JP2022114189A - Method for producing 6-halogenoisoindolinone derivative - Google Patents

Abstract

To provide a method for producing a 6-halogenoisoindolinone derivative with a high yield.SOLUTION: A method for producing a 6-halogenoisoindolinone derivative includes: bringing an isoindolinone derivative represented by formula (1) into contact with a halogenating agent in a temperature range of -10°C or higher to 50°C or lower in the presence of an acid; and obtaining a 6-halogenoisoindolinone derivative represented by formula (2). The method further includes: bringing a 3-hydroxyisoindolinone derivative represented by formula (3) into contact with at least one reducing agent selected from sodium cyanoborohydride and triacetoxy sodium borohydride in the presence of a methanol hydrochloric acid, thereby producing an isoindolinone derivative represented by the formula (1); and then bringing the obtained isoindolinone derivative represented by the formula (1) into contact with the halogenating agent.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a 6-halogenoisoindolinone derivative.

A 6-halogenoisoindolinone derivative is a useful compound used as an intermediate in the production of various pharmaceuticals such as the antibacterial drug garenoxacin. As a conventional production method, for example, in Patent Document 1, a halogenating agent (bromine) is added dropwise to 3-methylisoindolin-1-one in a 1,2-dichloroethane solvent, and these are heated to the reflux temperature of the solvent. A method for producing a 6-bromoisoindolinone derivative by mixing is reported (Patent Document 1).

WO2014/146490

However, when the inventor repeated the production method described in Patent Document 1, the yield of the 6-bromoisoindolinone derivative was only about 34% (see Comparative Example 2 described later). As shown by the results of such additional tests, according to the production method described in Patent Document 1, a sufficient yield of the 6-halogenoisoindolinone derivative may not be obtained in some cases, and there is room for improvement in this respect. .

Accordingly, an object of the present invention is to provide a method for producing a 6-halogenoisoindolinone derivative with a high yield.

As a result of intensive research to solve the above problems, the present inventors have found that the above reflux can be achieved by contacting an isoindolinone derivative and a halogenating agent in the presence of an acid at a temperature range of -10°C or higher and 50°C or lower. The inventors have found that the yield of the 6-halogenoisoindolinone derivative can be increased even at a temperature lower than the temperature, and have completed the present invention.

That is, in the method for producing a 6-halogenoisoindolinone derivative according to one embodiment of the present invention, an isoindolinone derivative represented by the following formula (1) and a halogenating agent are mixed in the presence of an acid to -10 C. to 50.degree. C. to produce a 6-halogenoisoindolinone derivative represented by the following formula (2).

In formula (1) above, R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, an aryl group, an aralkyl group, or a dialkylaminoalkyl group. R ² is a hydrogen atom or an amino group-protecting group.

In Formula (2) above, R ¹ and R ² have the same definitions as in Formula (1) above, and X is a halogen atom derived from the halogenating agent.

The isoindolinone derivative represented by the formula (1) and the halogenating agent are preferably contacted in at least one halogen solvent selected from the group consisting of methylene chloride and chloroform.

Preferably, the acid is aluminum chloride, and the halogenating agent is at least one brominating agent selected from bromine and 1,3-dibromo-5,5-dimethylhydantoin.

In this case, the amount of the aluminum chloride is 1.0 mol or more and 5.0 mol or less per 1 mol of the isoindolinone derivative represented by the formula (1). More preferably, the amount of the brominating agent is 0.5 mol or more and 1.5 mol or less per 1 mol of the isoindolinone derivative.

Preferably, the acid is sulfuric acid and the halogenating agent is 1,3-dibromo-5,5-dimethylhydantoin.

In this case, the amount of the sulfuric acid is 3.0 mol or more and 10.0 mol or less per 1 mol of the isoindolinone derivative represented by the formula (1). More preferably, the amount of the 1,3-dibromo-5,5-dimethylhydantoin per 1 mol of the indolinone derivative is 0.5 mol or more and 1.0 mol or less.

In the presence of methanolic hydrochloric acid, a 3-hydroxyisoindolinone derivative represented by the following formula (3) and at least one reducing agent selected from the group consisting of sodium cyanoborohydride and sodium triacetoxyborohydride. After producing the isoindolinone derivative represented by the formula (1) by contacting, the resulting isoindolinone derivative represented by the formula (1) is brought into contact with the halogenating agent. is preferred.

In formula (3) above, R ¹ and R ² have the same definitions as in formula (1) above.

Further, a method for producing an isoindolinone derivative according to another embodiment of the present invention comprises a 3-hydroxyisoindolinone derivative represented by the following formula (3), sodium cyanoborohydride, and sodium cyanoborohydride in the presence of methanolic hydrochloric acid. contacting with at least one reducing agent selected from the group consisting of sodium triacetoxyborohydride to obtain an isoindolinone derivative represented by the following formula (1).

