1'-diyl group, and a 2,2-dimethylpropane-1,3-diyl group. 2 and R 3 The ring formed by combining R is preferably a 5-membered or 6-membered ring, more preferably a 5-membered ring. 2 and R 3 When these are taken together to form a ring, specific examples of the (2-methylpyrimidin-5-yl)boronic acid derivative include compounds represented by the following formulas (4) to (7), and among these, compounds represented by the following formula (4) or (5) are preferred. [ka]

[0016] Examples of the substituent that the alkyl group having 1 to 6 carbon atoms may have include halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom; alkoxy groups such as methoxy group and ethoxy group; cyclic ether groups such as epoxy group; alkylthio groups such as methylthio group; acetyl group; cyano group; nitro group; alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; dialkylamino groups such as dimethylamino group and diethylamino group, etc. There is no particular limitation on the number of the substituents that the alkyl group having 1 to 6 carbon atoms may have.

[0017] Preferably R 2 and R 3 are both hydrogen atoms or isopropyl groups, or R 2 and R 3 is a 1,1,2,2-tetramethylethylene group, and more preferably R 2 and R 3 are both hydrogen atoms.

[0018] Next, regarding the method for producing the (2-methylpyrimidin-5-yl)boronic acid derivative represented by the formula (3), first, a step of synthesizing the 5-bromo-2-methylpyrimidine (2) (hereinafter sometimes referred to as compound (2)) by decarboxylating the carboxy group from the 5-bromopyrimidine derivative (1) (hereinafter sometimes referred to as compound (1)) will be described.

[0019] Compound (1), which is a raw material in the above step, can be obtained, for example, by hydrolyzing a compound represented by the following formula (1a) (hereinafter, sometimes referred to as compound (1a)).

[0020] [ka] (In the formula, R 1a is a hydrogen atom or -COOR 4a Represents R 4 and R 4a represents an alkyl group.

[0021] R 4 and R 4a The alkyl group represented by the formula (I) is preferably an alkyl group having 1 to 6 carbon atoms. 2 and R 3 Among them, a chain alkyl group is preferred, and a chain alkyl group having 1 to 4 carbon atoms is more preferred.

[0022] R 1a -COOR 4a It is preferable that:

[0023] The hydrolysis reaction is usually carried out in the presence of water and an acid or a base. A water-soluble organic solvent may be used together with the water as a solvent. Preferred water-soluble organic solvents include alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and ethylene glycol. Since an excessively large amount of the solvent is undesirable in terms of cost and post-treatment, the upper limit is preferably 50 times by weight or less, more preferably 20 times by weight or less, relative to the amount of compound (1a). The lower limit of the amount of the solvent is, for example, 1 time by weight or more relative to the amount of compound (1a).

[0024] Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc. One type of base may be used alone, or two or more types may be used in combination. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as sulfonic acids such as methanesulfonic acid, carboxylic acids such as acetic acid, citric acid, etc. One type of acid may be used alone, or two or more types may be used in combination. In the hydrolysis reaction, it is preferable to use 1 to 10 moles of an acid or a base per mole of compound (1a).

[0025] The reaction temperature is preferably 20 to 120° C., more preferably 30 to 80° C. The reaction time is usually 0.1 to 24 hours.

[0026] When the hydrolysis reaction is carried out in the presence of an acid, compound (1) can be directly synthesized. However, when the hydrolysis reaction is carried out in the presence of a base, a hydrolysate (salt) such as an alkali metal salt of compound (1) is obtained, and therefore a step of synthesizing compound (1) from the hydrolysate (salt) is required. When the hydrolysis reaction is carried out in the presence of a base, the hydrolyzate (salt) may be isolated or purified as needed after completion of the hydrolysis reaction. Alternatively, the hydrolyzate (salt) may be treated as a reaction mixture without isolation or purification to synthesize compound (1). Specifically, compound (1) can be synthesized by adding an acid to the reaction mixture. Hereinafter, the solution obtained by adding an acid to the reaction mixture may be referred to as a "compound (1)-containing acidic solution." Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as sulfonic acids such as methanesulfonic acid, carboxylic acids such as acetic acid, citric acid, etc. One type of acid may be used alone, or two or more types may be used in combination. The amount of acid used is preferably an amount that makes the pH of the acidic solution containing Compound (1) 2 to 5.

[0027] After hydrolysis in the presence of a base and subsequent addition of an acid, or when the hydrolyzate (compound (1)) remains without being decarboxylated after hydrolysis in the presence of an acid, compound (1) can be obtained by carrying out a general treatment for obtaining a product from the reaction solution. For example, compound (1) can be extracted by adding a general extraction solvent, such as toluene, methylene chloride, diethyl ether, ethyl acetate, hexane, tetrahydrofuran, or 2-methyltetrahydrofuran, to the reaction solution, and the reaction solvent and extraction solvent can be distilled off from the resulting extract by procedures such as reducing pressure and heating, to obtain compound (1). The compound (1) thus obtained has a purity sufficient to be used in the subsequent step, but the purity may be further increased by a common purification method such as fractional distillation, column chromatography, or activated carbon treatment in order to further increase the yield of the subsequent step or the purity of the compound obtained in the subsequent step.

[0028] Alternatively, the decarboxylation step may be carried out without isolating compound (1) from the acidic solution containing compound (1) or from the reaction solution obtained by carrying out the hydrolysis reaction in the presence of an acid. When the hydrolysis reaction is carried out in the presence of an acid, decarboxylation may proceed immediately after the hydrolysis.

