Highly selective oxidizing process for preparing pyridin-carboxylic acids

A highly selective oxidation process for preparing pyridin-carboxylic acids from pyridine compounds nucleus substituted with alkyl groups, through a carbon-carbon bond, and oxidizable to carboxyl, and from hydrosoluble hexavalent chromium compounds, in the presence of an acid. Particularly described is the oxidation of beta-picoline with sodium bichromate to obtain the sodium salt of nicotinic acid and 99.5% pure free acid, respectively.

This invention relates to a highly selective oxidizing process for 
preparing pyridin-carboxylic acids. Particularly, the oxidation is carried 
out on alkyl organic groups attached to a pyridine nucleus by 
carbon-carbon bonds and liable to oxidation to carboxylic groups. Under 
the specific conditions, as disclosed and claimed in the following, such 
an oxidation is carried out with water-soluble, hexavalent chromium salts. 
More particularly, the present invention refers to oxidizing beta-picoline 
with sodium bichromate to provide nicotinic acid and its sodium salt, 
which is a product of significant commercial interest. 
Processes for oxidizing pyridine compounds according to the above outlined 
general scheme are already known. 
Such processes are particularly disclosed in U.S. Pat. No. 2,415,147 and 
U.S. Pat. No. 3,313,821. 
In its primary claim, said U.S. Pat. No. 2,415,147 discloses the oxidation 
of heterocyclic compounds containing in the structure thereof a pyridine 
nucleus, substituted by organic groups, attached to said nucleus by one or 
more carbon to carbon bonds and oxidizable to carboxylic acid. This 
oxidation is carried out by means of neutral or alkaline aqueous solutions 
in the form of the soluble metal salt, for example sodium salt, being 
recovered therefrom in a per se known manner by acidification of 
carboxylic acid and nicotinic acid, respectively. The reaction is carried 
out in an environment with a pH close to 7 and at a temperature of at 
least 150.degree. C., in the presence of a pressure equivalent to the 
vapor pressure of the reactive mixture at the indicated temperature. 
Unlike the above described process (U.S. Pat. No. 3,313,821), the process 
according to the present invention does not use the step of altering the 
starting compound having the pyridine nucleus carrying a substituent 
oxidizable to carboxylic acid and, by oxidizing with water-soluble, 
hexavalent chromium salts. Under specific conditions, hereinafter 
discussed and claimed, important advantages over the process of said U.S. 
Pat. No. 3,313,821 are attained. 
Such advantages can be essentially summarized as follows: 
(1) High value of selectivity and yield, which is substantially around 
100%, this being of significant interest in an industrial process. 
(2) Possibility of certainly achieving complete reduction and 
insolubilization of the oxidant, formed of a water-soluble hexavalent 
chromium compound, in the form of trivalent chromium hydroxide as a result 
of using oxidant proportions in a lower amount than the equivalent 
stoichiometrical value required by the pyridine compound reacting 
therewith. Thus, the complicated removal of the unreacted oxidant is 
avoided, insuring the total absence of toxicity in the final product, 
which may have an essential significance for certain uses of the latter. 
(3) Reduction in processing times relative to those indicated in the above 
mentioned patents, since the reaction according to the process of the 
present invention is carried out in a "homogeneous" phase. However, such 
times do not exceed 4 hours, if the temperature is maintained at at least 
200.degree. C., at the pressure occurring in the autoclave at the vapor 
pressure of the mixture reacting at that temperature. 
(4) Possibility of using on a large scale less valuable and accordingly 
less expensive apparatus materials in that the reaction is carried out in 
the restricted range of pH between 4.5 and 8.5. 
(5) Obtainment of an exceedingly pure final product, both in the form of 
alkaline salt and in the form of acid, from a substantially neutral final 
solution containing only the above alkaline salt of carboxylic acid. 
The high yield, which is a further economic advantage, is derived partly 
from the carboxylic acid recovered in the final stage being recycled to 
the reaction phase, as well as the excess of pyridine compound. 
Some theoretical considerations will now be disclosed in the following for 
explaining the development of the process according to the present 
invention. Starting from beta-picoline (3-methylpyridine C.sub.5 H.sub.4 
N(CH.sub.3)), for example, the same is treated with aqueous solution of 
sodium bichromate. 
