Prodrug esters of diflunisal and related compounds

1-(Alkoxy or aroxy)carbonyloxyalkyl esters of diflunisal and related compounds are stable in aqueous medium and non-irritant to mucous membranes of mouth, throat, and stomach. Accordingly, they are useful Prodrugs of the analgesic and anti-inflammatory drug, diflunisal.

BACKGROUND OF THE INVENTION 
The present invention relates to novel and stable 1-(alkoxy or 
aroxy)carbonyl esters of diflunisal, i.e., 
2-hydroxy-5-(2,4-difluorophenyl)benzoic acid and related compounds 
characterized as being: 
(1) readily bioavailable; 
(2) stable in aqueous formulation; 
(3) non-irritant to mucous membranes of mouth, throat, and stomach when 
administered, and 
(4) having long duration. 
Diflunisal and its analogs are known analgesic and anti-inflammatory agents 
of high potency, long duration but low gastric irritation. It is disclosed 
in U.S. Pat. No. 3,714,226 issued Jan. 30, 1973 to William V. Ruyle et al. 
However, it has been found that because of its inherent property as a 
phenolic free acid, diflunisal is irritant to mucous membranes and is 
therefore unsuitable for oral aqueous or suppository formulations. 
Particularly, in long term chronic dosing, the irritancy of diflunisal 
especially its aqueous suspension may have undesirable effects on the 
histology of the mucous membranes, e.g., mucosa of mouth and throat. On 
the other hand, aqueous suspensions of the novel esters of this invention 
are devoid of the irritancy and can be administered to infants, the very 
old, or chronic patients having difficulty in swallowing tablets, capsules 
or other forms of oral dose. Furthermore, it should be noted that the 
novel esters of this invention are stable in vitro at physiological pH 
ranges (1.2-8) but are readily cleaved during absorption by the mucous 
membranes. The products of cleavage from the ester, i.e., carbon dioxide, 
acetaldehyde and alcohols are advantageously physiologic in nature. 
Another aspect of the present invention involves the improved solubility 
range of the novel alkoxycarbonylalkyl esters which are slightly less 
soluble in water but more soluble in organic solvents, e.g., 
1,3-butenediol, mono- or diglycerides, than diflunisal. This improved 
solubility facilitates the preparation of aqueous or oleaginous 
formulations for parenteral injections. 
Accordingly, it is an object of the present invention to provide novel and 
stable 1-(alkoxy or aroxy)carbonyloxyalkyl esters of diflunisal and 
related compounds particularly suitable for aqueous oral or suppository 
formulations. 
Another object of the present invention is to provide processes for the 
preparation of these novel esters. 
Still another object of the present invention is to provide a 
pharmaceutical composition particularly suitable for parenteral, oral 
and/or, suppository formulation comprising a pharmaceutically acceptable 
carrier and an effective amount of the novel esters for the treatment of 
pain, fever and inflammation. 
Finally, it is the ultimate object of the present invention to provide a 
method of treating inflammation, pain and fever comprising the 
administration of an effective amount of the novel esters or a 
pharmaceutical composition thereof to a mammal in need of such treatment. 
DETAILED DESCRIPTION OF THE INVENTION 
This invention relates to 1-(alkoxy or aroxy)carbonyloxyalkyl esters of 
diflunisal and related compounds having the structural formula (I): 
##STR1## 
wherein R is 
(a) lower alkyl especially C.sub.1-6 alkyl such as methyl, ethyl, i-propyl, 
t-butyl or hexyl; 
(b) lower cycloalkyl especially C.sub.3-8 cycloalkyl, e.g., cyclopropyl, 
cyclopentyl or cyclohexyl; 
(c) unsubstituted or substituted aryl for example, phenyl, 4-methoxyphenyl, 
4-methylthiophenyl, 2,4-dimethylphenyl, 3-chlorophenyl, 4-ethylthiophenyl, 
4-methylsulfinylphenyl or 4-methylsulfonylphenyl; and 
(d) aralkyl especially aryl C.sub.1-6 alkyl such as benzyl, 
4-methoxybenzyl, or benzhydryl; 
R.sup.1 is 
(a) hydrogen; 
(b) lower alkyl; 
(c) lower cycloalkyl; or 
(d) aryl 
R.sup.2 is 
(a) hydrogen; 
(b) lower alkanoyl especially C.sub.1-6 alkanoyl such as acetyl, propionyl 
and butyryl; or 
(c) lower alkoxycarbonyl such as ethoxycarbonyl or butoxycarbonyl; 
R.sup.3 is 
(a) hydrogen; or 
(b) lower alkyl; and 
X is halo especially chloro or fluoro, X being on one or more of the phenyl 
carbons. 