[0029] The method for producing the compound represented by formula (1a) is not particularly limited, and examples thereof include the following method a and method b described in Tetrahedron, 2009, 65, 757-764. Method a: 5-Bromo-2-chloropyrimidine is reacted with a malonic acid alkyl ester (e.g., tert-butyl malonate, methyl malonate, etc.) in the presence of sodium hydride to produce a 2-(5-bromopyrimidin-2-yl)malonic acid alkyl ester (e.g., tert-butyl 2-(5-bromopyrimidin-2-yl)malonate, methyl 2-(5-bromopyrimidin-2-yl)malonate, etc.), which is then hydrolyzed with an acid to produce a 2-(5-bromopyrimidin-2-yl)acetic acid alkyl ester (in formula (1a), R 1a is a hydrogen atom; for example, methyl 2-(5-bromopyrimidin-2-yl)acetate, etc. Method b: 5-Bromo-2-chloropyrimidine is reacted with a dialkyl malonate (e.g., diethyl malonate) in the presence of sodium hydride to give a dialkyl 2-(5-bromopyrimidin-2-yl)malonate (in formula (1a), R 1a Ga-COOR 4a For example, diethyl 2-(5-bromopyrimidin-2-yl)malonate.

[0030] Compound (1) undergoes a decarboxylation reaction under appropriate conditions (preferably under heating conditions), yielding the desired 5-bromo-2-methylpyrimidine (2). The reaction may be carried out without a solvent, or may be carried out with the addition of a solvent to improve heating efficiency and operability. The solvent is not particularly limited, but is preferably an alcoholic solvent or water, more preferably an alcohol having 1 to 5 carbon atoms or water. Specific examples include methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, or water, and even more preferably ethanol or water. These solvents may be used alone or in combination, with no particular limitation on the mixing ratio.

[0031] Since an excessively large amount of the solvent is undesirable in terms of cost and post-treatment, the upper limit is preferably 50 times by weight or less, more preferably 20 times by weight or less, relative to the amount of Compound (1). The lower limit of the amount of the solvent is, for example, 1 time by weight or more, preferably 5 times by weight or more, relative to the amount of Compound (1).

[0032] The upper limit of the reaction temperature in this step is preferably 150°C, more preferably 100°C, and particularly preferably 80°C. The lower limit is preferably 0°C, and more preferably 30°C.

[0033] The reaction time in this step is not particularly limited and may be set appropriately, but is preferably 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

[0034] In this step, the hydrolysis and decarboxylation of compound (1a) may be carried out continuously by placing the acidic solution containing compound (1) under appropriate conditions (preferably under heating conditions).

[0035] After the reaction is completed, a general treatment for obtaining a product from a reaction solution may be carried out. For example, a general extraction solvent, such as toluene, methylene chloride, diethyl ether, ethyl acetate, hexane, tetrahydrofuran, or 2-methyltetrahydrofuran, may be added to the reaction solution to extract compound (2). The reaction solvent and extraction solvent may then be distilled off from the resulting extract under reduced pressure, heating, or other procedures to obtain compound (2). The compound (2) thus obtained has a purity sufficient to be used in the subsequent step, but in order to further increase the yield in the subsequent step or the purity of the compound obtained in the subsequent step, the purity may be further increased by a common purification method such as fractional distillation, column chromatography, or activated carbon treatment.

[0036] According to the above process, 5-bromo-2-methylpyrimidine (2) can be efficiently synthesized without using heavy metal reagents, which have a large environmental impact. When 5-bromo-2-methylpyrimidine (2) is synthesized from compound (1a) by the above method, the overall yield is, for example, 75% or more, preferably 80% or more, and more preferably 85% or more.

[0037] Next, a method for producing the (2-methylpyrimidin-5-yl)boronic acid derivative (3) (hereinafter, sometimes referred to as compound (3)) from the 5-bromo-2-methylpyrimidine (2) will be described.

[0038] Specific production methods include, for example, the methods described in Patent Documents 1 and 2, which include a method of contacting 5-bromo-2-methylpyrimidine (2), a trialkoxyboron compound, and an organolithium reagent (hereinafter, sometimes referred to as Method c); and a method of contacting 5-bromo-2-methylpyrimidine (2), a diboronic acid ester compound, a palladium catalyst, and a base (hereinafter, sometimes referred to as Method d).

[0039] First, method c will be explained.

[0040] In method c, it is preferable to contact a mixture containing 5-bromo-2-methylpyrimidine (2) and a trialkoxyboron compound with an organolithium reagent. This allows the target compound (3) to be obtained in a higher yield. The mixture is preferably provided as a solution, and the organolithium reagent is also preferably provided as a solution. When the mixture is provided as a solution, it is preferable to dissolve 5-bromo-2-methylpyrimidine (2) and a trialkoxyboron compound in an organic solvent to form a raw material solution A. When the organolithium reagent is provided as a solution, it is preferable to dissolve the organolithium reagent in an organic solvent to form a raw material solution B.

[0041] The trialkoxy boron compound includes a compound represented by the following formula (30).

[0042] [ka] (In the formula, R 2 and R 3 is the same as above, and R 30 represents an alkyl group.

[0043] R 30 The alkyl group represented by the formula (I) is preferably an alkyl group having 1 to 6 carbon atoms. 2 and R 3 Among these, a chain alkyl group is preferred, a chain alkyl group having 1 to 4 carbon atoms is more preferred, and a methyl group, an ethyl group, or an isopropyl group is even more preferred.