The reaction develops according to the following scheme: 
EQU xC.sub.5 H.sub.4 N(CH.sub.3)+C.sub.5 H.sub.4 NCOOH+Na.sub.2 Cr.sub.2 
O.sub.7 +mH.sub.2 O.fwdarw. 
EQU (x-1)C.sub.5 H.sub.4 N(CH.sub.3)+2C.sub.5 H.sub.4 NCO.sub.2 Na+Cr.sub.2 
O.sub.3.nH.sub.2 O+(m+2-n)H.sub.2 O 
Namely an excess of beta-picoline is reacted in the presence of nicotinic 
acid, as acidificant, with an aqueous solution of sodium bichromate as 
oxidant, obtaining sodium nicotinate, an excess of beta-picoline in 
aqueous solution and insoluble chromic hydroxide. Substantially, under the 
disclosed operating conditions, index "n" is equal to 2, which means that 
the final amount of water corresponds to the initial amount of water. 
The concentration of the aqueous solution of sodium bichromate should be 
such that the sodium nicotinate being formed is in solution at all of the 
process stages. This facilitates solid-liquid separation and prevents, at 
reaction temperature, the possible phenomena of salt decomposition, which 
salt may be in crystalized state, with the development of carbon dioxide 
and appearance of pyridine, with a resulting yield loss. 
It was found that the desired conditions perfectly occur when the value of 
index "m" is not lower than 40. In such a case, the initial reaction 
mixture is present in the form of a homogeneous phase, provided that the 
value taken by x is at least 1.3. This because under these general 
conditions and with these molar ratios, the conditions as imposed by the 
solubility values of sodium bichromate in water and by the ternary diagram 
of mutual solubility between water, beta-picoline and nicotinic acid are 
met. 
The foregoing disclosure for the particular case of nicotinic acid 
oxidation of beta-picoline is also true for the other substituted 
pyridines, among which are particularly gamma-picoline and 
methylethyl-pyridine. 
Conveniently, the reaction temperature may be selected in the range of 
between 150.degree.-300.degree. C., depending on the selected reaction 
time and pyridine compound to be oxidized. However, the preferred range is 
between 175.degree. C. and 250.degree. C. 
When maintaining the above disclosed conditions, the nicotinic acid cited 
as an example, being recycled as acidificant in the reaction, is 
surprisingly stable under the reaction conditions and is completely 
recovered along with that being generated by oxidation. 
The process according to the present invention substantially consists of 
the following stages: 
(A) reaction in homogeneous phase carried out in an autoclave in aqueous 
solution, between a pyridine derivative and sodium bichromate, the latter 
being present in a lower amount than the stoichiometrical amount required 
by the pyridine derivative, in the presence of nicotinic acid in the same 
amount as that which will be formed by reaction at a temperature between 
150.degree. and 300.degree. C. (preferably between 175.degree. and 
250.degree. C.), at pH between 4.5 and 8.5 (preferably between 5.5 and 
8.0) and at a pressure corresponding to the vapor pressure of the mixture 
reacting at such a temperature, for the time as required for the complete 
reduction of hexavalent chromium which is between about 1 and 8 hours; 
(B) partial distillation of the slurry discharged from the autoclave, so as 
to separate the same in an aqueous condensate, of a nearly unitary 
specific gravity, containing the excess of the pyridine derivative which 
will be recycled following the reaction, and in a slurry residual from the 
distillation. The distillate amount is experimentally determined on the 
basis of distillation curves, by the possibility of almost completely 
recycling the excess of pyridine compound to the reaction step. 
Practically, it was found that this amount corresponds to 25-30% of the 
slurry and that, in this case the total balance of water is correct; 
(C) separation by filtering of chromic hydroxide from the filtrate, which 
is substantially neutral and contains only sodium nicotinate; 
(D) recovery of 99.5% pure nicotinic acid from the filtrate according to a 
known technique, for example consisting of acidification, filtering and 
extraction with solvent; and 
(E) recycling of a portion of the produced nicotinic acid corresponding to 
the required amount for reaction with the pyridine compound in the first 
stage. 
