JP6166996B2 - Method for producing hydrazinoarylcarboxylic acids - Google Patents

Description

  The present invention relates to a method for producing hydrazinoarylcarboxylic acids useful as functional intermediates in the fields of medicine and agrochemicals. More specifically, the present invention relates to a simple industrial production method for hydrazinobenzoic acids and hydrazinophthalic acids.

  As a method for producing an aryl hydrazine compound by reacting a substituted aryl compound with hydrazines, the methods described in JP-A-2005-60367 (Patent Document 1) and JP-A-9-176101 (Patent Document 2) are known. It has been. However, these methods are limited to aryl compounds having strong electron-withdrawing groups such as nitro groups and halogens, and do not react with other substituents or compounds having no substituents or have very low yields. It is. In the case of a compound having a high water affinity substituent such as a hydrazino group or a carboxyl group of the present invention, crystals are precipitated even if the extraction method for precipitation by aqueous dispersion as described in the patent literature is performed. Or only a small amount is deposited, which is not a practical method in actual production.

  In Japanese translations of PCT publication No. 2002-504535 (patent document 3) and Tetrahedron 69 (2013) 613 (non-patent document 1), a strong electron-withdrawing group is obtained by using a palladium or copper catalyst in a reaction similar to the above. It is described that the corresponding hydrazine compound can be obtained in a good yield even in the case of an aryl compound having no benzene. However, in addition to complicated operations such as extraction and concentration using a large amount of an organic solvent, the column chromatography method that is unsuitable for implementation on an industrial scale is used, and it cannot be put into practical use. . Further, there is no specific description about hydrazinoarylcarboxylic acids.

JP 2005-60367 A JP-A-9-176101 Special table 2002-504535 gazette

Tetrahedron, 69 (2013), 613

  An object of the present invention is to provide an industrial production method more advantageous than the conventional hydrazinoarylcarboxylic acid compound useful as a pharmaceutical, agrochemical raw material or intermediate.

  As a result of intensive studies to solve the above problems, the present inventors have reacted carboxyaryl halides or carboxyaryl sulfones and hydrazine in the presence of water using a copper and / or palladium catalyst and a base. It was found that the reaction proceeds smoothly. Furthermore, the inventors found that hydrazinoarylcarboxylic acids can be easily produced by adding acid to the reaction solution, acidifying it, precipitating it as crystals, and collecting it by filtration, thereby completing the present invention.

（式中、Ａｒは、ヘテロ原子で構成されることがあり、かつ電子吸引性置換基及び／又は電子供与性置換基を有することのあるアリール基であり、Ｒ¹からＲ³は何れも、水素原子、置換基を有することのある炭素数１から２０迄のアルキル基、又はヘテロ原子で構成されることがあり、かつ電子吸引性置換基及び／又は電子供与性置換基を有することのあるアリール基を表し、ｎは1以上の整数を示す。）
で示されるヒドラジノアリールカルボン酸類を製造する方法であって、
一般式（２）で示されるヒドラジン類と

（式中、Ｒ¹からＲ⁴は水素原子、アルキル基又はアリール基であり、式（１）のＲ¹からＲ³と同じ意味を表す。）
一般式（３）で示される

（式中、Ａｒは式（１）と同じ意味を表し、Ｘはハロゲン原子（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、メシル基、トシル基、スルホニル基、スルフリル基、スルホニルアミノ基、アミノスルホニル基又はトリフルオロメタンスルホニル基を表し、複数個有っても良い。）
カルボキシアリールハライド類、又はカルボキシアリールスルホン類とを、銅、銅塩類、及び／又は、パラジウム、パラジウム塩類及び塩基類を用いて、水の共存下反応させた後、酸析してヒドラジノアリールカルボン酸類を取得することを特徴とするヒドラジノアリールカルボン酸類の製造方法に関するものである。
なお、一般式（１）や一般式（３）で示されている置換基Ａｒに於いて、ヘテロ原子で構成されることがあり、かつ電子吸引性置換基及び／又は電子供与性置換基を有することのあるアリール基としては、例えばフェニル基、ナフチル基、ピリジル基、オキサゾリル基、チアゾリル基等が挙げられ、かかるアリール基が有していてもよい電子吸引性置換基としては、例えば、ハロゲン原子、アシル基、アミド基、ニトロ基、シアノ基、フェニル基等が、また、電子供与性置換基としては、アルキル基、アルコキシ基、アミノ基、水酸基等が挙げられる。一方、一般式（１）や一般式（２）で示されている置換基Ｒ¹からＲ³における置換基を有することのあるアルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、シクロペンチル基等のアルキル基やシクロアルキル基が挙げられ、かかるアルキル基やシクロアルキル基が有することのある置換基としては、例えばハロゲン原子、水酸基、アルコキシ基、カルボニル基、ビニル基等があり、また、置換基を有することのあるアリール基としては、上記置換基Ａｒに於いて例示したアリール基と同様の基が挙げられる。 That is, the present invention relates to the general formula (1)