[0044] Specific examples of the trialkoxyboron compound include trimethoxyborane, triethoxyborane, triisopropoxyborane, ethylene glycol methoxyboronate, pinacol methoxyboronate, pinacol ethoxyboronate, and pinacol isopropoxyboronate. Preferred are triisopropoxyborane, pinacol methoxyboronate, pinacol ethoxyboronate, and pinacol isopropoxyboronate, and more preferred is triisopropoxyborane.

[0045] The amount of the trialkoxy boron compound used relative to the amount of the 5-bromo-2-methylpyrimidine (2) is, for example, 0.1 to 10 equivalents, preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, and particularly preferably 1 to 2 equivalents, where the equivalent is a value calculated by dividing the amount of the trialkoxy boron compound by the amount of the 5-bromo-2-methylpyrimidine (2).

[0046] Examples of the organolithium reagent include methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, n-hexyllithium, n-heptyllithium, phenyllithium, etc. Preferred are n-butyllithium and n-hexyllithium, and more preferred is n-butyllithium.

[0047] The amount of the organolithium reagent used is, for example, 0.1 to 10 equivalents, preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, and particularly preferably 1 to 2 equivalents, relative to compound (2). Furthermore, by adjusting the amount of the organolithium reagent to preferably 1.05 to 5 equivalents, more preferably 1.10 to 3 equivalents, and even more preferably 1.13 to 2 equivalents, relative to compound (2), the target (2-methylpyrimidin-5-yl)boronic acid derivative (3) can be produced more efficiently. Here, the equivalent is a value calculated by dividing the amount of the organolithium reagent by the amount of the compound (2).

[0048] A solution containing 5-bromo-2-methylpyrimidine (2) and a trialkoxy boron compound (preferably raw material solution A) is prepared by dissolving 5-bromo-2-methylpyrimidine (2) and a trialkoxy boron compound in an organic solvent (hereinafter, sometimes referred to as organic solvent A). Examples of organic solvent A include aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, methyl tert-butyl ether, 1,4-dioxane, and cyclopentyl methyl ether. These organic solvents A may be used alone or in combination, with no particular limitation on the mixing ratio. In the method c, from the viewpoints of reactivity, post-treatment, and the like, it is preferable to use at least one solvent selected from the group consisting of aromatic hydrocarbon solvents and ether solvents, and more preferably at least one solvent selected from the group consisting of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, methyl tert-butyl ether, and cyclopentyl methyl ether.

[0049] The amount of the organic solvent A used is, relative to 1 part by weight of the compound (2), for example, 0.1 parts by weight or more, preferably 0.5 parts by weight or more, more preferably 1.0 part by weight or more, and for example, 100 parts by weight or less, preferably 50 parts by weight or less, more preferably 30 parts by weight or less, and particularly preferably 10 parts by weight or less.

[0050] The raw material solution B is prepared by dissolving an organolithium reagent in an organic solvent (hereinafter, sometimes referred to as organic solvent B). Examples of the organic solvent B include aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, methyl tert-butyl ether, 1,4-dioxane, and cyclopentyl methyl ether. These organic solvents B may be used alone or in combination, with no particular limitation on the mixing ratio. In step c, from the viewpoint of storage stability of the organolithium reagent, it is preferable to use at least one solvent selected from the group consisting of aliphatic hydrocarbon solvents and aromatic hydrocarbon solvents, and more preferably at least one solvent selected from the group consisting of n-hexane, n-heptane, cyclohexane, methylcyclohexane, and toluene.

[0051] The amount of the organic solvent B used is, for example, 0.1 part by weight or more, preferably 0.5 part by weight or more, more preferably 1.0 part by weight or more, and for example, 100 parts by weight or less, preferably 50 parts by weight or less, more preferably 30 parts by weight or less, relative to 1 part by weight of the compound (2). The amount of the organic solvent B used is, for example, 0.1 part by weight or more, preferably 0.5 part by weight or more, more preferably 1.0 part by weight or more, and for example, 100 parts by weight or less, preferably 50 parts by weight or less, more preferably 30 parts by weight or less, relative to 1 part by weight of the organolithium reagent.

[0052] The reaction temperature in Method c can be, for example, 100° C. or lower, preferably 50° C. or lower, and more preferably 25° C. or lower. However, when a batch system is employed in Method c, extremely low temperature conditions such as below −70° C. are required to increase the yield. The lower limit of the reaction temperature is, for example, −90° C. or higher.

[0053] The reaction solution thus obtained is appropriately post-treated as needed. For example, the reaction of the reaction solution may be stopped (quenched) by adding a reagent (quenching agent) to stop the reaction, such as water; an acidic aqueous solution such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, or ammonium chloride; or an alkaline aqueous solution such as sodium hydroxide, potassium carbonate, or sodium bicarbonate. If necessary, an organic solvent such as ethyl acetate or toluene may be added to the obtained reaction solution or the quenched solution to extract the target compound.

[0054] The amount of water, acidic aqueous solution, or alkaline aqueous solution used in the quenching is not particularly limited, but the lower limit is usually 0.1 times by weight, preferably 0.5 times by weight, and more preferably 1 times by weight, and the upper limit is 100 times by weight, preferably 80 times by weight, and more preferably 50 times by weight, relative to the reaction substrate (i.e., compound (2) as a raw material). Note that the product (2-methylpyrimidin-5-yl)boronic acid derivative (3) is converted into a boronic acid ester (i.e., R 2 and R 3 at least one of R is an alkyl group having 1 to 6 carbon atoms which may have a substituent, or R 2 and R 3 When the reaction mixture is added to water, an acid or the like is added simultaneously to maintain the pH at approximately neutral. Alternatively, the product can be obtained as (2-methylpyrimidin-5-yl)boronic acid (i.e., a compound in which R in formula (3) 2 and R 3 In order to obtain the desired compound as a quenched product (a compound in which all of the nuclei are hydrogen atoms), the pH of the reaction mixture should be kept acidic during quenching. If necessary, an organic solvent such as ethyl acetate or toluene may be added to perform the quenching in a two-layer system of water and organic solvent. The extract can also be washed with acidic water, inorganic salt water, or water, as needed. The target compound can be obtained by distilling off the reaction solvent and extraction solvent from the obtained extract by heating under reduced pressure, etc.

