Method of preparing 5-amino salicylic acid

The disclosure relates to a method of producing 5-amino salicylic acid from salicylic acid, with sulphanilic acid as the recyclable auxiliary chemical. The method according to the present invention includes linking between the diazonium salt of the sulphanilic acid and the salicylic acid, followed by a splitting by hydrogenation with hydrogen gas and catalyst, and selective precipitation of the desired product.

TECHNICAL FIELD 
The present invention relates to a novel method of preparing 5-amino 
salicylic acid (5-ASA) from salicylic acid, with sulphanilic acid as the 
auxiliary chemical. The reaction carried out according to the present 
invention by linking and splitting gives, as its final product, an 
extremely pure 5-amino salicylic acid well suited for pharmaceutical 
preparation. 
BACKGROUND ART 
5-amino salicylic acid (5-ASA) has previously been produced from, for 
instance, 3-nitrobenzoic acid which is partially reduced to the 
corresponding hydroxylamine, which is converted in an acidic environment 
to 5-ASA (Ref. 1 and 2). However, the difficulties involved in purifying 
thus produced 5-ASA of undesired isomers restricts the usability of the 
method for producing pharmaceutical qualities. 
Attempts have also been made in this art to produce 5-ASA by nitration of 
salicylic acid, but in such a method, considerable amounts of 3-isomers 
are obtained, which drastically reduces product yield and results in an 
impure end product (Ref. 3). 
A further method of producing 5-ASA by reaction of carbon dioxide with 
p-aminophenol under high pressure, a so-called Kolbe reaction is described 
in the literature in this art (Ref. 4). However, this method requires 
access to high pressure equipment, and, furthermore, the toxicity of the 
p-aminophenol restricts the usability of this method from purely practical 
points of view. 
Finally, it is previously known in the art that 5-ASA may also be produced 
by direct amination of salicylic acid by diazonium linking and splitting 
of the thus formed azo compounds. This method has also been employed in 
production of 5-ASA on an industrial scale. In such production, aniline 
(Ref. 5) is normally employed as the source of the diazonium salt, thus 
the use of sulphanilic acid is also described in the literature in the art 
(Ref. 6). For splitting of the azo bonds, use has been made of dithionite 
or any analogous sulphur compound which has been added in such excessive 
amount that this has entailed a considerable hazard to the immediate 
environment in the industrial production of 5-ASA. According to a recently 
published method (Ref. 7) the azo compound obtained according to the above 
method may also be split electro-chemically in a basic environment. 
However, this method can only be used by manufacturers who have access to 
the highly specialized equipment required for industrial electro-chemical 
synthesis. 
It follows that all of the above-described methods for the production of 
5-ASA suffer from manifest shortcomings either in the form of high 
contents of undesirable isomers in the end product paired with low product 
yield, or in the form of stringent requirements in respect to the handling 
of environmentally hazardous chemicals, or alternatively the need of 
expensive and complex specialized equipment. 
OBJECT OF THE PRESENT INVENTION 
The object of the present invention is to offer a novel method for the 
production of 5-ASA which may be carried out using standard production 
equipment and which neither requires the handling of toxic discharge 
chemicals nor results in environmentally hazardous waste, and which gives 
a final substance of high pharmaceutical purity. 
SUMMARY OF THE INVENTION 
According to the present invention, 5-amino salicylic acid is, thus, 
produced from salicylic acid with sulphanilic acid as the recyclable 
auxiliary chemical. Thus, the double sodium salt of the salicylic acid is 
reacted in a previously known manner with the diazonium salt of 
sulphanilic acid, whereupon the thus obtained 
5-(p-sulphophenylazo)salicylic acid is split by hydrogenation with 
hydrogen gas and a catalyst at elevated pressure, and a temperature of 
40.degree.-60.degree. C., whereafter the thus obtained 5-amino salicylic 
acid is precipitated from the mother liquor by acidification thereof to a 
pH at which the 5-amino salicylic acid is precipitated, but not the 
recovered sulphanilic acid, which, in its turn, is precipitated at a later 
stage in the process by further acidification of the mother liquor. 