(In the formula, Ar is an aryl group that may be composed of heteroatoms and may have an electron-withdrawing substituent and / or an electron-donating substituent, and R ¹ to R ³ are all It may be composed of a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a substituent, or a hetero atom, and may have an electron-withdrawing substituent and / or an electron-donating substituent Represents an aryl group, and n represents an integer of 1 or more.)
A process for producing hydrazinoarylcarboxylic acids represented by the formula:
Hydrazines represented by the general formula (2)

(In the formula, R ¹ to R ⁴ are a hydrogen atom, an alkyl group or an aryl group, and have the same meaning as R ¹ to R ³ in formula (1).)
Shown by general formula (3)

(Wherein Ar represents the same meaning as in formula (1), X represents a halogen atom (F, Cl, Br, I), mesyl group, tosyl group, sulfonyl group, sulfuryl group, sulfonylamino group, aminosulfonyl group or Represents a trifluoromethanesulfonyl group, and there may be a plurality thereof.)
Carboxyaryl halides or carboxyaryl sulfones are reacted with copper, copper salts, and / or palladium, palladium salts, and bases in the presence of water, and then acidified for hydrazinoarylcarboxylic acid. The present invention relates to a method for producing hydrazinoarylcarboxylic acids characterized by obtaining acids.
In addition, in the substituent Ar represented by the general formula (1) or the general formula (3), it may be composed of a heteroatom, and an electron-withdrawing substituent and / or an electron-donating substituent may be used. Examples of the aryl group that may have include a phenyl group, a naphthyl group, a pyridyl group, an oxazolyl group, a thiazolyl group, and the like. Examples of the electron-withdrawing substituent that the aryl group may have include, for example, halogen An atom, an acyl group, an amide group, a nitro group, a cyano group, a phenyl group, and the like, and examples of the electron donating substituent include an alkyl group, an alkoxy group, an amino group, and a hydroxyl group. On the other hand, examples of the alkyl group which may have a substituent in the substituents R ¹ to R ³ represented by the general formula (1) or the general formula (2) include a methyl group, an ethyl group, a propyl group, and butyl. Group, an alkyl group such as a cyclopentyl group, and a cycloalkyl group. Examples of the substituent that the alkyl group or cycloalkyl group may have include a halogen atom, a hydroxyl group, an alkoxy group, a carbonyl group, and a vinyl group. In addition, examples of the aryl group that may have a substituent include the same groups as the aryl groups exemplified in the substituent Ar.

  According to the method for producing hydrazinoarylcarboxylic acids of the present invention, the reaction can proceed smoothly in an aqueous solvent or an aqueous mixed solvent, and then the target product is extracted from the aqueous solvent or aqueous mixed solvent by acid precipitation. It can be filtered by a simple operation. This eliminates the need for a troublesome take-out operation as found in the prior art, and thus makes it possible to produce the target product more advantageously industrially.

The production method of the present invention will be described in detail below.
In the method of the present invention, hydrazinoarylcarboxylic acids are produced by reacting carboxyaryl halides or carboxyaryl sulfones with hydrazine using a catalyst and a base in the presence of water.