As it results from the above, the amount of oxidant in a lower than 
stoichiometrical ratio characteristic of the first stage, is equivalent to 
the excess of reducing agent introduced with the pyridine compound. The 
reacting pyridine compound may comprise-beta-picoline, gamma-picoline and 
methylethylpyridine, accordingly a pyridine-3-carboxylic (or nicotinic) 
acid or a pyridine-4-carboxylic (or isonicotinic) acid, a mixture of 
nicotinic acid and isocinchomeronic acid (2-5-pyridine-dicarboxylic acid), 
which is continuously partially recycled, respectively, will be obtained. 
Where beta-picoline is employed, it may be reacted with sodium bichromate 
at a temperature in the range of 200.degree.-280.degree. C., at a pressure 
of between 16 and 45 Kg/sq.cm. for 6-2 hours, and at a pH of between 4.5 
and 8.5. 
It should be emphasized that the reducing pyridine compound used in excess 
is recovered by distillation and recycled to the subsequent reactions, and 
it should be also emphasized that in this operation advantage can be taken 
of the latent heat of the final reacted mass. 
Finally, as to the useful limit of the excess of reducing agent to be used, 
practically it is to be deduced--which is not to be intended as 
limitative--that an excess of the reducing agent in a range between 30% 
and 50% of that foreseen from the stoichiometrical ratio permits recovery 
by distillation and condensation, in the form of aqueous solution, 90.0% 
of unreacted reducing agent, this conveniently and without any correction 
problems.

Some illustrative examples of the present invention follow. These examples 
are not intended as limitations on the present invention, which is defined 
by the appended claims. 
EXAMPLE 1 
An autoclave, maintained under stirring and capable of withstanding an 
internal pressure up to 100 kg/sq.cm, was charged with 2058 g water, 894 g 
sodium bichromate crystalized with two molecules of water, 360 g 
beta-picoline at a titer of 98% and 369 g nicotinic acid at a titer of 
99.5%. The resulting pH of the solution in homogeneous phase at 20.degree. 
C. was 5.6. 
The autoclave was heated to an inner mass temperature of 175.degree. C., 
having a pressure of 10 kg/sq.cm corresponding thereto. The temperature 
was raised gradually from 175.degree. C. to 250.degree. C. having a 
pressure of 38 kg/sq.cm corresponding thereto. After 60 minutes, the mass 
was cooled to room temperature, and, at temperatures lower than 
100.degree. C., no further residual pressure was found in the autoclave. 
The slurry containing chromic hydroxide thus precipitated was then 
discharged. The value of this slurry was 7.5. 27.2% by weight of this 
slurry was then distilled, thus totally recovering the excess of 
beta-picoline and collecting a condensate of specific gravity 
substantially close to one, wherein the percentage of beta-picoline was 
7.5%. By gas chromatography analysis, only traces of pyridine were found 
in this aqueous phase, thus showing that no decomposition of nicotinic 
acid had occurred. 
From the slurry, which was a residue from the distillation, chromic 
hydroxide was removed by filtering, and in the filtrate, which was free of 
soluble hexavalent chromium, the presence was found by analysis of 860 g 
of sodium salt of nicotinic acid. After isolation of nicotinic acid, as 
effected by any of the conventional techniques (such as by acidification, 
filtering and extraction with solvent), a total weight of 720 g of 
substantially pure product (titer 99.5%) was obtained, corresponding to a 
yield of 98.5%. The total yield (including losses during recovery step) 
corresponds to 95.0%. 
369 g of the 720 g of product were recycled for the successive reaction. 
EXAMPLE 2 
In accordance with Example 1, an autoclave was charged with 258 g water, 
894 g sodium bichromate crystalized with two molecules of water, 360 g 
gamma-picoline having a titer of 99% and 350 g substantially pure 
isonicotinic acid. 
At 20.degree. C., the pH of the resulting solution in homogeneous phase was 
5.8. 