前記式（３）において、Ｒ^１は、水素原子、アルキル基、アルコキシ基、ハロゲン原子、アリール基、アラルキル基、又はジアルキルアミノアルキル基である。また、Ｒ^２は、水素原子、又はアミノ基保護基である。

In formula (3) above, R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, an aryl group, an aralkyl group, or a dialkylaminoalkyl group. Also, R ² is a hydrogen atom or an amino group-protecting group.

前記式（１）において、
Ｒ^１及びＲ^２は、前記式（３）のものと同義である。

In the above formula (1),
R ¹ and R ² have the same definitions as in formula (3) above.

According to the method for producing a 6-halogenoisoindolinone derivative according to the present invention, the yield of the 6-halogenoisoindolinone derivative can be increased.

An embodiment according to the present invention will be described in detail below. A method for producing a 6-halogenoisoindolinone derivative according to one embodiment of the present invention comprises: [1] from a 3-hydroxyisoindolinone derivative represented by the following formula (3), as shown in the following reaction scheme; [2] a method for producing an isoindolinone derivative represented by the following formula (1) (hereinafter sometimes simply referred to as “first production method”); and a method for producing a 6-halogenoisoindolinone derivative represented by the following formula (2) from an indolinone derivative (hereinafter sometimes referred to as “second production method”). The details of each will be described below in order.

[1] First manufacturing method (method for manufacturing an isoindolinone derivative)
First, the first manufacturing method will be described. The first production method relates to a method for producing an isoindolinone derivative by reductively eliminating the hydroxyl group of the 3-hydroxyisoindolinone derivative. Specifically, in the first production method, a 3-hydroxyisoindolinone derivative, sodium cyanoborohydride and sodium triacetoxyborohydride are combined in the presence of methanolic hydrochloric acid (hereinafter also referred to as “HCl-MeOH”). with at least one reducing agent selected from the group consisting of to obtain an isoindolinone derivative.

<3-hydroxyisoindolinone derivative>
A 3-hydroxyisoindolinone derivative is the substrate in the first production method. A 3-hydroxyisoindolinone derivative is a compound represented by the following formula (3).

式（３）において、Ｒ^１は、水素原子、アルキル基、アルコキシ基、ハロゲン原子、アリール基、アラルキル基、又はジアルキルアミノアルキル基である。また、Ｒ^２は、水素原子、又はアミノ基保護基である。

In formula (3), R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, an aryl group, an aralkyl group, or a dialkylaminoalkyl group. Also, R ² is a hydrogen atom or an amino group-protecting group.

R ¹ is preferably a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom, and an aryl group having 6 to 20 carbon atoms. , an aralkyl group having 7 to 30 carbon atoms, or a dialkylaminoalkyl group having 3 to 20 carbon atoms. The aryl group and aralkyl group may have a substituent, and the substituent may be an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a halogen atom, or a 30 aralkyl groups and alkylamino groups. R ¹ is more preferably a methyl group.

^R2 is preferably a hydrogen atom. When R ² is an amino group-protecting group, the amino group-protecting group is preferably benzyl group, benzhydryl group, trityl group, benzyloxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, t- butoxycarbonyl group (Boc), fluorenylmethyloxycarbonyl group, formyl group, acetyl group, or pivaloyl group.

(Suitable 3-Hydroxyisoindolinone Derivatives)
As the 3-hydroxyisoindolinone derivative represented by the above formula (3), 3-methyl-3-hydroxyisoindolin-1-one represented by the following formula (3A) is preferable in view of its usefulness. can be cited as a A compound represented by the following formula (3A) is a compound in which R ¹ is a methyl group and R ² is a hydrogen atom in the above formula (3).

<Reducing agent>
In the manufacturing method according to the present embodiment, at least one selected from the group consisting of sodium cyanoborohydride (NaBH ₃ CN) and sodium triacetoxyborohydride (NaBH(OAc) ₃ ) is used as the reducing agent.

The amount of reducing agent used is not particularly limited. The reducing agent is preferably used in an amount of 0.66 mol or more and 4.0 mol or less, more preferably 1 mol or more and 3 mol or less, per 1 mol of the 3-hydroxyisoindolinone derivative.

<HCl—MeOH>
The contact between the 3-hydroxyisoindolinone derivative and the above reducing agent is carried out in the presence of HCl-MeOH. The concentration of HCl-MeOH is not particularly limited. % or less HCl-MeOH. Further, HCl-MeOH is preferably used in terms of the number of moles of HCl of 0.5 mol or more and 3 mol or less, and more preferably of 0.7 mol or more and 2 mol of HCl, with respect to 1 mol of the reducing agent. used below.

<Method for producing isoindolinone derivative>
As described above, in the production method according to the present embodiment, an isoindolinone derivative is obtained by contacting a 3-hydroxyisoindolinone derivative with a reducing agent in the presence of HCl-MeOH. In the present embodiment, contacting the 3-hydroxyisoindolinone derivative with the reducing agent is preferably carried out in a solvent.

(solvent)
Solvents include ethers such as THF, 2-methyl THF, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and diglyme; halogenated hydrocarbons such as methylene chloride; Organic solvents such as alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol and t-butanol can be used. These solvents can be used alone or as a mixed solvent thereof. Among them, methanol is particularly preferable because it has excellent dissolving power for reagents used such as reducing agents.