Specific examples of the carboxyaryl halides (3) or carboxyaryl sulfones (3) represented by the general formula (3) used as a starting material in the present invention include 4-chlorobenzoic acid, 4-bromobenzoic acid, 4-fluorobenzoic acid, 4-iodobenzoic acid, 4-tosylbenzoic acid, 4-sulfobenzoic acid, 3-chlorobenzoic acid, 3-bromobenzoic acid, 3-fluorobenzoic acid, 3-iodobenzoic acid, 3- Tosylbenzoic acid, 3-sulfobenzoic acid, 2-chlorobenzoic acid, 2-bromobenzoic acid, 2-fluorobenzoic acid, 2-iodobenzoic acid, 2-tosylbenzoic acid, 2-sulfobenzoic acid, 4-chlorophthalic acid 4-bromophthalic acid, 4-fluorophthalic acid, 4-iodophthalic acid, 4-tosylphthalic acid, 4-sulfophthalic acid, 3-chlorophthalic acid, 3-bromophthalic acid 3-fluorophthalic acid, 3-iodophthalic acid, 3-tosylphthalic acid, 3-sulfophthalic acid, 2-chloroterephthalic acid, 2-bromoterephthalic acid, 2-fluoroterephthalic acid, 2-iodoterephthalic acid, 2-tosylterephthalic acid Acid, 2-sulfoterephthalic acid, 4-chloroisophthalic acid, 4-bromoisophthalic acid, 4-fluoroisophthalic acid, 4-iodoisophthalic acid, 4-tosylisophthalic acid, 4-sulfoisophthalic acid, 5-chloroisophthalic acid, 5-bromoisophthalic acid, 5-fluoroisophthalic acid, 5-iodoisophthalic acid, 4-tosylisophthalic acid, 5-sulfoisophthalic acid, 6-chloro-2-pyridinecarboxylic acid, 6-bromo-2-pyridinecarboxylic acid, 6-fluoro-2-pyridinecarboxylic acid, 6-iodo-2-pyridinecarboxylic acid , 6-tosyl-2-pyridine carboxylic acid, and 6-sulfo-2-pyridinecarboxylic acid.
Of these, carboxyaryl halides are preferred in that inorganic salts such as by-product potassium bromide are easily dissolved in an aqueous solvent, and chlorinated products or brominated products are more preferable in terms of availability of raw materials and economical efficiency. preferable.

  The hydrazines (2) used for the reaction can be any of anhydrides, hydrates, salts, aqueous solutions or solutions. Specific examples of the hydrazines (2) include hydrazine hydrate, hydrazine sulfate, hydrazine hydrochloride, methyl hydrazine, 1,1-dimethyl hydrazine, 1,2-dimethyl hydrazine, tert-butyl hydrazine, phenyl hydrazine and the like. In addition, these hydrazines can be obtained as commercial products from, for example, Nippon Finechem Co., Ltd.

  The amount of hydrazines (2) used is preferably 1.0 to 20.0, more preferably in the range of 1.5 to 3.0 in terms of molar ratio to carboxyaryl halides or carboxyaryl sulfones (3). It is. If it is used in a large amount, the productivity will be hindered. Conversely, if it is too small, the yield tends to decrease.

  Examples of the catalyst used in the reaction include copper, copper salts, and / or palladium, palladium salts, and the like, and copper salts and palladium salts are preferable in that they can be dissolved in the reaction solution. In addition, copper or copper salts are preferable because they are inexpensive and within a range that can be satisfied in terms of yield.

Examples of copper include copper powder, a copper-supported catalyst, and copper compounds such as copper oxide. Examples of palladium include palladium powder and palladium carbon. As such a form of a metal or a copper compound, a powder form is preferable from the viewpoint of efficiently performing the reaction.
On the other hand, specific examples of copper salts include copper chloride, copper bromide, copper iodide, copper fluoride, copper nitrate and the like, and specific examples of palladium salts include palladium chloride, palladium bromide, palladium iodide. , Palladium acetate, palladium nitrate, phenylallylchloro [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] palladium (II) (trade name: Umicore CX31, manufactured by Umicore), phenylallylchloro [1 , 3-bis (2,6-diisopropylphenyl) -2-imidazolidinylidene] palladium (II) (trade name: Umicore CX32, manufactured by Umicore).
Among these, copper iodide and copper chloride are preferable in that they are dissolved in the reaction solution, yield of the target product is good, and they are inexpensive. These catalysts may be used alone or in combination of two or more.

  The amount of catalyst used is not particularly limited, but the molar ratio to the reaction substrate carboxyaryl halides or carboxyaryl sulfones is preferably 0.0001 to 1, more preferably 0.01 to 0.4. Thus, the target product can be obtained with good yield.

Examples of the base used together with the above catalyst include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate, and alkali metal phosphates such as potassium phosphate and sodium phosphate. Alternatively, organic bases such as pyridine and morpholine can be used. Of these, alkali metal carbonates and alkali metal phosphates are preferable from the viewpoint of solubility in water and reactivity. Among them, potassium carbonate or sodium carbonate is particularly preferable because the yield of the target product is good and inexpensive. preferable.
The molar ratio of the base used is preferably 0.1 to 10.0, more preferably 0.2 to 5.0, based on carboxyaryl halides or carboxyaryl sulfones (3). The range of 0.5 to 2.0 is particularly preferable in terms of yield.

