Process for the preparation of substituted indazoles

Substituted indazoles that have the structural formula ##STR1## wherein X represents halogen, trihalomethyl, nitro, --SO.sub.2 R, cyano, acoyl, acoylamino, aroylamino, or --COOR'; R represents hydroxyl, halogen, alkyl, haloalkyl, alkylamino, phenyl, or substituted phenyl; R' represents hydrogen, halogen, alkyl, haloalkyl, phenyl, or substituted phenyl; and n represents a number in the range of 1 to 4 are prepared by the direct nitrosation of the corresponding 2-methylacetanilide with an alkali metal nitrite or alkaline earth metal nitrite under conditions of controlled acidity in the presence of a dehydrating agent at a temperature in the range of 50.degree.-120.degree. C.

This invention relates to a process for the production of indazoles. More 
particularly, it relates to an improved process for the production of 
indazoles that have certain substituents on the aromatic nucleus. 
The preparation of indazole and substituted indazoles by the cyclization of 
N-nitroso-o-toluidines is well known. The preparation of indazole by 
heating N-nitrosobenzo-o-toluidine in boiling benzene was described by 
Jacobson and Huber in Ber. 41, 660 (1908). A similar approach using 
substituted N-nitroso-o-acetotoluidides was used by Auwers et al. (Ber. 
55, 1139 (1922); Ann. 478, 154 (1930)) to prepare 5-chloroindazole and 
5,7-dichloroindazole. In these processes, nitrogen oxides were used to 
effect nitrosation of the toluidides. This general method was further 
developed by Ruechardt and Hassmann (Ger. Offen. No. 2,155,545 (1973); 
Chem. Commun. 1972, 375), who prepared substituted indazoles by the 
nitrosation of substituted 2-methyl-o-toluidines using an alkyl nitrite or 
externally-generated nitrogen oxides. This process requires the use of an 
inert organic solvent, such as benzene or cyclohexane, together with an 
alkali metal salt of an alkanoic acid, for example, potassium acetate, and 
at least two molar equivalents of acetic anhydride to consume the water 
from the nitrosation and for reaction with the indazole compound as it is 
formed. The resulting 1-acetylindazole compound must be hydrolyzed prior 
to isolation of the free indazole product. When nitrogen oxides are used 
as the nitrosating agent, extra alkali metal alkanoate is required to 
neutralize the higher nitrogen oxides resulting by dismutation. In a 
modification of this work, which is described in Ger. Offen. No. 2,210,169 
(1973), Ruechardt et al. used a glycol nitrite in the nitrosation step. 
This invention relates to an improved process for the production of 
substituted indazoles. This one-step process, which can be used for the 
commercial production of haloindazoles, nitroindazoles, and certain other 
substituted indazoles, gives high yields of these compounds rapidly and 
efficiently. Unlike the previously-known procedures described 
hereinbefore, this process does not require the use of an inert organic 
solvent medium or an alkali metal alkanoate, and it does not employ 
sizeable excesses of the dehydrating agent. In addition, it does not 
include a step in which an acetylated indazole is hydrolyzed to give the 
desired product. A further advantage of this process is that it uses as 
the nitrosating agent an alkali metal nitrite or an alkaline earth metal 
nitrite rather than the more hazardous nitrite esters or 
externally-generated nitrous gases. 
Nitrosation using the preferred sodium nitrite/acetic acid system also 
produces sodium acetate which forms with the acetic acid a buffer system 
that serves to maintain the reaction mixture at the level of acidity that 
is most favorable for the process to operate with minimum regulation. The 
sodium nitrite/acetic acid system is particularly well suited to the 
production of 5,7-di-chloroindazole and trichloroindazoles from the 
corresponding 2-methylchloroacetanilides because these 
2-methylchloroacetanilides are readily synthesized by the nuclear 
chlorination of 2-methylacetanilide in glacial acetic acid. The in-situ 
processing of 2-methylacetanilide through the 2-methylchloroacetanilides 
to the chloroindazoles without isolation of intermediate products is 
practical and economical. 
