Process for the preparation of 2-nitro-3-aminopyridine, and the intermediates which are formed in the reaction

2-Nitro-3-aminopyridine is prepared by PA0 (a) reacting 3-aminopyridine with phosgen COCl.sub.2 or urea H.sub.2 NCONH.sub.2 to give N,N'-di-(3-pyridyl)-urea, PA0 (b) nitrating and N,N'-di-(3-pyridyl)-urea with nitric acid or with a mixture of nitric acid and sulfuric acid to give N,N'-di-(2-nitor-3-pyridyl)-urea, and PA0 (c) hydrolyzing said N,N'-di-(2-nitro-3-pyridyl)-urea to give 2-nitro-3-amino-pyridine. N,N'-di-(3-pyridyl)-urea and N,N'-di-(2-nitro-3-pyridyl)-urea, which are formed in the course of the reaction as intermediates are new compounds. The end product of the process, 2-nitro-3-aminonpyridine, is an intermediate in various specialized fields.

2-Nitro-3-aminopyridine is the compound of the formula 
##STR1## 
It is principally a valuable intermediate in various specialized fields, 
such as the pharmaceutical, dyestuff and plant protection sector. Thus, 
for example, 2-nitro-3-aminoalkylaminopyridines which can be employed in 
the pharmaceutical sector for combating amebic infections (German Patent 
No. A-2,334,401) are obtained by reacting 2-nitro-3-aminopyridine with 
aminoalkyl halides. 
2-Nitro-3-aminopyridine is not obtainable, or, if so, only in traces, by 
the direct nitration of 3-aminopyridine, which is readily accessible--for 
example by Hofmann's degradation of nicotinamide--and is also commercially 
available; this is scarcely surprising because of the known sensitivity of 
the (unprotected) amino group toward nitrating agents--which have usually 
also an oxidizing action. 
If, therefore--following the article by J. W. Clark-Lewis and M. J. 
Thompson in J. Chem. Soc. (London) 1957, pages 442 to 446, in particular 
pages 445/446 -3-ethoxycarbonyl-aminopyridine is used as the starting 
material, the nitration is stated to take place in a yield up to 65%, if, 
and only if, the nitration is carried out in small batches, since the 
nitro compound formed is not stable under the conditions applied and tends 
to explosion in larger batches. The 2-nitro-3-ethoxycarbonylaminopyridine 
formed in the reaction then affords the desired 2-nitro-3-aminopyridine by 
alkaline hydrolysis; the yield quoted for the hydrolysis stage is 86%. 
Relative to the 3-ethoxycarbonylaminopyridine, the yield is thus about 
56%. 
In outline, the equations on which this reaction is based are as follows: 
##STR2## 
Following the literature reference mentioned above, the starting material 
for this reaction (3-ethoxycarbonylaminopyridine) is obtained, starting 
from nicotinic acid, by the following reaction sequence: 
##STR3## 
The introduction of other protective groups for the amino group has--as our 
own experiments have shown--proved unsuitable, since in some cases 
decomposition takes place in the course of the nitration (as in the 
reaction according to J. W. Clark-Lewis and M. J. Thompson, loc. cit.); in 
some cases the nitro group enters a position in the pyridine ring other 
than the desired 2-position. The protective groups and classes of 
protective groups tested were as follows: 
##STR4## 
In the purely aromatic (not heterocyclic) series, disclosure has also been 
made of the nitration of an aniline derivative (2-methoxyaniline) which 
has been converted into a urea derivative (bis-2-methoxyphenylurea) before 
the nitration in order to protect the amino group. In this case the 
nitration took place in the 4-position. The reaction is published in 
Chemical Abstracts, Volume 49 (1955), 5341i to 5342b; the publication 
represents the abstract of a paper by D. F. Kutepov and Z. G. Vukolova, 
Zh. Obsc. Khim. 24, 698-792 (1954). 