The reaction can be carried out without a solvent if the reaction raw material such as hydrazine also serves as a solvent, but it is preferable to use a solvent containing water from the viewpoint of the stirring ability of the reaction system. The solvent containing water may be water alone or a mixed solvent of water and an organic solvent. Examples of the organic solvent include aliphatic alcohols such as methanol, ethanol, ethylene glycol and butanediol, ethers such as methyl tert-butyl ether and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide and dimethylacetamide, and toluene. And aromatic hydrocarbons such as xylene and chlorobenzene.
Two or more kinds of these solvents can be used as necessary, and these organic solvents and water can be mixed and used. Although there is no restriction | limiting in particular in the mixing amount of the organic solvent with respect to water, About 1 time amount (mass) or less with respect to the amount of water is preferable at the point of removal of an inorganic salt and stirring property.
In addition, when water is included, such as when hydrazine is a hydrate or is supplied as an aqueous solution, the reaction may be carried out using only an organic solvent without using water as a solvent. I can do it.
Depending on the type of carboxyaryl halides or carboxyaryl sulfones and hydrazines to be reacted and the characteristics of the hydrazinoaryl carboxylic acids to be obtained, the solvent may be water alone or mixed with water as described above. Although the reaction is performed using a solvent, it is generally preferable to react with water alone. By using an aqueous solvent, the reaction proceeds smoothly, which is advantageous in terms of cost because no organic solvent is used. In addition, after the reaction, the target product is precipitated as crystals and collected by filtration, whereby the inorganic salt is removed from the mother liquor and high-quality hydrazinoarylcarboxylic acids can be obtained.

  Although the usage-amount of a solvent is not specifically limited, According to the reaction raw material, it can select suitably. Usually, the mass ratio to the carboxyaryl halides or carboxyarylsulfones represented by the formula (3) is preferably 1 to 20 times, particularly preferably 2 to 10 times.

  The reaction temperature at the time of synthesis is preferably 50 to 180 ° C, more preferably 80 to 120 ° C. The reaction time is not particularly limited under the above reaction temperature conditions, but preferably in the range of 1 to 20 hours from the viewpoint of suppressing by-products.

  Depending on the bases used, the solution of hydrazinoarylcarboxylic acids obtained by the reaction may be a salt of a metal derived from a carboxylic acid and a base (for example, a salt such as potassium or sodium) or an amine salt (for example, a pyridine salt). It is dissolved in a reaction solution using an aqueous solvent. However, by adjusting the pH to around 4 by adding acids to the reaction solution, the solubility in water is lowered, and the target product can be precipitated as crystals. Thus, it can be taken out as a crystal by filtration without performing complicated operations such as extraction and concentration, and is also suitable for industrial production.

  Specific examples of acids used for acid precipitation include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as sulfonic acid and carboxylic acid. As the acid to be used, hydrochloric acid is particularly preferable from the viewpoint of the solubility of the by-product inorganic salt and the low cost.

  The appropriate pH is 2.0 to 6.0, and particularly preferably in the range of 3.0 to 5.0 in terms of yield. A salt with a hydrazino group is formed on the acid side when the pH is higher, and a salt with a carboxylic acid group is formed on the alkali side, so that the solubility in water is increased and it is difficult to take out the crystals.

  By the above method, a compound having high water solubility such as hydrazinoarylcarboxylic acids and difficult to take out by water dispersion can be easily filtered out from an aqueous solvent, and at the same time, impurities such as inorganic salts can be obtained by the aqueous solvent. It has also become possible to suppress mixing. This eliminates the need for a complicated removal operation and consumption of a large amount of organic solvent as found in the prior art, making it possible to produce the target product more advantageously industrially.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited by these examples. In the following examples and comparative examples, hydrazinoarylcarboxylic acids were analyzed by high performance liquid chromatography (HPLC).

Example 1
4-Bromophthalic acid 25.0 g (0.10 mol), potassium carbonate 29.0 g (0.21 mol), copper iodide 1.0 g (0.005 mol), water 75.6 g, 100% hydrazine 11 0.1 g (0.22 mol) was mixed, the temperature was raised to 90 ° C., and the mixture was heated and stirred for 9 hours. After cooling to room temperature, the precipitated insoluble matter containing copper was separated by filtration and washed with 21.2 g of water. The pH of the obtained filtrate was 9.0, and the target product was completely dissolved at this stage. When 47.3 g (0.47 mol) of 36% hydrochloric acid was added to this filtrate over 20 minutes, pale yellow powder crystals were precipitated, and the pH after addition was 3.5. The precipitated crystals were collected by filtration, washed with 30.2 g of water, and then dried at 40 ° C. under vacuum (1 Torr) for 10 hours to obtain 17.6 g of 4-hydrazinophthalic acid. The purity determined by the absolute calibration curve method of HPLC analysis was 96%, and the yield was 84%. By this method, the reaction smoothly proceeded even in an aqueous solvent, and hydrazinoarylcarboxylic acid was obtained by a simple operation of acid precipitation and filtration, which was a better result than Comparative Examples 1 and 2 below.