In the process of this invention, a substituted 2-methylacetanilide is 
reacted with an alkali metal nitrite or an alkaline earth metal nitrite, 
which is preferably sodium nitrite, in a reaction medium that comprises an 
alkanoic acid having 2 to 4 carbon atoms and a dehydrating agent at a 
temperature above 50.degree. C. The reaction that takes place is shown in 
the following equations: 
##STR2## 
The indazole that is formed is separated from the reaction mixture, washed 
free of salts and reaction by-products, and dried. 
The process of this invention can be used in the preparation of substituted 
indazoles that have the structural formula 
##STR3## 
wherein X represents chlorine, bromine, iodine, fluorine, trichloromethyl, 
tribromomethyl, triiodomethyl, trifluoromethyl, nitro, --SO.sub.2 R, 
cyano, acetyl, butyryl, acetamino, propionamino, benzamino, or --COOR'; R 
represents hydroxyl, chlorine, bromine, fluorine, iodine, alkyl having 1 
to 12 carbon atoms, chloroalkyl having 1 to 12 carbon atoms, bromoalkyl 
having 1 to 12 carbon atoms, iodoalkyl having 1 to 12 carbon atoms, 
fluoroalkyl having 1 to 12 carbon atoms, monoalkylamino, dialkylamino, 
phenyl, chlorophenyl, bromophenyl, iodophenyl, fluorophenyl, nitrophenyl, 
or alkylphenyl wherein the alkyl group has 1 to 4 carbon atoms; R' 
represents hydrogen, chlorine, bromine, fluorine, iodine, alkyl having 1 
to 12 carbon atoms, chloroalkyl having 1 to 12 carbon atoms, bromoalkyl 
having 1 to 12 carbon atoms, iodoalkyl having 1 to 12 carbon atoms, 
fluoroalkyl having 1 to 12 carbon atoms, phenyl, chlorophenyl, 
bromophenyl, iodophenyl, fluorophenyl, nitrophenyl, or alkylphenyl wherein 
the alkyl group has 1 to 4 carbon atoms; and n represents a number in the 
range of 1 to 4. 
Illustrative of these substituted indazoles are the following: 
4-nitroindazole, 5-nitroindazole, 6-nitroindazole, 7-nitroindazole, 
5,7-dinitroindazole, 7-chloroindazole, 4,7-dichloroindazole, 
5,7-dichloroindazole, 4,5,7-trichloroindazole, 4,5,6-trichloroindazole, 
4,5,6,7-tetrachloroindazole, 5-trichloromethyl-7-chloroindazole, 
6-nitro-7-chloroindazole, 7-bromoindazole, 5,7-dibromoindazole, 
4,5,6,7-tetrabromoindazole, 4,7-diiodoindazole, 5,7-difluoroindazole, 
4-chloro-7-trichloromethylindazole, 7-tribromomethylindazole, 
5-iodo-7-triiodomethylindazole, 7-trifluoromethylindazole, 
5,7-dimethylaminoindazole, 5-(benzenesulfonyl)-indazole, 
6-(chlorohexylsulfonyl)indazole, 5,6-di(butylsulfonyl)-indazole, 
6-(p-toluenesulfonyl)indazole, 4,6-di(nitrobenzenesul-fonyl)indazole, 
5,6-dicyanoindazole, 4,5,7-triacetylindazole, 5,7-diacetaminoindazole, 
7-benzaminoindazole, 5,7-dicarbomethoxyindazole, 
4,7-dicarboethoxyindazole, 7-carbophenoxyindazole, 5,7-dicarboxyindazole, 
and the like. 
When the X substituent on the aromatic nucleus of the 2-methylacetanilide 
is strongly electronegative, for example, nitro(--NO.sub.2), the 
nitrosation/ring closure reaction is readily effected regardless of the 
position of the substituent on the aromatic nucleus, the number of such 
substituents, and the presence of other substituents. When the substituent 
represented by X is either weakly electronegative or electropositive, for 
example, halogen, the substituent must be in a position adjacent to the 
acetamido (--NHCOCH.sub.3) group, that is, in the 6-position of the 
aromatic nucleus, if a satisfactory yield of the desired indazole is to be 
obtained. Particularly good results are obtained when there are two or 
more of these substituents on the ring. Thus, it has been found that best 
results are obtained when the substituted acetanilide has either the 
structural formula 
##STR4## 
wherein Y represents a strongly electronegative substituent, such as 
nitro, --SO.sub.2 R, or cyano; Y' represents halogen, trihalomethyl, or 
--COOR'; R and R' have the aforementioned significance; and m represents a 
number in the range of 0 to 3, or the structural formula 
##STR5## 
wherein Z represents a wealky electronegative substituent or an 
electropositive substituent, such as halogen, trihalomethyl, acoyl, 
acoylamino, aroylamino, or --COOR; Z' represents halogen, trihalomethyl, 
--COOR, nitro, or --SO.sub.2 R; and R, R', and m have the aforementioned 
significance. 
