JP2022022957A - Method for producing isoindolinone derivative - Google Patents

Abstract

To provide a method for producing isoindolinone derivatives with high production efficiency.SOLUTION: A method includes bringing, in the presence of a cobalt catalyst and sodium percarbonate, an amide derivative and a carbon monoxide source compound including an azo derivative into contact with each other, resulting in an isoindolinone derivative of the following formula (3), where R1 is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group or the like; R2 and R3 independently represent a hydrogen atom, a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group or the like.SELECTED DRAWING: None

Description

The present invention relates to a method for producing an isoindolinone derivative.

Isoindolinone derivatives are useful compounds used as manufacturing intermediates for various pharmaceutical products. As a production method thereof, a method of contacting a benzylpicoline amide compound derived from a benzylamine compound with diethyl azodicarboxylate (DEAD) in the presence of a cobalt catalyst, a carboxylic acid and silver carbonate has been reported (Non-Patent Document 1). ).

Advanced Synthesis and Catalyst 359, 2017, 3707-3712

An object of the present invention is to provide a method for producing an isoindoleinone derivative having high production efficiency.

According to one embodiment, a method for producing an isoindolinone derivative is provided. This production method is at least selected from the group consisting of an amide derivative represented by the following formula (1), N-formylmethionyl and an azo derivative represented by the following formula (2) in the presence of a cobalt catalyst and sodium percarbonate. It includes contacting with a carbon monoxide source compound containing one kind of compound to obtain an isoindolinone derivative represented by the following formula (3).

In formula (1), R ¹ is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl. A group, substituted or unsubstituted alkylcarbonyloxy group, or substituted or unsubstituted aromatic ring group which may contain a hetero atom. l is an integer from 0 to 5. When l is 2 or more, R ¹ may be the same group or a different group, and R ¹ may be bonded to each other to form a ring. ^R5 is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted. Alkoxycarbonyloxy group of, or substituted or unsubstituted aromatic ring group which may contain a hetero atom. m is an integer from 0 to 4. When m is 2 or more, R ⁵ may be the same group or a different group, and R ⁵ may be bonded to each other to form a ring. R ² , R ³ and R ⁴ are independently hydrogen atom, halogen atom, nitro group, nitrile group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aralkyl group, respectively. A substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyloxy group, or a substituted or unsubstituted aromatic ring group which may contain a hetero atom.

In formula (2), R ⁷ is a substituted or unsubstituted alkyl group. X is an oxygen atom or a nitrogen atom. n is 1 or 2.

In the formula (3), R ¹ , R ² , R ³ , and l are synonymous with those represented by the formula (1).

According to the method for producing an isoindolinone derivative according to the embodiment, the isoindoleinone derivative can be produced with high production efficiency.

The production method according to the embodiment includes an amide derivative represented by the above formula (1) (hereinafter, also referred to as an amide derivative) and a carbon monoxide source compound (hereinafter, CO source compound) in the presence of a cobalt catalyst and sodium percarbonate. It is included to obtain an isoindolinone derivative represented by the above formula (3) (hereinafter, also referred to as an isoindolinone derivative) by contacting with (referred to as). The CO source compound contains at least one compound selected from the group consisting of N-formylmethionyl saccharin and an azo derivative represented by the above formula (2) (hereinafter, also referred to as an azo derivative).

In a cobalt-catalyzed reaction, an oxidizing agent may be used in combination to accelerate the reaction. That is, in a reaction using a cobalt catalyst, for example, monovalent cobalt ion (Co ⁺ ) or divalent cobalt ion (Co ²⁺ ) is oxidized to trivalent cobalt ion (Co ³⁺ ). Promotes the CH activation reaction. Therefore, an oxidizing agent may be added to promote the oxidation of monovalent or divalent cobalt ions.

As described in Non-Patent Document 1, silver carbonate (Ag ₂ CO ₃ ) has been used as this oxidizing agent in the process of producing an isoindolinone derivative. However, silver carbonate is highly toxic and requires careful handling. Also, silver carbonate is a relatively expensive reagent. Therefore, it has been difficult to safely mass-produce isoindoleinone derivatives by the method using silver carbonate.

As a result of diligent research by the present inventors on such problems, by using sodium percarbonate as an oxidizing agent in the manufacturing process of the isoindolinone derivative, the production efficiency is almost the same as that when silver carbonate is used. Was found to be possible. Sodium percarbonate is a highly safe substance with a relatively low cost and a small impact on the human body and the environment. Therefore, according to the production method according to the embodiment, the production efficiency of the isoindoleinone derivative can be improved, and thus mass production can be realized.

Hereinafter, the present invention will be described in detail.

<Amid derivative>
The amide derivative is a substrate in the production method according to the embodiment. The amide derivative is a compound represented by the following formula (1).

In formula (1), R ¹ is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl. A group, substituted or unsubstituted alkylcarbonyloxy group, or substituted or unsubstituted aromatic ring group which may contain a hetero atom.

In ^R1 , the number of carbon atoms in the main chain of the alkyl group and the alkoxy group is preferably 1 or more and 6 or less. The number of carbon atoms in the main chain of the aralkyl group is preferably 7 or more and 13. The carbon number of the main chain of the alkoxycarbonyl group and the alkylcarbonyloxy group is preferably 1 or more and 12 or less. The number of elements constituting the aromatic ring group is preferably 6 or more and 12 or less. Further, the substituent which can be contained in the alkyl group, the alkoxy group, the aralkyl group, the alkoxycarbonyl group, the alkylcarbonyloxy group and the aromatic ring group is a group consisting of a methyl group, a methoxy group, a nitro group, an amino group and a halogen group. It is preferable that it is at least one selected from the above. R ¹ is preferably a halogen group, more preferably a bromo group.

l is an integer from 0 to 5. When l is 2 or more, R ¹ may be the same group or a different group, and R ¹ may be bonded to each other to form a ring. l is preferably 0 or 1.

^R5 is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted. Alkoxycarbonyloxy group of, or substituted or unsubstituted aromatic ring group which may contain a hetero atom.

^In R5, the number of carbon atoms in the main chain of the alkyl group and the alkoxy group is preferably 1 or more and 6 or less. The number of carbon atoms in the main chain of the aralkyl group is preferably 7 or more and 13. The carbon number of the main chain of the alkoxycarbonyl group and the alkylcarbonyloxy group is preferably 1 or more and 12 or less. The number of elements constituting the aromatic ring group is preferably 6 or more and 12 or less. Further, the substituent which can be contained in the alkyl group, the alkoxy group, the aralkyl group, the alkoxycarbonyl group, the alkylcarbonyloxy group and the aromatic ring group is a group consisting of a methyl group, a methoxy group, a nitro group, an amino group and a halogen group. It is preferable that it is at least one selected from the above.

m is an integer from 0 to 4. When m is 2 or more, R ⁵ may be the same group or a different group, and R ⁵ may be bonded to each other to form a ring. m is preferably 0 or 1, more preferably 0.