In the preferred aspects of this invention, 
R is lower alkyl or unsubstituted or substituted aryl; 
R.sup.1 is hydrogen or lower alkyl; 
R.sup.2 is hydrogen; and 
X is fluoro; X being on the 2- and/or 4-position of the benzene ring. 
In the more preferred aspects of this invention, the compounds are the 
1-(alkoxy or aroxy)carbonyloxyalkyl esters of diflunisal of the formula: 
##STR2## 
wherein R is loweralkyl especially C.sub.1-6 alkyl or aryl; and 
R.sup.1 is hydrogen or C.sub.1-6 alkyl. 
In the most preferred embodiment of this invention, the compound is of the 
formula: 
##STR3## 
The novel esters of the present invention are prepared by a process 
comprising the treatment of a compound of structural formula: 
##STR4## 
with a base and an .alpha.-halo carbonate of formula (II): 
##STR5## 
wherein X.sup.1 is halo especially chloro or bromo with or without a 
solvent. 
The base used in the esterification may be a hydroxide, a carbonate or a 
bicarbonate of Na.sup.+, K.sup.+, Li.sup.+, Ca.sup.++, Ag.sup.+, Cu.sup.+ 
or Hg.sup.++ ; tetralkylammonium hydroxide, i.e., (loweralkyl).sub.4.sup.+ 
OH.sup.-, such as tetramethyl ammonium hydroxide and 
tetra(n-butyl)ammonium hydroxide; trialkylamine, i.e., (loweralkyl).sub.3 
NH, such as triethylamine, tripropylamine and tri(t-butyl)amine; or sodium 
hydride. Although solvent is not necessary to the esterification, it is 
preferable that a solution of diflunisal or its derivative in an organic 
solvent such as benzene or substituted benzene including toluene, xylene, 
chlorobenzene, ethylbenzene, methoxybenzene, p-methoxytoluene, or the 
like, dimethylformamide (DMF), chloroform, methylchloroform, methylene 
chloride, ethylacetate, a dialkyl ether including diethylether, 
tetrahydrofuran, or a mixture thereof, is treated with a base such as 
triethylamine, sodium hydride or sodium hydroxide to form the 
corresponding salt of diflunisal or its derivative. Subsequently, an 
.alpha.-halocarbonate such as ethyl 1-chloroethyl carbonate i.e. 
1-chloro-diethyl carbonate is added and the resulting mixture is stirred 
at from about 0.degree. C. to about 150.degree. C., preferably at about 
25.degree. C. to about 120.degree. C. until the esterification is 
substantially complete. 
The .alpha.-halocarbonates of formula (II) are either available 
commercially or can be prepared from known compounds via conventional 
methods. 
Alternatively, the novel esters of the present invention are prepared by a 
process whereby a 1-(alkoxy or aroxy)carbonyloxyalkyl ester of salicylic 
acid is prepared according to the esterification procedures described 
above followed by direct coupling with a halogenated benzene: 
##STR6## 
The coupling reaction is usually conducted under an oxygen atmosphere (from 
atmospheric to about 750 psig) in the presence of a palladium catalyst 
such as palladium acetate or palladium chloride. A preferred procedure of 
coupling involves a palladium catalyst system which comprises: 
A. A catalyst portion comprising: 
(1) palladium together with 
(2) C.sub.1-2 COO-- ligands and halo ligands selected from the group 
consisting of bromo, chloro and fluoro, such that the molar weight 
percent, based on total ligand molar weight, of the the C.sub.1-2 COO-- 
ligands is from 30 to 60%; wherein the C.sub.1-2 COO-- ligands are 
provided as palladium or alkali metal, acetate or propionate, and said 
halo ligands are provided as the appropriate halo salt of palladium, 
lithium, sodium, or tetra(alkyl)ammonium; wherein the ratio of the total 
molar weight amount of the ligands to the molar weight amount of palladium 
utilized is from 4:1 to 10:1; and 
(3) from 10 to 100 parts of a reaction promoting acid, per part, on a molar 
basis of palladium catalyst; and 
B. a catalyst regeneration portion comprising: 
(1) from 0.1 to 8.0 parts of phosphomolybdenovanadic acid per part, on a 
molar basis, of palladium catalyst; and 
(2) at least 20 parts of a solubilizing agent selected from the group 
consisting of ethylene carbonate, propylene carbonate, and sulfolane, per 
part, on a molar basis, of palladium catalyst. 