[0055] The target compound thus obtained has a purity sufficient for use in the subsequent step, but in order to further increase the yield in the subsequent step or the purity of the compound obtained in the subsequent step, the purity may be further increased by a common purification method such as fractional distillation, column chromatography, or activated carbon treatment.

[0056] Next, method d will be explained.

[0057] The diboronic acid ester compound used in the method d includes a compound represented by the following formula (31).

[0058] [ka] (In the formula, R 2 and R 3 is the same as above. R 21 and R 31 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent. 21 and R 31 may join together to form a ring.)

[0059] R 21 and R 31 The alkyl group having 1 to 6 carbon atoms and optionally having a substituent represented by the formula: 2 and R 3 The alkyl group having 1 to 6 carbon atoms and optionally having a substituent represented by the formula (I) is the same as the group described above, and the preferred embodiments thereof are also the same. 21 and R 31 The rings that can be formed by combining these are R 2 and R 3 The embodiment is the same as that described above as a ring formed by R 2 and R 3 is R 21 and R 31 may be the same as or different from, but it is preferable that they are the same as.

[0060] Specific examples of diboronic acid ester compounds include bis(neopentylglycolato)diboron, bis(pinacolato)diboron, bis(hexyleneglycolato)diboron, bis(catecholato)diboron, bis(ethanediolato)diboron, bis(n-propandiolato)diboron, and bis(neopentanediolato)diboron. Of these, bis(neopentylglycolato)diboron, bis(pinacolato)diboron, and bis(hexyleneglycolato)diboron are preferred.

[0061] The amount of the diboronic acid ester compound used is preferably 0.5 to 10 equivalents relative to the amount of compound (2), more preferably 0.8 to 5 equivalents, and particularly preferably 1 to 2 equivalents, where the equivalent is a value calculated by dividing the amount of diboronic acid ester compound by the amount of compound (2).

[0062] Examples of the palladium catalyst used in method d include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride.

[0063] The amount of the palladium catalyst used is, for example, 0.0001 to 0.1 equivalents, and preferably 0.001 to 0.01 equivalents, relative to the compound (2), where the equivalent is a value calculated by dividing the amount of the palladium catalyst by the amount of the compound (2).

[0064] Examples of the base used in method d include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal salts of organic acids such as sodium acetate and potassium acetate, etc. Of these, alkali metal salts of organic acids are preferred, and alkali metal salts of acetic acid are more preferred.

[0065] The amount of the base used is preferably 0.5 to 10 equivalents relative to the amount of compound (2), more preferably 0.8 to 5 equivalents, and particularly preferably 1 to 3 equivalents, where equivalent is the amount of base per substance of compound (2).

[0066] In the method d, it is preferable to carry out the reaction in the presence of a solvent. Examples of the solvent used in the method d include aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, and ether solvents, which are described above as the organic solvent A. These solvents may be used alone or in combination of two or more, with no particular limitation on the mixing ratio. In the method d, it is preferable to use an ether solvent.

[0067] The amount of the solvent used is, for example, 0.1 parts by weight or more, preferably 0.5 parts by weight or more, more preferably 1.0 part by weight or more, and for example, 100 parts by weight or less, preferably 50 parts by weight or less, more preferably 30 parts by weight or less, relative to 1 part by weight of the compound (2).

[0068] In the method d, the reaction temperature is preferably 20 to 120°C, more preferably 50 to 100°C, and even more preferably 70 to 90°C. In the method d, the reaction time is not particularly limited, but is, for example, 30 minutes to 24 hours, and preferably 1 hour to 12 hours.

[0069] The reaction solution thus obtained is subjected to an appropriate post-treatment as needed. For example, the reaction solution obtained may be filtered as needed, and then the reaction solvent may be distilled off by heating under reduced pressure or the like to obtain the target compound.

[0070] The target compound thus obtained has a purity sufficient for use in the subsequent step, but in order to further increase the yield in the subsequent step or the purity of the compound obtained in the subsequent step, the purity may be further increased by a common purification method such as fractional distillation, column chromatography, or activated carbon treatment.

[0071] The above-mentioned methods c and d may be carried out batchwise or using a flow reactor. In particular, the use of a flow reactor in method c allows efficient implementation without the need for ultralow-temperature conditions such as the reaction at −78° C. as practiced in Patent Document 1, making it preferable from the viewpoint of industrial-scale production. When method c is carried out using a flow reactor, the (2-methylpyrimidin-5-yl)boronic acid derivative (3) may be produced by reacting a solution (raw material solution A) containing the 5-bromo-2-methylpyrimidine (2) and a trialkoxyboron compound introduced through raw material supply route 1 of the flow reactor with a solution (raw material solution B) of an organolithium reagent introduced through a separate raw material supply route 2.