The amount of solvent used is not particularly limited. The solvent is preferably used in an amount of 3 mL or more and 30 mL or less, more preferably 5 mL or more and 20 mL or less per 1 g of the 3-hydroxyisoindolinone derivative. In addition, when using a mixed solvent as a solvent, the whole amount of a mixed solvent should just satisfy said range.

(Method of contacting (mixing) each component)
The method of contacting each component is not particularly limited. For example, each component may be added and mixed in a reaction vessel equipped with a stirring mechanism. By mixing each component, the 3-hydroxyisoindolinone derivative and the reducing agent can be brought into contact in the presence of methanolic hydrochloric acid. There are no particular restrictions on the procedure for charging each component into the reaction vessel. For example, after dissolving a 3-hydroxyisoindolinone derivative in a solvent, this solution, a reducing agent, and methanolic hydrochloric acid may be mixed. In this case, a reducing agent may be added to the solution, and HCl-MeOH may be added dropwise.

In addition, the reducing agent may be added to the solution over a period of 5 minutes or longer and 30 minutes or shorter, for example. The temperature of the solution at this time may be, for example, 10° C. or higher and 40° C. or lower. Further, HCl-MeOH may be added dropwise to the solution over a period of time of, for example, 1 hour or more and 4 hours or less. The temperature of the solution at this time may be, for example, 0° C. or higher and 35° C. or lower.

The above reaction can be carried out by mixing (contacting) a 3-hydroxyisoindolinone derivative and a reducing agent in the presence of methanolic hydrochloric acid. At this time, the reaction temperature at which these components are stirred and mixed is preferably −10° C. or higher and 60° C. or lower, and more preferably 10° C. or higher and 45° C. or lower. The reaction time may be appropriately determined by confirming the conversion rate to the isoindolinone derivative and allowing the reaction to complete. The reaction time may be 0.5 hours or more and 17 hours or less, preferably 1 hour or more and 8 hours or less.

After completion of the reaction, it is preferable to purify the isoindolinone derivative by the following method. First, impurities deposited by the reaction are dissolved. Concentrated sulfuric acid, for example, may be used to dissolve impurities. Next, the reaction solution is concentrated under reduced pressure to distill off methanol. Furthermore, methylene chloride and water are added to the concentrated residue, and the reaction solution is separated. Next, the organic layer is concentrated, and the concentrated residue is subjected to silica gel column chromatography. As a solvent for silica gel column chromatography, for example, a mixed solvent of n-hexane and ethyl acetate may be used. The crude product obtained by silica gel column chromatography is dried, and the mixed solvent of n-hexane and ethyl acetate is removed and recrystallized to obtain the isoindolinone derivative. In addition, although the method using a silica gel column was exemplified above, in the case of purification, a known purification method such as recrystallization can also be employed.

<Isoindolinone Derivative>
The isoindolinone derivative represented by the following formula (1) is obtained by contacting the 3-hydroxyisoindolinone derivative with the reducing agent in the presence of methanolic hydrochloric acid by the method described above.

In formula (1), R ¹ and R ² have the same definitions as in formula (3).

(Suitable isoindolinone derivatives)
When 3-methyl-3-hydroxyisoindolin-1-one represented by the formula (3A), which is a suitable raw material, is used as a substrate, the isoindolinone derivative represented by the above formula (1) is represented by the following formula: An isoindolinone derivative (3-methylisoindolin-1-one) represented by (1A) can be obtained. A compound represented by the following formula (1A) is a compound in which R ¹ is a methyl group and R ² is a hydrogen atom in the above formula (1).

The isoindolinone derivatives represented by formulas (1) and (1A) are known compounds. Therefore, the method for producing the isoindolinone derivative is not particularly limited, and it can be produced by other known methods. For example, triethylsilane (Et ₃ SiH) may be used as a reducing agent. When triethylsilane is used as the reducing agent, the contact between the substrate and the reducing agent does not necessarily have to be carried out in the presence of methanolic hydrochloric acid.

However, by using the first production method, the yield of the isoindolinone derivative can be increased as compared with the conventional example using triethylsilane as a reducing agent. Therefore, when producing an isoindolinone derivative, it is preferable to adopt the first production method.

[2] Second Manufacturing Method Next, a second manufacturing method will be described. The second production method relates to a method of halogenating an isoindolinone derivative to produce a 6-halogenoisoindolinone derivative. Specifically, in the second production method, an isoindolinone derivative and a halogenating agent are contacted in the presence of an acid in a temperature range of -10°C to 50°C to obtain a 6-halogenoisoindolinone derivative. Including.

<Isoindolinone Derivative>
The isoindolinone derivative is the substrate in the second production method. An isoindolinone derivative is a compound represented by the above formula (1).