In this one-step process for the production of substituted indazoles, an 
alkali metal nitrite or an alkaline earth metal nitrite, for example, 
sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, or 
strontium nitrite, is added to a reaction mixture that contains the 
appropriate 2-methylacetanilide, an alkanoic acid having 2 to 4 carbon 
atoms, and a dehydrating agent until 1.0 mole to 1.5 moles of the nitrite 
has been added per mole of the 2-methylacetanilide in the mixture. The 
nitrosation/ring closure reaction is usually and preferably carried out by 
adding solid sodium nitrite in the amount of 1.2 to 1.3 moles per mole of 
the 2-methylacetanilide portionwise to the reaction mixture which is being 
maintained at a temperature between 50.degree. C. and its reflux 
temperature, which is generally about 120.degree. C. A reaction 
temperature between 70.degree. C. and 100.degree. C. is preferred because 
it provides a sufficiently rapid rate of reaction while allowing for the 
monitoring of the acidity of the system. 
The reaction mixture to which the alkali metal or alkaline earth metal 
nitrite is added contains the appropriate 2-methylacetanilide, from 1 part 
to 20 parts by weight of an alkanoic acid having from 2 to 4 carbon atoms 
per part by weight of the 2-methyl acetanilide, and from about 1.0 mole to 
1.5 moles of a dehydrating agent per mole of the 1-methylacetanilide. It 
preferably contains from 2 parts to 10 parts by weight of the alkanoic 
acid per part by weight of the 2-methylacetanilide and from 1.0 mole to 
1.2 moles of the dehydrating agent per mole of the 2-methylacetanilide. 
The alkanoic acid in the reaction medium functions both as a solvent and as 
the primary acidifying agent for generating nitrous acid from the nitrite 
that is added. In most cases, the alkanoic acid is acetic acid because of 
its low cost and because it combines with the sodium acetate formed during 
the addition of sodium nitrite to form an anhydrous buffer system that is 
ideal for the nitrosation reaction. The use of acetic acid also permits 
the use of such dehydrating agents as acetic anhydride, polyphosphoric 
acid, and boron oxide without compatibility problems. 
During the addition of the nitrite, the acidity of the reaction is 
monitored using a pH meter that is capable of measuring both pH and redox 
potential. For example, a Beckman Zeromatic SS-3 pH Meter or a Beckman 
Century SS-1 pH Meter may be used. Any electrode system that includes 
separate glass or metallic electrodes coupled with a reference electrode 
and that is capable of operating at temperatures up to 100.degree. C. may 
be used with the pH meter. During the addition of the nitrite, the 
millivolt potential of the reaction mixture is maintained in the range of 
250 mv. to 450 mv. In general, +MV potentials below this range inhibit 
N-nitrosation by protonating the amide substrate to a less reactive 
cationic-like species (--NH.sub.2 .+-. COCH.sub.3), while too basic a 
medium (450 mv. to 500 mv.) leads to an unfavorable equilibrium for the 
formation of the nitrous acid required for nitrosation. When the reaction 
mixture contains acetic acid, the normal anhydrous acetic acid/sodium 
acetate buffer range, which corresponds to a +MV potential range of 400 
mv. to 440 mv., is preferred. The initial acidity level of the reaction 
mixture, which is usually below 300 mv., can be brought to the preferred 
range by the addition of sodium acetate. During the course of the 
reaction, the sodium nitrite that is added also contributes to sodium 
acetate buildup. The acidity of the reaction mixture can be maintained at 
the desired level during the course of the reaction by the addition of the 
necessary amounts of an anhydrous acid, such as sulfuric acid, 
polyphosphoric acid, phosphoric acid, trifluoroacetic acid, or hydrogen 
chloride. 