[0072] Here, the term "flow reactor" refers to a microflow reactor that utilizes minute channels on the order of submillimeters, as well as chemical reaction devices that are scaled-up versions of such microflow reactors. Due to their minute reaction fields (microchannels), microflow reactors possess unique advantages, such as high-speed mixing (for example, mixing two liquids in a microspace shortens the mass diffusion distance between the two liquids, dramatically accelerating mass transfer), heat removal (the small reaction field results in extremely high thermal efficiency and easy temperature control), reaction control, and interface control. Furthermore, they offer advantages such as improved safety and significant reductions in equipment costs due to the compactness of the entire process, process enhancement through incorporation into existing processes, and the ability to produce substances that could not be produced using existing production methods. Flow reactors also include chemical reaction devices with improved operability achieved by enlarging the channel diameters to the order of millimeters to centimeters without compromising the characteristics of microflow reactors. These devices can increase throughput, making them suitable for practical use. Specifically, the flow reactor comprises two or more raw material supply channels (which may be raw material liquid delivery sections or raw material supply lines; sometimes referred to as "raw material supply ports"); a mixing section for mixing the supplied raw materials; a reaction section (also referred to as a reactor channel, retention channel, etc.; sometimes referred to as a reactor line or retention line) for circulating the reaction liquid containing the mixed raw materials; and a reaction liquid discharge channel (which may be a reaction liquid discharge section or reaction liquid discharge line; sometimes referred to as "reaction liquid discharge port") for discharging the reaction liquid that has circulated through the reaction section. As long as mixing is sufficient, the boundary between the mixing section and the reaction section need not be clear, may vary continuously, or may be integrated without distinction (hereinafter, sometimes referred to as the mixing / reaction section), or the mixing section and the reaction section may be independent. The channels in the mixing section and the reaction section may be fine channels, or may be linear or spiral channels such as tubes.

[0073] The flow reactor may include a reaction solution storage vessel for receiving the reaction solution discharged from the reaction solution discharge channel. The reaction solution storage vessel may contain a quenching agent to terminate the reaction in advance, or the reaction may be terminated by adding the quenching agent after the reaction solution has been stored in the reaction solution storage vessel.

[0074] The flow reactor may be equipped with a liquid delivery device such as a pump.

[0075] The flow reactor may also be equipped with a temperature control device (such as a temperature-controlled chamber, a temperature-controlled bath, a jacketed vessel, or a heat transfer medium channel) that can control the temperature of at least one of the raw material supply channel, the mixing section, and the reaction section (which may be both the mixing and reaction sections).The flow reactor may also be equipped with a temperature sensor for checking the temperature of the reaction solution.

[0076] FIG. 1 is a schematic diagram of an example of the configuration of a chemical reaction apparatus usable in the present invention. As shown in this example, the chemical reaction apparatus (flow reactor 12) preferably has two or more raw material supply channels (raw material supply channels 1, 5, and 2, 6 in the example of FIG. 1) for separately introducing raw material liquid A and raw material liquid B, a mixing section and a reaction section (mixing / reaction section 7 in the example of FIG. 1) for mixing raw material liquid A and raw material liquid B supplied from these raw material supply channels to cause a reaction in the reaction solution, and a reaction solution discharge channel (reaction solution discharge channel 10 in the example of FIG. 1) for discharging the reaction solution. If necessary, the chemical reaction apparatus may also be equipped with a temperature regulator (temperature regulator 9 in the example of FIG. 1) for regulating the reaction temperature and a temperature sensor (temperature sensor 8 in the example of FIG. 1) for monitoring the internal temperature.

[0077] In FIG. 1, liquid delivery devices 3 and 4 for supplying raw material liquids to the mixing / reaction section 7 may generally be liquid delivery pumps such as a diaphragm pump, a syringe pump, a plunger pump, or a peristaltic pump.

[0078] Although FIG. 1 shows a static mixer as the mixer used in the mixing / reaction section 7, a helix mixer may also be used. Furthermore, when the mixing section and the reaction section are separate, the mixing section and the reaction section may have various shapes. For example, the mixing section may be a T-shaped mixer (also called a T-tube), a Y-shaped mixer (also called a Y-tube), or a V-shaped mixer (also called a V-tube). The reaction section may have a structure in which minute flow channels are engraved on a plate-like plate, a structure in which these plate plates are stacked, or a tubular tube with an extremely small diameter. The tubular tube may have a straight structure, a structure with multiple bends, or a spiral structure.

[0079] The mixing / reaction section 7 is preferably tubular, and the shape of the cross section of the flow path may be any of circular, polygonal, and distorted circular (e.g., convex or concave), more preferably circular or polygonal.

[0080] The length of the mixing / reaction section 7 may be appropriately set depending on the reaction time (residence time), and is, for example, 0.5 cm or more, preferably 1.0 cm or more. The upper limit of the length of the mixing / reaction section 7 is, for example, 100 m or less, preferably 10 m or less.

[0081] The cross-sectional area of ​​the flow channel of the mixing and reaction section 7 is, for example, 0.01 mm 2 or more, preferably 0.15 mm 2 More preferably, it is 0.3 mm or more. 2 The upper limit of the cross-sectional area of ​​the flow channel in the mixing and reaction section is, for example, 300 cm 2 less than 70cm, preferably 2 and more preferably 30 cm or less. 2 The following is the result.

[0082] The material of the mixing / reaction section 7 is not particularly limited and may be appropriately selected depending on the requirements for solvent resistance, pressure resistance, heat resistance, etc. For example, metals such as stainless steel, Hastelloy, titanium, copper, nickel, and aluminum, resins such as PEEK resin, silicone resin, and fluororesin, glass, ceramics, and SiC can be used.