As described above, the isoindolinone derivative does not necessarily have to be obtained by the first production method, and may be obtained by a known production method. However, in order to increase the purity of the 6-halogenoisoindolinone derivative, it is preferable to use a highly pure isoindolinone derivative as a substrate. For this purpose, it is preferable to use the isoindolinone derivative produced by the above-described first production method as the substrate in the second production method.

Further, in the second production method, when using the isoindolinone derivative produced by the first production method, for example, the isoindolinone derivative produced by the first production method can be isolated and purified before use. can. Further, according to the first production method, the isoindoline boronic acid derivative can be obtained in a high yield, so that the isoindoline boronic acid derivative may be used after distilling off the solvent and the like without purification.

<Halogenating agent>
A halogenating agent is a reactant that substitutes one of the hydrogen atoms in the aromatic ring in the isoindolinone derivative with a halogen atom derived from the halogenating agent (hereinafter also referred to as “halogenation”). The halogenating agent includes at least one selected from simple halogen, N-halogenosuccinimide, N-halogenophthalimide, and 1,3-dihalogeno-5,5-dimethylhydantoin.

Here, the halogen atom includes a chlorine atom, a bromine atom, or an iodine atom. That is, the halogenating agent includes a chlorinating agent, a brominating agent, or an iodinating agent.

Chlorinating agents include chlorine (Cl ₂ ) alone (hereinafter also simply referred to as “chlorine”), N-chlorosuccinimide (NCS), N-chlorophthalimide, and 1,3-dichloro-5,5-dimethylhydantoin ( hereinafter also referred to as “DCDMH”).

The brominating agent includes bromine (Br ₂ ) alone (hereinafter also simply referred to as “bromine”), N-bromosuccinimide (NBS), N-bromophthalimide, and 1,3-dibromo-5,5-dimethylhydantoin ( hereinafter also referred to as “DBDMH”).

The iodinating agent includes iodine (I ₂ ) alone (hereinafter also simply referred to as “iodine”), N-iodosuccinimide (NIS), N-iodophthalimide, and 1,3-diiodo-5,5-dimethylhydantoin ( hereinafter also referred to as "DIDMH").

A brominating agent or an iodinating agent is preferably used as the halogenating agent because of its excellent reactivity with the substrate. Moreover, it is preferable to use a chlorinating agent or a brominating agent as the halogenating agent because it is inexpensive. That is, it is more preferable to use a brominating agent as the halogenating agent because it has excellent reactivity with the substrate and is inexpensive.

The amount of halogenating agent used is not particularly limited. The halogenating agent is preferably used in an amount of 0.3 mol or more and 2.0 mol or less, more preferably 0.3 mol or more and 1.5 mol or less, based on 1 mol of the isoindolinone derivative, based on the halogenating agent. use.

(brominating agent)
As the halogenating agent, it is preferable to use a brominating agent as described above. Specific further explanations are given when preferred brominating agents are used. The amount of the brominating agent relative to 1 mol of the isoindolinone derivative is preferably 0.3 mol or more and 2.0 mol or less, more preferably 0.3 mol or more and 1.5 mol, based on the bromine molecule. It is below.

As the brominating agent, among those mentioned above, bromine is preferable from the viewpoint of increasing the regioselectivity of the reaction for obtaining the 6-halogenoisoindolinone derivative to be synthesized. When bromine is used as the brominating agent, the amount of bromine relative to 1 mol of the isoindolinone derivative is preferably 1.0 mol or more and 2.0 mol or less, more preferably 1.1 mol, based on the bromine molecule. It is mol or more and 1.5 mol or less. Further, when DBDMH is used as the brominating agent, the amount of DBDMH relative to 1 mol of the isoindolinone derivative is preferably 0.3 mol or more and 1.0 mol or less, more preferably, based on the DBDMH molecule. It is 0.3 mol or more and 0.7 mol or less.

<Acid>
Contact between the isoindolinone derivative and the halogenating agent is carried out in the presence of an acid. The acid oxidizes the isoindolinone derivative, suppresses loss of pi electrons in the benzene ring by oxygen atoms, and promotes the electrophilic substitution reaction between the isoindolinone derivative and the halogenating agent. Acids include at least one selected from the group consisting of Lewis acids and Bronsted acids. Lewis acids include aluminum chloride (aluminum trichloride, AlCl ₃ ), tin tetrachloride, and titanium tetrachloride. The Lewis acid is preferably aluminum trichloride. Bronsted acids include sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and trichloroacetic acid. The Bronsted acid is preferably sulfuric acid.

As the acid, it is preferable to use aluminum chloride (specifically, aluminum trichloride) in order to increase the selectivity of the halogen atom to the isoindolinone derivative. The amount of acid used is not particularly limited. When aluminum trichloride is used as the acid, the amount of aluminum trichloride relative to 1 mol of the isoindolinone derivative is preferably 1.0 mol or more and 5.0 mol or less, more preferably 2.5 mol or more. It is 3.5 mol or less. The amount of acid used is the amount (number of moles) of the acid itself. When aluminum trichloride is used, it is the amount (number of moles) of aluminum trichloride itself used.

