JPS604825B2 - Method for producing 1H-indazole acetic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing an IH-indazole acetate derivative, and the method is shown in the following formula.

(In the formula, X means a hydrogen atom, a halogen atom, or a lower alkoxy group.

) The inventors of this invention first conducted repeated research on the method of obtaining (1) from (excluding compounds where is a lower alkoxy group).

However, the above invention is not necessarily satisfactory as a method for industrially advantageously producing IH-indazole acetic acid derivatives, for example, in the following points.

That is, in the above invention, a method in which a metal such as aluminum or zinc is applied under basic conditions, a method in which a metal amalgam such as zinc amalgam or sodium amalgam is combined with water, alcohol or ether, and a method in which palladium on carbon is applied under basic conditions The target substance (b) is obtained by catalytic reduction in the presence of a metal catalyst such as platinum oxide or colloidal platinum, but methods using aluminum or zinc or their amalgams require removal of these metal salts. In addition to often requiring cumbersome and complicated operations, these metal salts and metal amalgams also pose problems, such as causing various problems in terms of wastewater treatment and the working environment. are doing. In addition, the method using catalytic reduction has the problem that it is difficult to increase the yield of the target substance (b) because carbostyryl derivatives, which are thought to be formed by ring-closing deamidation/formation, are created in the reaction solution. have The inventors of this invention have determined that these problems should be solved.As a result of intensive study, the inventors of the present invention found that by reacting the substituted propionic acid shown in (1) above or its salts with hydrazine, carbostyril derivatives etc. can be almost completely removed. I shown in (b) without being born
They obtained a new finding that H-indazole acetic acid derivatives can be produced in extremely high yields, and as a result of further research, they completed this invention. ○} Regarding the manufacturing method of the raw material: The method of the present invention is carried out by allowing hydrazines to act on substituted propionic acid (1) or its salts.

In the substituted propionic acid (1), examples of the halogen atom include fluoro, chlorofrom, and iodo, and examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and the like. Examples of the salts of substituted propionic acid include alkali metal salts such as sodium salts and potassium salts, ammonium salts, hydrochlorides, and sulfates. This substituted propionic acid (1) or its salts include novel compounds (compounds where x in the formula is a lower alkoxy group) and known compounds (for example,
2-5766, publication date, January 17, 1972)
These compounds can be produced by a method similar to the method described in the above-mentioned literature, but can also be produced by the following method. (In the formula, × has the same meaning as above, and R has the formula -CHO or -CH(OCOC
H3)2 means a group represented by 2, and when X is a hydrogen atom or a halogen atom, R is
2)) As the lower fatty acid used in this reaction, for example, acetic acid, propionic acid, butyric acid, pivalic acid, etc. are often used.

Further, ammonium ions are usually supplied to the reaction system by adding the above-mentioned ammonium salt of lower fatty acid to the reaction system, but it may also be supplied by introducing ammonia. This reaction is usually carried out in a solvent,
As the solvent, it is convenient to use the above lower fatty acids which also serve as a solvent. Although the reaction temperature is not particularly limited, the reaction is generally carried out with or under heating. Substituted phenyl 8-chrysine is obtained by subsequent hydrolysis of the reaction mixture thus obtained. This hydrolysis reaction is usually preferably carried out by treatment in the presence of an acid such as hydrochloric acid or sulfuric acid, and more preferably by heating under reflux in hydrochloric acid. [2' Regarding reaction reagents and reaction conditions: Hydrazines used in the reaction of the method of this invention include, for example, hydrazine (usually it is convenient to use a hydrate), hydrazines such as phenylhydrazine, and hydrazine. Examples include hydrazines obtained by reacting with carboxylic acids, and among these, it is convenient to use hydrazine, which is industrially available at relatively low cost.

This reaction is usually carried out in a solvent.

As the solvent, in addition to water, methanol, ethanol, tetrahydrofuran, dioxane, general organic solvents that do not adversely affect this reaction, or any mixed solvent thereof can be used. In addition, this reaction is generally preferably carried out under basic conditions, and is often carried out by adding an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or a base such as ammonia to the solvent. Since the hydrazine salt used in the method of this invention itself exhibits basicity, the method can be carried out without necessarily adding these bases.

This reaction is preferably carried out in the presence of a metal catalyst,
Examples of such metal catalysts include Raney nickel, palladium on carbon, platinum oxide, colloidal platinum, and the most preferred example is Raney nickel.

Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or under heating.

The target substance (b) obtained by this reaction is isolated and purified by conventional methods. The IH-indazole acetic acid derivative (D) obtained in this way can be converted into sodium salt,
This can lead to desired salts such as potassium salts.

As mentioned above, the method of the present invention has the advantage that the reaction operation is simpler than the conventional method, and that the number of created substances is small, so the yield is good and the target substance (0) can be obtained with high purity. .

Furthermore, among the target substances (0) obtained by the method of the present invention, the compound in which X is a lower alkoxy group is a new compound, and is not only useful as a plant growth regulator, but also as a useful anti-inflammatory agent. It is also useful as an intermediate for synthesis.

The present invention will be explained below based on Examples.

Example 1 Synthesis of 5-chloroIH-indazol-3-yl acetic acid 3-Amino-3-(5-chloro-2-nitrophenyl)-propionic acid was dissolved in 75% aqueous 5% sodium hydroxide solution, and hydrazine was dissolved in 75% aqueous sodium hydroxide solution. monster 2.5
Add evening. This solution was heated under a sieve, and Raney nickel was added to it at 80°C.
After praying for a minute, add about 10 to 20 Rane nickels.
9 and continue enriching at storm temperature for approximately 20 minutes until no nitrogen gas is observed to be produced. Filter the reaction solution,
After making the furnace liquid into spots 2 with hydrochloric acid, it is cooled. The precipitated crystals are collected in an oven, washed with water, and then dissolved in a 5% aqueous sodium bicarbonate solution while hot, the insoluble matter is removed in an oven, and prepared as bait 2 with hydrochloric acid. After cooling, the precipitated crystals are collected in a furnace, washed with water, and dried to obtain 12 crystals of the target substance. Yield 93%. mp209-210
qo (decomposition). Example 2 Synthesis of 6-chloroIH-indazol-3-yl acetic acid 01 3-amino-3-(4
-Synthesis of chloro-2-nitrophenyl)propionic acid a
・a-diacetoxy-4-chloro-2-nitrotoluene 10 times, malonic acid 4.8 times and ammonium acetate 6 times.
Dissolve 8 ml of formic acid in a mixture of 5.2 ml of formic acid and 10 ml of acetic acid, and heat for 2 hours at 80-85 qC and 2 hours at 90-95 qC.
Next, the mixture is heated at a temperature of 95 to 100 qO for 1 hour while gradually increasing the temperature, and further heated under reflux for 1 hour.

Next, 15 parts of 35% hydrochloric acid and 15 parts of water were added to this reaction solution, and after heating under reflux for 5 hours, the reaction solution was concentrated to dryness under reduced pressure. After heating and dissolving the residue in 50M water, it is treated with activated carbon and filtered. Add the same amount of ethanol to the furnace liquid, adjust to volume 5 with ammonia water, and cool. The precipitated crystals are collected in an oven, washed with water, and dried to give pale yellow crystals of 6.5 kg. Yield 76%. mp 211-213°C (decomposed). ■ Synthesis of 6-chloroIH-indazol-3-yl acetic acid [
3-amino/-3-(4-chloro) obtained in 1-.

-2nitrophenyl)-propionic acid 7.5% 6%
Dissolved in sodium hydroxide aqueous solution 42, hydrazine 1
Add 1.5 liters of hydrate. This solution was heated under condensation, and
Add about 5 females of Raney Nickel at 0, 75-80℃
After praying for 10 minutes at
Add the female and keep at the same temperature for another 3 minutes. This reaction solution was post-treated in the same manner as in Example 1 to obtain 5.9 g of the target substance in the form of colorless crystals. Yield 91%. mp180-18 is ○(
Disassembly). Example 3 Synthesis of 4-chloro-IH-indazol-3-yl acetic acid 3-amino-3-(2-chloro-6-nitrophenyl)
- Dissolve propionic acid in 5% sodium hydroxide,
Add 0.5 ml of hydrazine monohydrate.

