Process for the preparation of 3,4-dialkoxyanilines

A new process for the production of 3,4-dialkoxyanilines in which the two alkyl groups are different from each other is disclosed. The process comprises the stepwise introduction of the alkyl groups in different stages of the process by converting pyrocatechol into its monoalkyl ether, coupling said monoalkyl ether with a phenyldiazonium salt, alkylating the 3-alkoxy-4-hydroxy-azobenzene obtained to form 3,4-dialkoxyazobenzene and reductively cleaving the latter to the corresponding 3,4-dialkoxyaniline. The 3,4-dialkoxyanilines obtainable by the new process are valuable intermediates for the preparation of 4-hydroxy-6,7-dialkoxy-3-quinoline carboxylic acid esters which are excellent coccidiostats.

The present invention relates to a process for the production of 
3,4-dialkoxyanilines of formula I 
##STR1## 
wherein (a) R.sub.1 and R.sub.2 are different from each other and each of 
R.sub.1 and R.sub.2 represents a member of the group consisting of C.sub.1 
-C.sub.20 alkyl and C.sub.3 -C.sub.6 cycloalkyl C.sub.1 -C.sub.4 alkyl (b) 
or R.sub.1 is a C.sub.1 -C.sub.4 alkyl group and R.sub.2 is a C.sub.8 
-C.sub.10 alkyl group. 
Among the compounds of formula I those are preferred wherein one of the 
groups R.sub.1 and R.sub.2 is a C.sub.8 -C.sub.16 alkyl group while the 
other is a C.sub.3 -C.sub.6 cycloalkyl C.sub.1 -C.sub.4 alkyl group. Other 
preferred compounds of formula I are those wherein R.sub.1 is a C.sub.1 
-C.sub.4 alkyl group and R.sub.2 is a C.sub.8 -C.sub.10 alkyl group. The 
specific preferred compounds of formula I are 
3-n-decyloxy-4-cyclopropylmethoxyaniline and 3-ethoxy-4-n-decyloxyaniline. 
Compounds of formula I are valuable intermediates for the preparation of 
4-hydroxy-6,7-dialkoxy-3-quinoline carboxylic acid esters of the formula 
##STR2## 
wherein R is a lower alkyl group and R.sub.1 and R.sub.2 have the meaning 
given above. These compounds are excellent coccidiostats. In this 
connection reference is made to U.S. Pat. Nos. 3,485,845 and 3,496,184 
wherein such compounds, their preparation and their coccidiostatic action 
is described in detail. 
According to a method described in U.S. pat. No. 3,485,845 
3,4-dialkoxyanilines of formula I are prepared by converting pyrocatechol 
into its dialkylether, introducing a nitro group into the 4-position, 
selectively hydrolysing the 1-alkoxy group of the 
1,2-dialkoxy-4-nitrobenzene formed to obtain 
3-alkoxy-4-hydroxy-nitrobenzene which is realkylated and subsequently 
reduced to obtain the desired 3,4-dialkoxyaniline containing different 
alkyl groups from pyrocatechol in a five step process. 
According to a further method described in U.S. Pat. No. 3,485,845 
3,4-dialkoxyanilines of formula I are prepared by alkylating the 
monosodium salt of 4-nitro-pyrocatechol to obtain a 
2-alkoxy-5-nitro-phenol which is converted in a further alkylation step 
into a 3,4-dialkoxy-nitrobenzene which in turn is reduced to form the 
desired 3,4-dialkoxyaniline formula I. Since the 4-nitro pyrocatechol used 
as starting material has to be prepared by bis-alkylation or bis-acylation 
of pyrocatechol, nitration of the pyrocatechol diether or diester obtained 
and subsequent hydrolysis of the 4-nitropyrocatechol diether or diester 
the 3,4-dialkoxyanilines of formula I are obtained from pyrocatechol in a 
six step process. Further, according to a method described in U.S. Pat. 
No. 3,496,184 the 3,4-dialkoxyanilines of formula I can be prepared by 
monoalkylation of pyrocatechol followed by acylation, for example with 
benzoylchloride, to form a 2-alkoxy-phenlyester, subsequent nitration of 
said 2-alkoxy-phenylester to form a 2-alkoxy-5-nitro-phenyl ester, 
hydrolysis of the latter to obtain a 3-hydroxy-4-alkoxy-nitrobenzene which 
is alkylated to form a 3,4-dialkoxynitrobenzene which is reduced to the 
desired 3,4-dialkoxyanilines. According to this method the 
3,4-dialkoxyanilines of formula can be obtaned in a six step process. 
