JPS604826B2 - Manufacturing method of indazole acetic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing indazole acetic acids or salts thereof, and the reaction formula is illustrated as follows.

(In the formula, RI represents a carboxy group or an esterified carboxy group, R2 represents an acyl group, and x represents hydrogen or a halogen.) It is known as a compound that has a growth regulating effect (for example,
See No. 6-32773 and Tsubaki Publication No. 48-37270.

), and the manufacturing method described in the above-mentioned literature is known, for example. However, these production methods are not necessarily satisfactory as methods for industrially obtaining indazole acetic acids (0). The inventors have developed a new industrially advantageous manufacturing method for indazole acetic acids (b), which is completely different from conventional manufacturing methods, and have completed this invention.

The reaction of this invention is carried out by first allowing an N-nitrosation agent to act on the acylaminophenylpropionic acids (1) or their salts.

Raw material acylaminophenylpropionic acids (1)
are all new compounds, and can be produced, for example, from known 2-oxotetrahydroquinolines or N-acyltolidines, as described below. The raw material acylaminophenylpropionic acids have the general formula (1
), more particularly a carboxy group or, for example, methoxycarbonyl, ethoxycarbonyl, f.

Alkoxycarbonyl such as lopoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, aryloxycarbonyl such as phenoxycarbonyl, tolyloxycarbonyl, P-nitrophenoxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, etc. Having an esterified carpoxy group such as aralkyloxycarbonyl as RI, for example, alkanoyl such as formyl, acetyl, propionyl, butyryl, haloalkanoyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Alkoxycarbonyl such as butoxycarbonyl, imbutoxycarbonyl, tertiary butoxycarbonyl, haloalkoxycarbonyl such as chloroethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl, aroyl such as benzoyl, toluoyl, aralkanoyl such as phenylacetyl, phenylpropionyl, etc. has an acyl group as R2, hydrogen or fluorine,
It means a compound having a halogen such as chlorine, bromine, iodine, etc. as x. Further, examples of the salts of this raw material (1) include sodium salts, potassium salts, calcium salts, and the like.

Next, the raw material (
It means a substance capable of nitrosating the amino/moiety of the acylamino group in 1), such as nitric acid, nitrogen trioxide,
In addition to nitrosyl chloride, examples include leech nitrate esters such as isoamyl nitrite and butyl nitrite. This reaction is usually carried out in a solvent, and examples of the solvent include acetic acid, acetic anhydride, chloroform, carbon tetrachloride, N,N-dimethylformamide, dimethyl sulfoxide, and any solvent that does not adversely affect this reaction. Either can be used. The temperature of the reaction is not particularly limited, but it is usually carried out under cooling. The nitroso compound thus produced is isolated and purified once, or is subjected to the next ring-closing reaction in its crude form without being isolated or purified, thereby leading to the target substance (0).

Here, the ring-closing reaction is usually carried out in a solvent at room temperature or around the boiling point of the solvent, and examples of the solvent include benzene, toluene, chloroform, carbon tetrachloride, ether, N,N-
In addition to dimethylformamide, dimethyl sulfoxide, and the like, any solvent that does not adversely affect this reaction can be used. The target substance (0) thus obtained is isolated and purified by a conventional method.

The raw material (1) for the method of the present invention can be produced, for example, by the method illustrated below.

Production method of acylaminophenylpropionate ester (la) {1} (wherein, RI' represents an esterified carboxy group, R2 represents an acyl group, and x represents hydrogen or halogen) The details of the law are as follows.

(i) Process for producing N-acyl-2-oxotetrahydroquinolines (W): The reaction in this step is carried out by reacting 2-oxotetrahydroquinolines (m) with an acylating agent.

Here, among the 2-oxotetrahydroquinolines (m), 6-chloro-2-oxo-1,2,3,4-tetrahydroquinoline is, for example, published in Humische Berichte Section 6 Registration, pp. 858-864 (1927). It is manufactured by the method described in , and other compounds can be manufactured in the same manner. The acylating agent used in this reaction is an organic acid (the organic acid has the formula R2-OH, R2
means an acyl group), its reactive derivatives, and isocyanic acids (eg, potassium isocyanate, alkyl isocyanate, aryl isocyanate), and the like. Examples of the above-mentioned organic acids include, for example, monobasic or dibasic organic carboxylic acids, organic carbonic acids and organic carbamic acids, the corresponding thioacids and imidic acids, and organic sulfonic acids.