R ² , R ³ and R ⁴ are independently hydrogen atom, halogen atom, nitro group, nitrile group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aralkyl group, respectively. A substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyloxy group, or a substituted or unsubstituted aromatic ring group which may contain a hetero atom.

In R ² , R ³ and R ⁴ , the number of carbon atoms in the main chain of the alkyl group and the alkoxy group is preferably 1 or more and 6 or less. The number of carbon atoms in the main chain of the aralkyl group is preferably 7 or more and 13. The carbon number of the main chain of the alkoxycarbonyl group and the alkylcarbonyloxy group is preferably 1 or more and 12 or less. The number of elements constituting the aromatic ring group is preferably 6 or more and 12 or less. Further, the substituent which can be contained in the alkyl group, the alkoxy group, the aralkyl group, the alkoxycarbonyl group, the alkylcarbonyloxy group and the aromatic ring group is a group consisting of a methyl group, a methoxy group, a nitro group, an amino group and a halogen group. It is preferable that it is at least one selected from the above. At least one of R ² and R ³ is preferably an alkyl group or a hydrogen atom, and more preferably a methyl group or a hydrogen atom. ^R4 is preferably a hydrogen atom.

As the amide derivative, a synthesized derivative may be used, or a commercially available derivative may be used.

As the amide derivative represented by the above formula (1), a compound represented by the following chemical formula is preferably mentioned.

The amide derivatives (1A to 1D) can be produced by the method described in Non-Patent Document 1. In particular, when (R) -N- (1- (4-bromophenyl) ethyl) picoline amide represented by the above formula (1A) is used as the amide derivative, (R) -6 represented by the following (3A). -Bromo-3-methylisoindoline-1-one can be obtained as an isoindolinone derivative. (R) -6-bromo-3-methylisoindoline-1-one is particularly useful as a pharmaceutical production intermediate.

<Carbon monoxide source compound>
The carbon monoxide source compound produces carbon monoxide (CO) and ester radicals that react with the amide derivative in the production method according to the embodiment.

The CO source compound comprises at least one compound selected from the group consisting of N-formylmethionyl saccharin and azo derivatives.

The azo derivative is represented by the following formula (2).

In formula (2), R ⁷ is a substituted or unsubstituted alkyl group. The number of carbon atoms in the main chain of the alkyl group is preferably 1 or more and 7 or less, and more preferably 1 or more and 3 or less. It is more preferable that R ⁷ is an ethyl group. X is an oxygen atom or a nitrogen atom. X is preferably an oxygen atom. n is 1 or 2.

Specific examples of the azo derivative represented by the above formula (2) include azodicarboxylate diethyl (DEAD), diisopropylazodicarboxylate, dimethylazodiamide, diethylazodiamide and the like.

N-formylmethaccharin is represented by the following formula (4).

The CO source compound preferably contains N-formylmethionyl saccharin. When N-formylmethaccharin is used, the safety of the production method according to the embodiment is further enhanced. That is, N-formylmethionyl saccharin is a substance that is cheaper, less toxic, and more safe than an azo derivative. Further, the reaction between N-formylmethionyl saccharin and the amide derivative is milder than the reaction between the azo derivative and the amide derivative, and the amount of gas generated tends to be small.

The amount of the CO source compound used is not particularly limited. It is preferable to use 1 to 10 mol, more preferably 1 to 8 mol, and particularly preferably 1 to 5 mol with respect to 1 mol of the amide derivative.

<Cobalt catalyst>
Contact between the amide derivative and the CO source compound is carried out in the presence of a cobalt catalyst. The cobalt catalyst coordinates with the amide derivative and promotes the reaction of the amide derivative with the carbon monoxide and ester radicals generated from the CO source compound.

As the cobalt catalyst, it is preferable to use at least one selected from the group consisting of cobalt acetate and pivalate. As the acetate of cobalt, it is preferable to use cobalt acetate tetrahydrate represented by Co ₍ OAc) _2.4H2O . As the cobalt pivalate, it is preferable to use cobalt (II) pivalate. As the cobalt catalyst, it is particularly preferable to use cobalt acetate tetrahydrate.

The amount of the cobalt catalyst used is not particularly limited. The cobalt catalyst is preferably used in an amount of 0.05 to 3 mol, more preferably 0.1 to 2 mol, still more preferably 0.3 to 1 mol, based on 1 mol of the amide derivative. It is particularly preferable to use 0.5 to 0.8 mol.

<Oxidizing agent>
In the production method according to the embodiment, sodium percarbonate is used as an oxidizing agent. Sodium percarbonate is an addition compound in which sodium carbonate and hydrogen peroxide are mixed in a molar ratio of 2: ₃ , and is represented by Na ₂ CO 3.1.5H ₂ O ₂ . Sodium percarbonate is also referred to as sodium percarbonate or sodium percarbonate adduct.

Since sodium percarbonate has an appropriate oxidizing power and solubility and also becomes a base in the reaction system, it is considered that the reaction can be promoted almost in the same manner as silver carbonate. That is, if the oxidizing power of the oxidizing agent is excessively large, a side reaction may occur and the yield of the isoindoleinone derivative may decrease. Since the oxidizing power of sodium percarbonate is moderate, the reaction can be promoted without causing a side reaction or the like. In addition, the presence of a base in the reaction system further promotes the reaction.

The amount of sodium percarbonate with respect to 1 mol of the amide derivative is preferably 1 mol or more and 20 mol or less, more preferably 2 mol or more and 10 mol or less, and further preferably 2 mol or more and 5 mol or less. ..

The amount of the oxidizing agent with respect to 1 mol of the cobalt catalyst is preferably 0.1 mol or more and 50 mol or less, more preferably 1 mol or more and 20 mol or less, and further preferably 2 mol or more and 10 mol or less. preferable.

As the oxidizing agent, sodium percarbonate and a conventional oxidizing agent may be used in combination. Specific examples of conventional oxidizing agents include silver salts such as silver carbonate and silver acetate, manganese dioxide, sodium hypochlorite, sodium hypochlorite pentahydrate and the like. However, as mentioned above, silver carbonate is highly toxic and is preferably not used. From the viewpoint of safety and cost, it is preferable to use only sodium percarbonate as the oxidizing agent as a solid.

<Carboxylic acid>
The contact between the amide derivative and the CO source compound is preferably carried out in the presence of a carboxylic acid in addition to the cobalt catalyst and sodium percarbonate. Carboxylic acid acts as a ligand for the cobalt catalyst and promotes the dehydrogenation reaction of the substrate. Carboxylic acid can also function as an oxidizing agent.

As the carboxylic acid, for example, at least one selected from the group consisting of formic acid, acetic acid, pivalic acid, adamantan carboxylic acid, and mesitylene carboxylic acid is used. A suitable carboxylic acid is the following formula (5).