The methods known from the prior art referred to above are disadvantageous 
in several respects. Thus, known processes are very complicated because a 
large number of steps is necessary to produce the desired products. The 
large number of reaction steps detrimentally affects the yield of the 
final products. This is particularly true with respect to the nitration 
which is involved in each of the known methods. 
Therefore, it is the object of the present invention to avoid the 
disadvantages inherent to the prior art methods and to provide a 
simplified process according to which the intermediates of formula I can 
be obtained in better yields than in the known processes while the number 
of reaction steps is reduced. According to the present invention the 
3,4-dialkoxyanilines of formula I are produced by reacting pyrocatechol 
with a reactive ester of an alcohol derived from the group R.sub.1 as 
defined above, to form the monoalkyl ether of the formula II 
##STR3## 
which is reacted with a phenyl diazonium salt to give an azobenzene of 
formula III 
##STR4## 
which is reacted with a reactive ester of an alcohol derived from the 
group R.sub.2, as defined above to form a 3,4-dialkoxyazobenzene of 
formula IV 
##STR5## 
and this 3,4-dialkoxy azobenzene is then reductively split to a 
3,4-dialkoxyaniline of formula I. 
The conversion of pyrocatechol into its monoalkyl ether of formula II can 
advantageously be performed according to methods described in Houben-Weyl 
VI 13, p. 49 and following, J. Am. Chem. Soc. 54 (1932) 298-305, dt. 54 
(1932) p. 1204 and following, J. Chem. Soc. Japan 72 (1952) p. 546 and 
following. 
According to a preferred embodiment, pyrocatechol is reacted with a 
compound of formula R.sub.1 X, by which is meant corresponding halides, 
sulphuric acid esters and sulphonic acid esters, in the presence of a 
base, in a solvent or diluent inert to the reactants. Suitable bases are 
preferably; hydrides, carbonates, oxides, hydroxides or alcoholates of 
alkali metals and alkaline-earth metals. Used as solvents or diluents 
inert to the reactants are, for example: water, lower and higher 
alocohols, lower and higher ketones, open-chain and cyclic ethers or 
aromatic hydrocarbons. For the preparation of pyrocatechol monoalkylethers 
of formula II, it is advantageous to operate with an excess of 
pyrocatechol exceeding the molar ratio of 1:1, this can be recovered by 
suitable methods after the reaction. It is advantageous to employ a molar 
ratio of 2:1 to 4:1. Pyrocatecholmonoalkyl ethers of formula II are then 
reacted with a suitable diazonium salt to obtain azobenzenes of formula 
III. The substituent "phenyl" in formula III is merely given as an example 
of the preferably used aniline; it is of course possible to use also 
diazonium salts of substituted anilines, such as, e.g. of toluidine, of 
sulphanilic acid, etc.. Suitable phenyldiazonium salts are essentially all 
diazonium salts capable of coupling which are known from the literature. 
Especially suitable are diazonium salts of which the coupling products 
offer preparative advantages in the carrying out of the overall synthesis 
according to the invention. These advantages can be that few or no 
by-products are formed; that the reaction products can be easily isolated, 
e.g. by virtue of their difficult solubility in the employed solvent; or 
that, after reductive splitting, readily separable phenylamines are 
formed. Water is most suitable as the reaction medium; but also organic 
solvents may be used. If water is employed, then it is advantageous to 
operate in the neutral to alkaline pH-range. The reaction temperature is 
between -20.degree. and +50.degree. C, preferably between -10.degree. and 
10.degree. C. The most favourable molar ratio of the reactants is 1:1; 
however, deviations of up to 20 mol-% can also lead to good results being 
obtained. In the course of the overall synthesis according to the 
invention, it is possible, and, depending on the consequent reaction, in 
certain cases advantageous to continue processing the reaction mixture 
from the coupling reaction without further preparation; the reaction 
products, however, can also be separated and purified, e.g. by 
crystallisation or chromatography. The alkylation of the azobenzenes of 
formula III is performed by reacting said azobenzenes with a compound of 
the formula R.sub.2 X by which is meant corresponding halides, sulphuric 
acid esters and sulphonic acid esters, in the presence of a base, in a 
solvent or diluent inert to the reactants. Suitable bases are preferably 
hydrides, carbonates oxides, hydroxides or carbonates of alkali metals and 
alkaline-earth metals. As solvents or diluents inert to the reactants for 
example water, lower and higher alcohols, lower and higher ketones, 
open-chain and cyclic ethers, aromatic hydrocarbons or 
N,N-dialkylformamide, particularly N,N-dimethyl formamide, may be used. 
