Preparation of salicylic acid and derivatives

The invention relates to an improved method of preparing salicylic acid and derivatives from phenyl esters which comprises the step of fusing acetoxyphenyl, or derivative suitable for preparing the desired salicylic acid derivative, with M.sub.2 CO.sub.3 where M is potassium or sodium in the presence of carbon dioxide, at a temperature of from 150.degree. to 250.degree. C., and at a pressure of from atmospheric to 500 p.s.i.g.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention is concerned with an improved method of preparing 
salicylic acid and derivatives thereof employing as a starting material 
acetoxyphenyl, or a derivative thereof suitable for preparing the desired 
derivative of salicylic acid. 
More particularly, the present invention is concerned with preparation of 
2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, an important 
anti-inflammatory and analgesic therapeutic agent. 
2. Description of the Prior Art 
Industrial preparation of salicylic acid has long been carried out by the 
Kolbe-Schmitt reaction in which sodium phenoxide and carbon dioxide are 
heated at 120.degree.-140.degree. C. under pressure. A small amount of the 
p-derivative is formed at the same time, and if the temperature rises 
above 140.degree. C., the p-isomer is the main product. The Kolbe-Schmitt 
reaction, in turn, is one step in a potentially important process of 
preparing 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, 
referred to above. See U.S. Pat. No. 3,992,459. In that process, the 
intermediate which is converted to the starting material for the 
Kolbe-Schmitt reaction is a phenyl acetate ester. Accordingly, that 
process is characterized by the disadvantages of involving cumbersome 
ester saponification and requiring sodium salt isolation, with attendant 
drying problems. Thus, the method of the present invention constitutes an 
improvement of that potentially important process whereby the described 
disadvantages are avoided and one step is removed from the overall 
process. 
It is known to carry out selective cleavage of aryl esters with anhydrous 
alkali carbonates. See H. E. Zaugg, J. Org. Chem., Vol. 41, No. 21, (1976) 
3419-3421. However, knowledge of this process would not have suggested the 
novel improvement of the phenyl ester to salicylic acid process 
accomplished by the method of the present invention, with the unexpected 
result of achieving a facile, one-step preparation characterized by high 
yields.

SUMMARY OF THE INVENTION 
The present invention relates to an improved method of preparing salicylic 
acid and derivatives thereof having the following formula: 
##STR1## 
wherein: R.sub.1 is selected from the group consisting of hydrogen, 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, benzyl, C.sub.1-4 alkenyl and halo; and 
R.sub.2 is hydrogen or 
##STR2## 
where n is 1 to 5, X is halogen and 
R.sub.3 is selected from the group consisting of C.sub.1-4 alkyl and 
C.sub.1-4 alkoxy. 
More particularly, the present invention relates to an improved method of 
preparing compounds of the formula: 
##STR3## 
wherein: R.sub.1 and R.sub.3 are hydrogen or C.sub.1-4 alkyl; 
n is 2; and 
X is chloro or fluoro. 
Most particularly, the present invention relates to an improved method of 
preparing the compound 
2',4'-diluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, which has the 
following structural formula: 
##STR4## 
The starting materials for the method of the present invention are 
compounds of the formula: 
##STR5## 
wherein R.sub.1 and R.sub.2 have the same meanings as above. 
Where, in accordance with a preferred aspect of the present invention, the 
compound prepared is 2'-4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic 
acid, the starting material is 2',4'-difluoro-4-acetoxy-1,1'-biphenyl. 
The acetoxyphenyl starting materials for the method of the present 
invention may be prepared in accordance with procedures described in U.S. 
Pat. No. 3,992,459, referred to above. 
The improved preparation method of the present invention is a one step 
method in which the starting material is fused with a substantially 
anhydrous compound of formula: M.sub.2 CO.sub.3, where M is potassium or 
sodium. Potassium carbonate is preferred. The carbonate material may be 
employed in amounts such that 1 to 5 moles of carbonate for every mole of 
starting material are present in the reaction mixture. Preferably, the 
molar ratio is about 2:1. 
Since water interferes with the overall reaction, it is necessary that the 
method of the present invention be carried out under substantially 
anhydrous conditions, although a trace of water can be tolerated. 