A carboxylic acid having a branched structure represented by (hereinafter, also referred to as “branched carboxylic acid”) can be mentioned. In the formula (5), R ⁸ , R ⁹ and R ¹⁰ are phenyl groups which may have an alkyl group, an aralkyl group, an aryl group, or a substituent, respectively. In addition, one of R ⁸ , R ⁹ and R ¹⁰ may be a hydrogen atom. Further, at least two of R ⁸ , R ⁹ and R ¹⁰ may be bonded to form a hydrocarbon ring.

The alkyl group preferably has 1 to 20 carbon atoms constituting the group, the aralkyl group preferably has 7 to 30 carbon atoms constituting the group, and the aryl group constitutes the group. The number of carbon atoms is preferably 6 to 20, and the phenyl group is preferably a phenyl group having no substituent. When the phenyl group has a substituent, examples of the suitable substituent include a methyl group and a methoxy group. Further, examples of the hydrocarbon ring in which at least two of R ⁸ , R ⁹ and R ¹⁰ are bonded include a 1-adamantyl group.

The branched carboxylic acid is represented by a pivalic acid represented by the following formula (5A) (a compound in which R ⁸ , R ⁹ and R ¹⁰ are all methyl groups in the above formula (5)) and a formula (5B). ² -Phenylisobutyric acid (in the above formula ( ⁵ ), any two of R8, ^R9 and R10 are methyl groups, and the remaining one is a phenyl group having no substituent. For convenience, in the following formula (5B), R ⁸ and R ¹⁰ are used as a methyl group, and R ⁹ is used as a phenyl group having no substituent) or 1-adamantan carboxylic acid represented by the formula (5C) (1-adamantan carboxylic acid). In the above formula (5), a compound having a 1-adamantyl group in which at least two of R ⁸ , R ⁹ and R ¹⁰ are bonded) can be mentioned.

Among them, as the carboxylic acid, it is preferable to use at least one selected from the group consisting of 1-adamantane carboxylic acid and pivalic acid.

The amount of the carboxylic acid with respect to 1 mol of the amide derivative is preferably 1 mol or more and 10 mol or less, more preferably 1 mol or more and 8 mol or less, and further preferably 1 mol or more and 5 mol or less.

The amount of the carboxylic acid with respect to 1 mol of the cobalt catalyst is preferably 0.1 mol or more and 20 mol or less, more preferably 1 mol or more and 10 mol or less, and further preferably 2 mol or more and 8 mol or less. It is preferably 2 mol or more and 6 mol or less.

<Base>
The contact between the amide derivative and the CO source compound is preferably carried out in the presence of a base in addition to the cobalt catalyst, sodium percarbonate and the optional component carboxylic acid. When a base is present in the reaction system, CO is likely to be generated from the CO source compound, so that the reaction can be further promoted.

As the base, either an organic base or an inorganic base may be used. As the organic base, it is preferable to use amines. Examples of amines include alkylamines having 3 to 10 carbon atoms such as triethylamine and diisopropylethylamine, pyridine, lutidine, diethylaniline, 1-azabicyclo [2.2.2] octane (quinuclidine), and 1,8-. Cyclic amines such as diazabicyclo [5.4.0] undecene-7 are included.

Among the alkylamines, triethylamine or diisopropylethylamine is preferable. Among the cyclic amines, quinuclidine represented by the following formula (6A) is preferable.

As the inorganic base, it is preferable to use an alkali metal salt. Examples of alkali metal salts include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and potassium hydrogen carbonate. As the base, a single type may be used, or a plurality of types may be mixed and used.

The base consists of triethylamine, diisopropylethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, pyridine, lutidine, diethylaniline, quinuclidine, and 1,8-diazabicyclo [5.4.0] undecene-7. It is preferable to use at least one selected from the group. As the base, it is more preferable to use at least one selected from the group consisting of triethylamine and diisopropylethylamine.

The amount of the base for 1 mol of the amide derivative is preferably 0.1 mol or more and 100 mol or less, more preferably 1 mol or more and 50 mol or less, and further preferably 1 mol or more and 40 mol or less. Most preferably, it is 1 mol or more and 10 mol or less.

The amount of the base for 1 mol of the CO source compound is preferably 0.1 mol or more and 20 mol or less, more preferably 0.5 mol or more and 15 mol or less, and 1 mol or more and 10 mol or less. Is more preferable.

<Organic solvent>
The contact between the cobalt catalyst, sodium percarbonate, and the amide derivative in the presence of the optional component carboxylic acid and base and the CO source compound is preferably carried out in an organic solvent.

Examples of the organic solvent include alcohols such as ethanol, isopropanol, 1-butyl alcohol, 2-butyl alcohol, t-butyl alcohol, 2,2,2-trifluoroethanol and 1-methoxy-2-propanol; 1,4- Ethers such as dioxane, t-butylmethyl ether (MTBE), diethylene glycol dimethyl ether, cyclopentylmethyl ether (CPME); halogenated hydrocarbons such as chlorobenzene; aromatic hydrocarbons such as toluene and xylene; hexane, heptane Etc., such as aliphatic hydrocarbons; N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), N, N-dimethylimidazolidine-one ( Amides such as DMI); nitriles such as acetonitrile; dimethylsulfoxide (DMSO) and the like can be mentioned. These organic solvents can be used alone or as a mixed solvent thereof.

Preferred are t-butyl alcohol, diethylene glycol dimethyl ether, 2-butyl alcohol, 1,4-dioxane, 2,2,2-trifluoroethanol, MTBE, CPME, acetonitrile, isopropanol, or a mixed solvent thereof. 1,4-dioxane is particularly preferable because it has an excellent ability to dissolve carbon monoxide. Further, diethylene glycol dimethyl ether and 2-butyl alcohol are more preferable in that they can dissolve an inorganic reactant while being an organic solvent and are inexpensive. The t-butyl alcohol has a point of appropriately dissolving a reactant such as the above-mentioned cobalt catalyst and an oxidizing agent, a point of having a polarity to promote the reaction between the amide derivative and the CO source compound, and a point of having a hydrogen bond with the amide derivative. It is particularly preferable because it is excellent in that it activates the reaction with the CO source compound and that it has low toxicity and is easy to use industrially.

The amount of the organic solvent used is not particularly limited. For 1 g of the amide derivative, it is preferable to use 0.5 to 100 mL of the organic solvent, more preferably 1 to 50 mL, more preferably 10 to 50 mL, and most preferably 20 to 50 mL. preferable. When a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent may satisfy the above range.

<Manufacturing method of isoindoleinone derivative>
In the production method according to the embodiment, the amide derivative and the CO source compound are brought into contact with each other in the presence of a cobalt catalyst, sodium percarbonate and an optional component, and these are reacted to obtain an isoindolinone derivative.