The reductive splitting of the azobenzenes of formula III to the 
corresponding anilines of formula IV is advantageously performed according 
to the method described in Houben-Weyl XI/1, from p. 522. Suitable 
reducing agents are the usually employed reagents, such as sodium 
dithionite, hydrogen sulphide and salts thereof, sodium bisulphite zinc or 
tin (II) chloride; however, the reductive splitting is advantageously 
perform with catalytically activated hydrogen at normal pressure or at 
elevated pressure. Hydrogenation catalysts may be, for example: 
Raney-nickel, palladium or platinum, optionally on suitable carriers. 
Suitable reaction media are, e.g. water, alcohols, dioxane, pyridine, 
dimethylformamide and methylcellosolve. The temperatures are 
advantageously between 0.degree. and 50.degree. C. 
The working up of the reaction mixture consists essentially in the 
separation and, optionally, recovery of the arylamine occurring as 
by-product in the course of the hydrogenating splitting. Separation of 
arylamine can be effected by distillation (for example, as azeotropic 
distillation), extraction, fractional crystallisation or chromatography. 
After separation of the by-products, the further processing of the 
reaction product can be performed directly without further purification, 
optionally with use of the solvent system used for the reduction process, 
or, alternatively, purificaton of the products by crystallisation, 
dissolving and reprecipitation, distillation or chromatography can be 
carried out. 
The 3,4-dialkoxy anilines of formula I can be further converted into 
4-hydroxy-6,7-dialkoxy-3-quinoline carboxylic acid esters according to 
method described in U.S. Pat. Nos. 3,485,845 and 3,496,184. For this 
purpose the 3,4-dialkoxyanilines of formula I are first reacted with an 
alkoxymethylenemalonic acid-dialkyl ester to form a 
3,4-dialkoxy-anilinomethylenemalonic acid-dialkylester, which is 
subsequently thermally cyclised to a 4-hydroxy-6,7-dialkoxy-3-quinoline 
carboxylic acid ester. 
According to the present invention the 3,4-dialkoxyanilines of formula I 
can be obtained in a process which is considerably less complicated than 
the previously known processes while the yield of 3,4-dialkoxyanilines of 
formula I is significantly increased. Thus, according to the present 
invention the 3,4-dialkoxyanilines of formula I are obtained from 
pyrocatechol an starting material in a four step process whereas five and 
six reaction steps are necessary to produce the same compounds according 
to known methods. 
Further, the 3,4-dialkoxyanilines of formula I are obtained according to 
the invention in a yield of about 70% or more of the theoretical amount 
calculated on pyrocatechol whereas according to a known method comprising 
dibenzoylation of pyrocatechol, nitration of the pyrocatechol dibenzoate, 
hydrolysis 4-nitropyrocatechol dibenzoate, successive introduction of 
alkyl groups R.sub.1 and R.sub.2 into 4-nitropyrocatechol and reduction of 
3,4-dialkoxy-nitrobenzene the 3,4dialkoxyanilines of formula I are 
obtained in a yield of less than 50% of the theoretical amount calculated 
on pyrocatechol.

The following examples serve to illustrate the process according to the 
invention. Temperature values are expressed in degrees centigrade. 
EXAMPLE 1 
a. 165 g of pyrocatechol in 400 ml of ethanol is heated with 78 g of 
ethyliodide under nitrogen to the reflux temperature, and an addition is 
made in the course of three hours of a solution of 33 g of potassium 
hydroxide in 70 ml of water. After 5 hours heating at reflux temperature, 
the reaction mixture is concentrated to dryness. After addition of a 
solution of 50 g potassium hydroxide in 70 ml of water the mixture is 
steam distilled in order to remove pyrocatechol diethyl ether formed as 
by-product and unreacted ethyliodide. Than the resulting aqueous solution 
is slightly acidified with 6N hydrochloric acid, and again 
steam-distilled. The crude pyrocatechol monoethyl ether obtained is 
separated from the aqueous layer, dried and distilled in vacuo. Yield 55 
g, b.p. 68.degree. C / 4 Torr. 