When the addition of the nitrosating agent has been completed, the 
substituted indazole that has been formed is recovered from the reaction 
mixture and purified using conventional techniques. For example, after the 
acetic acid or other alkanoic acid has been removed from the reaction 
mixture by distillation, the residue can be added to a large volume of 
water to precipitate the crude product. This product can then be washed 
with water and extracted with dilute sodium hydroxide solution to remove 
salts and other reaction by-products from it. 
When there are stable, non-reducible substituents, such as halogen or 
trihalomethyl, on the benzene ring, the crude substituted indazole may be 
treated with a reducing agent, such as sodium hydrosulfite, to convert 
nitro and nitroso substituted by-products to amine derivatives that are 
soluble in strong aqueous acid. In this way, the substituted indazole 
product can be upgraded with possible regeneration of an additional amount 
of the product. 
In a preferred embodiment of the invention, the starting material is a 
substituted o-toluidine. In this process, the o-toluidine is reacted with 
a stoichiometric excess of glacial acetic acid and acetic anhydride to 
form a reaction mixture that contains the corresponding 
2-methylacetanilide as well as acetic acid and acetic anhydride. Sodium 
nitrite or another alkali metal or alkaline earth metal nitrite is added 
to this reaction mixture to effect nitrosation and ring closure and 
thereby form the corresponding substituted indazole. 
In another preferred embodiment of the invention, o-toluidine is reacted 
with a stoichiometric excess of glacial acetic acid and acetic anhydride 
to form a reaction mixture that contains 2-methylacetanilide, acetic acid, 
and acetic anhydride. Chlorine is introduced into this reaction mixture 
until an average of from 1 gram atom to 4 gram atoms of chlorine has 
reacted per mole of 2-methylacetanilide. During the chlorination, the 
reaction mixture is maintained at a temperature in the range of about 
50.degree. to 100.degree. C. The resulting 2-methylchloroacetanilides may 
then, without isolation or purification, be converted to the corresponding 
chloroindazoles. In a modification of this process, the 
2-methylchloroacetanilides are separated from the reaction mixture and 
purified, for example, by washing, by recrystallization from nitroethane, 
methanol, N,N-dimethylformamide, or a mixture of these solvents, by 
treatment with activated carbon, or by other conventional techniques. The 
purified 2-methylchloroacetanilides are then mixed with glacial acetic 
acid and acetic anhydride to form a reaction mixture to which sodium 
nitrite is added to effect nitrosation and ring closure. 
The substituted indazoles that are prepared by the process of this 
invention are useful as intermediates in the preparation of preservatives, 
dyestuffs, and pharmaceuticals. For example, they can be reacted with 
formaldehyde or a formaldehyde-yielding substance to form the 
corresponding N'-hydroxymethylindazoles, which are useful as bactericides, 
fungicides, and pesticides. The use of N'-hydroxymethyl-substituted 
indazoles as preservatives for latex paints and other aqueous compositions 
that are subject to deterioration resulting from bacterial action is 
disclosed in U.S. Pat. No. 3,814,714.

The invention is illustrated by the following examples. 
EXAMPLE 1 
A. To a mixture of 321 grams (3.00 moles) of orthotoluidine and 1800 grams 
of glacial acetic acid was added 330 grams (3.24 moles) of acetic 
anhydride over a period of 15 minutes during which the temperature was 
maintained at 50.degree.-60.degree. C. The mixture was heated at 
70.degree.-75.degree. C. for 15 minutes and then maintained at this 
temperature while chlorine was bubbled through it at the rate of about 120 
grams per hour. The chlorination was continued for 3.5 hours during which 
time about 2.0 gram atoms of chlorine reacted per mole of o-toluidine. The 
chlorinated reaction mixture was distilled at 50 mm. to a pot temperature 
of 80.degree. C. About 1800 grams of acetic acid was recovered. 
