Selective oxidation of 1,2-diphenyl-4-(2-phenylthio)ethyl)-3,5-pyrazolidinedione to the sulfinyl compound

Herein is described a process for oxidizing 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with peroxymonosulfuric acid to obtain 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione.

BACKGROUND OF THE INVENTION 
This invention describes a novel and useful process for oxidizing 
1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with 
peroxymonosulfuric acid to obtain 
1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. The latter 
compound is useful as an uricosuric agent. 
An oxidation of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione 
using hydrogen peroxide is described by R. Pfister and F. Hafliger, Helv. 
Chim. Acta, 44, 232 (1961). Although the latter report describes the 
preparation of 
1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione in 
reasonable yield, hydrogen peroxide is not suitable as an oxidizing agent 
when a number of large scale reactions have to be performed. In large 
scale preparations, use of hydrogen peroxide gives unpredictable yields of 
the sulfinyl compound, sometimes unacceptably low. Furthermore, with 
hydrogen peroxide, a major side reaction is the concurrent oxidation of 
the sulfoxide to the corresponding sulfone which is very difficult to 
remove. Several other oxidizing agents, for example, N-bromosuccinimide, 
sodium metaperiodate, chromic acid-pyridine, chromic acid-glacial acetic 
acid, perbenzoic acid and manganese dioxide, were tried. Each of these 
agents failed to produce the desired sulfinyl compound. Although 
m-chloroperbenzoic acid, when used as the oxidizing agent, gave the 
sulfinyl compound in reasonable yield, m-chloroperbenzoic acid is not 
acceptable because of its high cost. 
Surprisingly, use of peroxymonosulfuric acid, also known as Caro's acid, as 
the oxidizing agent gave consistent and acceptable yields (about 60%) of 
the desired sulfinyl compound and very small amounts of the undesired 
sulfone (less than 5%). Furthermore, Caro's acid is a very inexpensive 
oxidizing agent. 
The effectiveness of Caro's acid as an oxidizing agent is unexpected. More 
explicitly, diphenyl sulfide has been oxidized by Caro's acid to give 
diphenyl sulfoxide in 39% yield by I. P. Gragerov and A. F. Levit, Zh. 
Obshch. Khim., 33, 543 (1963). Diphenyl sulfide is a typical aromatic 
sulfide. The starting material used in this invention also is an aromatic 
sulfide and would be expected to behave as a typical aromatic sulfide; 
however, it does not. Most aromatic sulfides can be oxidized in 70% 
dioxane in water to the corresponding sulfoxide with an equivalent amount 
of N-bromosuccinimide. On the other hand, the reaction of 
N-bromosuccinimide with alkyl sulfides gives no sulfoxides, W. Tagaki et 
al., Chemistry and Industry (London), September 19, 1964, p 1624. The 
starting sulfide used in this invention failed to be oxidized to the 
sulfinyl compound under similar conditions using N-bromosuccinimide. Thus, 
the lack of reactivity of 
1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, when compared 
to typical aromatic sulfides, would predict that oxidation of the starting 
sulfide used in this invention with Caro's acid should give very low 
yields of the corresponding sulfinyl compound. However, the reverse was 
discovered, Caro's acid is an effective and safe oxidizing agent for 
selectivity converting 
1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione to the 
corresponding sulfinyl compound. 
SUMMARY OF THE INVENTION 
Herein is described a process for oxidizing 
1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with 
peroxymonosulfuric acid to obtain 
1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. 
DETAILS OF THE PROCESS 
The peroxymonosulfuric acid (Caro's acid) is prepared by stirring a mixture 
of potassium persulfate with about 0.26 molar equivalents of conc. 
sulfuric acid until a homogenous paste is obtained. To the paste, about 20 
molar equivalents of cold water is slowly added. After stirring for about 
one hour, the resulting solution of Caro's acid is ready for use as an 
oxidizing agent. 
Oxidation of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione 
with the above solution of Caro's acid gives 
1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. With 
respect to 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, 
about 1.0 to 2.0 molar equivalents, preferably 1.3 to 1.5 molar 
equivalents, of Caro's acid is required. These amounts of Caro's acid are 
based upon the potassium persulfate used to make up the Caro's acid. When 
performing the oxidation, a solvent is used to dissolve the starting 
material, 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione. 
Suitable solvents are inert water miscible solvents; for example, lower 
alkanols containing up to four carbon atoms and lower alkanoic acids 
containing two to four carbon atoms, or mixtures thereof. A useful solvent 
is acetic acid which can be used in amounts ranging from about 100 to 200 
molar equivalents of acetic acid with respect to the starting material. 
The starting material is first dissolved in the glacial acetic acid and 
then the Caro's acid is added. The solution of 
1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, aqueous Caro's 
acid and acetic acid is allowed to react until the oxidation is complete 
and 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione is 
formed. Usually, the solution is maintained at about 0.degree. to 
30.degree. C., preferably 5.degree. to 25.degree. C., for about 10 to 30 
hours. From the solution, 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl] 
-3,5-pyrazolidinedione is isolated in a conventional manner, for example, 
decomposition of excess Caro's acid, extraction and crystallization.

The following examples illustrate further the invention. 
EXAMPLE 1 
Preparation of Caro's Acid 
To 20 g (0.074 moles) of finely ground potassium persulfate (K.sub.2 
S.sub.2 O.sub.8), 15 ml of conc. sulfuric acid was added with stirring 
until a homogenous paste was obtained. Next, 260 ml of ice cold water was 
added (very exothermic) and the solution was stirred for one hour to 
obtain a solution of Caro's acid. 
EXAMPLE 2 
Oxidation of 1,2-Diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione 
1,2-Diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione (20 g, 0.052 
moles) was dissolved in 400 ml of glacial acetic acid. To this solution, 
240 ml of Caro's acid solution (described in Example 1) was added dropwise 
over a 30 minute period. A TLC taken three hours after the addition was 
begun showed starting material. The remainder of the Caro's acid solution 
was added and the reaction mixture was kept at 5.degree. C. for eighteen 
hours. Thereafter, the reaction mixture was stirred for two more hours 
while it came to room temperature. TLC showed no starting material. A 5% 
sodium bisulfite solution (200 ml) was added to the reaction mixture 
followed by the addition of 300 ml of ethyl acetate. Water (500 ml) and 
300 ml more of ethyl acetate were added. The layers were separated and the 
organic layer was washed with 500 ml of 5% sodium bicarbonate solution. 
The solvent was evaporated under reduced pressure and toluene (150 ml) was 
added. The toluene was removed by evaporation under reduced pressure to 
give a residue (20.2 g). The residue was crystallized from ethanol (60 ml) 
to give 9.7 g of 
1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. The mother 
liquors were concentrated to give another 2.8 g of the sulfinyl compound 
(total 12.5 g, 60% of theory). The sulfinyl compound exhibited the 
following characteristics: mp 130.degree.-131.5.degree. C.; 
nmr(CDCl.sub.3).delta. 2.45 (m, 2H), 3.3 (m, 3H), 7.25 (m, 10H) and 7.5 
(m, 5H); and Anal. Calcd for C.sub.23 H.sub.20 O.sub. 3 N.sub.2 S: C, 
68.30% H, 4.99% N, 6.93% and Found: C, 67.94% H, 5.09% N, 6.84%.