The method of mixing each component is not particularly limited. For example, each component is put into a reaction vessel equipped with a stirring mechanism and mixed. The procedure for charging each component into the reaction vessel is not particularly limited. After dissolving the amide derivative and the CO source compound in the organic solvent, a cobalt catalyst, sodium percarbonate and an optional component may be added to the solution.

The reaction vessel is preferably a pressure-resistant vessel that can be sealed. This is because a large amount of gas may be generated in the reaction between the amide derivative and the CO source compound in the presence of a cobalt catalyst, sodium percarbonate and an optional component. As the pressure-resistant container, for example, an autoclave or the like may be used. This is to prevent carbon monoxide and oxygen from being exposed to the outside of the system.

The above reaction is preferably carried out in a closed state of the reaction vessel, that is, in a closed system. This is because carbon monoxide generated from the CO source compound contributes to the reaction. When the above reaction is carried out in an open system, or when the closed state is released during the reaction, a CO source compound may be further added in order to supplement the carbon monoxide that has flowed out of the reaction system. The amount of the CO source compound added is appropriately determined according to the progress of the reaction.

The above reaction is preferably carried out at a high temperature. The reaction temperature is preferably 10 ° C to 200 ° C, preferably 40 ° C to 180 ° C, and particularly preferably 80 ° C to 170 ° C. By carrying out the reaction in the temperature range, the reaction can proceed in a high yield and in a short time.

The reaction time may be appropriately determined by confirming the conversion rate to the isoindolinone derivative and appropriately determining the time when the reaction is completed, but usually it may be 0.1 hours or more and 48 hours or less, preferably 0.3. It is an hour or more and 36 hours or less, and particularly preferably 0.5 hour or more and 24 hours or less.

The reaction atmosphere is not particularly limited. It may be under an inert gas atmosphere or an air atmosphere.

After completion of the reaction, it is preferable to purify the isoindoleinone derivative by the following method. First, the reaction solution is filtered through Celite to obtain a filtrate. If the reaction solution is hot, it may be cooled to room temperature before being subjected to Celite filtration. The filter paper after filtering with Celite may be washed with methanol, and the washed methanol may be added to the filtrate. The treatment liquid after the Celite filtration may contain an amide derivative and a by-product in addition to the isoindoleinone derivative. By-products include, for example, aromatic ketones. Next, the obtained filtrate is dried under reduced pressure to remove the solvent to obtain a residue. This residue is dissolved in a solvent and the resulting solution is subjected to silica gel chromatography. As the solvent, for example, a mixed solvent of n-hexane and ethyl acetate is used. The solution after silica gel chromatography is dried under reduced pressure to remove the solvent to obtain a solid substance. This solid may contain an amide derivative in addition to the isoindoleinone derivative.

The proportion of the isoindoleinone derivative in the treatment liquid and the solid matter after the Celite filtration can be confirmed by, for example, high performance liquid chromatography (HPLC). Alternatively, the reaction solution may be analyzed by HPLC to determine the proportion of the isoindoleinone derivative.

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.

<Microwave>
The contact between the amide derivative and the azo derivative may be carried out under microwave irradiation in the presence of a cobalt catalyst, sodium percarbonate and any component. By performing microwave irradiation, an isoindolinone derivative can be produced in an extremely short time. In general, the principle that the reaction is accelerated by microwave irradiation is that in the electric field formed by microwave irradiation, the dipoles of the molecule follow the change of the electric field and change their direction, resulting in vigorous movement. It is believed that this happens and, as a result, heat is generated by the friction between the molecules. In the production method of the present invention, the amide derivative represented by the above formula (1) and the CO source compound represented by the above formula (2), which are reaction substrates, are directly activated by microwave irradiation. It is presumed that the isoindolinone derivative represented by the above formula (3) can be produced in an extremely short time and in a high yield.

Further, while the conventional heating method depends on the transfer of heat from an external heat source, the object to be heated itself generates heat when irradiated with microwaves. Therefore, heating by microwave irradiation enables rapid and uniform heating as compared with the conventional heating method, and temperature control is easy.

The timing of irradiating the microwave is not particularly limited, but from the viewpoint of operability and reaction control, it is preferable to mix each component to a predetermined reaction temperature and then irradiate. Further, in the production method of the present invention, the reaction is promoted by irradiation with microwaves. Therefore, the microwave irradiation time may be appropriately set in consideration of the reaction time described later.

Reactors equipped with a microwave irradiation mechanism are roughly classified into a multi-mode type and a single-mode type. Any device can be used in the manufacturing method of the present invention. The multi-mode method is the same type as a microwave oven, in which a sample is placed in a box-shaped device and microwaves are sprayed. On the other hand, the single mode method is a method of placing a sample in the center of the waveguide. It is preferable to use a single-mode reactor because the microwave irradiation can be easily controlled. Further, as the reaction vessel, since carbon monoxide is generated during the reaction, it is preferable to use a reaction vessel made of a material having excellent pressure resistance, such as borosilicate glass or quartz glass.

The type of microwave is not particularly limited, and millimeter wave, centimeter wave, ultra high frequency wave and the like can be used. The microwave to be used may be appropriately determined in consideration of the surrounding environment (interference with the microwave emitted from the peripheral device) and the like. Further, the frequency of the microwave is not particularly limited, and is preferably 300 MHz to 300 GHz, more preferably 500 MHz to 50 GHz.

The irradiation intensity of microwaves is not particularly limited and may be appropriately determined in consideration of the performance of the device to be used and the like. Usually, the range of 1 to 300 W is sufficient, and the range of 1 to 20 W is preferable.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto, but is a specific example.

<Manufacturing example 1>
(Synthesis of amide derivative)
The (R) -N- (1- (4-bromophenyl) ethyl) picoline amide represented by the above formula (1A) was synthesized by the following method.

First, 2.0 g (10.0 mmol) of (R)-(+)-1- (4-bromophenyl) ethylamine, 1.48 g (12.0 mmol) picolinic acid, and 1.84 g (12.0 mmol). ) 1-Hydroxybenzotriazole monohydrate and 30 mL of N, N-dimethylformamide were mixed and stirred at room temperature. 2.3 g (12.0 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.55 g (12.0 mmol) of N, N-diisopropylethylamine were added to the stirred solution. , In this order and stirred for 5 hours to obtain a mixture.

30 mL of water was added to this mixture to terminate the reaction. A mixed solvent of n-hexane and ethyl acetate was added to the mixture to which water was added, and the mixture was stirred for 10 minutes. The volume ratio in the mixed solvent was n-hexane: ethyl acetate = 4: 1. After adding 400 mL of saturated aqueous sodium hydrogen carbonate solution to the mixture to which the mixed solvent was added, anhydrous magnesium sulfate was added and dried. The mixture after adding anhydrous magnesium sulfate was dried under reduced pressure to remove the solvent to obtain crystals. The amount of crystals was 2.97 g and the yield was 97%.