b. 105 g of aniline is dissolved in 290 ml of conc. hydrochloric acid and 
350 ml of water, and the solution is cooled to 0.degree. to 5.degree.. At 
this temperature, an addition is made dropwise, with stirring, of a 
solution of 84 g of sodium nitrite in 250 ml of water. After 10 minutes' 
stirring at 0.degree. to 5.degree., the diazonium salt solution is 
rendered neutral with 105 g of sodium bicarbonate, and 48 g of sodium 
acetate (anhydrous) is added. This solution is added dropwise, with 
stirring, to a solution, cooled to 0.degree. to 5.degree., of 138 g of 
2-ethoxy-phenol in 4300 ml of ethanol, with the temperature being 
maintained at 0.degree. to 5.degree.. After four hours' stirring at this 
temperature the greater part of ethanol becomes distilled off. After 
stirring of the residue with 2000 ml of water, the product is taken up in 
chloroform. The chloroform layer is subsequently washed with water, dried 
by means of magnesium sulphate and concentrated by evaporation. There is 
obtained 3-ethoxy-4-hydroxy-azobenzene, which, as liquid crude product, is 
used in the next reaction stage. 
c. 24.2 g of 3-ethoxy-4-hydroxy-azobenzene is heated with 4 g of sodium 
hydroxide (pulverised) and 500 ml of toluene on a water separator until 
anhydrous solvent distills off. To the reaction mixture are then added 100 
ml of dimethylformamide (anhydrous) and 0.5 g of sodium iodide, and the 
toluene is removed by distillation (internal temperature 130.degree.). 
After cooling to 80.degree., 25 g of n-decylbromide is added dropwise, and 
the mixture is subsequently refluxed for 2 hours. After the mixture has 
cooled to room temperature, water is added and the whole is repeatedly 
extracted with toluene. The combined toluene extracts are dried over 
magnesium sulphate; the solvent is distilled off, and the residue, 
3-ethoxy-4-n-decyloxyazobenzene, is taken up, without further 
purification, in 400 ml of ethanol. 5 g of Raney nickel is added, and 
hydrogenation is performed at normal pressure until the absorption of 
hydrogen ceases. After removal of the catalyst, the filtrate is 
concentrated by evaporation and, after fractional distillation, there is 
obtained 3-ethoxy-4-n-decyloxy-aniline, B.P. 188.degree./ 0.005 Torr. 
EXAMPLE 2 
a. 165 g of pyrocatechol in 400 ml of ethanol is heated with 110.6 g of 
n-decylbromide under nitrogen to the reflux temperature, and an addition 
is made in the course of one hour of a solution of 33 g of potassium 
hydroxide in 70 ml of water. After about 20 hours' heating at reflux 
temperature, the reaction mixture is concentrated to dryness. The residue 
is taken up in water, slightly acidified with concentrated hydrochloric 
acid, and repeatedly extracted with chloroform. After drying and 
distillation of the extract, the residue is fractionated; the resulting 
2-n-decyloxyphenol has the boiling point 124.degree. to 129.degree. / 0.15 
torr. 
b. 21 g of ailine is dissolved, in a beaker, in 58 ml of concentrated 
hydrochloric acid and 70 ml of water, and the solution is cooled to 
0.degree. to 5.degree.. An addition is made dropwise at this temperature 
of a solution of 16.8 g of sodium nitrite in 50 ml of water, with stirring 
being maintained. After 10 minutes' stirring at 0.degree. to 5.degree., 
the diazonium salt solution is rendered neutral with 21 g of sodium 
bicarbonate, and 9.6 g of sodium acetate (anhydrous) is added. This 
solution is added dropwise with stirring, to the solution, cooled to 
0.degree. to 5.degree., of 50 g of 2-n-decyloxyphenol in 860 ml of 
ethanol, with the temperature being kept at 0.degree. to 5.degree.. After 
4 hours' stirring at this temperature, 500 ml of water is added. The 
product is taken up in chloroform; the chloroform layer is subsequently 
washed with water, and dried with magnesium sulphate. After concentration 
by evaporation, there remains crude 3-n-decyloxy-4-hydroxy-azobenzene 
(M.P.: 40.degree. to 45.degree.). 
c. A suspension of 35.4 g of 3-n-decyloxy-4-hydroxyazobenzene and 4 g of 
pulverised sodium hydroxide in 500 ml of toluene is heated on a water 
separator until pure toluene distills over. To the mixture there are then 
added 100 ml of dimethylformamide (anhydrous) and 0.5 g of sodium iodide. 