When aluminum trichloride is used as the acid, bromine and/or DBDMH is preferably used as the halogenating agent, more preferably DBDMH. This is because when aluminum trichloride is used as the acid, DBDMH can increase the yield of the 6-bromoisoindolinone derivative more than bromine. In this case, the amount of the brominating agent per 1 mol of the isoindolinone derivative is preferably 0.5 mol or more and 1.5 mol or less based on bromine molecules.

When sulfuric acid is used as the acid, the amount of sulfuric acid is preferably 3.0 mol or more and 10.0 mol or less, and 3.5 mol or more and 8.5 mol or less per 1 mol of the isoindolinone derivative. is more preferred. The amount of acid used is the amount (number of moles) of the acid itself. That is, when sulfuric acid (H ₂ SO ₄ ) is used, it is the amount (number of moles) of sulfuric acid itself.

When sulfuric acid is used as the acid, DBDMH is preferably used as the halogenating agent. In this case, the amount of DBDMH with respect to 1 mol of the isoindolinone derivative is preferably 0.5 mol or more and 1.0 mol or less based on bromine molecules.

<Method for producing 6-halogenoisoindolinone derivative>
As described above, in the production method according to the present embodiment, an isoindolinone derivative and a halogenating agent are brought into contact with each other in the presence of an acid to react with each other to obtain a 6-halogenoisoindolinone derivative. In the production method according to the present embodiment, it is preferable to bring the isoindolinone derivative and the halogenating agent into contact with each other in a solvent.

<Solvent>
The contact between the isoindolinone derivative and the halogenating agent in the presence of an acid is preferably carried out in at least one halogen solvent selected from the group consisting of methylene chloride and chloroform.

As the solvent, in addition to the above-described halogen-based solvents, or in addition to the above-described halogen-based solvents, nitriles such as acetonitrile and propionitrile; THF, 2-methylTHF, 1,4-dioxane, tert Ethers such as -butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as 1,2-dichloroethane; and organic solvents such as ketones such as acetone.

The amount of solvent used is not particularly limited. It is preferable to use 1 mL or more and 30 mL or less of the solvent, more preferably 3 mL or more and 20 mL or less, per 1 g of the isoindolinone derivative. In addition, when using a mixed solvent as a solvent, the whole amount of a mixed solvent should just satisfy said range.

(Method of contacting (mixing) each component)
The method of contacting each component is not particularly limited. For example, each component may be added and mixed in a reaction vessel equipped with a stirring mechanism. By mixing each component, the isoindolinone derivative and the halogenating agent can be contacted in the presence of an acid. The procedure for charging each component into the reaction vessel is not particularly limited. For example, after dissolving the isoindolinone derivative in a solvent, the solution may be mixed with the acid. Furthermore, after that, the resulting mixture may be mixed with a solution of a halogenating agent dissolved in the same solvent in which the isoindolinone derivative was dissolved, if necessary. In this case, the solution may be added dropwise to the mixture.

The temperature of the solution when mixing the solution and the acid may be 5°C or higher and 25°C or lower. Alternatively, the halogenating agent may be added to the solution over a period of time of, for example, 5 minutes or more and 60 minutes or less.

The mixture of the isoindolinone derivative solution and the acid is added with isoindolinone in order to sufficiently mix the isoindolinone derivative solution and the acid before mixing this mixture with the halogenating agent solution. The solution of the linone derivative may be stirred. At this time, the time for mixing the isoindolinone derivative solution and the acid depends on the amount of the isoindolinone derivative solution and the amount of the acid to be added, but may be, for example, 5 minutes or more and 40 minutes or less.

(reaction temperature)
The isoindolinone derivative and the halogenating agent are brought into contact within a temperature range of -10°C to 50°C. When bromine is used as the halogenating agent, the reaction temperature is preferably 0°C or higher and 40°C or lower. When DBDMH is used as the halogenating agent, the reaction temperature is preferably 0°C or higher and 50°C or lower, more preferably 5°C or higher and 40°C or lower. By contacting the isoindolinone derivative and the halogenating agent in the presence of an acid, the reaction between the isoindolinone derivative and the halogenating agent can proceed at a temperature lower than the reflux temperature of the 1,2-dichloroethane solvent. can. Even if the reaction temperature is lower than the reflux temperature of the 1,2-dichloroethane solvent, the 6-halogenoisoindolinone derivative can be obtained in high yield.

The reaction temperature does not necessarily have to be maintained at the same temperature from the start of the reaction (starting stirring and mixing each component) to the end (stopping stirring and mixing) of the reaction. good too. For example, the reaction temperature may be raised in two steps. Specifically, for example, a mixture of an isoindolinone derivative and a halogenating agent is reacted at a temperature of −10° C. or more and less than 15° C. for 1 hour or more and 6 hours or less, and then 1 hour at 15° C. or more and 50° C. or less. The reaction may be further carried out in a temperature range of 1 hour or more and 5 hours or less.

