DE2155545A1 - Indazoles prepn - by diazotization and cyclization of o-toluidine derivs - Google Patents

Abstract

Indazoles of formula (I): (where each R1 (same or different) is H, an aliphatic, cycloaliphatic or aromatic residue, or halogen, and R2 is H or an aliphatic residue), which are starting materials for dyes, pharmaceuticals and pesticides, are prepd. by (a) reacting o-toluidines of formula (II) with alkyl nitrite and/or nitrous gases in the presence of acetic anhydride, an alkali salts of a lower alkanoic acid and an inert organic solvent, and (b) removing the acetyl group from the resulting l-acetyl-indazole in a conventional manner. The process is simple and economical, is suitable for industrial use, and gives (I) in better yields and purity than by known processes.

Description

Process for the preparation of indazoles The invention relates to a Process for the production of indazoles by reacting o-doluidines with alkyl nitrite and / or nitrous gases in the presence of acetic anhydride, an alkali salt of an alkanecarboxylic acid and an organic solvent and subsequent cleavage of the acetyl group from the 1-acetyl-indazole formed.

It is from the Annalen der Chemie, Volume 586 (1954), pages 84 to 109, and Elderfield, Heterocyclic Compounds, Volume 5, pages 162 to 192 (J. Wiley, N.Y. 1957) known that substituted o-doluene-diazonium salts cyclized to indazoles will. The yields are only high if the substituents are electron-withdrawing are (Albert, Chemie der Heterocyclen (Verlag Chemie, Weinheit 1962), page 192 and 193). For example, m-nitro-o-uoluene-diazonium compounds are in glacial acetic acid cyclized to 6-nitro-indazole (Elderfield, loc. cit., pages 171 and 172). It will pointed out that the substituent may be a nitro group or a halogen atom got to. It is also known to add benz-o-toluidide in glacial acetic acid with nitrous gases nitrosate, to separate off the nitrosoc body thus formed and precipitated with water and to convert it in benzene with heating into indazole itself (Elderfield, loc. cit., page 172; Annals, loc. cit., page 89). o-Toluene diazonium salts provide as the aforementioned article in the Annals (loc. cit., page 85.) teaches in sour or neutral solution no indazole, but give normal exchange reactions with release of diazo nitrogen. It is recommended (Ann., Loc. Cit., Page 90), Aceto-toluidid to nitrosate the nitroso body in a mixture of glacial acetic acid and acetic anhydride to be set free with water, to dry and then to cyclize in benzene at 40 ° C.

All of these procedures are cumbersome and especially industrial Standard in terms of ease of operation, economy and yield End product unsatisfactory. The aforementioned nitroso compounds are used as starting materials unstable, difficult to isolate and completely dry as it is for the subsequent Cyclization is necessary.

It has now been found that indazoles of the general formula in which the individual radicals R1 can be identically or differently and each hydrogen atom is an aliphatic, cycloaliphatic, araliphatic or aromatic radical, a halogen atom, R2 denotes a water atom or an aliphatic radical, which is advantageously obtained when o-toluidines of the general formula where R1 and R2 have the aforementioned meaning, in the presence of acetic anhydride, an alkali salt of an alkanecarboxylic acid and an organic solvent inert under the reaction conditions, reacts with alkyl nitrite and / or nitrous gases and converts the acetyl group from the 1-acetyl-indazole thus obtained in a known manner separates.

In the case of using o-toluidine and isoamyl nitrite, the reaction can be represented by the following formulas: In comparison to the known processes, the process according to the invention surprisingly provides indazole itself and indazoles substituted with electron-repelling substituents in a simpler and more economical way in better yield and purity. A cumbersome and uneconomical production and isolation of the nitroso derivative is not necessary. The simple, one-step cyclization procedure means that the process can also be carried out on an industrial scale.

Preferred starting materials II and correspondingly preferred end materials I are those in whose formulas the individual radicals R1 are identical or different can and each have a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 6 carbon atoms, an aralkyl group with 7 to 12 carbon atoms or a phenyl radical, a chlorine atom, bromine atom, iodine atom, and R2 denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The radicals mentioned can also be replaced by groups which are inert under the reaction conditions, e.g. alkgl or alkoxy groups each having 1 to 3 carbon atoms, substituted be. The radicals R1 are preferably all 2-, 3- and / or 4 position to the amino group of starting material TT.

For example, the following starting materials TI come into consideration: o-toluidine ; 2-methyl, 2,3-diisopropyl, 2-chloro, 3-chloro, 4-chloro, 5-chloro, 3-phenyl, 4-ethyl-, 2,4-dichloro-, 5-cyclohexyl-, 2-13romo-, 2-iodine, 4-benzyl-o-toluidine, o-ethylaniline, o-n-butylaniline.