This coupling method is described in detail in U.S. Pat. No. 4,237,315 
issued to Ulf H. Dolling on Dec. 2, 1980, and is herein incorporated by 
reference. 
Furthermore, the novel esters of the present invention wherein R.sup.1 is 
methyl can be prepared by a process involving the formation of a vinyl 
ester (III) followed by hydrochlorination and treatment with a compound of 
structural formula: 
##STR7## 
wherein R is as previously defined to form the esters of formula (I): 
##STR8## 
This invention also relates to a method of treating inflammation comprising 
the administration of a compound of Formula (I) as the active constituent. 
It has been found that the compounds of Formula (I) possess 
anti-inflammatory, antipyretic and analgesic activities. More specifically 
the compounds of the present invention are prodrugs of diflunisal and 
related compounds useful for reducing inflammation and relieving pain in a 
variety of diseases, e.g., rheumatoid arthritis, osteoarthritis, gout, 
infectious arthritis and rheumatic fever. At similar dosages as prescribed 
for the parent compounds, they may be administered by conventional methods 
to a patient suffering from inflammation, pain and fever. It has been 
established that compounds of Formula (I) are readily hydrolyzed in vivo 
by enzymes and/or gut fluora to release tne parent compounds, e.g., 
diflunisal. Other products from the hydrolysis, for example, those from 
1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl) salicylate, are carbon 
dioxide, acetaldehyde or alcohol, all of which are easily disposed of 
physiologically by the body and therefore present no problems of toxicity 
or adverse side effects. 
Accordingly, for treatment of inflammation, the compounds of this invention 
may be administered orally, parenterally, topically or rectally to a 
patient in need of such treatment in dosage unit formulations containing a 
non-toxic pharmaceutically acceptable carrier. The term parenteral as used 
above includes subcutaneous, intramuscular or intrasternal injection or 
infusion techniques. 
Preferably, the compounds of this invention are administered orally in 
aqueous, tablet or suppository formulations. The term aqueous formulation 
includes all pharmaceutical compositions or formulations which contain 
water. Parenteral administrations with aqueous or oleaginous suspensions 
are also the preferred method of treatment of this invention. 
The pharmaceutical compositions containing the active ingredient may be in 
a form suitable for oral use, for example, as tablets, troches, lozenges, 
aqueous or oily suspensions preferably in aqueous suspensions; dispersible 
powders; dry or wet granules; emulsions; hard or soft capsules; syrups; or 
elixirs. Compositions intended for oral use may be prepared according to 
any method known to the art for the manufacture of pharmaceutical 
compositions and such compositions may contain one or more agents selected 
from the group consisting of sweetening agents, flavoring agents, coloring 
agents and preserving agents in order to provide a pharmaceutically 
elegant and palatable preparation. 
Tablets usually contain the active ingredient in admixture with non-toxic 
pharmaceutically acceptable excipients which are suitable for the 
manufacture of tablets. These excipients may be for example, inert 
diluents such as calcium carbonate, sodium carbonate, lactose, calcium 
phosphate or sodium phosphate; granulating and disintegrating agents, for 
example, maize starch, or alginic acid; binding agents, for example 
starch, gelatine or acacia; and lubricating agents, for example magnesium 
stearate, stearic acid or talc. The tablets may be uncoated or they may be 
coated by known techniques to delay disintegration and absorption in the 
gastrointestinal tract and thereby provide a sustained action over a 
longer period. For example, a time delay material such as glyceryl 
monostearate or glyceryl distearate may be employed. 