The residue was dissolved in 2000 grams of nitroethane at 
90.degree.-95.degree. C., cooled with stirring to 10.degree.-15.degree. C. 
in 2 hours, filtered, and washed with 800 grams of cold 
(0.degree.-5.degree. C.) methanol. The product was air-dried to constant 
weight. There was obtained 458 grams of a mixture of 
methylchloroacetanilides, a white crystalline solid having the following 
composition as determined by gas chromatography: 
2-Methyl-6-chloroacetanilide: 1.8% 
2-Methyl-4,6-dichloroacetanilide: 79.3% 
2-Methyltrichloroacetanilides (2 isomers): 14.2% 
By-products: 4.7% 
B. A 155 gram portion of this product was dissolved in a mixture of 1000 
grams of methanol and 50 grams of N,N-dimethylformamide. The resulting 
solution was passed through a column containing 129 grams of activated 
carbon. The clear carbon-treated liquid was evaporated to a volume of 
about 100 ml. and then poured into 1 liter of water. The white solid that 
precipitated was collected and air-dried. There was obtained 129 grams of 
a product that contained the following components: 
2-Methyl-6-chloroacetanilide: 1.1% 
2-Methyl-4,6-dichloroacetanilide: 81.4% 
2-Methyltrichloroacetanilides (2 isomers): 17.2% 
By-products: 0.3% 
When this product was recrystallized from nitroethane, there was obtained 
98.4 grams of a product that contained the following components: 
2-Methyl-6-chloroacetanilide: 0.4% 
2-Methyl-4,6-dichloroacetanilide: 85.9% 
2-Methyltrichloroacetanilides (2 isomers): 13.1% 
By-products: 0.6% 
C. To a mixture of 200 grams of glacial acetic acid and 16.0 grams (0.157 
mole) of acetic anhydride was added a 34.0 gram portion of the 
aforementioned mixture of 2-methylchloroacetanilides, which contained 
85.9% (0.134 mole) of 2-methyl-4,6-dichloroacetanilide. The resulting 
solution was heated at 90.degree.-95.degree. C. for about 2 hours while 
13.0 grams (0.188 mole) of solid sodium nitrite was added to it 
portionwise. During the addition of the sodium nitrite, the acidity of the 
reaction mixture was monitored by means of a Beckman Zeromatic SS-3 pH 
Meter equipped with a Beckman 39013 probe combination electrode filled 
with 4M potassium chloride saturated with silver chloride, which was 
inserted into the reaction mixture. As the sodium nitrite was added, the 
+MV potential, which was initially below 300 mv., rose rapidly to about 
400 mv. and was maintained between 420 mv. and 440 mv. by the addition of 
small amounts of a 50/50 (wt. wt.) mixture of 100% sulfuric acid and 
glacial acetic acid. The dark amber reaction product was heated at 50 mm. 
to 80.degree. C. to recover 215 grams of acetic acid. The residue was 
poured into 250 grams of water; the slurry that formed was stirred at 
70.degree. C.-80.degree. C. for a few minutes, cooled to 
20.degree.-25.degree. C., and filtered. The product was washed with water 
and then treated with 500 grams of 5% sodium hydroxide solution at 
90.degree.-95.degree. C. The resulting mixture was filtered and acidified 
to pH 2 with hydrochloric acid. The slurry that formed was cooled to 
20.degree.-25.degree. C. and then filtered. After washing with water and 
air-drying at 60.degree.-70.degree. C., 25 grams of a chlorinated indazole 
product was obtained. Gas chromatographic analysis of the corresponding 
trimethylsilyl derivatives indicated that the product contained the 
following components: 
7-chloroindazole: 0.8% 
5,7-dichloroindazole: 77.7% 
Trichloroindazoles (2 isomers): 10.3% 
By-products: 11.2% 
The yield of 5,7-dichloroindazole from 2-methyl-4,6-dichloroacetanilide was 
78.7% 
To 15 grams of the product were added 80 grams of methanol, 8 grams of 
water, and 5 grams of sodium hydrosulfite. This mixture was heated at 
reflux temperature (69.degree.-70.degree. C.) for 1 hours, and then 400 
grams of water was added to it. The product, which was isolated by 
filtration, was washed with water, air-dried, and reslurried in a mixture 
of 180 grams of methanol and 34 grams of 37% hydrochloric acid. This 
slurry was diluted with 500 grams of water, cooled to 
20.degree.-25.degree. C., and filtered. The product, after washing with 
water and drying at 70.degree.-80.degree. C., weighed 14.4 grams and 
contained the following components: 
7-chloroindazole: 0.7% 
5,7-dichloroindazole: 85.8% 
Trichloroindazoles (2 isomers): 11.4% 
By-products: 2.1% 
EXAMPLE 2 
To a mixture of 28.3 grams (0.20 mole) of 2-methyl-6-chloroaniline and 150 
grams of glacial acetic acid was added 41 grams (0.40 mole) of acetic 
anhydride over a period of 15 minutes during which the temperature of the 
reaction mixture was maintained at 50.degree.-60.degree. C. The amount of 
acetic anhydride added was that required for the acetylation of the 
2-methyl-6-chloroaniline plus that required for the removal of water of 
reaction in the subsequent nitrosation step. 