The method of the present invention is carried out in the presence of 
carbon dioxide, the introduction of which is preferably accomplished by 
pressurizing the reaction vessel, which is sealed, with carbon dioxide. 
Pressurization is not, however, required. Where pressure is employed, 
pressures of from 10 to 500 p.s.i.g. are useful, while pressures of from 
50 to 400 p.s.i.g. are preferred. Thus, the total pressure range if from 
atmospheric to 500 p.s.i.g. The use of pressure assures that the carbon 
dioxide will again access to the other reactants, which are in solid form 
and have been fused. The volume of the pressurized reaction vessel should 
be adequate to assure that there will be a considerable excess of carbon 
dioxide when the vessel is pressurized with carbon dioxide to within the 
range of pressures described above. 
Introduction of the carbon dioxide may also, optionally, be by employing an 
excess of the carbonate material, whereby, upon a partial decomposition 
thereof, carbon dioxide gas is released to the reaction environment. 
The temperature at which the method of the present invention is carried out 
should be in the range of from 150.degree. to 250.degree. C., preferably 
in the range of from 150.degree. to 200.degree. C. Most preferably, the 
temperature will be in the range of from 175.degree. to 195.degree. C. 
The method of the present invention possesses the advantages of being 
easily carried out, and of resulting in high yields of final product of 
90% and higher. 
It is considered that the reactions taking place during the method of the 
present invention are a combination of a concerted process and a stepwise 
process, with the stepwise route predominating. The concerted reaction 
route may be illustrated as follows: 
##STR6## 
The stepwise reaction route may be illustrated as follows: 
##STR7## 
The following example will serve to illustrate the manner in which the 
method of the present invention may be carried out. 
EXAMPLE 
A mixture of 12.4 g (0.05 m) of 2,4-difluoro-4'-acetoxybiphenyl plus 13.8 g 
(0.1 m) freshly ground and vacuum dried (70.degree. C., 12 hr.,50 mm. Hg) 
potassium carbonate was charged to a sealed bomb and pressurized with 
carbon dioxide to 400 p.s.i.g. The reaction mixture was then heated to 
190.degree. C. and maintained there for six hours with agitation. After 
cooling, a pressure of 380 pounds was observed. The bomb was vented and 
the solid mass broken up with a spatula and rinsed from the bomb with 
about 200 ml. 2.5 N hydrochloric acid. This mixture was aged with stirring 
for 30 minutes at 70.degree.-75.degree. C. The precipitate was then 
isolated, washed with about 75 ml. water and was dried at 70.degree. C. in 
vacuo for 16 hours. In this fashion, 13.33 g. (106%) of crude 
2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid was obtained. 
This crude product was dissolved in 150 ml. water containing 8.0 g. 50% 
sodium hydroxide solution at 90.degree. C. Then 0.25 g. disodium salt of 
ethylenediaminetetracetic acid plus 1 g. charcoal (Merck ACM) were 
introduced and the solution aged 20 minutes at 90.degree.-95.degree. C. 
The solution was filtered hot and the cake washed with 4 .times. 25 ml. of 
hot water (75.degree. C.). Then 130 ml. of 2-propanol were added and the 
solution heated to 80.degree. C. To this well-stirred solution was added 
dropwise 5 ml. of concentrated sulfuric acid. The reaction mixture was 
allowed to cool to 78.degree. C. and was seeded with 
2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid. After aging 1 
hr. at 75.degree.-80.degree. C., the solution was allowed to slowly cool 
to 20.degree. C. (about 11/2 hr.). The colorless precipitate was isolated 
and washed with 100 ml. of 2:1 water: 2-propanol, followed with 75 ml. of 
water. After drying at 70.degree. C. for 16 hrs. in vacuo 50 mm. Hg. 11.25 
g. (90%) of colorless 
2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid was obtained. A 
second crop was obtained by chilling the mother liquors overnight; the 
yield was 0.30 g. (2.4%), M.P., 165-190.degree. C. 
The salicylic acid and salicylic acid derivatives prepared by the method of 
the present invention are valuable compounds which are useful in a variety 
of important areas. Salicylic acid, for example, is useful as an 
antiseptic agent, and as an intermediate in the manufacture of dye-stuffs. 
In particular, 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid 
and derivatives thereof are valuable anti-inflammatory and analgesic 
agents for therapeutic use. See U.S. Pat. No. 3,714,226.