(reaction time)
The reaction time may be appropriately determined by checking the conversion rate to the 6-halogenoisoindolinone derivative and determining the time to complete the reaction. When bromine is used as the halogenating agent, the reaction time may be 1 hour or more and 17 hours or less, preferably 2 hours or more and 8 hours or less. When DBDMH is used as the brominating agent, the reaction time may be 1 hour or more and 48 hours or less, preferably 2 hours or more and 24 hours or less.

After completion of the reaction, it is preferable to purify the 6-halogenoisoindolinone derivative by the following method. First, the reaction solution is cooled by, for example, pouring into ice water or the like, and made alkaline by adding strong hydrochloric acid such as sodium hydroxide aqueous solution. Next, the reaction liquid is liquid-separated and the water layer is extracted. Methylene chloride, for example, may be used to extract the aqueous layer. Next, the organic layers are mixed, dehydrated and concentrated under reduced pressure to obtain a 6-halogenoisoindolinone derivative. For dehydration, for example, magnesium sulfate may be used.

The proportion of the isoindolinone derivative in the treated liquid and solid matter after the treatment can be confirmed by, for example, high performance liquid chromatography (HPLC). Moreover, the synthesis of the isoindolinone derivative can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis, infrared (IR) spectroscopic analysis, and melting point measurement.

<6-bromoisoindolinone derivative>
By the method described above, the isoindolinone derivative and the halogenating agent are brought into contact in the presence of an acid to obtain a 6-halogenoisoindolinone derivative represented by the following formula (2).

In formula (2), R ¹ and R ² are synonymous with those represented by formula (1). Moreover, X is a halogen atom derived from the halogenating agent. Specifically, X includes a chlorine atom, a bromine atom, or an iodine atom. Among them, when a brominating agent suitable as a halogenating agent is used, X is preferably a bromine atom. Also, considering reactivity and stability, X is preferably a bromine atom. Also, X is present at the 6th position.

(Suitable 6-halogenoisoindolinone Derivatives)
When 3-methylisoindolin-1-one represented by the formula (1A), which is a suitable raw material, is used, the 6-bromoisoindolinone derivative represented by the above formula (2) is represented by the following formula (2A) A 6-bromoisoindolinone derivative (6-bromo-3-methylisoindolin-1-one) represented by can be obtained. The compound represented by the following formula (2A) is a compound in which R ¹ is a methyl group, R ² is a hydrogen atom, and X is a bromine atom in the above formula (2).

(isomer)
According to the method described above, an isomer represented by the following formula (2') may be produced. This isomer is a 4-halogenoisoindolinone derivative in which the halogen atom X is present at the 4-position.

In formula (2′), R ¹ , R ² and X have the same definitions as in formula (2).

The present invention will be described in detail with reference to examples below. The following examples are illustrative examples, and the present invention is not limited to them. Moreover, Production Example 1 is an example relating to the synthesis of 3-methyl-3-hydroxyisoindolin-1-one as an example of a 3-hydroxyisoindolinone derivative which is a substrate in the first production method. 1 and Comparative Example 1 are examples according to the first production method (that is, examples according to the method for producing an isoindolinone derivative), and Examples 2 to 8 and Comparative Example 2 are examples according to the second production method. (that is, an example relating to a method for producing a 6-bromoisoindolinone derivative).

<Production Example 1>
(Synthesis of 3-methyl-3-hydroxyisoindolin-1-one)
As shown in the reaction formula below, 3-methyl-3-hydroxyisoindolin-1-one represented by the following formula (3A) was synthesized from phthalimide (see formula (4)) by the following method.

Phthalimide (50 g, 0.34 mol) was dissolved in methylene chloride (500 mL), and methylmagnesium bromide (MeMgBr, 1.04 mol) was added dropwise at -10 to 7°C over 1 hour. After the mixture was stirred at 7° C. for 2 hours, saturated aqueous ammonium chloride solution (500 mL) was added. This "mixture is concentrated under reduced pressure, water (200 mL) is added to the concentrated residue, the resulting slurry is filtered, washed with water and hexane, and dried to obtain 3-methyl-3-hydroxyl represented by the above formula (3A). Isoindolin-1-one was obtained (39.2 g, 71%).

The analysis results of NMR spectroscopy were as follows.
¹ H-NMR (DMSO-d6) δ: 8.80 (br, 1H), 7.62-7.56 (m, 3H), 7.49-7.44 (m, 1H), 6.09 ( s, 1H), 1.59 (s, 3H).

<Example 1; First manufacturing method>
(Synthesis of isoindolinone derivative)
In the following method, using 3-methyl-3-hydroxyisoindolin-1-one shown in the following reaction formula (3A) as the 3-hydroxyisoindolinone derivative represented by the above formula (3), the formula ( 3-methylisoindolin-1-one shown in 1A) was synthesized.

3-methyl-3-hydroxyisoindolin-1-one (33.7 g, 0.207 mol) was dissolved in methanol (525 mL) and NaBH ₃ CN (27 g, 0.43 mol) was added over 10 minutes at 25°C. . To this solution, HCl-MeOH (238 mL, 0.491 mol) with a mass concentration of HCl of 7.5% was added dropwise over 2 hours and 30 minutes at 35°C or lower.