In outline, the decisive reaction sequence here is as follows: 
##STR5## 
In the endeavour to provide an improved process for the preparation of 
2-nitro-3-aminopyridine, it has now been found that this object is 
achieved by the nitration and hydrolytic cleavage of 
N,N'-di-(3-pyridyl)-urea. 
The invention relates, therefore, to a process for the preparation of 
2-nitro-3-aminopyridine by 
(a) reacting 3-aminopyridine with phosgene COCl.sub.2 or urea H.sub.2 
NCONH.sub.2 to give N,N'-di-(3-pyridyl)-urea, 
(b) nitrating said N,N'-di(3-pyridyl)-urea with nitric acid or with a 
mixture of nitric acid and sulfuric acid to give 
N,N'-di-(2-nitro-3-pyridyl)-urea, and 
(c) hydrolyzing said N,N'-di-(2-nitro-3-pyridyl)-urea to give 
2-nitro-3-amino-pyridine. 
The process is based on the following reaction equations: 
##STR6## 
The reaction (a) of the process according to the invention is performed in 
a customary manner as for example, described for the reaction of 
2-aminopyridine with phosgene or urea in Beilstein H 22, 330, with a 
nearly quantitative yield. 
Reaction (b) of the process according to the invention--i.e. the nitration 
of the N,N'-di-(3-pyridyl)-urea--takes place safely, in a very readily 
controllable manner and extremely selectively only in the (desired) 
2-position in the pyridine ring and in high yields (consistently over 90% 
of theory). 
Reaction (c)--i.e. the hydrolysis of the 
N,N'-di-(2-nitro-3-pyridyl)-urea--also takes place in yields consistently 
over 90% of theory, so that the overall yield of the process is usually 
around or over 80% of theory, relative to the starting compound 
3-aminopyridine. 
In particular, the extremely selective and smooth nitration in general, and 
in particular in the 2-position, is very surprising, because as shown by 
our own tests mentioned earlier and described below, the nitration either 
leads to decomposition or proceeds in an undesired position, when the 
3-aminopyridine is protected by protective groups other than the urea 
group applied according to the present invention. 
The conversion of 3-aminopyridine into N,N'-di-(3-pyridyl)-urea is 
preferably performed analogous to the reaction of 2-aminopyridine with 
phosgene or urea as described in the before-mentioned Beilstein reference. 
For this purpose the 3-aminopyridine is heated with COCl.sub.2 or H.sub.2 
NCONH.sub.2 in a molar ratio of about 2:1, whereby minor deviations form 
the stoichiometric proportions are possible without impairing the 
reaction. The reaction can also be performed in inert organic solvents 
such as chlorobenzene, dichlorobenzenes, toluene and/or chlorotoluenes, 
etc. In the event of the reaction with COCl.sub.2, usual temperatures are 
between about 30.degree. and 120.degree. C., in the event of the reaction 
with H.sub.2 NCONH.sub.209 2 between about 120.degree. and 190.degree. C. 
Both reactions can be carried out under atmospheric pressure as well as 
under superatmospheric pressure; sub-atmospheric pressure is less 
advantageous. Superatmospheric pressure is particularly advisable when an 
inert organic solvent is used, the boiling point of which is below the 
reaction temperature. 
The nitration of the N,N'-di-(3-pyridyl)-urea is carried out in the manner 
customary for nitration reactions of this type by means of nitric acid, in 
the presence of sulfuric acid. For example, it is possible initially to 
take N,N'-di-(3-pyridyl)-urea in sulfuric acid or oleum and then to add 
nitric acid or a mixture of nitric and sulfuric acid (nitrating acid), or, 
for instance, also to introduce solid N,N'-di-(3-pyridyl)-urea into a 
previously taken mixture of nitric acid and sulfuric acid. 
The reaction temperature is not particularly critical in this process, but 
the temperature should not substantially exceed about 90.degree. C. for 
reasons of process safety and quality of the product. The reaction is 
preferably carried out at about 50.degree.-70.degree. C. 