Suitable examples of these acids include organic acids containing an acyl group as explained in the example of the acyl group in R2 of the raw material (1) above. When the organic acids mentioned above are used as acylating agents, they are usually used in the form of activated organic acids, i.e. reactive derivatives of the acids, examples of such reactive derivatives being e.g. acid halides (e.g. saddles). chloride, etc.), acid azides, active amides (for example, active amides with pyrazole, etc.), and active esters (for example, methylthioester, etc.).

This reactive derivative is appropriately selected and used depending on the type of acid used. When the acylating agent is used in the form of a free acid or its salt, it is preferably carried out in the presence of a condensing agent, and examples of such a condensing agent include N,N-dicyclohexylcarbodiimide,
Examples include N-cyclohexyl-N'-morpholinoethylcarbodiimide.

This acylation reaction is usually carried out in a solvent, and examples of reaction solvents include pyridine, chloroform, dichloroethane, carbon tetrachloride, tetrahydrofuran, dioxane, N,
In addition to N-dimethylformamide and dimethylsulfoxide, solvents that do not adversely affect this reaction may be used.

This acylation reaction is usually preferably carried out in the presence of a base, examples of such bases include, for example, alkali metals, alkali metals, alkali or alkali metal hydroxides, alkali carbonates or alkali metals. Examples include metals, alkali or alkali metal alcoholates, trialkylamines, pyridine, bicyclodiaza compounds, and the like. Among such bases, liquid ones can be used also as a reaction solvent. The temperature of this reaction is not particularly limited, but it is usually carried out at room temperature to a temperature around the boiling point of the solvent.

(ii) Acylaminophenylpropionate ester (
Production step of la): The reaction in this step is carried out by reacting a hydroxy compound with N-acyl-2-oxotetrahydroki/phosphorus (N).

The hydroxy compound used in this reaction is an alkanol (
(e.g., methanol, ethanol, propanol, isoprobanol, butanol, etc.), alkanols (e.g., benzyl alcohol, phenethyl alcohol, etc.)
, annoles (e.g. phenol, cresol, P-
Contains nitrophenol, etc.).

This reaction is usually carried out in a solvent.

Examples of such a solvent include ether, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, and other solvents that do not adversely affect this reaction. It is often used also as a solvent. In this reaction, when using a free hydroxy compound, the reaction can be carried out in the presence of an acid. Examples of such acids include inorganic acids such as hydrochloric acid and sulfuric acid, benzenesulfonic acid, and trichloroacetic acid. Organic acids such as

This reaction is usually carried out at room temperature or at a temperature around the boiling point of the solvent.

The thus obtained acylaminophenylpropionic acid ester (la) is isolated from the reaction solution by a conventional method.
Can be purified.

Process for producing acylaminophenylpropionic acid (lb) and its ester (la) [2' (wherein RI' is an esterified carboxy group, R2 is an acyl group, x is hydrogen or halogen, and X' (means halogen, respectively) The details of the above manufacturing method are as follows.

(i) Production process of N-acyl-Q-halotolidines (of): The reaction in this step is to produce N-acyltolidines (V).
This is done by allowing a halogenating agent to act on the halogenating agent.

The N-acyltoluidines (V) used in this reaction include known and new compounds, including known compounds such as 5-
Chloro-2-ethoxycarponyltoluene is the 42nd entry in the Journal of Medicinal Chemistry, No. 12.
It can be produced by the method described on pages 6 to 428 (196 g), and other compounds can be produced in the same manner.

Examples of the halogenating agent used in this reaction include:
Halogens such as chlorine and bromine, N-promosuccinimide,
N-halimide such as N-chlorosuccinimide and N-promophthalimide, hypohalous acid or its salts such as hypochlorous acid, hypobromous acid, and sodium hypochlorite, sulfuryl chloride, trichloromethanesulfuryl chloride and isocyanuric acid chloride.

This halogenation reaction is carried out in the presence of free radical initiators such as light such as ultraviolet light, peroxides such as penzoyl peroxide and ditertiary butyl peroxide, and azo compounds such as azobisisobutyronitrile. It is preferable to do this at the bottom.