The toluene is removed by distillation from the reaction mixture (internal 
temperature 130.degree.). At 80.degree. there is subsequently added 11 g 
of cyclopropylmethyl chloride whilst stirring is maintained. After slow 
heating to 120.degree.-125.degree., the mixture is allowed to stand for 2 
hours at this temperature. The mixture is then cooled; 300 ml of water is 
added and the whole is repeatedly extracted with toluene. The combined 
toluene extracts are dried with magnesium sulphate, and the toluene is 
distilled off. After recrystallisation from ethanol, there is obtained 
3-n-decyloxy-4-cyclopropylmethoxyazobenzene, M.P. 58.degree.-60.degree.. 
d. 400 ml of 2N sodium hydroxide solution and a 3% aqueous sodium 
hyposulphite solution are added to the mixture, heated to 80.degree., 
consisting of 40.8 g of 3-n-decyloxy-4-cyclopropylmethoxy-azobenzene in 
2500 ml of ethanol. The reaction mixture must be vigorously stirred in 
order to prevent the formation of two layers. After decolorisation of the 
reaction mixture, the ethanol is distilled off, and the remaining solution 
is repeatedly extracted with chloroform. The extracts are dried by means 
of sodium sulphate, the chloroform is distilled off and the residue is 
distilled. The resulting 3-n-decyloxy-4-cyclopropylmethoxy-aniline has the 
boiling point 183.degree./0.003. 
EXAMPLE 3 
a. A mixture of 42 g of sulphanilic acid dihydrate, 26.5 g of anhydrous 
sodium carbonate and 200 ml of water is heated until everything has 
dissolved, and then cooled to 15.degree.. A solution of 14.8 g of sodium 
nitrite in 40 ml of water is then added, and the whole reaction mixture is 
poured into a mixture of 42.5 ml of concentrated hydrochloric acid and 250 
g of ice. 50 g of 2-n-decyloxy-phenol (prepared according to Example 2a) 
is suspended in a warm solution of 44 g of sodium hydroxide in 240 ml of 
water; the suspension is stirred for one hour and cooled to 5.degree. by 
the addition of ice. There is then added, with stirring, the previously 
prepared sulphanilic acid/diazonium salt suspension; stirring is 
maintained for a further one to two hours at 20.degree.-30.degree., and 
the mixture is acidified with 80 ml of concentrated hydrochloric acid. 
After 20 minutes' stirring, filtration is performed and the precipitate is 
dried at 80.degree.. The result is crude 
3-n-decyloxy-4-hydroxy-azobenzene-4'-sulphonic acid sodium salt, which is 
used without further purification in the next reaction stage. 
b. 46 g of crude 3-n-decyloxy-4-hydroxy-azobenzene-4'-sulphonic acid sodium 
salt is heated with 4 g of powdered sodium hydroxide and 500 ml of toluene 
on a water separator until anhydrous solvent distills over. To the 
reaction mixture are then added 100 ml of dimethylformamide (anhydrous) 
and 0.5 g of sodium iodide, and the toluene is removed by distillation 
(internal temperature 130.degree.). After the mixture has cooled to 
80.degree., 11 g of cyclopropylmethyl chloride is added. The reaction 
temperature is now raised within one hour to 120.degree.-125.degree. and 
held there for a further 2 hours. After cooling, the mixture is acidified 
with conc. hydrochloric acid; it is then filtered to obtain, after 
recrystallisation of the residue from 80% ethanol, 
3-n-decyloxy-4-cyclopropylmethoxy-azobenzene-4'-sulphonic acid sodium 
salt. 
c. 26 g of 3-n-decyloxy-4-cyclopropylmethoxy-azobenzene-4'-sulphonic acid 
sodium salt is dissolved in 500 ml of methylcellosolve, and the solution, 
after addition of 6 g of Raney nickel, is hydrogenated at 20.degree. to 
40.degree. under normal pressure, until the absorption of hydrogen ceases. 
Filtration is performed, the filtrate is concentrated by evaporation, the 
residue is treated with 2N sodium hydroxide solution and extracted with 
chloroform. The organic phases are dried with sodium sulphate, 
concentrated by evaporation and the residue is distilled. The resulting 
product is 3-n-decyloxy-4-cyclopropyl-methoxy-aniline, B.P. 185.degree. C 
/ 0.003 Torr.