Comparative Example 1
4-Bromophthalic acid 5.1 g (0.02 mol) and 100% hydrated hydrazine 20.8 g (0.42 mol) were mixed, and the mixture was heated to 100 ° C. and heated and stirred for 24 hours. As a result of quantitative analysis of the reaction solution by HPLC, the reaction yield was 6.2%.

Comparative Example 2
4-bromophthalic acid 5.1 g (0.02 mol), potassium carbonate 3.0 g (0.02 mol), copper iodide 0.2 g (0.001 mol), 1,3-butanediol 20.0 g, 100 % Hydrazine 2.3 g (0.05 mol) was mixed, heated to 120 ° C. and heated and stirred for 8 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with 79 g of water, and dried in vacuo at 50 ° C. for 4 hours to obtain 8.1 g of 4-hydrazinophthalic acid. The purity determined by the absolute calibration curve method of HPLC analysis was 29%, and the yield was only 57%.

Example 2
4-Bromobenzoic acid 4.2 g (0.02 mol), potassium carbonate 1.5 g (0.01 mol), copper iodide 0.4 g (0.002 mol), water 30.0 g, 100% hydrazine hydrate 3.2 g (0.06 mol) was mixed, and this was heated to 90 ° C. and heated and stirred for 8 hours. After cooling to room temperature, 0.2 g of the insoluble matter containing precipitated copper was separated by filtration and washed with 5.2 g of water. The pH of the obtained filtrate was 7.9, and the target product was completely dissolved at this stage. When 3.9 g (0.04 mol) of 36% hydrochloric acid was added to the filtrate, pale yellow powder crystals were precipitated, and the pH after the addition was 4.0. The precipitated crystals were collected by filtration, washed with 2.1 g of water, and then dried at 40 ° C. under vacuum (1 Torr) for 18 hours to obtain 2.7 g of 4-hydrazinobenzoic acid. The purity determined by the absolute calibration curve method of HPLC analysis was 91%, and the yield was 77%.

  According to the present invention, it is possible to obtain hydrazinoarylcarboxylic acid used as an intermediate for medicines and agricultural chemicals by a simple operation. In addition, since complicated operations such as extraction with an organic solvent, which is a problem in mass production, are not required, a simple and economical production method can be provided. Significance is high.

Claims (6)

General formula (1)

(In the formula, Ar is an aryl group that may be composed of heteroatoms and may have an electron-withdrawing substituent and / or an electron-donating substituent, and R ¹ to R ³ are all It may be composed of a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a substituent, or a hetero atom, and may have an electron-withdrawing substituent and / or an electron-donating substituent Represents an aryl group, and n represents an integer of 1 or more.)
A process for producing hydrazinoarylcarboxylic acids represented by the formula:
Hydrazines represented by the general formula (2);

(In the formula, R ¹ to R ³ are a hydrogen atom, an alkyl group or an aryl group, and have the same meaning as R ¹ to R ³ in formula (1).)
Shown by general formula (3)

(Wherein Ar represents the same meaning as in formula (1), X represents a halogen atom (F, Cl, Br, I), mesyl group, tosyl group, sulfonyl group, sulfuryl group, sulfonylamino group, aminosulfonyl group or Represents a trifluoromethanesulfonyl group, and there may be a plurality thereof.)
Carboxyaryl halides or carboxyaryl sulfones are reacted in a water solvent using copper, copper salts, and / or palladium, palladium salts and bases and water as a solvent , and then acidified. To obtain a hydrazinoarylcarboxylic acid, a method for producing a hydrazinoarylcarboxylic acid.   The method according to claim 1, wherein the base is at least one compound selected from the group consisting of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, and pyridine.   The method according to claim 1 or 2, wherein the reaction is carried out using copper or a copper salt.   The compound represented by the general formula (2) is one or more compounds selected from hydrazine hydrate, hydrazine sulfate, hydrazine hydrochloride, methyl hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine and phenylhydrazine. Item 4. The method according to any one of Items 1 to 3.   The method according to any one of claims 1 to 4, wherein the compound represented by the general formula (3) is a carboxyaryl halide.   The method according to any one of claims 1 to 5, wherein the compound represented by the general formula (1) is 4-hydrazinobenzoic acid or 4-hydrazinophthalic acid.