The results of NMR spectroscopic analysis of crystals were as follows.
^{1 1} H-NMR (400 MHz, CDCl ₃ )
δ: 1.60 (d, J = 7.3Hz, 3H)
5.26 (m, 1H)
7.28 (m, 2H)
7.45 (m, 3H)
7.85 (dt, J = 1.4Hz, 7.8Hz, 1H)
8.18 (d, J = 7.8Hz, 1H)
8.30 (br, 1H)
8.55 (d, J = 4.6Hz, 1H).

<Example 1>
(Synthesis of isoindoleinone derivative)
(R) -6-bromo-3-methylisoindoline-1-one represented by the above formula (3A) was synthesized by the following method.

150.0 mg (0.492 mmol, 1.0 quiv.) Of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide prepared by the method of Production Example 1 and 61.2 mg (0. 246 mmol, 50 mol%) cobalt acetate (II) tetrahydrate, 385.9 mg (2.458 mmol, 5.0 equiv.) Sodium percarbonate, and 100.4 mg (0.983 mmol, 2.0 equiv.). Picoline, 171.2 mg (0.983 mmol, 2.0 equiv.) Of diethyl azodicarboxylate (DEAD) and 2.5 mL (0.2 M) of 1,4-dioxane are placed in a pressure resistant container under an air atmosphere. In addition, the pressure resistant container was sealed.

The contents of the closed pressure-resistant container were heated to 120 ° C. using a microwave device, and stirred at the reaction temperature for 2 hours while irradiating with microwaves. The contents after stirring were cooled to room temperature and then subjected to Celite filtration to obtain a filtrate. The filter paper after filtering with Celite was washed with methanol, and the washed methanol was added to the filtrate to obtain a treatment liquid after filtering with Celite.

The treatment liquid after filtration of Celite was dried under reduced pressure to remove the solvent, and a residue was obtained. This residue was dissolved in a solvent and the resulting solution was subjected to silica gel chromatography. As the solvent, a mixed solvent in which n-hexane and ethyl acetate were mixed in a volume ratio of 1: 1 was used. The solution after silica gel chromatography was dried under reduced pressure to remove the solvent to obtain a solid substance. The amount of the isoindolinone derivative contained in the solid substance was 80.0 mg (0.354 mmol), and the yield was 71.9%.

<Example 2>
Examples except that 171.2 mg (0.983 mmol, 2.0 equiv.) Diethyl azodicarboxylate (DEAD) was changed to 415.2 mg (1.966 mmol, 4.0 equiv.) N-formylmethionide. A solid substance was obtained by the same method as described in 1.

<Example 3>
A solid substance was obtained in the same manner as described in Example 2 except that 0.199 g (1.966 mmol, 4.0 equiv.) Of triethylamine was further added to the contents of the pressure-resistant container.

<Example 4>
A solid substance was obtained by the same method as described in Example 3 except that the irradiation with microwaves was omitted.

<Example 5>
A solid substance was obtained by the same method as described in Example 1 except that 2,2,2-trifluoroethanol was used instead of 1,4-dioxane.

<Example 6>
A solid was obtained in the same manner as described in Example 3, except that 0.254 g (1.966 mmol, 4.0 equiv.) Of diisopropylethylamine was used instead of 0.199 g of triethylamine.

<Example 7>
The amount of sodium percarbonate was changed from 385.9 mg to 154 mg (0.983 mmol, 2 equiv.), And the amount of N-formylmethaccharin was changed from 415.2 mg to 156 mg (0.737 mmol, 1.5 quiv.). The solid matter was prepared in the same manner as described in Example 4 except that the amount of triethylamine was changed from 0.199 g to 74.6 mg (0.737 mmol, 1.5 equiv.). Obtained.

<Reference example 1>
Described in Example 1 except that 251.4 mg (0.983 mmol, 2.0 equiv.) Of silver carbonate was used in place of 385.9 mg (2.458 mmol, 5.0 equiv.) Sodium percarbonate. A solid substance was obtained in the same manner as in. The amount of the isoindolinone derivative contained in the solid substance was 62.3 mg (0.276 mmol), and the yield was 56.0%.

<Reference example 2>
A solid substance was obtained by the same method as in Reference Example 1 except that 2,2,2-trifluoroethanol was used instead of 1,4-dioxane as a solvent.

<Comparative Example 1>
Instead of 385.9 mg (2.458 mmol, 5.0 equiv.) Sodium percarbonate, 404 mg (2.458 mmol, 5.0 equiv.) Sodium hypochlorite pentahydrate (NaOCl. 5H ₂ O) was used. A solid substance was obtained by the same method as described in Example 1 except that it was used.

<Microwave>
In Examples 1 to 4 and Comparative Example 1, a reaction device having the following specifications was used for microwave irradiation.
Equipment: Monowave 450 made by Antonio Par
Microwave output: 850W.
Magnetron frequency: 2455MHz.
Vials: G30 wide-mouthed borosilicate glass 30 mL, G30 borosilicate glass 30 mL, G10 borosilicate glass 10 mL, G4 borosilicate glass 4 mL
Pressure: 0 to 30 bar.
Stirrer: PTFE coating cap: Snap cap, PTFE disc.
Sepram: PTFE septum, silicon septum.

The microwave irradiation conditions were as follows.
Microwave output: 1-20W.
Pressure: 10-25 bar.

<Instrumental analysis>
The analysis results obtained for (R) -6-bromo-3-methylisoindoline-1-one contained in the solids obtained in Examples 1 to 5 and Comparative Example 1 were as follows.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 (d, J = 6.4 Hz, 3H), 4.66 (q, J = 6.4 Hz, 1H), 6.40 (br, 1H) , 7.31 (d, J = 8.2Hz, 1H), 7.70 (dd, J = 1.8Hz, 8.2Hz, 1H), 7.98 (d, J = 1.8Hz, 1H)
IR (KBr) cm ^-1 : 3243, 2969, 1653, 1431, 1262, 1219, 1112, 821, 598
Melting point: 163 to 167 ° C.

<HPLC analysis>
The abundance ratio of the isoindoleinone derivative, the substrate, and the by-product in the treatment liquid after the Celite filtration obtained in Examples 1 to 5 and Comparative Example 1 was measured by using HPLC. The HPLC measurement conditions were as follows.

Equipment: ACQUITY UPLC® H-CLASS PLUS (Waters)
Detector: Ultraviolet-visible absorptiometer (detection wavelength: 254 nm)
Column: X-Bridge C18, 5 μm, 4.6 × 150 mm Volume
Column temperature: 40 ° C
Sample temperature: Room temperature Sample injection volume: 5 μL
Liquid transfer time: 40 minutes The liquid transfer for the mobile phase was as shown in Table 1 below. As the mobile phase A, a 0.1% formic acid aqueous solution was used, and as the mobile phase B, 0.1% formic acid-containing acetonitrile was used.