Formulations for oral use may also be presented as hard gelatine capsules 
wherein the active ingredient is mixed with an inert solid diluent, for 
example, calcium carbonate, calcium phosphate or kaolin, or as soft 
gelatine capsules wherein the active ingredient is mixed with water or an 
oil medium, for example peanut oil, liquid paraffin, or olive oil. 
The preferred oral aqueous suspensions of this invention generally contain 
the active materials in admixture with excipients suitable for the 
manufacture of aqueous suspensions. Such excipients are suspending agents, 
for example sodium carboxymethylcellulose, methylcellulose, 
hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidine, gum 
tragacanth and gum acacia; dispersing or wetting agents which may be a 
naturally-occurring phosphatide, for example lecithin; condensation 
products of an alkylene oxide with fatty acids, for example 
polyoxyethylene stearate; condensation products of ethylene oxide with 
long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol; 
condensation products of ethylene oxide with partial esters derived from 
fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or 
condensation products of ethylene oxide with partial esters derived from 
fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan 
monooleate. The said aqueous suspensions may also contain one or more 
preservatives, for example, ethyl- or n-propyl- p-hydroxybenzoate, one or 
more coloring agents, one or more flavoring agents, and one or more 
sweetening agents, such as sucrose or saccharin. 
Oily suspension may be formulated by suspending the active ingredient in a 
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut 
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may 
contain a thickening agent, for example beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents such a those set forth above, and flavoring 
agents may be added to provide a palatable oral preparation. These 
compositions may be preserved by the addition of an antioxidant such as 
ascorbic acid. 
Dispersible powders and granules suitable for preparation of an aqueous 
suspension by the addition of water provide the active ingredient in 
admixture with a dispersing or wetting agent, suspending agent and one or 
more preservatives. Suitable dispersing or wetting and suspending agents 
are exemplified by those already mentioned above. Additional excipients, 
for example, sweetening, flavoring and coloring agents, may also be 
present. 
The pharmaceutical compositions of the invention may also be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil, for example 
olive oil or arachis oils, or a mineral oil, for example liquid paraffin 
or mixtures of these. Suitable emulsifying agents may be 
naturally-occurring gums, for example gum acacia or gum tragacanth, 
naturally-occurrng phosphatides, for example soya bean lecithin, and 
esters or partial esters derived from fatty acids and hexitol anhydrides, 
for example sorbitan mono-oleate, and condensation products of the said 
partial esters with ethylene oxide, for example polyoxyethylene sorbitan 
mono-oleate. The emulsions may also contain sweetening and flavoring 
agents. 
Syrups and elixirs may be formulated with sweetening agents, for example 
glycerol, sorbitol or sucrose. Such formulations may also contain a 
demulcent, a preservative and flavoring and coloring agents. 
The pharmaceutical compositions may be in the form of a sterile injectable 
preparation, for example as a sterile injectable aqueous or oleagenous 
suspension. This suspension may be formulated according to the known art 
using those suitable dispersing or wetting agents and suspending agents 
which have been mentioned above. The sterile injectable preparation may 
also be a sterile injectable solution or suspension in a non-toxic 
parenterally-acceptable diluent or solvent, for example as a solution in 
1,3-butane diol or other suitable nontoxic organic solvent. Among the 
acceptable vehicles that may be employed are water, Ringer's solution and 
isotonic sodium chloride solution. In addition, sterile, fixed oils are 
conventionally employed as a solvent or suspending medium. For this 
purpose any bland fixed oil may be employed including synthetic mono- or 
diglycerides. In addition, fatty acids such as oleic acid find use in the 
preparation of injectables. 
Preferably, the compounds of this invention may be administered in the form 
of suppositories for rectal administration of the drug. These compositions 
can be prepared by mixing the drug with a suitable non-irritating 
excipient which is solid at ordinary temperatures but liquid at the rectal 
temperature and will therefore melt in the rectum to release the drug. 