The components N,N'-di-(3-pyridyl)-urea and HNO.sub.3 are preferably 
employed in a molar ratio of 0.5:about 1-2, in particular 0.5:about 
1.2-1.4. 
The N,N'-di-(2-nitro-3-pyridyl)-urea formed in the nitration can be 
isolated in a customary manner, for example by adding water to the 
reaction mixture when the reaction is complete and thus precipitating the 
desired product in a solid form, so that it can be obtained in a pure form 
by filtration or centrifuging. 
N,N'-di-(2-nitro-3-pyridyl)-urea is a new compound. 
In principle, the hydrolysis of the latter compound can be carried out in 
excess water; it is preferably, however, to add polar solvents, in 
particular alcohols. Acids or bases can be added to accelerate the 
reaction, as is known per se in the case of the hydrolysis of urea 
derivatives. In the present case, a preferred method of carrying out the 
hydrolysis is to effect it by means of inorganic bases (NaOH, KOH, 
NH.sub.3 etc.) in an aqueous C.sub.1 -C.sub.4 -alcohol (methanol, ethanol, 
isopropanol etc.), because the CO.sub.2 formed in the course of the 
hydrolysis is then immediately fixed as the carbonate or bicarbonate of 
the particular base. 
For example, aqueous sodium hydroxide solution is metered into a suspension 
of N,N'-di-(2-nitro-3-pyridyl)-urea in a lower alcohol, such as methanol 
or ethanol, the urea derivative: NaOH molar ratio being preferably about 
1:1-3, especially about 1:1.5-2. The 2-nitro-3-aminopyridine crystallizes 
out toward the end of the reaction, and can be isolated in a pure form. 
The examples which follow are intended to illustrate the invention further. 
The examples of the invention (A) are followed by a number of comparison 
examples (B) which show that the nitration of 3-aminopyridine in which the 
amino group is substituted by other protective groups does not lead to the 
desired objective (nitration in the 2-position in good yields and in a 
controllable reaction).

(A) EXAMPLES OF THE INVENTION 
EXAMPLE 1 
(a) Reaction of 3-aminopyridine with urea: 
To 1000 g of o-Cl-toluene (=solvent), which was placed in a 4 liter flask 
provided with stirrer, thermometer and reflux-condenser, 
470 g=5 moles of 3-aminopyridine, and 
150 g=2.5 moles of urea 
were added. 
For preventing the NH.sub.3 -formation from becoming too vehement, the 
reaction was carried out in several temperature-stages. First, the 
reaction mixture was heated for about 1 hour to 130.degree. C.; the 
NH.sub.3 -formation, which began between 120.degree.-130.degree. C., 
became slower at the end of this heating period. Then, the temperature was 
elevated and kept for 1 hour at 140.degree. C., and further elevated and 
again kept for 1 hour at 150.degree. C. Thereafter at 150.degree. C. about 
20 liters of nitrogen (N.sub.2) per hour were blown through the reaction 
mixture up to the crystallization of the di-(3-pyridyl)-urea, which had 
first been formed as an oily layer. For completing the reaction, the 
reaction mixture was heated with refluxing to about 160.degree. C. for ca. 
4-5 hours without N.sub.2 passing through. The reaction mixture was then 
allowed to cool up to room temperature, at which temperature the 
di-(3-pyridyl)-urea that has precipitated was sucked off. 
Thus, about 578 g of a violet-pink-coloured crystalline product being still 
moist with solvent was obtained. The product was dried at about 
100.degree. C. under reduced pressure. 
The yield of the dried (raw) di-(3-pyridyl)-urea was ca. 519 g=97% of 
theory; m.p. 225.degree.-227.degree. C. (the purified product melted at 
ca. 228.degree. C.). 