This solution was heated under a rope, and about 5 to 9 of Raney nickel was added to it at 80°C, and after stirring for 15 minutes, further Raney nickel was added.
Add 5 pieces of nickel and 9 pieces of nickel and stir between 3 pieces. This reaction solution is post-treated in the same manner as in Example 1 to obtain crystals of the target substance. Yield 30.0%. mp205-206°C (decomposition).
Example 4 Synthesis of 7-methoxy-IH-indazol-3-yl acetic acid (1) Synthesis of 3-amino-3-(3-methoxy-2nitrophenyl)propionic acid 9.3 times of 3-methoxy-2-nitrobenzaldehyde, 6.9 times of malonic acid and 9.8 parts of ammonium acetate is dissolved in a mixture of 20 parts of acetic acid and 10 parts of formic acid, heated at 55 to 6000 for 2 hours, then 3 hours at 90 to 95 quarts, and then heated under reflux for 1 hour.

To this were added 159 parts of 35% hydrochloric acid and 15 parts of water, heated under reflux for 2 hours, and then concentrated to dryness under reduced pressure. Rinse the residue with hot water 1
00', treated with activated carbon, and separated in a furnace together with unmelted materials. Add 100% ethanol to the furnace solution, and adjust the pH to 5 with aqueous ammonia. After cooling, the precipitated crystals are collected in an oven, washed with water, and dried to obtain 8.9 g of the target substance as pale yellow crystals. Yield 72%. mP218qo (degraded). '2}
Synthesis of 7-methoxy-IH-indazol-3-yl acetic acid.
Dissolve in 21% aqueous sodium hydroxide solution, add 0.5 ml of hydrazine monohydrate, add about 5 to 9 ml of Raney nickel at 75 to 8,000, and stir in batches at the same temperature.

'' The unmelted material is removed from the furnace, and the furnace liquid is neutralized with formic acid to a pH of 3. After cooling, the precipitated crystals are collected in a furnace and washed with water. The obtained crude crystals are recrystallized from an aqueous sodium bicarbonate solution, washed with water, and dried to obtain 0.9 g of crystals of the target substance. Yield 52
．． 4%. mp180-18100 (decomposed). Example 5
Synthesis of 5-chloroIH-indazol-3-yl acetic acid [Synthesis of 113-amino-3-(5-chloro-2nitrophenyl)propionic acid]
3. Charge 2 quarts into a reaction vessel and heat to 40-45 qo.

To this mixed solution, 85.2 g of ammonium chloride acid was added at the same temperature. Further, this mixed solution was heated at 60-70q○ for 1 hour and at 90-95pm for 4 hours, and then heated under reflux at 115°C for 1 hour. Add 192 ml of 35% hydrochloric acid and 8 8 ml of water to this reaction mixture.
5' was added and heated under reflux at 110 qo for 1 hour. After the reaction is completed, the reaction solution is cooled to 90-95°C, and 320 parts of water and 320 parts of methyl isobutyl ketone are added. The lachrymal fluid is soaked at 50-60 oo and the aqueous layer is separated. The methyl isobutyl ketone layer is washed with 100% water and combined with the previous water layer. This aqueous layer is adjusted to pH 5-6 with a 48% aqueous sodium hydroxide solution at 50q0 or less. Cool, 1oo○
Leave the following overnight. The precipitated crystals are taken up the furnace and added with 30 ml of water.
Washing with 3-amino-3-(5-chloro-2-nitrophenyl)propionic acid gives 110 g of 3-amino-3-(5-chloro-2nitrophenyl)propionic acid. Yield 7
7%. Melting point 209-21100 (decomposed). 2' Synthesis of 5-chloroIH-indazol-3-yl acetic acid 42.8 parts of 3-amino-3-(5-chloro-2nitrophenyl)propionic acid and 21 parts of sodium hydroxide were added to 1 part of water.
95 dissolves in the skin.

To this solution at 30-4°C are added 4.7 parts of activated carbon and 18.5 parts of hydrazine monohydrate. This solution is boiled at the same temperature for 15 minutes, heated to 60-65q0, lit for 1 hour at the same temperature, and further raised to 80-85oo for 3 hours. 156 parts of water was added to the reaction solution, and this solution was dropped into 81 parts of 35% hydrochloric acid over 30 minutes. The obtained crystals were separated by furnace and washed with 200 g of water to give 37.0 g of crude crystals of 5-chloroIH-indazol-3-yl acetic acid.
Get the evening. This product was purified according to the conventional method.
-Chloro IH-indazol-3-yl acetic acid is obtained.
M. p. 209-21000 (decomposition).

Claims (1)

[Claims] 1 Substituted propionic acid or its salts represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. of the 1H-indazoleacetic acid derivative or its salts represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, X has the same meaning as before). Production method.