[0083] In FIG. 1, a flask is shown as the reaction liquid storage container 11 for receiving the reaction liquid, but the container is not limited to this and can be set appropriately depending on the size of the device, and may be a large tank or reaction vessel.

[0084] Furthermore, the chemical reaction device that can be used in the present invention is not limited to the flow reactor shown in FIG. 1, and known devices such as a plate-type microflow reactor, a cyclone-type reactor, and a stacked microfluidic chip can also be used as appropriate.

[0085] The time (reaction time, residence time) during which the reaction liquid obtained by mixing raw material liquid A and raw material liquid B flows through the mixing / reaction section of the flow reactor may be appropriately set depending on the types and concentrations of raw material liquid A and raw material liquid B and the flow rate at which raw material liquid A and raw material liquid B flow through the flow path, and is, for example, 0.001 millisecond or more, preferably 0.005 millisecond or more, and more preferably 0.01 millisecond or more, and is, for example, 15 minutes or less, preferably 10 minutes or less, and more preferably 5 minutes or less.

[0086] The flow rate at which raw material liquid A and raw material liquid B flow through the raw material supply flow path and the flow rate at which the reaction solution of raw material liquid A and raw material liquid B flows through the mixing / reaction section may be set appropriately depending on the types of raw material liquid A and raw material liquid B and the residence time in the mixing / reaction section, and is, for example, 0.01 mL / min or more, preferably 0.1 mL / min or more, and more preferably 0.5 mL / min or more, and is, for example, 5000 mL / min or less, preferably 3000 mL / min or less, and more preferably 1000 mL / min (60 L / hour) or less.

[0087] The amount of organolithium reagent in the reaction section (which may be the mixing / reaction section) is, for example, 0.1 to 10 equivalents, preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, and particularly preferably 1 to 2 equivalents relative to compound (2). Furthermore, by adjusting the amount of organolithium reagent in the reaction section (which may be the mixing / reaction section) to preferably 1.05 to 5 equivalents, more preferably 1.10 to 2 equivalents relative to compound (2), the target (2-methylpyrimidin-5-yl)boronic acid derivative (3) can be produced more efficiently. Here, the equivalent is a value calculated by dividing the amount of substance of organolithium reagent by the amount of substance of compound (2). The amount of organolithium reagent relative to compound (2) in the reaction section (which may be the mixing / reaction section) can be adjusted by adjusting the concentrations of compound (2) and organolithium reagent in raw material solutions A and B, and the flow rates of raw material solutions A and B.

[0088] The flow reactor may be equipped with a device (such as a temperature-controlled chamber, a temperature-controlled bath, or a jacketed vessel; in FIG. 1 , temperature control device 9) for controlling the temperature of the mixing / reaction zone, either independently for each mixing / reaction zone or in common with the other mixing / reaction zone. The reaction temperature (set temperature of the temperature control device) between raw material liquid A and raw material liquid B can be the same as the reaction temperature in the above-mentioned method c. As described above, when a flow reactor is used in method c, it can be carried out efficiently without requiring ultra-low temperature conditions. Therefore, the reaction temperature between raw material liquid A and raw material liquid B is, for example, −70°C or higher, preferably −50°C or higher, more preferably −40°C or higher, and for example, 100°C or lower, preferably 50°C or lower, more preferably 25°C or lower, and even more preferably 0°C or lower.

[0089] The reaction liquid discharged from the mixing / reaction section is appropriately post-treated as necessary. In FIG. 1, the reaction liquid discharged from the mixing / reaction section 7 is collected in a reaction liquid storage container 11, and then a post-treatment step is carried out. However, the quenching agent may be placed in the reaction liquid storage container 11 to stop (quench) the reaction of the reaction liquid collected in the reaction storage container 11. Post-treatment steps such as quenching are similar to those described in the above-mentioned method c.

[0090] According to the present invention, compound (2), a synthetic intermediate of compound (3), which is useful as a pharmaceutical intermediate, can be efficiently produced without using heavy metal reagents. Furthermore, according to a preferred embodiment of the present invention, the yields of the two steps immediately preceding the production of the target compound (3) (a step of synthesizing compound (2) by decarboxylating the carboxy group from compound (1) and a step of producing compound (3) from compound (2)) or the three steps (a step of synthesizing compound (1) by hydrolyzing compound (1a), a step of synthesizing compound (2) by decarboxylating the carboxy group from compound (1), and a step of producing compound (3) from compound (2)) are good. This allows for the efficient production of compound (3), which is useful as a pharmaceutical intermediate. The overall yield of the two or three steps is preferably 35 mol % or more, more preferably 50 mol % or more, and even more preferably 70 mol % or more.

[0091] This application claims the benefit of priority to Japanese Patent Application No. 2021-056124, filed on March 29, 2021. The entire contents of the specification of Japanese Patent Application No. 2021-056124, filed on March 29, 2021, are incorporated herein by reference. [Example]

[0092] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is possible to carry out the invention by making appropriate modifications within the scope of the above and / or below-described purpose, and all such modifications are included in the technical scope of the present invention.

