Process and intermediate for preparing auranofin

The S-gold salt of 2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose reacts with triethylphosphine in an organic solvent to produce auranofin.

This invention comprises a new method for preparing the orally active gold 
containing antiarthritic agent, auranofin, which uses as starting material 
a new intermediate, 
S-gold-2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose. 
Auranofin has been demonstrated to be useful as an antiarthritic agent in 
man [J. Med. Chem. 15 1095 (1972); U.S. Pat. No. 3,635,945]. In these 
prior art references auranofin is prepared by reacting an alkali metal 
salt of a 1-thio-.beta.-D-glucopyranose with a triethylphosphine gold 
halide. It also will be noted that the new intermediate S-gold salt used 
as starting material in this invention is the tetra acetyl derivative of 
the known gold compound aurothioglucose, see Merck Index 7th Ed. page 495. 
The invention claimed here is believed patentable over prior art known to 
the applicants. 
The synthetic process here described may be illustrated by the following: 
##STR1## 
In this reaction, as is known to the art, Ac represents acetyl. 
The method for preparing auranofin in the references referrred to above 
comprises reacting the potassium or sodium salt of 
2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose with triethylphospine 
gold (I) chloride in an aqueous alcohol solvent in the cold. The alkali 
metal salt starting material was generated from the 1-thiopseudourea 
derivative using sodium or potassium carbonate in water at below zero 
temperatures. We have now found that the gold salt of 
2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose can be prepared 
directly from its alkali metal salt by reaction with aurous chloride 
generated in situ from the reaction of gold acid chloride with 
thiodiglycol in the presence of an alkali metal base. This gold salt, 
never to our knowledge previously reported, reacts with tertiary 
phosphines readily under simple reaction conditions to give tertiary 
phosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranosides in 
excellent yield and purity. 
The reaction of this invention is most conveniently carried out by reacting 
the new S-gold-2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose with a 
stoichiometric amount of triethylphospine in an inert aprotic organic 
solvent in which the two reactants are soluble such as a common 
halogenated hydrocarbon solvent such as chloroform, carbon tetrachloride, 
ethylene tetrachloride or methylene chloride, a benzenoid solvent such as 
benzene, toluene or xylene, diethyl carbonate, dimethylformamide, 
dimethylacetamide, ethereal solvents such as diethyl ether or dioxane, 
ethylacetate, dimethyl sulfoxide, lower alkanols such as methanol, ethanol 
or isopropanol. Methylene chloride is a most convenient solvent. 
The reaction most conveniently run and proceeds to completion at room 
temperature almost immediately. The desired auranofin is easily isolated 
and purified by methods known to the art. 
The new gold salt (I) which is also part of this invention may also be 
prepared by other methods as will be apparent to those skilled in the art 
for example by O-acetylation of aurothioglucose (Solganol) but the methods 
detailed hereafter are simple and give excellent yields of pure product. 
The reaction outlined above is generally applicable to the gold salts of 
any thio sugar especially their O-acylated or O-methylated derivatives as 
well as to any organic thiol which is capable of forming either a gold 
salt or a known alkali metal salt which can be converted into such a gold 
salt. Other thio sugars which may be substituted in equimolar quantities 
in the example are: hepta-O-acetylthiomaltose, thiofructose or 
thioglucofuranose. 
The following example is to illustrate but not to limit this invention. 
Other modifications will be obvious to those skilled in the art. All 
temperatures are on the Centigrade scale.

EXAMPLE 1 
Thiodiglycol 6.4 g (0.052 mole) in ethanol (20 ml) was added to 10 g (0.025 
mole) of gold acid chloride trihydrate in water (50 ml) at 0.degree.. To 
this was added, after filtering, a solution of 9.4 g (0.026 mole) of 
2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose and 6.6 g (0.048 
mole) of potassium carbonate in 25 ml of ethanol and 60 ml of water. After 
stirring 1 hour at 0.degree. (foaming) the precipitate was removed by 
filtration, washed with water and air-dried. Recrystallization from 
isopropanol-ether gave 
S-gold-2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose as a light 
yellow solid, m.p. 146-148.degree.; [.alpha.].sub.D.sup.25 = -56.9 (1% 
methanol). 
Triethylphosphine 0.2 g (1.7 mmole, 0.25 ml) was added to 1.0 g (1.7 mmole) 
of S-gold-2,3,4,6-tetra-O-acetyl-1-thio-.beta.-D-glucopyranose in 6 ml of 
chloroform kept at room temperature. The solution immediately becomes 
colorless and after 15 minutes the solvent was removed at reduced 
pressure. Chromotagraphy (silica gel/ethyl acetate) gave 0.76 g of 
auranofin as a white solid which was recrystallized from methanol (3 ml) 
to give 0.55 g (45%) of product, m.p. 106.degree.-108.degree.; 
[.alpha.].sub.D.sup.25 = -56.1 (1% methanol). 
Equimolar quantities of the following tertiary phosphines may be 
substituted for triethylphosphine in this reaction such as 
butyldiethylphosphine, triallylphosphine, triisopropylphosphine, 
phenyldiethylphosphine, p-chlorophenyldiethylphosphine, 
p-methoxyphenyldiethylphosphine or diphenylethylphosphine.