Such materials are cocoa butter and polyethylene glycols. For example, a 
molten solution of the diflunisal ester and polyethylene glycol is 
prepared, to which is added glycerol. This product may be prepared at 
those temperatures which will provide a molten state. The mass is then 
sub-divided into suppository doses and allowed to congeal by lowering the 
temperature of the system. It is preferred to congeal at room temperature. 
The polyethylene glycol base may be made from any suitable pharmaceutical 
grade polyethylene glycol or mixtures thereof of various molecular weights 
which are used to prepare suppositories that are soluble in water and in 
the secretions of mucous membranes. Representative polyethylene glycol 
bases are polyethylene glycol 1000, 1540, 4000 and 6000. The selection of 
the exact composition of the base will, of course, depend on the 
properties desired in the suppository, such as solubility, congealing 
temperature, size, etc. The more preferred bases are those prepared from 
polyethylene glycol 4000 and polyethylene glycol 6000. The amount of the 
base employed in this invention is not critical and will depend on the 
overall size of the suppository, the desired use, and the dosage of 
diflunisal in each suppository. For example, the amount of base can vary 
from about 50% to 95% by weight of the suppository. 
For topical use, creams, ointments, jellies, solutions, or suspensions, 
etc., containing the anti-inflammatory agents are employed. 
Dosage levels of the order from 0.2 mg to 140 mg per kilogram of body 
weight per day are useful in the treatment of the above-indicated 
conditions (10 mg to 7 gms per patient per day). For example, inflammation 
is effectively treated and anti-pyretic and analygesic activity manifested 
by the administration from about 0.5 to 50 mg of the compound per kilogram 
of body weight per day (25 mg to 3.5 gms per patient per day). 
Advantageously, from about 2 mg to about 20 mg per kilogram of body weight 
per daily dosage produces highly effective results (100 mg to 2 gm per 
patient per day). 
The amount of active ingredient that may be combined with the carrier 
materials to produce a single dosage form will vary depending upon the 
host treated and the particular mode of administration. For example, a 
formulation intended for the oral administration of humans may contain 
from 5 mg to 5 gm of active agent compounded with an appropriate and 
convenient amount of carrier material which may vary from about 5 to about 
95 percent of the total composition. Dosage unit forms will generally 
contain between from about 25 mg to about 500 mg of active ingredient. 
It will be understood, however, that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
activity of the specific compound employed, the age, body weight, general 
health, sex, diet, time of administration, route of administration, rate 
of excretion, drug combination and the severity of the particular disease 
undergoing therapy.

EXAMPLE 1 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
To a solution of diflunisal (5.0 g) in 40 ml DMF was added 0.8 g of sodium 
hydride (oil suspension containing 60% of NaH). The resultant mixture was 
stirred for 1.5 hours at room temperature before 3.0 ml of ethyl 
1-chloroethyl carbonate was added dropwise. The reaction mixture was 
stirred at room temperature overnight and concentrated in vacuo. The 
concentrate was partitioned between ether/ethyl acetate and acidified 
water. The organic layer was separated and the aqueous layer was extracted 
again with ether. The organic layers were combined, washed well with 
water, dried over anhydrous sodium sulfate and concentrated to 6.6 g of 
crude product. After further purification by chromatography (eluted 
through 120 g of silica gel with hexane, and then 5% ethyl acetate in 
hexane), the product was crystallized from hexane to afford 3.71 g of 
1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate. 
m.p. 63.5.degree.-65.0.degree. C. (lower melting form I). 
Anal. Calcd. for C.sub.18 H.sub.16 F.sub.2 O.sub.6 : C, 59.02; H, 4.40. 
Found: C, 59.11; H, 4.34. 
EXAMPLE 2 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
Diflunisal (2.5 g) was dissolved in 30 ml of chloroform containing 1.1 g 
triethylamine. While stirring at room temperature, ethyl 
1-chloroethylcarbonate (1.66 g) was added slowly and the resulting 
reaction mixture was heated and refluxed for about 67 hours. After 
cooling, the mixture was concentrated in vacuo. The concentrate was 
partitioned twice between ether (200 ml) and water, and the organic 
extracts combined. After chromatography and crystallization as described 
in Example 1, there was afforded 38.5 g of crystalline product 
(crystallized from 5% ethylacetate in hexane), m.p. 