The reaction is carried out in the presence of acetic anhydride, preferably in an amount from 100 to 2500, in particular from 280 to 860 wt., Based on the starting material II, and of an alkali salt of an alkanecarboxylic acid, preferably in an amount from 10 to 560, in particular from 90 to 190% by weight, based on starting material II, ' carried out. There are preferably sodium and potassium salts and, as acids, those with 1 to 6 carbon atoms in question. For example are the sodium or potassium salts of propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid and in particular Potassium acetate suitable.

As an organic solvent which is inert under the reaction conditions are used in the reaction: aromatic hydrocarbons such as xylenes, toluene and especially benzene; aliphatic hydrocarbons such as ligroin, petroleum ether, cycloaliphatic hydrocarbons such as cyclohexane and mixtures thereof. The amounts generally range from 800 to 25,000, in particular from 2,000 to 3,000 % By weight of solvent, based on starting material II.

Nitrosating agents in the form of Alkyl nitrite, preferably of an alkyl nitrite having 1 to 5 carbon atoms, or used by nitrous gases.

For example, methyl, ethyl, amyl, isobutyl and especially Tsoamyl nitrite suitable. The nitrous gases are used here as nitrosating agents or diazotizing agents known nitrogen oxides, nitrogen monoxide, nitrogen dioxide, Nitrogen tetroxide, nitrogen trioxide understood. They can be used individually or appropriately in an appropriate mixture, advantageously of nitrogen monoxide and nitrogen dioxide, used earth. In general, amounts of 1.1 to 5 moles of alkyl nitrite are used andZoder nitrous gases per mole of starting material FI, expediently 1.1 to 2.7, in particular 1.1 to 1.7 moles of alkyl nitrite or 1.5 to 5, in particular 2 to 4 moles of N2O3 per mole of starting material LT, into consideration. The nitrogen oxides or gas mixtures mentioned can also be used under gases inert to the reaction conditions, e.g.

Nitrogen.

The reaction is usually carried out at a temperature between 45 and 150, preferably between 60 and 1100C, without pressure or under pressure, continuously or carried out batchwise. For example, you can use the starting materials in in the following way: A mixture of starting material LT, alkyl nitrite, acetic anhydride, The alkali salt and solvent are left for 12 to 20 hours at the reaction temperature cloaked. The mixture is then filtered and the filtrate is concentrated in the filtrate the end product is in the form of its i-acetyl compound. The acetyl group is separated off in a known manner, expediently by treatment with acid, e.g. in an amount of 2 to 10 moles per mole of 1-acetyl compound for 30 to 90 minutes at 40 to 60 ° C. In the case of chlorine indazoles is expediently at 60 to 70 ° C and optionally saponified somewhat higher amounts of acid. It is advantageous to use 15 to 38 percent by weight hydrochloric acid. One can split off the acetyl group but also with other acids, e.g. 48% by weight sulfuric acid, 64% by weight phosphoric acid or 55% by weight nitric acid.

After the acetyl group has been split off, the end product becomes more customary Way isolated, e.g. by extracting the mixture with benzene, extracting the benzene extract with hydrochloric acid, supersaturation of the hydrochloric acid extract with ammonia and filtration.

If nitrous gases are used instead of alkylnitrite, then one conducts for example continuously or discontinuously for 1.5 to 4 hours the aforesaid nitrogen oxide or mixtures of nitrogen oxides, usually N205, optionally together with inert gas, through the starting mixture at the Reaktton Temperatur 'leads the reaction continues for 0.5 to 1.5 hours and then isolates the end product in the described way.

The compounds that can be produced by the method of the invention are valuable starting materials for the production of dyes, Pharmaceutica and Pesticides.

The parts by weight given in the following examples. They aged to the parts by volume eu as kilograms to liters.

Example 1 isoamyl nitrite as a diazotizing agent 3.51 parts [soamyl nitrite are distilled into a suspension of 2.14 parts over a period of vO minutes o-'Coluidine and 2.0 parts of anhydrous potassium acetate in 5.15 parts of acetic anhydride and entered 60 parts by volume of benzene. The reaction solution is under constant Stirring kept at 80 to 85 ° C. After a reaction time of 18 hours, meanwhile the solution has turned an orange-red color, the cooled reaction solution becomes filtered off from the potassium acetate; the potassium acetate is washed out several times with benzene. The entire filtrate is concentrated on a rotary evaporator at 40 ° C. and split off the acetyl group slowly with a mixture of 10 parts by volume of 5N hydrochloric acid and 5 parts by volume conc. Hydrochloric acid added.