The retention time of each target component is as shown in Table 2 below.

The production methods and HPLC measurement results according to Examples 1 to 5 and Comparative Example 1 are summarized in Table 3 below.

As is clear from Table 3, the production ratio of the isoindolenone derivative in Examples 1 to 7 using sodium hypochlorite as an oxidizing agent is the isoindolenone derivative of Reference Examples 1 and 2 using silver carbonate as an oxidizing agent. It was almost equal to or higher than the production ratio of the isoindolenone derivative of Comparative Example 1 using sodium hypochlorite pentahydrate as an oxidizing agent.

<Example 8>
In an autoclave, (R) -N- (1- (4-bromophenyl) ethyl) picolinamide (250 mg, 0.820 mmol) and N-formylsaccharin (0.332 g, 1.64 mmol) produced by the method of Production Example 1 were added. ), Cobalt acetate (II) tetrahydrate (0.153 g, 0.615 mmol), sodium percarbonate (0.322 g, 2.05 mmol), pivalic acid (0.618 g, 1.64 mmol), t-butyl alcohol. (8.0 mL, 32 v / w) was added, and finally triethylamine (17.9 g, 177 mmol) was added. Here, "v / w" indicates the volume (mL) of t-butyl alcohol with respect to 1 g of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide. Hereinafter, the same description will be omitted.

The autoclave was sealed and stirred at 100 ° C. for 4 hours. The internal pressure of the autoclave was 0.66 MPa at the maximum at 100 ° C. When the reaction solution was analyzed by HPLC, the assay yield was 93.33%.

<Example 9>
In Example 8, diethylene glycol dimethyl ether (8.0 mL, 32 v / w) was used instead of t-butyl alcohol (8.0 mL, 32 v / w), and the amount of cobalt (II) acetate tetrahydrate was determined. , 0.153 g was changed to 0.102 g (0.410 mmоl), the reaction temperature was changed from 100 ° C to 120 ° C, and the reaction time (stirring time) was changed from 4 hours to 2 hours. Except for this, a reaction solution was obtained in the same manner as described in Example 8.

<Example 10>
In Example 9, the reaction solution was prepared in the same manner as in Example 9 except that 2-butyl alcohol (8.0 mL, 32 v / w) was used instead of diethylene glycol dimethyl ether (8.0 mL, 32 v / w). Got

<Example 11>
In Example 9, the same method as in Example 9 except that methyl tert-butyl ether (MTBE, 8.0 mL, 32 v / w) was used instead of diethylene glycol dimethyl ether (8.0 mL, 32 v / w). A reaction solution was obtained.

<Example 12>
The same method as in Example 9 except that 1-methoxy-2-propanol (8.0 mL, 32 v / w) was used instead of diethylene glycol dimethyl ether (8.0 mL, 32 v / w). The reaction solution was obtained in.

<Example 13>
In Example 9, the reaction was carried out in the same manner as in Example 9 except that cyclopentyl methyl ether (CPME, 8.0 mL, 32 v / w) was used instead of diethylene glycol dimethyl ether (8 m.0 L, 32 v / w). Obtained liquid.

<Example 14>
In Example 9, the reaction solution was prepared in the same manner as in Example 9 except that 1-butyl alcohol (8.0 mL, 32 v / w) was used instead of diethylene glycol dimethyl ether (8.0 mL, 32 v / w). Got

Various manufacturing conditions and results in Examples 8 to 14 are summarized in Table 4 below. In Examples 8 to 14, common conditions other than those shown in Table 4 are as follows.
As the amide derivative as a substrate, 250 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.82 mmоl.
As an oxidizing agent, 2.05 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As the CO source compound, 1.64 mmol of N-formyl saccharin was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the carboxylic acid, 1.64 mmоl of pivalic acid was used, that is, 2.0 mol per 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the base, 1.64 mmol of triethylamine, ie 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide, was used.
Further, (A) and (B) in Table 4 indicate the following contents, respectively. The same applies to Tables 5 to 9 described later.
(A): Amount of substance (mol) per 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide (substrate)
(B): Volume (mL) per 1 g of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide (substrate) (“v / w” in the text)

<Example 15>
A reaction solution was obtained in the same manner as described in Example 9 except that 4.0 mL (16 v / w) of t-butyl alcohol was used instead of the diethylene glycol dimethyl ether in Example 9.

<Example 16>
In Example 15, the reaction solution was prepared in the same manner as in Example 15 except that diethylene glycol dimethyl ether (4.0 mL, 16 v / w) was used instead of t-butyl alcohol (4.0 mL, 16 v / w). Got

<Example 17>
In Example 15, instead of t-butyl alcohol (4.0 mL, 16 v / w), toluene (3.6 mL, 14.4 v / w) and dimethyl sulfoxide (DMSO, 0.40 mL, 1.6 v / w) ) Was used, and the reaction solution was obtained in the same manner as in Example 15.

<Example 18>
The same method as in Example 15 except that 1,4-dioxane (4.0 mL, 16v / w) was used instead of t-butyl alcohol (4.0 mL, 16v / w). The reaction solution was obtained in.

The various production conditions and results of Examples 15 to 18 are summarized in Table 5 below. In Examples 15 to 18, common conditions other than those shown in Table 5 are as follows.
As the amide derivative as a substrate, 250 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.82 mmоl.
As an oxidizing agent, 2.05 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As a cobalt catalyst, 0.410 mmol of cobalt (II) acetate tetrahydrate, that is, 0.50 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide is used. did.
As the CO source compound, 1.64 mmol of N-formyl saccharin was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the carboxylic acid, 1.64 mmоl of pivalic acid was used, that is, 2.0 mol per 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the base, 1.64 mmol of triethylamine, ie 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide, was used.
The reaction temperature was 120 ° C.
The reaction time was 2 hours.

<Example 19>
A reaction solution was obtained in the same manner as described in Example 8 except that the reaction time (stirring time) was changed from 4 hours to 2 hours in Example 8.

<Example 20>
In Example 8, the amount of cobalt (II) acetate tetrahydrate was changed from 0.153 g to 0.102 g (0.410 mmоl), and the reaction time (stirring time) was changed from 4 hours to 2 hours. A reaction solution was obtained in the same manner as described in Example 8 except that the reaction solution was changed to.

Various manufacturing conditions and results in Examples 19 and 20 are summarized in Table 6 below. In Examples 19 and 20, common conditions other than those shown in Table 6 are as follows.
As the amide derivative as a substrate, 250 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.82 mmоl.
As an oxidizing agent, 2.05 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As the CO source compound, 1.64 mmol of N-formyl saccharin was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the carboxylic acid, 1.64 mmоl of pivalic acid was used, that is, 2.0 mol per 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the base, 1.64 mmol of triethylamine, ie 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide, was used.
As a solvent, 8.0 mL of t-butyl alcohol was used, that is, 32 mL was used with respect to 1 g of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
The reaction temperature was 100 ° C.
The reaction time was 2 hours.