(b) Nitration: 
400 g of 10% strength oleum and 100 g (0.47 mol) of 
N,N'-di-(3-pyridyl)-urea were placed in a 1.5 liter stirred apparatus and 
238 g of nitrating acid of the composition 32% of HNO.sub.3 and 68% of 
H.sub.2 SO.sub.4 were added in the course of 1.5 hours at a reaction 
temperature of 60.degree. C. Stirring was then continued for 3 hours at 
this temperature, and the mixture was cooled to room temperature and 
diluted with 780 ml of water. The suspension was subsequently stirred at 
20.degree. C.; the reaction product was then filtered off with suction and 
washed until neutral. 
Yield: 133 g of N,N'-di-(2-nitro-3-pyridyl)-urea=93% of theory, melting 
point: 230.degree.-233.degree. C. with decomposition. The NMR and IR 
spectra were in agreement with the structure mentioned. 
(c) Hydrolysis: 
Hydrolysis was carried out by placing 415 g of ethanol in a 1.5 liter 
stirred apparatus and introducing 133 g (0.44 mol) of 
N,N'-di-(2-nitropyridyl)-urea. The suspension was heated at 70.degree. C. 
and 300 g of 10% strength sodium hydroxide solution were added. The 
2-nitro-3-aminopyridine was partially precipitated during the reaction. In 
order to achieve complete precipitation of the reaction product, the 
mixture was diluted with approx. 500 ml of water after the completion of 
the reaction and cooled to 0.degree. to +5.degree. C., the suspension was 
filtered with suction and the reaction product was washed until neutral. 
Yield: 109.6 g of 2-nitro-3-aminopyridine=90.4% of theory, relative to 
N,N'-di-(2-nitro-3-pyridyl)-urea. Melting point: 199.degree.-200.degree. 
C. 
EXAMPLE 2 
400 g of 10% strength oleum and 238 g of nitrating acid of the composition 
32% of HNO.sub.3 and 68% of H.sub.2 SO.sub.4 were placed in a 1.5 liter 
stirred apparatus, and 100 g of N,N'di-(3-pyridyl)-urea (prepared as in 
Example 1a) were introduced in the course of 1.5 hours at a reaction 
temperature of 60.degree. C. The working-up and saponification to give 
2-nitro-3-amino-pyridine corresponds to that of Example 1. The yield and 
quality of the reaction product was also identical with Example 1. 
(B) COMISON EXAMPLES 
Various 3-aminopyridine derivatives, prepared by introducing other 
protective groups for the amino group, were nitrated analogously to 
Example (of the invention) 1b. In so doing, the reaction was carried out 
under the following reaction conditions: 
Reaction temperature: approx. 30.degree.-80.degree. C.; 
concentration H.sub.2 SO.sub.4 (96% strength); 
starting material: H.sub.2 SO.sub.4 molar ratio=1:(5-10); 
Amount of HNO.sub.3 : 120-200%, relative to the starting material. 
The reaction products were hydrolyzed as in Example (of the invention) 1C. 
The results are summarized in the following table: 
______________________________________ 
Behavior of the pyridine derivatives 
when nitrated in sulfuric acid 
no selective 
nitration in the 
Protective group X 
Decomposition 
2-position 
______________________________________ 
COCH.sub.3 + 
COC.sub.6 H.sub.5 + 
COC.sub.6 H.sub.5NO.sub.2 (-meta) 
+ 
COOCH.sub.3 + 
COOC.sub.6 H.sub.5 + 
CON (n-C.sub.4 H.sub.9).sub.2 
+ 
CON (i-C.sub.4 H.sub.9).sub.2 
+ 
CONH C.sub.4 H.sub.9 (n) 
+ 
CONH C.sub.4 H.sub.9 (i) 
+ 
SO.sub.2 C.sub.6 H.sub.5 + 
##STR7## + 
______________________________________ 
As can be seen from the Table, either the protective groups introduced are 
split off under the conditions of nitration or, if the protective group is 
stable, there is no selective nitration in the 2-position in the pyridine 
ring.