The mixture is then stirred at 45 to 50 ° C. for one hour and heated briefly to 55 ° C. The reaction solution is with 55 parts by volume of benzene shaken out, the benzene phase then once with 10 parts by volume of 2N acidic acid and extracted twice with 5 parts by volume of 5N hydrochloric acid. The sour extracts will be with 10 to 15 parts by volume conc. Treated ammonia, whereby Tndazole is precipitated. After standing in the ice bath for 2 hours, the end product is suctioned off with cold water washed and in vacuo over conc. Dried sulfuric acid. The yield is 1.86 parts (78.5% of theory) of endazole with a melting point of 146.5 to 148.0 ° C.

If the reaction is carried out in other solvents instead of benzene by, one obtains the yields of [ndazole.

Table I Olvens temperature response yield mp ° C duration in in % ° C hours cyclohexane 80 20 68 146-147 ligroin 80 20 60 144-145 petroleum ether 45 48 51 147-148 Examples 2 to 8 Analogously to Example 1, Example II is used as starting materials 2) 3-methyl-6-aminotoluene (2.42 parts) 3) 4-methyl-6-aminotoluene (2.42 parts) 4) 5-methyl-6-aminotoluene (2.42 parts) 5) 2-chloro-6-aminotoluene (2.82 parts) 6) 3-chloro-6-aminotoluene (2.82 parts) 7) 4-chloro-6-aminotoluene (2.82 parts) 8) 5-chloro-6-aminotoluene (2.82 parts) implemented. The saponification temperature in Examples 5 to 8 is 60 to 700C, the amount of acid a mixture of 10 parts by volume of conc. Hydrochloric acid and 5 parts by volume 5 N hydrochloric acid.

The results are set out in the following table.

Table II Example indazole parts Yield in%, mp @ final product of theory in C 2 5-methyl-indazole 1.71 64.8 114-116 3 6-methyl-indazole 1.82 68.9 175-176 4 7-methyl-indazole 1.45 54.9 134-135 5 4-chloro-indazole 2.53 83.0 155-156 6 5-chloro-indazole 2.46 80.8 114-116 7 6-thloro-indazole 2.51 82.4 174-176 8 6-thloro-indazole 1.66 54.5 135-136 Example 9 Nitrous gases as nitrosating agent 2.14 parts distilled o-toluidine are dissolved in a suspension of 4.0 parts of anhydrous potassium acetate added to 9.20 parts of acetic anhydride and 60 parts by volume of benzene. The reaction solution is kept at 80 to 850 ° C. for 3 hours with constant stirring. Simultaneously are 100 parts of nitrous gases in a closed reaction vessel made of sodium nitrite and conc. Nitric acid can be developed with nitrogen as the carrier gas through the Reaction solution passed. After a reaction time of 4 hours, the solution was red-brown Color accepted.

The reaction solution is worked up as in Example 1.

The crude yield of indazole is 1.47 tonnes (62.0% of theory) with a melting range of 110 to 135 ° C. By sublimation of the end product an oil bath temperature of 80 ° C. at 0.05 torr gives 1.13 parts (47.5 ff Theory) Indazole with a melting point of 144 to 14700.

Examples 10 to 12 The following reactions are carried out analogously to Example 9, the results of which are shown in Table III.

Table III Yield, Ex. Starting materials, parts of indazole end product Share% d. Theory mp in ° C 10 2-chloro-6-aminotoluene 2.82 4-chloro-indazole 2.32 76.1 155.5-156 11 3-chloro-6-aminotoluene 2.82 5-chloro-indazole 1.90 62.4 114.5-116 12 4-chloro-6-aminotoluene 2.82 6-chloro-indazole 1.76 57.5 174-176 Examples 13 bis 14 The reaction (Table IV) in Example 13 takes place with isoamyl nitrite analogously to Example 1 and in example 14 with nitrous gases and N2 as carrier gas analogous to example 9.

Table IV Example starting materials parts final product yield parts% Theory m.p. in ° C 13 o-ethylaniline 2.42 3-methylindazole 1.44 54.6 109-111 14 o-ethylaniline 2.42 3-methylindazole 0.88 33.4 108-110

Claims (1)

Process for the preparation of indazoles of the general formula in which the individual radicals R1 can be identical or different and each represent a hydrogen atom, an aliphatic, cycloaliphatic, araliphatic or aromatic radical, a halogen atom, and R2 denotes a hydrogen atom or an aliphatic radical, characterized in that o-toluidines of the general formula where R1 and R2 have the aforementioned meaning, in the presence of acetic anhydride, an alkali salt of an alkanecarboxylic acid and an organic solvent inert under the reaction conditions, reacts with alkyl nitrite and / or nitrous gases and converts the acetyl group from the 1-acetyl-indazole thus obtained in a known manner separates.