<Example 21>
In Example 8, the amount of cobalt (II) acetate tetrahydrate was changed from 0.153 g to 0.102 g (0.410 mmоl), and the reaction time (stirring time) was changed from 4 hours to 2 hours. A reaction solution was obtained in the same manner as described in Example 8 except that the reaction temperature was changed from 100 ° C. to 120 ° C.

<Example 22>
In Example 8, the amount of cobalt (II) acetate tetrahydrate was changed from 0.153 g to 0.204 g (0.820 mmоl), and the reaction time (stirring time) was changed from 4 hours to 2 hours. A reaction solution was obtained in the same manner as described in Example 8 except that the reaction temperature was changed from 100 ° C. to 120 ° C.

Various manufacturing conditions and results in Examples 21 and 22 are summarized in Table 7 below. In Examples 21 and 22, common conditions other than those shown in Table 7 are as follows.
As the amide derivative as a substrate, 250 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.82 mmоl.
As an oxidizing agent, 2.05 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As the CO source compound, 1.64 mmol of N-formyl saccharin was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the carboxylic acid, 1.64 mmоl of pivalic acid was used, that is, 2.0 mol per 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the base, 1.64 mmol of triethylamine, ie 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide, was used.
As a solvent, 8.0 mL of t-butyl alcohol was used, that is, 32 mL was used with respect to 1 g of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
The reaction temperature was 120 ° C.
The reaction time was 2 hours.

<Example 23>
A reaction solution was obtained in the same manner as in Example 9 except that the addition of triethylamine was omitted.

<Example 24>
In Example 9, except that cobalt (II) pivalate (0.0749 g, 0.410 mmоl) was used instead of cobalt (II) acetate tetrahydrate (0.153 g, 0.615 mmol). A reaction solution was obtained in the same manner as in Example 9.

The various manufacturing conditions and results of Examples 23 and 24 are summarized in Table 8 below. In Examples 23 and 24, the common conditions other than those shown in Table 8 are as follows.
As the amide derivative as a substrate, 250 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.82 mmоl.
As an oxidizing agent, 2.05 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As the CO source compound, 1.64 mmol of N-formyl saccharin was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As the carboxylic acid, 1.64 mmоl of pivalic acid was used, that is, 2.0 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide.
As a solvent, 8.0 mL of diethylene glycol dimethyl ether, that is, 32 mL with respect to 1 g of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
The reaction temperature was 120 ° C.
The reaction time was 2 hours.

<Example 25>
In an autoclave, (R) -N- (1- (4-bromophenyl) ethyl) picolinamide (27.0 g, 88.5 mmol) and N-formyl saccharin (37.4 g, 177 mmol) produced by the method of Production Example 1 were added. ), Cobalt acetate (II) tetrahydrate (16.5 g, 66.4 mmol), sodium percarbonate (34.7 g, 221 mmol), pivalic acid (18.1 g, 177 mmol), t-butyl alcohol (864 mL). And finally triethylamine (17.9 g, 177 mmol) was added. The autoclave was sealed and stirred at 100 ° C. for 4 hours. The internal pressure of the autoclave was 0.66 MPa at the maximum at 100 ° C. When the reaction solution was analyzed by HPLC, the assay yield was 93.33%.

<Example 26>
150.0 mg (0.492 mmol, 1.0 quiv.) Of (R) -N- (1- (4-bromophenyl) ethyl) picolinamide and 36.7 mg (0. 148 mmol, 30 mol%) cobalt acetate (II) tetrahydrate, 154 mg (0.983 mmol, 2.0 equiv.) Sodium percarbonate, and 177 mg (0.983 mmol, 2.0 equiv.) 1-adamantan carboxylic. Acid, 156 mg (0.737 mmol, 1.5 equiv.) N-formyl saccharin, 74.6 mg (0.737 mmоl, 1.5 equiv.) Triethylamine, and 2.5 mL (16 v / w) 1,4. -Dioxane was added to the pressure-resistant container in an air atmosphere, and the pressure-resistant container was sealed.

The contents of the closed pressure-resistant container were heated to 120 ° C. using a microwave device, and stirred at the reaction temperature for 2 hours while irradiating with microwaves. Then, through the same post-treatment as described in Example 1, (R) -6-bromo-3-methylisoindoline-1-one was obtained (192.9 mg, 0.854 mmоl, yield 58. 7%).

As shown in Example 26, when sodium percarbonate is used as the oxidizing agent, the desired isoindoleinone derivative can be obtained even if 1-adamantane carboxylic acid is used as the carboxylic acid. That is, 1-adamantane carboxylic acid is one of the suitable carboxylic acids when sodium percarbonate is used as an oxidizing agent.

<Example 27>
60.2 mg (0.590 mmol, 1.2 equiv.) Of pivalic acid was used in place of 1-adamantane carboxylic acid, and 81.94 mg (0.737 mmol, 1.5 equiv.) Was used in place of triethylamine. (R) -6-bromo-3-methylisoindoline-1-one was obtained in the same manner as described in Example 26, except that quinuclidine was used (143.6 mg, 0.636 mmol, Yield 43.7%).

As shown in Example 27, when sodium percarbonate is used as the oxidizing agent, the desired isoindoleinone derivative can be obtained even if quinuclidine is used as the base. That is, quinuclidine is one of the suitable bases when sodium percarbonate is used as an oxidizing agent.

<Example 28>
150.0 mg (0.492 mmol, 1.0 quiv.) Of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide prepared by the method of Production Example 1 and 61.2 mg (0. 246 mmol, 50 mol%) cobalt acetate (II) tetrahydrate, 193 mg (1.23 mmol, 2.5 equiv.) Sodium percarbonate, and 100.4 mg (0.983 mmol, 2.0 equiv.) Picoline acid. , 208 mg (0.983 mmol, 2.0 equiv.) Of N-formyl saccharin, 99.5 mg (0.983 mmоl, 2.0 equiv.) Of triethylamine, and 2.5 mL (1.6 v / w) of diethylene glycol dimethyl ether. Was added to the pressure-resistant container in an air atmosphere, and the pressure-resistant container was sealed.

The contents of the closed pressure-resistant container were heated to 120 ° C. using a microwave device, and stirred at the reaction temperature for 2 hours while irradiating with microwaves. Then, through the same post-treatment as described in Example 1, (R) -6-bromo-3-methylisoindoline-1-one was obtained (223.1 mg, 0.988 mmоl, yield 67. 9%).

<Example 29>
(R) -6-bromo-3 in the same manner as described in Example 28, except that 2.5 mL (16.4 v / w) of t-butylmethyl ether was used instead of the diethylene glycol dimethyl ether. -Methylisoindoline-1-one was obtained (165.9 mg, 0.735 mmol, yield 50.5%).