To the reaction mixture, which had been heated at 70.degree.-75.degree. C. 
for 15 minutes, was added 17.4 grams (0.25 mole) of solid sodium nitrite 
over a period of 90 minutes while the temperature was maintained at 
90.degree.-95.degree. C. During the addition of the sodium nitrite, the 
+MV potential of the reaction mixture as measured by the pH meter 
described in Example 1 rose from 275 mv. to 330 mv. The reaction mixture 
was heated at 50 mm. to 80.degree. C. to remove acetic acid from it and 
then poured into water. The resulting slurry was stirred at 
70.degree.-80.degree. C. for a few minutes, cooled to 
20.degree.-25.degree. C., and filtered. The product was washed with water 
and then treated with 5% sodium hydroxide solution at 
90.degree.-95.degree. C. The resulting mixture was acidified to pH 0.5; 
after removal of insoluble tarry material, the pH of the mixture was 
brought to 4. The precipitated product was collected, washed with water, 
and dried. There was obtained 23.4 grams of an amber-colored solid that 
contained 93.5% of 7-chloroindazole and 6.5% of reaction by-products. 
The yield of 7-chloroindazole from 2-methyl-6-chloroaniline was 76.6%. 
EXAMPLE 3 
A. A mixture of 100 grams of the product of Example 1A, which contained 
79.3% of 2-methyl-4,6-dichloroacetanilide, with 500 grams of glacial 
acetic acid and 1 gram of iodine was stirred at 85.degree.-90.degree. C. 
for 8 hours while a total of 330 grams (4.65 moles) of chlorine was 
bubbled through it. 
The chlorinated reaction mixture was sparged with dry air for a few 
minutes. Then 10 grams of sodium hypophosphite monohydrate was added to 
it. The resulting mixture was heated with stirring at 
65.degree.-70.degree. C. for 2 hours to reduce the by-products that 
contained labile chlorine; it was then distilled at 50 mm. to a pot 
temperature of 80.degree. C. to remove 475 grams of acetic acid. The 
residue was stirred with 300 grams of methanol at 60.degree.-70.degree. C. 