79.degree.-80.5.degree. C. (higher melting form II). 
EXAMPLE 3 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
A suspension of diflunisal (12.51 g) in 40 ml of methylchloroform was 
stirred at room temperature while 5.2 g triethylamine and 9.0 g of ethyl 
1-chloroethylcarbonate were added sequentially. The resultant solution was 
heated and refluxed for 90 hours before it was cooled and then poured into 
50 ml of diluted aqueous hydrochloric acid (5 ml of concentrated HCl in 45 
ml of water). The mixture was stirred vigorously and precipitation 
occured. The resultant precipitate was filtered, washed with 20 ml 
methylchloroform-hexane (1:1) to afford 1.65 g of unreacted diflunisal. 
The filtrates were combined and the organic layer separated. It was washed 
with water (100 ml), dried over anhydrous sodium sulfate and concentrated 
in vacuo. Crystallization occured upon seeding and 14.60 g (91.8%) of 
purified 1-(ethyoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)-salicylate was 
obtained. M.p. 78.degree.-79.5.degree. C. 
Following substantially the same procedure as described above, but 
substituting for ethyl 1-chloroethylethylcarbonate used therein the 
following chlorocarbonates as shown in Table I, there are obtained the 
corresponding 1-(alkoxy or aroxy) carbonyloxyalkyl esters of diflunisal 
also shown in Table I. 
TABLE I 
______________________________________ 
##STR9## 
##STR10## 
X R.sup.1 R 
______________________________________ 
Cl C.sub.2 H.sub.5 
C.sub.2 H.sub.5 
Cl CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 
Br n-C.sub.3 H.sub.7 
t-C.sub.4 H.sub.9 
Br CH.sub.3 CH(C.sub.6 H.sub.5).sub.2 
Cl C.sub.6 H.sub.5 
CH.sub.3 
Br cycloC.sub.6 H.sub.11 
p-CH.sub.3 OC.sub.6 H.sub.5 
______________________________________ 
EXAMPLE 4 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
Triethylamine (885 mg) was added to a stirred slurry of 
5-(2,4-difluorophenyl)salicylic acid in toluene (6.5 ml) under nitrogen. 
The resulting mixture was stirred for about 2 hours before ethyl 
1-chloroethylcarbonate (1.53 g) was added, and the resulting solution 
heated at reflux until reaction was complete. 
The reaction mixture was cooled and then added to aqueous hydrochloric acid 
solution. After thorough mixing, the layers were separated and the organic 
layers washed with water, dried and filtered. The solvent was removed 
under reduced pressure, leaving a pale oil which was crystallized from 
aqueous methanol to afford 2.84 g (91%) of 1-(ethoxycarbonyloxy) 
5-(2,4-difluorophenyl)salicylate, m.p. 79.degree.-80.degree. C. 
EXAMPLE 5 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
A mixture of 1.76 g of the triethylamine salt of diflunisal and 1.0 g of 
1-chloroethyl ethyl carbonate are heated in an oil bath at 
100.degree.-110.degree. with magnetic stirring for 3 hours. The reaction 
mixture is then cooled to room temperature and 5 ml of methanol are added. 
After cooling to 0.degree.-5.degree., the resulting precipitate is 
collected by filtration, washed with 3 ml of cold methanol then with 5 ml 
of 10% ethyl ether in hexane. After air drying there is obtained 1.38 g ( 
75%) of 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate, m.p. 
76.degree.-78.degree.. 
EXAMPLE 6 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate 
Step A: Preparation of 1-(ethoxycarbonyloxy)ethylsalicylate 
A mixture of 2.76 g salicylic acid, 2.02 g triethylamine and 3.5 gm 
1-chloroethyl ethyl carbonate in 25 ml of toluene is refluxed for three 
hours. The reaction mixture is cooled and 25 ml of ether and 25 ml of 
water added. The organic layer is separated, washed 2.times. with 25 ml 
water, dried through sodium sulfate and concentrated in vacuo. The residue 
(3.88 g) is chromatographed on 200 g silica gel. Elution with 25% 
methylene chloride in hexane gives 1-(ethoxycarbonyloxy)ethyl salicylate 
which is directly used in the next step. 