DESCRIPTION OF PREFERRED EMBODIMENT 
According to the present invention, requisite amounts of sulphanilic acid 
or a salt thereof are slurried in water, a strong acid, preferably 
sulphuric acid or hydrochloric acid, being added to the solution in such 
an amount that at least three hydrogen ions correspond to each equivalent 
sulphanilic acid. Thereafter, slightly more than one mole equivalent of 
sodium nitrite dissolved in water is added. 
The sodium nitrite is added at a temperature which does not appreciably 
exceed 20.degree. C., since the desired diazonium salt begins to break up 
at approximately this temperature. The thus started diazoting is then 
allowed to react to completion before the thus produced diazonium salt is 
further employed. 
Furthermore, to a solution of sodium hydroxide in water, there is 
separately added salicylic acid in such an amount that it is present as a 
double sodium salt. To this salt, there is subsequently added the produced 
diazonium salt at a regulated temperature which, during addition phase, is 
kept below 20.degree. C. so as to avoid break-up of the diazonium salt. 
Once all additions have been completed, the reaction is allowed to proceed 
to completion and since elevated temperature will hasten the reaction, the 
reaction temperature may now be permitted to rise to 20.degree.-25.degree. 
C. 
At this reaction stage, it is appropriate that the salicylic acid in the 
form of its double sodium salt be present in a certain mole surplus in 
relation to the sulphanilic acid. 
The above described reaction gives, as end product, 5-(p-sulphophenyl azo) 
salicylic acid, which is a per se previously known product which may also 
be produced by other means and which has been put to certain uses 
previously, for example as a colorant. 
The thus obtained 5-(p-sulphophenyl azo) salicylic acid may now, according 
to the present invention, be split by hydrogenation with hydrogen gas in 
the presence of a preferably palladium or platinum based catalyst. The 
5-(p-sulphophenyl azo) salicylic acid is, here, mixed with an amount of 
catalyst adapted to conform to the available cooling capacity (the 
reaction is slightly exothermic), whereafter the mixture is exposed to 
excess pressure of hydrogen gas as long as hydrogen gas continues to be 
absorbed. The pressure of the hydrogenation is not particularly critical 
but we have found that it is practical to carry out said hydrogenation at 
an elevated pressure of about 1-10 atm above the atmospheric pressure. In 
order to obtain a reasonable reaction time, the temperature should exceed 
50.degree. C. in this stage. 
When no hydrogen gas is consumed, the splitting reaction according to the 
present invention may be considred as completed and the catalyst is 
filtered off at unchanged temperature. The splitting reaction according to 
the present invention gives sodium sulphanilate and 5-amino salicylic 
acid. By a thickening of the system and by slowly cooling to approx 
20.degree. C., the thus formed sodium sulphanilate can, to a certain 
degree, be precipitated and filtered off, since its solubility at this 
temperature has been exceeded. 
In order to ensure a complete splitting of 5-(p-sulphophenyl azo) salicylic 
acid, it may be appropriate to heat the thus obtained filtrate to approx 
60.degree. C. in a nitrogen gas atmosphere and to add, under agitation, a 
minor amount (or up to 5 percent by weight) of sodium dithionite dissolved 
in water. This amount of sodium dithionite is to be compared with the 
plurality of mole equivalents required according to prior art splitting 
processes. For this reaction stage, a duration of approx 5 minutes under 
agitation is to be expected. 
The thus obtained solution is subsequently acidified with a strong acid, 
preferably sulphuric acid or hydrochloric acid, to a pH level of 4.5. 
At this point, the desired 5-amino salicylic acid precipitates out of the 
solution, while the sulphanilic acid remains in solution as its sodium 
salt. After filtering off and washing with water, there will be obtained a 
product of extremely high purity. Liquid chromatographic examinations have 
shown that purities of 95 percent or over can be attained according to 
this methodology without difficulty. 