for 15 minutes, cooled to 10.degree.-15.degree. C., and filtered. The 
product was washed free of color with cold methanol, triturated with 
water, filtered, and washed with water. After air-drying, 71.6 grams of a 
white solid product was obtained that contained the following components: 
2-Methyl-4,6-dichloroacetanilide: 5.3% 
2-Methyl-3,4,6-trichloroacetanilide: 61.3% 
2-Methyl-4,5,6-trichloroacetanilide: 24.2% 
By-products: 9.2% 
B. A mixture of 25.3 grams of the product of Ex. 3A, which contained a 
total of 85.5% of 2-methyltrichloroacetanilides, with 150 grams of glacial 
acetic acid and 11 grams of acetic anhydride was treated with 8.7 grams of 
sodium nitrite at 90.degree.-95.degree. C. During the addition of the 
sodium nitrite, the +MV potential as measured by the pH meter described in 
Example 1 rose rapidly to 410 mv. The crude product isolated after removal 
of acetic acid and drowning with water was a light buff-colored solid that 
weighed 21 grams and that contained the following components: 
5,7-dichloroindazole: 2.9% 
4,5,7-trichloroindazole: 35.5% 
5,6,7-trichloroindazole: 15.6% 
By-products: 46.0% 
Treatment with aqueous sodium hydroxide of 18.3 grams of this crude product 
by the procedure described in Example 1C yielded 8.0 grams of an upgraded 
product that contained the following components: 
5,7-dichloroindazole: 3.7% 
4,5,7-trichloroindazole: 57.0% 
5,6,7-trichloroindazole: 23.7% 
By-products: 15.6% 
EXAMPLE 4 
The acetylation/chlorination of o-toluidine was carried out by the 
procedure described in Example 1A until 2.22 gram atoms of chlorine had 
reacted per mole of o-toluidine. The reaction product was shown by gas 
chromatography to have the following composition: 
2-Methyl-6-chloroacetanilide: 2.9% 
2-Methyl-4,6-dichloroacetanilide: 63.5% 
2-Methyl-3,4,6-trichloroacetanilide: 15.6% 
2-Methyl-4,5,6-trichloroacetanilide: 11.6% 
By-products: 6.4% 
An aliquot of this product that corresponded to 0.53 mole of o-toluidine 
was mixed with 340 grams of glacial acetic acid and 52.7 grams of acetic 
anhydride, and the mixture was stirred at 70.degree.-75.degree. C. for 1 
hour with 2.2 grams of sodium hypophosphite monohydrate to reduce 
by-products containing labile chlorine. The product obtained contained the 
following components: 
2-Methyl-6-chloroacetanilide: 3.7% 
2-Methyl-4,6-dichloroacetanilide: 64.7% 
2-Methyl-3,4,6-trichloroacetanilide: 15.6% 
2-Methyl-4,5,6-trichloroacetanilide: 12.9% 
By-products: 3.1% 
This product was treated with 47 grams (0.68 mole) of sodium nitrite at 
90.degree.-95.degree. C. by the procedure described in Ex. 1C. During the 
addition of the sodium nitrite, the +MV potential rose from 155 mv. to 360 
mv. The product was purified by extraction with alkali and then treatment 
with sodium hydrosulfite by the procedures described in Ex. 1C. The yield 
and distribution of components in the alkali-treated product and in the 
subsequently-obtained hydrosulfite-treated product were as follows: 
______________________________________ 
Alkali- Hydrosulfite- 
Extracted treated 
Product Product 
______________________________________ 
Yield 60.4% 59.1% 
Distribution of Components 
7-Chloroindazole 1.6 0.5 
5,7-Dichloroindazole 
58.5 64.8 
4,5,7-Trichloroindazole 
11.8 13.4 
5,6,7-Trichloroindazole 
9.0 10.1 
By-products 19.1 11.2 
______________________________________ 
EXAMPLE 5 
A mixture of 30.4 grams (0.20 mole) of 2-methyl-4-nitroaniline, 150 grams 
of glacial acetic acid, and 41 grams (0.40 mole) of acetic anhydride was 
treated with 17.3 grams (0.25 mole) of sodium nitrite by the procedure 
described in Example 1C. During the addition of sodium nitrite, the +MV 
potential, which was originally 270 mv., rose rapidly to 430 mv. After it 
had been purified by treatment with 5% sodium hydroxide solution by the 
procedure described in Example 1C, the product, which was an amber-colored 
solid that weighed 22.7 grams, was found by gas chromatographic analysis 
to contain 89.3% of 5-nitroindazole and 11.7% of reaction by-products. The 
yield of 5-nitroindazole was 62.1%. 
EXAMPLE 6 
The conversion of 2-methyl-5-nitroaniline to 6-nitroindazole was carried 
out by the procedure described in Example 5. There was obtained a 96.1% 
yield of a product that contained 97.8% of 6-nitroindazole. 
EXAMPLE 7 
The conversion of 2-methyl-6-nitroaniline to 7-nitroindazole was carried 
out by the procedure described in Example 5. The product obtained 
contained 61.8% of 7-nitroindazole. 
Each of the other substituted indazoles disclosed herein can be prepared 
similarly by the reaction of the appropriate 2-methylacetanilide with 
sodium nitrite in the presence of an alkanoic acid having 2 to 4 carbon 
atoms and a dehydrating agent at a temperature above 50.degree. C.