This reaction is usually carried out in a solvent at a temperature ranging from room temperature to the boiling point of the solvent.

As the reaction solvent, in addition to carbon tetrachloride, chlorobenzene, nitrobenzene, cyclohexane, etc., any solvent that does not adversely affect this reaction can be used.
(ii) Acylamide/pendylmalonic acid ester (skin)
Production process: This reaction is carried out by reacting malonic acid ester with N-acyl-a-halotolidine (W).

Here, malonic acid ester refers to methyl ester, ethyl ester, and phthalate of malonic acid. It refers to esters of malonic acid, including alkyl esters such as lopylester, aralkyl esters such as benzine ester and phenethyl ester, or mixed esters thereof. This reaction is usually carried out in a solvent in the presence of a base.

Examples of the base used in this reaction include alkali metals, alkali metal alkoxides, alkali metal hydroxides, alkali metal amides, and alkali metal hydrides. Further, as a solvent, methanol, ethanol, tetrahydrofuran, dioxane, N.I. In addition to N-dimethylformamide, dimethyl sulfoxide, and the like, any solvent that does not adversely affect this reaction can be used.
Further, this reaction is usually carried out at room temperature or under heating. (fii) Acylaminophenylpropionic acid (lb
) Manufacturing process: The reaction in this step is carried out by hydrolyzing acylaminobenzyl malonic acid esters (skin) and then decarboxylating if necessary.

For this hydrolysis reaction, hydrolysis in the presence of an acid or isokinetic hydrolysis in the presence of a base can be applied.
Here, hydrolysis in the presence of a base usually proceeds easily under mild conditions and frees the corresponding free malonic acid or the salts with the base used in the reaction (especially alkali metal salts and alkali metal salts). May be given as a product. In such a case, acylaminophenylpropionic acid (lb) can be obtained by carrying out a decarboxylation reaction by simply heating or treating the product with an acid. here,
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydroxides such as barium hydroxide and calcium hydroxide, and alkali metal hydrogencarbonates such as sodium hydrogen carbonate.

This reaction is often carried out under cooling or heating. Hydrolysis in the presence of acid is carried out according to conventional methods,
Acylaminophenylpropionic acid (lb) is often obtained directly by hydrolysis and decarboxylation.

M acylaminophenylpropionate (la)
Production step: The reaction in this step is carried out by reacting acylaminophenylpropionic acid (lb) or its reactive derivative with an esterifying agent.

Examples of the reactive derivatives of acylaminophenylpropionic acid (lb) include acid halides, acid azides, active amides, and active esters.

Preferred examples of the esterification agent used in this reaction include the hydroxy compound described in step (ii) of 11 of the above-mentioned method for producing acylaminophenylpropionate (la), and others. and reactive derivatives of hydroxy compounds.

Examples of such reactive derivatives include, for example, the corresponding halides, diazo compounds (e.g. diazoalkanes, etc.), esters with sulfonic acids (e.g. alkanesulfonate esters, etc.), esters with sulfuric acid (e.g. alkyl sulfuric acid, etc.), as well as alkali metals (e.g., lithium,
(eg, sodium, potassium, etc.) or salts with alkali metals (eg, magnesium, calcium, etc.) (eg, sodium ethoxide, sodium penzyl alkoxide, potassium phenoxide, etc.).
This reaction is usually carried out in a solvent. Examples of such solvents include ether, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, and other solvents that do not adversely affect this reaction, but hydroxy compounds, which are usually reaction reagents, may be used. is often used also as a solvent. Furthermore, when acylaminophenylpropionic acid (lb) is used in the form of a free acid or its salt, it is usually carried out in the presence of a condensing agent.

Such condensing agents include, for example, phosphorus oxychloride.
Phosphorus trichloride, thionylc. Ride, oxalyl chloride, triphenylphosphine and the like. Further, this reaction is usually carried out at room temperature or at a temperature around the boiling point of the solvent.

Acylaminophenylpropionic acid (lb) and its ester (la) obtained by the above method can be isolated and purified from the reaction solution by a conventional method.

Intermediates (W), (of) and (skin) obtained in each step of the above-mentioned production method of acylaminophenylpropionic acid (lb) and its ester (la) {1) and (■)
are all new compounds, and can be isolated and purified from the reaction solution by conventional methods, but they may also be subjected to the next step in their crude form without being isolated or purified.