After that, concentrated hydrochloric acid was added to adjust the pH to 2. The reaction solution was concentrated under reduced pressure to distill off methanol. Methylene chloride and water were added to the concentrated residue and the layers were separated. The organic layer was concentrated, and the concentrated residue was purified with a silica gel column (ethyl acetate). Further, the resulting crude product was recrystallized from ethyl acetate and hexane to obtain an isoindolinone derivative (26.5 g, 87%).

The analysis results of NMR spectroscopy were as follows.
¹ H-NMR (CDCl3) δ: 7.92 (br, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5, 1.2 Hz , 1H), 7.50 - 7.41 (m, 2H), 4.72 (q, J = 6.7 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H).

<Comparative Example 1>
3-methyl-3-hydroxyisoindolin-1-one (3 g, 0.0184 mol) was dissolved in methanol (46 mL) and NaBH ₃ CN (1.29 g, 0.0205 mol) was added over 10 minutes at 25°C. . Concentrated hydrochloric acid (9 drops, 0.36 mL, moles of HCl: 4.32 mmol) having a mass concentration of HCl of 35% was added to this solution at 25°C, and the mixture was stirred at the same temperature for 2 hours. As a result, 3-methylisoindolin-1-one, which is the target product, was produced only in a trace amount (very small amount).

The production methods and HPLC measurement results according to Example 1 and Comparative Example 1 are summarized in Table 1 below.

<Example 2; Second manufacturing method>
(Synthesis of 6-bromoisoindolinone derivative)
6-bromo-3-methylisoindolin-1-one represented by formula (2A) was synthesized by the following method using 3-methylisoindolin-1-one represented by reaction formula (1A) below. As shown in the reaction formula below, 4-bromo-3-methylisoindolin- shown in the following formula (2'A) as an isomer of the target 6-bromo-3-methylisoindolin-1-one 1-ons are also produced.

Aluminum trichloride (1.76 g, 13.2 mmol, 3.0 eq) was added to a methylene chloride (7 mL) solution of 3-methylisoindolin-1-one (1.00 g, 4.42 mmol) at 8°C for 20 minutes. Stirred. To this solution, a solution of bromine (0.92 g, 5.76 mmol, 1.3 eq) in methylene chloride (3 mL) was added dropwise over 30 min (temperature increased to 7°C). The mixture was stirred at 5°C for 3 hours and at 25°C for 2 hours.

This reaction solution was slowly poured into ice water (10 mL), and a large amount of NaOH aqueous solution with a mass concentration of 24% was added to adjust the pH to 11. The mixture was separated and the aqueous layer was extracted with methylene chloride (10 mL). The organic layers were combined, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude product.

When this crude product was analyzed by HPLC, the crude product was 3-methylisoindolin-1-one (raw material): 6-bromo-3-methylisoindolin-1-one (target product): 4-bromo-3- A 15:62:12 mixture of methylisoindolin-1-ones (isomers) was found. This crude product was purified with a silica gel column (hexane:ethyl acetate was 1:1) to obtain 6-bromo-3-methylisoindolin-1-one (0.81 g, yield 53 %).

The analysis results of NMR spectroscopy were as follows.
¹ H-NMR (DMSO-d ₆ ) δ: 8.00 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.52 (s, lH), 7.34 ( d, J = 8.0 Hz, 1H), 4.73-4.68 (m, lH), 1.53 (d, J = 6.8 Hz, 3H).

The analysis results of HPLC analysis were as follows.
Analysis conditions:
Sample concentration: 0.5% THF
Injection volume: 5 μL
Detection wavelength: 254 nm
Flow rate: 1.0 mL/min
Column temperature: 30°C
Mobile phase: 20% acetonitrile (0-10min), 20-100% acetonitrile (10-20min)
Filler: X Bridge C18 5μm (4.6x150mm)
The retention time was 14.277 min for 6-bromo-3-methylisoindolin-1-one and 14.594 min for 4-bromo-3-methylisoindolin-1-one.

<Example 3>
In Example 2, the amount of aluminum trichloride was changed from 1.76 g to 1.17 g (8.80 mmol, 2.0 equiv.) and the amount of bromine was changed from 0.92 g to 1.13 g (7. 09 mmol, 1.6 equiv.), the reaction was carried out in the same manner as described in Example 2.

<Example 4>
In Example 2, the reaction was carried out in the same manner as described in Example 2, except that the amount of aluminum trichloride was changed from 1.76 g to 1.47 g (11.0 mmol, 2.5 equiv.). gone.

<Example 5>
Sulfuric acid (0.55 g, 8.3 eq, 5.64 mmol) was added to a solution of 3-methylisoindolin-1-one (0.10 g, 0.679 mmol) in methylene chloride (1 mL) at 25°C. DBDMH (0.10 g, 0.346 mmol, 0.51 equiv.) was added to this solution and stirred at 25° C. for 18 hours.