In continued acidification of the mother liquor to a pH of 3, the 
sulphanilic acid will precipitate and may be reused in the process. Hence, 
the method according to the present invention makes it possible to recover 
80-85 percent of the sulphanilic acid batch, including the previously 
described filtering off of sodium sulphanilate.

The present invention has been defined in the appended claims and will now 
be described in greater detail in conjunction with a number of relevant 
Examples. 
The following general formula applies for the reaction according to the 
present invention: 
##STR1## 
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REFERENCES AS ABOVE 
______________________________________ 
1. Gatterman, B. 26 1850 
2. Hochst, D.R.P. 96853 
3. Beilstein, A. 130, 243 
4. Wessely, Benedikt, Benger 
M. 80 (1949) 197,200 
5. Fischer, Shaar-Rosenberg, 
B. 32 81 
6. Griess, B. 11 2196 
7. Patent application from Ferring A/S, Vanlose, Denmark 
______________________________________ 
B = Berichte der Deutschen Chemischen Gesellschaft 
M = Monatshefte fur Chemie 
A = Annalen der Chemie 
EXAMPLE 1 
Sulphanilic acid (138.4 g, 0.80 mol) is slurried in water (192 ml) and 96 
percent sulphuric acid (25 ml) is added during cooling. The reaction 
mixture is cooled to 5.degree. C. Sodium nitrite (57.4 g, 0.83 mol) 
dissolved in water (104 ml) is slowly added (1 h) beneath the surface of 
the reaction mixture which maintains a temperature of 5.degree.-10.degree. 
C. When all of the sodium nitrate has been added, the temperature is 
allowed to rise to 10.degree.-15.degree. C. The thus formed diazonium salt 
of sulphanilic acid is used in the manner described below. 
In another vessel, 46 percent sodium hydroxide sol. (100 ml) in water (184 
ml) is batched and salicylic acid (112 g, 0.81 mol) is added during 
cooling. When all of the addition has been completed, the solution is 
cooled to 10.degree. C. To this solution there is then added the 
above-described cooled reaction mixture with the diazonium salt of 
sulphanilic acid. This addition is effected under cooling and the 
temperature is permitted to rise from 10.degree. C. to 22.degree. C. 
The link product, 5-(p-sulphophenyl azo)salicylic acid, is batched in an 
autoclave and 5 percent Pd/C (2.5 g, 54 percent moisture) is added. The 
mixture is heated to 75.degree. C. and, after nitrogen gas aspiration, 
hydrogen gas is led in at a pressure of 5 atmospheres. When no further 
hydrogen gas is absorbed, the reaction is allowed to proceed after 
reaction under the same conditions for 0.5-1.0 hours. 
The catalyst is filtered off at 60.degree.-70.degree. C. and sodium 
dithionite (2.8 g) dissolved in water (24 ml) is added. Agitation is 
effected at 60.degree. C. for 5 minutes in a nitrogen gas atmosphere. The 
solution is cooled to 20.degree. C. and the thus formed sodium 
sulphanilate is filtered off. Thereafter, the solution is reheated. 
Concentrated sulphuric acid (approx. 25 ml) is added at 60.degree. C. and 
nitrogen gas atmosphere to a pH of 4.5. The thus formed slurry is cooled 
to 20.degree. C., and the product is removed by filter suction. After 
washing with water (4x60 ml) and drying, there is obtained 112 g of 
5-amino salicylic acid. 
Liquid chromatic inspection showed that the thus obtained 5-ASA has a 
purity of 95 percent, which corresponds to a yield of 91 percent. 
EXAMPLE 2 
A corresponding experiment to that of Example 1 is also undertaken on a 
semi-industrial scale with 1000 times of each respective batch, but 
otherwise with unchanged methodology. In this case, there is obtained 143 
kg of centrifuge-dry 5-amino salicylic acid at a purity, after drying, of 
97 percent.