Next, the present invention will be explained using examples.

Example '1' Production example of raw material 'a) 3-(5-chloro-2-benzamidophenyl)
Ethyl propionate: 6-chloro 2-oxo 1,2
, 3,4-tetrahydroquinoline 2.0 pyridine 4
Dissolve the solution in 3.0 ml of benzoic acid chloride, and add 3.0 ml of benzoic acid chloride dropwise thereto.

The reaction solution is heated to reflux at 140 to 150 oO for 3 hours. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, and the residue is dissolved in 10 parts of chloroform and washed with dilute hydrochloric acid. The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual solution was dissolved in 70% ethanol saturated with dry HCI gas and heated under reflux for 1 hour. Next, the solvent was distilled off under reduced pressure, and a mixed solution of benzene-n-hexane was added to the residue for crystallization to obtain crystalline 3-(5-chloro-2).
-2.7 ml of ethyl (penzamidophenyl)propionate are obtained. M circle: 105 to 10 is O NMR (CC14) 6 (leg) 10,60 (IH, s), 8, 1 to 7.7 (ga, m),
7.68 (IH, d, J = 9HZ), 7.6-7.1 (
3 days, m), 7.08 (IH, d, d, J = 2 and 9
HZ) 7.04 (IH, d, J = 2HZ), 4.08 (
2 days, q, J=7HZ), 2.4-3.1 (4 days, m)
, 1.14 (Chihito, t, J=7Hz) {b} 3-(
Methyl 5-chloro-2-ethoxycarbonylphenyl)propionate: H} 2-ethoxycarbonyl-5,Q
-Dichlorotoluene: Dry 40 minutes of 5-chloro-2-ethoxycarbonyltoluene to 250M of carbon tetrachloride and 18 minutes of chlorine.
．． The suspension was suspended in a solution containing 500 mg of mercury, and exposed to ultraviolet rays emitted from a high-pressure mercury lamp for 1 hour at room temperature.

After completion of the reaction, the precipitated crystals were collected by filtration and dried to obtain 29.5 kg of colorless needle-like crystals of 2-ethoxycarbonyl-5,Q-dichlorotoluene.

This is recrystallized from a mixture of ethyl acetate and n-hexane to obtain 29 colorless needle crystals of purified 2-ethoxycarbonyl-5,Q-dichlorotoluene. M yen 137~1
39q○ Elemental analysis value (%) C, broadside, . As NC1202:○
H N ○ and calculated value 48.41 4.47
5.65 28.58 Actual value 48.66 4
．． 41 5.64 28.62 [5-chloro 2-ethoxycarbonylbenzyljetylmalonate 2-ethoxycarbonyl-5,Q- Add 28.5 ml of dichlorotoluene,
Boil for 1 hour at room temperature.

Next, the solvent is distilled off under reduced pressure, and Suncheng is dissolved in benzene and washed with water. After drying the organic layer over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The resulting residue was crystallized from benzene and further recrystallized from isopropyl ether to obtain 15.0 kg of colorless needle crystals of diethyl 5-chloro-2-ethoxycarbonylbenzylmalonate. MP86
~88qON 5-chloro-2-ethoxycarbonylbenzylmalonic acid: 19 ml of diethyl 5-chloro-2-ethoxycarbonylbenzylmalonate and 19 ml of barium hydroxide (octahydrate) were dissolved in 100 m' of methanol and 5 ml of water.
Suspend the suspension in 100ml of water and incubate at room temperature for 30 minutes.

The precipitated crystals are collected in a furnace, suspended in water, adjusted to pHI with hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, then dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and benzene to give 14.4 hours of colorless crystals of 5-chloro-2-ethoxycarbonylbenzylmalonic acid. MP 133-13
is o (decomposition) NMR (mu DMSO) 6 (leg) 8.95 (IH, s), 7.2 (3 days, m), 4.13
(but, q, J = 7HZ), 3.62 (IH, t, J = 8
HZ), 3.10 (2 days, d, J=8HZ), 1.25
(Spot, t, J: 7HZ) Piece 3-(5-chloro-2-ethoxycarbonylphenyl)propionic acid: Crystals of 5-chloro-2-ethoxycarbonylbenzylmalonic acid 14
．． 4. Heat in an oil bath at 140-145° C. for 40 minutes.