<Example 30>
(R) -6-bromo-3-methyl in the same manner as described in Example 28, except that 2.5 mL (16.4 v / w) of cyclopentyl methyl ether was used instead of the diethylene glycol dimethyl ether. Isoindoline-1-one was obtained (156.0 mg, 0.691 mmol, yield 47.5%).

<Example 31>
(R) -6-bromo-3-methylisoindoline in the same manner as described in Example 28, except that 2.5 mL (16.4 v / w) of acetonitrile was used instead of the diethylene glycol dimethyl ether. -1-one was obtained (140.0 mg, 0.620 mmol, yield 42.6%).

<Example 32>
(R) -6-bromo-3-methylisoindoline in the same manner as described in Example 28, except that 2.5 mL (16.4 v / w) of isopropanol was used instead of the diethylene glycol dimethyl ether. -1-On was obtained (102.9 mg, 0.456 mmol, yield 31.3%).

<Example 33>
(R) -6-bromo-3-in the same manner as described in Example 28, except that 2.0 mL (13.7 v / w) of 2-butyl alcohol was used instead of the diethylene glycol dimethyl ether. Methylisoindoline-1-one was obtained (115.4 mg, 0.511 mmol, yield 35.1%).

<Example 34>
(R) -6-bromo-3-in the same manner as described in Example 28, except that 2.5 mL (16.4 v / w) of t-butyl alcohol was used instead of the diethylene glycol dimethyl ether. Methylisoindoline-1-one was obtained (178.2 mg, 0.789 mmol, yield 54.2%).

The various manufacturing conditions and results of Examples 28 to 34 are summarized in Table 9 below. In Examples 28 to 34, common conditions other than those shown in Table 9 are as follows.
As the amide derivative as a substrate, 150 mg of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used, 0.492 mmоl.
As an oxidizing agent, 1.23 mmоl of sodium percarbonate, that is, 2.5 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As a cobalt catalyst, 0.246 mmol of cobalt (II) acetate tetrahydrate, that is, 0.50 mol with respect to 1 mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide is used. did.
As the CO source compound, 0.983 mmol of N-formyl saccharin, that is, 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As the carboxylic acid, 0.983 mmоl of pivalic acid, that is, 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
As a base, 0.983 mmol of triethylamine, that is, 2.0 mol per mol of (R) -N- (1- (4-bromophenyl) ethyl) picoline amide was used.
The reaction temperature was 120 ° C.
The reaction time was 2 hours.

As shown in Table 9, when sodium percarbonate is used as the oxidizing agent, the desired isoindoleinone derivative can be obtained even when the mixture is irradiated with microwaves. Further, among the solvents, diethylene glycol dimethyl ether or t-butyl alcohol is preferable because the yield of the target isoindoleinone derivative can be increased.

Claims (10)

In the presence of a cobalt catalyst and sodium percarbonate, at least one compound selected from the group consisting of an amide derivative represented by the following formula (1), N-formylmethionyl saccharin and an azo derivative represented by the following formula (2). A method for producing an isoindolinone derivative, which comprises contacting the containing carbon monoxide source compound to obtain an isoindolinone derivative represented by the following formula (3):

In equation (1)
R ¹ is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted. Alkoxycarbonyloxy group of, or substituted or unsubstituted aromatic ring group which may contain a hetero atom.
l is an integer from 0 to 5
When l is 2 or more, R ¹ may be the same group or a different group, and R ¹ may be bonded to each other to form a ring.
^R5 is a halogen atom, a nitro group, a nitrile group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted. Alkoxycarbonyloxy group of, or substituted or unsubstituted aromatic ring group which may contain a hetero atom.
m is an integer from 0 to 4,
When m is 2 or more, R ⁵ may be the same group or a different group, and R ⁵ may be bonded to each other to form a ring.
R ² , R ³ and R ⁴ are independently hydrogen atom, halogen atom, nitro group, nitrile group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aralkyl group, respectively. A substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyloxy group, or a substituted or unsubstituted aromatic ring group which may contain a hetero atom.

In equation (2)
R ⁷ is a substituted or unsubstituted alkyl group.
X is an oxygen atom or a nitrogen atom,
n is 1 or 2

In equation (3)
R ¹ , R ² , R ³ , and l have the same meaning as those represented by the above formula (1). The method for producing an isoindoleinone derivative according to claim 1, wherein the amide derivative represented by the formula (1) is brought into contact with the carbon monoxide source compound in the presence of a carboxylic acid. The method for producing an isoindolinone derivative according to claim 2, wherein the carboxylic acid is at least one carboxylic acid having a branched structure selected from the group consisting of pivalic acid and 1-adamantane carboxylic acid. The isoindolinone according to any one of claims 1 to 3, wherein the amount of the cobalt catalyst with respect to 1 mol of the amide derivative represented by the formula (1) is 0.5 mol or more and 0.8 mol or less. Derivative manufacturing method. The method for producing an isoindoleinone derivative according to any one of claims 1 to 4, wherein the cobalt catalyst is cobalt (II) acetate tetrahydrate. The production of the isoindolinone derivative according to any one of claims 1 to 5, wherein the amount of the sodium percarbonate with respect to 1 mol of the amide derivative represented by the formula (1) is 1 mol or more and 20 mol or less. Method. 1,4-dioxane, t-butyl alcohol, 2-butyl alcohol, ethanol, 2,2,2-trifluoroethanol, isopropanol, t-butylmethyl ether, chlorobenzene, toluene, xylene, N, N-dimethylformamide, N , N-dimethylacetamide, N-methyl-2-pyrrolidone, diethylene glycol dimethyl ether, cyclopentylmethyl ether, acetonitrile and N, N-dimethylimidazolidine-one in at least one solvent selected from the group consisting of the above formula (1). The method for producing an isoindolinone derivative according to any one of claims 1 to 6, wherein the amide derivative represented by () and the carbon monoxide source compound are brought into contact with each other. The method for producing an isoindoleinone derivative according to any one of claims 1 to 7, wherein the amount of the solvent with respect to 1 g of the amide derivative represented by the formula (1) is 20 mL to 50 mL. Triethylamine, diisopropylethylamine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, pyridine, lutidine, diethylaniline, 1-azabicyclo [2.2.2] octane, and 1,8-diazabicyclo [5.4.0] ] Any one of claims 1 to 8 in which the amide derivative represented by the formula (1) and the carbon monoxide source compound are brought into contact with each other in the presence of at least one base selected from the group consisting of undecene-7. The method for producing an isoindolinone derivative according to. In the presence of the cobalt catalyst and the sodium percarbonate, the amide derivative represented by the formula (1) is brought into contact with the carbon monoxide source compound to obtain a mixture, and then the mixture is irradiated with microwaves. The method for producing an isoindolinone derivative according to any one of claims 1 to 9, further comprising.