Step B: Preparation of 1-(ethoxycarbonyloxy)ethyl 
5-(2,4-difluorophenyl)salicylate 
A glass-lined autoclave is charged with 1 mmole of palladium acetate, 5 
mmole of sodium chloride, 1.6 mmole of sodium acetate, 2 mmole of 
phosphomolybdenovanadic acid, 10 g of ethylene carbonate, 5.0 ml of acetic 
acid, 465 mmole of 1-(ethoxycarbonyloxy)ethyl salicylate, and 510 mmole of 
m-difluorobenzene. The mixture is stirred for 48 hours at 90.degree. C. 
and under 200 psi oxygen pressure. The solution is cooled to 25.degree. C. 
and excess m-difluorobenzene is removed by distillation. Fifty ml of water 
and 150 ml of toluene are then added to the residue. The pH is adjusted to 
7-8 with aqueous sodium hydroxide (80 mmoles). The layers are separated 
and the aqueous solution is extracted with 150 ml of toluene. The toluene 
and then the excess starting materials are removed by distillation. The 
resulting residue is recrystallized from methanol to obtain pure 
1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate. 
EXAMPLE 7 
1-(Ethoxycarbonyloxy)ethyl 5-(2,4-fluorophenyl)salicylate 
Step A: Preparation of vinyl 5-(2,4-difluorophenyl)salicylate 
5-(2,4-Difluorophenyl)salicylic acid (1 mol), an excess amount of vinyl 
acetate (10 mole) and catalytic amounts of Hg(OAc).sub.2 (6 g) and conc. 
H.sub.2 SO.sub.4 (0.1 ml) are mixed at room temperature for 5 days. Excess 
5-(2,4-difluorophenyl)salicylic acid is removed and sodium acetate is 
added to neutralize the reaction. Excess vinyl acetate is removed to 
obtain the product, vinyl 5-(2,4-difluorophenyl) salicylate. 
Step B: Preparation of 1-chloroethyl 5-(2,4-difluorophenyl)salicylate 
To a mixture of vinyl 5-(2,4-difluorophenyl)salicylate (15 g) and 0.1 g dry 
PCl.sub.5, HCl gas is passed for about one hour at about 
120.degree.-125.degree. C. Upon cooling, the crude product crystallizes 
and is collected by filtration. Recrystallization from methanol yields 
pure 1-chloroethyl 5-(2,4-difluorophenyl)salicylate. 
Step C: Preparation of 1-(ethoxycarbonyloxy)ethyl 
5-(2,4-difluorophenyl)salicylate 
To a solution of 1-chloroethyl 5-(2,4-difluorophenyl)salicylate (5.0 g) in 
about 40 ml of DMF is added portionwise 3.0 g of sodium ethyl carbonate. 
The reaction is stirred at room temperature and then concentrated in 
vacuo. The concentrate is partitioned between ether/ethyl acetate and 
acidified water. The organic layer is separated and the aqueous layer is 
again extracted with ether, the organic layers are pooled and washed with 
water followed by drying and concentration to the crude product. After 
further purification by chromatography as described in Example 1, the 
product is crystallized from hexane to afford pure 
1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate. 
EXAMPLE 8 
Oral Suspension of 1-(ethoxycarbonyloxy)ethyl 
5-(2,4-difluorophenyl)salicylate 
______________________________________ 
Component mg/ml 
______________________________________ 
1-(ethoxycarbonyloxy) 366.25 
ethyl 5-(2,4-difluorophenyl) 
salicylate 
AVICEL 50.00 
Microcrystalline Cellulose NF 
Sodium Carboxymethylcellulose USP 
Methylcellulose USP 25.00 
Sorbic Acid NF 5.00 
Docusate Sodium USP 0.50 
Purified Water USP 2.50 
Antifoam Emulsion q.s. 
Sorbitol Solution 70% w/v to 5.0 ml 
______________________________________ 
The docusate sodium was dissolved in a small volume of water and added to 
the bulk in a suitable vessel. The Avicel was dispersed with agitation and 
allowed to hydrate. The remaining materials were then added with agitation 
and the suspension made to volume with Sorbitol Solution. The completed 
suspension was homogenized.