[0093] In the Examples and Reference Examples, the progress of the reaction was confirmed by HPLC, and the molar conversion rate and reaction yield were determined. The molar conversion rate refers to the ratio of the amount of the target product to the total amount of the reaction substrate and the target product contained in the reaction solution. The HPLC analysis conditions are as follows:

[0094] Column: Tosoh TSK-GEL ODS-120T (250 x 4.6 mm, 5 μm) Mobile phase: Phosphate buffer (pH = 2.5) / acetonitrile = 7 / 3 (v / v) Flow rate: 1.0ml / min Detection wavelength: UV254nm Column temperature: 40℃

[0095] (Reference Example 1) Preparation of diethyl 2-(5-bromopyrimidin-2-yl)malonate Under a nitrogen atmosphere, sodium hydride (65% purity, 14.0 g, 0.39 mol) and tetrahydrofuran (THF) (270 g) were added to a flask and cooled to 1°C. A solution of diethyl malonate (37.3 g, 0.23 mol) in tetrahydrofuran (30 g) was added over 35 minutes. After stirring for 20 minutes, a solution of 2-chloro-5-bromopyrimidine (30 g, 0.16 mol) in tetrahydrofuran (300 g) was added over 30 minutes. After stirring for 20 minutes, heating was initiated, the temperature was adjusted to 65°C, and stirring was continued for 19 hours. After confirming the progress of the reaction by HPLC, the mixture was cooled to 25°C, and toluene (300 g) and saturated aqueous ammonium chloride solution (596 g) were added. Next, 30% aqueous sodium hydroxide solution (54 g) was added to adjust the pH to 9. The aqueous layer was removed by separation, and the resulting organic layer was concentrated to obtain 69.5 g of diethyl 2-(5-bromopyrimidin-2-yl)malonate (purity: 56%, yield: 79 mol %).

[0096] Example 1: Preparation of 5-bromo-2-methylpyrimidine Under a nitrogen atmosphere, ethanol (82.3 g) and 30% aqueous sodium hydroxide solution (82.3 g) were added to diethyl 2-(5-bromopyrimidin-2-yl)malonate (69.5 g, purity 56%, 0.12 mol) synthesized in Reference Example 1, and the mixture was stirred for 1 hour at a temperature adjusted to 55-59°C. After confirming the progress of the reaction by HPLC, the mixture was cooled to 25°C. 1 M aqueous citric acid solution (389.5 g) was added over 1.5 hours to adjust the pH to 4. The mixture was stirred at a temperature adjusted to 68-76°C for 20 hours, and after confirming the progress of the reaction by HPLC, the mixture was cooled to 25°C. Toluene (200 g) was added, followed by separation to separate the organic and aqueous layers. Toluene (200 g) was added to the aqueous layer, followed by separation, and the aqueous layer was removed. The organic layer obtained in the first separation and the organic layer obtained in the second separation were mixed, and saturated brine (80 g) was added, followed by separation, and the aqueous layer was removed. The organic layer was concentrated to obtain 156.7 g of 5-bromo-2-methylpyrimidine. The HPLC area percentage of the concentrate excluding the solvent was 95%.

[0097] Example 2: Preparation of (2-methylpyrimidin-5-yl)boronic acid Under a nitrogen atmosphere, 5-bromo-2-methylpyrimidine (155.5 g, 0.90 mol) prepared in Example 1, triisopropoxyborane (35.9 g, 0.19 mol), and THF (225 ml) were mixed and cooled to -71°C. A n-butyllithium / hexane solution (1.6 M, 115.4 ml, 0.18 mol) was added over 1.5 hours. After stirring at -71°C for 1 hour and confirming the progress of the reaction by HPLC, the mixture was heated to 0°C. A 20% aqueous ammonium chloride solution (351.3 g) was added over 1 hour to adjust the pH to 8.8. The organic layer was removed by separation, and the aqueous layer was cooled to 0°C. Concentrated hydrochloric acid (19 g) was added to the aqueous layer to adjust the pH to 4.0. After stirring for 4 hours, the crystals were filtered. The crystal cake was washed with cold water (84 g) and then dried under reduced pressure at 40°C for 23 hours to give (2-methylpyrimidin-5-yl)boronic acid as white crystals (12.2 g, purity 99%, overall yield from diethyl 2-(5-bromopyrimidin-2-yl)malonate 69 mol%).

[0098] Example 3: Preparation of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine Under a nitrogen atmosphere, 5-bromo-2-methylpyrimidine (0.499 g, 2.89 mmol) prepared in Example 1, bis(pinacolato)diboron (0.808 g, 1.1 equivalents), potassium acetate (0.567 g, 2.0 equivalents), PdCl(dppf) (94.7 mg, 0.04 equivalents), and dioxane (5.00 g) were added to a test tube and reacted at 85° C. for 5 hours. The reaction solution was filtered and then concentrated to give 1.1 g of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (overall yield from diethyl 2-(5-bromopyrimidin-2-yl)malonate: 81 mol %, purity: 47%).

[0099] As in Examples 2 and 3, 5-bromo-2-methylpyrimidine was synthesized by decarboxylating the carboxy group of a 5-bromopyrimidine derivative produced in the reaction system from 2-(5-bromopyridin-2-yl)diethyl malonate, and then a (2-methyl-pyrimidin-5-yl)boronic acid derivative was produced, thereby enabling the efficient production of the target compound.