The heat cycle disclosed in the preceding example was followed to a final 
temperature of 225.degree. C., at which temperature the corresponding 
pressure was 25 kg/sq.cm. After 180 minutes of retention at this 
temperature and this pressure, a mass was cooled and discharged containing 
precipitated chromic hydroxide. The pH was 8.5. The product was distilled, 
collecting a condensate of 25% of the mass discharged from the autoclave, 
in which condensate the presence of 77.9 g .gamma.-picoline was found. 
Chromatographically, no presence of pyriridine was found in this aqueous 
phase. 
From the residual slurry of the distilling operation, chromic hydroxide was 
separated by filtering and in the filtrate, in which traces of soluble 
hexavalent chromium were present, a content of 845 g sodium isonicotinate 
was analytically found. 
From this filtrate, 700 g substantially pure (titer 99.8%) isoconitic acid 
were recovered. 
Yield at the reactor outlet=99.6% 
Total yield of the operation=94.6%. 
EXAMPLE 3 
As in Example 1, an autoclave was charged with 2058 g water, 894 g sodium 
bichromate crystalized with two molecules water, 160 g 
methyl-ethyl-pyridine, and 369 g nicotinic acid having a titer of 99.5%. 
The solution was homogeneous above 45.degree. C. and at 50.degree. C. the 
pH value was 4.5. 
The heat cycle as described in the preceding example was followed, 
according to the operative modalities also described therein. 
After 90 minutes of retention at 225.degree. C., the residual mass 
containing precipitated chromic hydroxide was cooled and discharged; the 
pH value was 8.3. 
By means of the distillation the unreacted organic phase was recovered, 
collecting a condensate, wherein in the ratios as shown in parenthesis, 
methyl-ethyl-pyridine (75%), ethyl-pyridine (15%), and pyridine (10%) were 
present together with water. The presence of ethyl-pyridine indicated a 
partial oxidation and the presence of pyridine indicated decomposition by 
total decarboxylation of isocinochomeric acid. 
Chromic hydroxide was separated by filtration in the distillation residue. 
In the aqueous phase of the filtrate thus obtained, not very high yield 
values for the acid were found upon analysis, corresponding to values not 
exceeding 50%. In fact the total presence of nicotinic acid used in the 
autoclave charging was found, plus an amount of mixture of isocinchomeric 
acid (12%) and nicotinic acid (88%), so that as calculated on the reacted 
methyl-ethyl pyridine, the yield did not exceed 50%. 
EXAMPLE 4 
An industrial type of autoclave was charged with 1340 kg aqueous solution 
of sodium bichromate, containing 546.7 kg Na.sub.2 Cr.sub.2 
O.sub.7.2H.sub.2 O and 793.3 kg water; 597 kg aqueous solution of 
beta-picoline, recovered by distillation from preceding reactions and 
containing 100% beta-picoline in an amount of 52.2 kg; 170 Kg 
beta-picoline having a titer of 98%; and 225 kg nicotinic acid having a 
titer of 98.4%. 
The resulting homogeneous solution, having a specific gravity of 1.23 g/cu 
cm and pH, measured at 20.degree. C., of 5.8 was heated to 235.degree. C. 
for one hour at a corresponding pressure of 35 kg/sq.cm. This temperature 
was maintained for 2 hours. 
An automatic control system permitted following a predetermined linear heat 
profile in temperature-time diagram, both during heating and reaction. 
This was achieved by introducing and circulating high pressure steam as a 
heating agent, and water as a cooling agent. A reaction completion, 800 kg 
aqueous solution containing 100% beta-picoline in an amount of 58.1 kg 
were distilled and collected by condensation. 
The mass from the autoclave was discharged at about 100.degree. C., such a 
mass still containing about 0.9 kg beta-picolina. 
The chromic hydroxide was filtered and a solution of sodium nicotinate 
containing 858.5 kg of this salt, as analytically determined was 
recovered. 
By known techniques, 425 kg nicotinic acid having a titer of 99.5% were 
recovered from the solution. Of these 425 kg, a portion of 202.5 kg was 
discharged as final product, and the remainder was recycled to the 
successive operation. 
Yield at the reaction end=99.2%. 
Total operation yield=94.8%. 
Consumption of 98% beta-picoline per kg of 99.5% produced nicotinic 
acid=0.81.