Water (3 mL) and ethyl acetate (4 mL) were added to the reaction mixture, and the organic layer was analyzed by HPLC. It was found to be a mixture of isoindolin-1-one (target):4-bromo-3-methylisoindolin-1-one (isomer) at a ratio of 5.4:56:20.

<Example 6>
In Example 5, the amount of sulfuric acid was changed from 0.55 g to 4.63 g (47.5 mmol, 70 equiv.) and the amount of DBDMH was changed from 0.10 g to 0.12 g (0.407 mmol, 0.407 mmol). 60 equiv.), the reaction was carried out in the same manner as described in Example 5.

<Example 7>
In Example 5, the reaction was carried out in the same manner as described in Example 5, except that the amount of sulfuric acid was changed from 0.55 g to 0.26 g (2.71 mmol, 4.0 equiv.). .

<Example 8>
The reaction was carried out in a similar manner as described in Example 5, except that 0.14 g (0.883 mmol, 1.3 equiv.) of bromine was used in Example 5 instead of 0.10 g of DBDMH. gone.

<Comparative Example 2>
To a solution of 3-methylisoindolin-1-one (147 mg, 1 mmol) in 1,2-dichloroethane (2 mL) at 25° C. was added aluminum trichloride (235 mg, 2.51 mmol) and bromine (0.105 g, 1.32 mmol). ) was added and heated to reflux for 15 hours. A saturated aqueous sodium thiosulfate solution (5 mL) and ethyl acetate (10 mL) were added to the mixture, and the mixture was filtered through celite. The organic layer of this filtrate was concentrated under reduced pressure, and the concentrated residue was purified with a silica gel column (hexane/ethyl acetate=1:1) to obtain a 6-bromoisoindolinone derivative (76.4 mg, 34%).

The production methods and HPLC measurement results of Examples 2 to 8 and Comparative Example 2 are summarized in Table 2 below.

Claims (8)

in the presence of acid,
an isoindolinone derivative represented by the following formula (1);
a halogenating agent;
in a temperature range of −10° C. or higher and 50° C. or lower to produce a 6-halogenoisoindolinone derivative represented by the following formula (2),
Method for producing 6-halogenoisoindolinone derivative:

In the above formula (1),
R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, an aryl group, an aralkyl group, or a dialkylaminoalkyl group;
R ² is a hydrogen atom or an amino group-protecting group,

In the above formula (2),
R ¹ and R ² have the same definitions as in formula (1) above, and X is a halogen atom derived from the halogenating agent. contacting the isoindolinone derivative represented by the formula (1) with the halogenating agent in at least one halogen solvent selected from the group consisting of methylene chloride and chloroform;
The method for producing the 6-halogenoisoindolinone derivative according to claim 1. the acid is aluminum trichloride,
The halogenating agent is at least one brominating agent selected from the group consisting of bromine and 1,3-dibromo-5,5-dimethylhydantoin.
The method for producing the 6-halogenoisoindolinone derivative according to claim 1 or 2. The amount of the aluminum trichloride is 1.0 mol or more and 5.0 mol or less per 1 mol of the isoindolinone derivative represented by the formula (1),
The amount of the brominating agent is 0.5 mol or more and 1.5 mol or less per 1 mol of the isoindolinone derivative represented by the formula (1).
The method for producing a 6-halogenoisoindolinone derivative according to claim 3. the acid is sulfuric acid,
the halogenating agent is 1,3-dibromo-5,5-dimethylhydantoin;
The method for producing the 6-halogenoisoindolinone derivative according to claim 1 or 2. The amount of the sulfuric acid is 3.0 mol or more and 10.0 mol or less per 1 mol of the isoindolinone derivative represented by the formula (1),
The amount of the 1,3-dibromo-5,5-dimethylhydantoin per 1 mol of the isoindolinone derivative represented by the formula (1) is 0.5 mol or more and 1.0 mol or less.
The method for producing a 6-halogenoisoindolinone derivative according to claim 5. In the presence of methanolic hydrochloric acid, a 3-hydroxyisoindolinone derivative represented by the following formula (3) and at least one reducing agent selected from the group consisting of sodium cyanoborohydride and sodium triacetoxyborohydride. After producing the isoindolinone derivative represented by the formula (1) by contacting
contacting the obtained isoindolinone derivative represented by the formula (1) with the halogenating agent;
A method for producing the 6-halogenoisoindolinone derivative according to any one of claims 1 to 6:

In the above formula (3),
R ¹ and R ² have the same meanings as in formula (1) above. In the presence of methanolic hydrochloric acid,
a 3-hydroxyisoindolinone derivative represented by the following formula (3);
at least one reducing agent selected from the group consisting of sodium cyanoborohydride and sodium triacetoxyborohydride;
to obtain an isoindolinone derivative represented by the following formula (1):
Method for producing isoindolinone derivatives:

In the above formula (3),
R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, an aryl group, an aralkyl group, or a dialkylaminoalkyl group;
R ² is a hydrogen atom or an amino group-protecting group,

In the above formula (1),
R ¹ and R ² have the same definitions as in formula (3) above.