During this time, the crystals melt and foam, and crystals are precipitated again. After cooling, the precipitated crystals were dissolved in a 5% aqueous sodium hydrogen carbonate solution.
Dissolve in 50' solution and wash with ethyl acetate. When the aqueous layer is separated and adjusted to pHI with hydrochloric acid, crystals are precipitated. The crystals are collected in a furnace, washed with water, dissolved in ethanol, treated with activated carbon, filtered, and then crystallized by adding water to the furnace solution.

The precipitated crystals are collected in a furnace, washed with water, and dried to obtain 11.1 colorless needle-like crystals of 3-(5-chloro-2-ethoxycarponylphenyl)propionic acid.

M yen 186-18700 NMR (Heiichi DMSO) 6 (Yanagi) 8.96 (IH, s), 7.3 (Chihito, m), 4.12
(crime, q, J = 6.5 days 2), 2.67 (nagi, m), 1
．． 22 (Gen, t, J = 6.5HZ) 3-Methyl (5-chloro-2-ethoxycarbonylphenyl)propionate: 3-(5-chloro-2-ethoxycarbonylphenyl)propionic acid 9.5% anhydride Dissolve in a mixture of 200 parts methanol and 0.5 parts concentrated sulfuric acid, and leave at room temperature for 24 hours.

Next, triethylamine was added to the reaction solution overnight, and the mixture was concentrated under reduced pressure. . The oily residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from a mixture of benzene-n-hexane to give 10 colorless needle-like crystals of methyl 3-(5-chloro-2-ethoxycarbonylphenyl)propionate. obtain.

MP 70~7〆○ Elemental analysis value (%) C, 3 days, as 6N04CI:○
H N ○mu calculated value 54.65 5.64
4.90 12.41 Actual value 54.67 5
．． 65 4.78 1248 ■ Production example of target substance 'a} Methyl 5-chloroIH-indazol-3-yl acetate: Methyl 3-(5-chloro-2-ethoxycarbonylphenyl)bropionate was mixed with acetic anhydride 6 [and acetic acid] Suspend in a mixture consisting of 8 birds, and keep this suspension at 5℃.
This nitric acid (dl
．． 47) Add nitrogen trioxide gas produced by dropping 7' to 1.
It takes 5 hours to install.

Next, the reaction solution was incubated at room temperature for 30 minutes, and then placed on ice for 100 minutes.
Pour in the saw and let it sit at room temperature for 1 hour. The reaction solution was extracted twice with 70 parts of benzene, the extracts were combined, 5 parts of methanol was added thereto, and the mixture was left at room temperature for 1 hour. The benzene layer is washed twice with water, dried over anhydrous sodium sulfate, and filtered. Next, the furnace liquid was heated under reflux for 1 hour, and then the solvent was removed under reduced pressure to obtain an oily liquid. The oily residue is dissolved in a small amount of methanol, treated with activated carbon, and concentrated under reduced pressure.
The resulting residue was crystallized from isopropyl ether and further recrystallized from isopropyl ether to obtain 2.6 ml of colorless needle-like crystals of methyl 5-chloroIH-indazol-3-yl acetate. . M circle 87-88℃ NMR (CDC13) 6 (leg) 7.64 (IH, d, J = 2HZ), 7, 2 (ga, m)
, 4-00 (2nd, S), 3-72 (milk day, S) {b'
Ethyl 5-chloro-IH-indazol-3-yl acetate: 1.5 mL of ethyl 3-(5-chloro-2-penzamidophenyl)propionate was treated in the same manner as in (a) above to obtain ethyl 5-chloro-IH-indazol-3-yl acetate. Obtained 700 capes of colorless crystals.

M yen 76-770

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a carboxy group or an esterified carboxy group, R^2 is an acyl group, and X is hydrogen or By treating acylaminophenylpropionic acids or their salts represented by halogen with an N-nitrosating agent and then subjecting them to a ring-closing reaction, the general formula ▲mathematical formula, chemical formula, table, etc.▼ (formula A method for producing an indazole acetic acid or a salt thereof, characterized in that an indazole acetic acid or a salt thereof is obtained, wherein R^1 and X each have the same meaning as above.