[0100] Example 4: Preparation of (2-methylpyrimidin-5-yl)boronic acid Under a nitrogen atmosphere, a 2.5 M n-butyllithium / hexane solution (500 mL) and toluene (500 mL) were placed in a 1 L medium bottle and mixed thoroughly to form a homogeneous solution (raw material solution B). Next, 5-bromo-2-methylpyrimidine (110 g, 0.64 mol), triisopropoxyborane (179 g, 0.95 mol), and tetrahydrofuran (1540 g) were placed in a 2 L medium bottle and mixed thoroughly to form a homogeneous solution (raw material solution A; 5-bromo-2-methylpyrimidine: 0.31 M, triisopropoxyborane: 0.31 M). The following reaction was carried out using the flow reactor 12 shown in Figure 1. Toluene and THF were delivered to the flow channel of the flow reactor using a diaphragm pump (liquid delivery devices 3 and 4). After completely distilling off the water in the flow channel, the jacket temperature of the chiller (temperature control device 9) was set to -40°C. Next, raw material solution B was delivered at a rate of 11.9 ml / min and raw material solution A at a rate of 32.2 ml / min to initiate the flow reaction (retention time: 0.2 ms). After the internal temperature stabilized, the reaction solution was collected in the reaction solution storage container 11 in an ice bath for 60 minutes. To the recovered reaction solution (2.271 kg), 20 wt% aqueous NH4Cl (1.76 kg) was added at a rate that maintained the internal temperature at 5°C or below, and the mixture was stirred at the same temperature for 10 minutes and then allowed to stand. After separation into two layers, the aqueous layer was recovered, the pH was adjusted to 4 using aqueous hydrochloric acid, and the mixture was stirred at -2°C for 15 hours. The precipitated crystals were then filtered, and the wet cake was washed twice with 50 ml of cold water and dried at 40°C under reduced pressure to obtain (2-methylpyrimidin-5-yl)boronic acid as white crystals (66.2 g, purity 99.8%, yield 80 mol%).

[0101] Example 5: Preparation of (2-methylpyrimidin-5-yl)boronic acid Preparation example of raw material solution A: 5-bromo-2-methylpyrimidine (100 g, 0.58 mol), triisopropoxyborane (164 g, 0.87 mol), and tetrahydrofuran (1736 g) were mixed well to obtain a homogeneous solution (5-bromo-2-methylpyrimidine: 0.245 M, triisopropoxyborane: 0.368 M). Preparation example of raw material solution B: A 2.72 M n-butyllithium / hexane solution (500 ml) and toluene (500 ml) were mixed well to prepare a homogeneous solution (n-butyllithium: 1.36 M). The following reaction was carried out using the flow reactor 12 shown in Figure 1. Toluene and THF were delivered to the flow channel of the flow reactor using a diaphragm pump (liquid delivery devices 3 and 4). After completely distilling off the water in the flow channel, the jacket temperature of the chiller (temperature control device 9) was set to -45°C. Next, raw material solution B was delivered at a rate of 0.36 mL / min and raw material solution A at a rate of 2.00 mL / min to initiate the flow reaction (retention time: 1.4 ms). After the internal temperature stabilized, the reaction solution containing (2-methylpyrimidin-5-yl)boronic acid was collected in the reaction solution storage container 11 in an ice bath (molar conversion rate: 49%, reaction yield: 47%).

[0102] (Examples 6 to 10) Preparation of (2-methylpyrimidin-5-yl)boronic acid (2-Methylpyrimidin-5-yl)boronic acid was produced in the same manner as in Example 5, except that the residence time was adjusted by changing the flow rate as follows. In Table 1 and Table 2 described below, "n-BuLi (eq)" indicates the equivalent of n-BuLi relative to 5-bromo-2-methylpyrimidine in the mixing / reaction section 7. [Table 1]

[0103] (Examples 11 to 17) Preparation of (2-methylpyrimidin-5-yl)boronic acid (2-Methylpyrimidin-5-yl)boronic acid was produced in the same manner as in Example 5, except that the flow rate and jacket temperature were changed as follows. [Table 2]

[0104] As in Examples 4 to 17, by using a flow reactor, (2-methylpyrimidin-5-yl)boronic acid could be produced from 5-bromo-2-methylpyrimidine at temperatures between -45°C and -25°C, without the need for ultra-low temperature conditions such as temperatures below -70°C. [Explanation of symbols]

[0105] 1, 2, 5, 6: Raw material supply channel 3, 4: Liquid delivery device 7: Mixing and reaction section 8: Temperature sensor 9:Temperature control device 10: Reaction liquid discharge flow path 11: Reaction solution storage container 12: Flow reactor

Claims

1. The following formula (1): 【Chemical Formula 1】 (In the formula, R 1 is a hydrogen atom, or CO 2 H), a 5-bromopyrimidine derivative represented by the following formula (2): 【Chemistry 2】 The method includes a step of synthesizing 5-bromo-2-methylpyrimidine represented by the following formula (3): 【Chemistry 3】 (In the formula, R 2 , R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent. 2 and R 3 may be taken together to form a ring.

2. The method according to claim 1, wherein the decarboxylation step is carried out at a temperature of 150°C or less.

3. 3. The method according to claim 1, wherein the decarboxylation step is carried out in at least one solvent selected from the group consisting of alcohols having 1 to 5 carbon atoms and water.

4. The method according to any one of claims 1 to 3, comprising the step of contacting the 5-bromo-2-methylpyrimidine, a trialkoxyboron compound, and an organolithium reagent in a flow reactor to produce the (2-methylpyrimidin-5-yl)boronic acid derivative.

5. 5. The method according to claim 4, wherein the 5-bromo-2-methylpyrimidine, the trialkoxyboron compound, and the organolithium reagent are contacted at a temperature of −50° C. or higher.

6. 6. The method according to claim 4, wherein a solution containing the 5-bromo-2-methylpyrimidine and the trialkoxyboron compound is contacted with the organolithium reagent.

7. The method according to any one of claims 4 to 6, wherein the trialkoxy boron compound is triisopropoxyborane.

8. The method according to any one of claims 4 to 7, wherein the organolithium reagent is n-butyllithium.

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