PROCEDURE FOR THE PRODUCTION OF AURANOFIN

The invention concerns a procedure for the production of Auranofin of the general formula CH2OAc SAuP (C2H) 2 AcO OAc where AC for acetyl stands, which by it is characterized that a 2,3,4,6-Tetra-O-acetylglucopyranosylderivat of the general formula CH2OAc AcO OAc CI) where Y stands for bromine, chlorine, Tosyloxy, Brosyloxy, Trifluormethansulfonyloxy or Mesyloxy, by Natriumoder Kaliumsulfid and tri ethyl pho fit gold [I) - chloride, - bromide is converted or - iodide. Auranofin is an orally effective therapeutically working connection. with humans like a antiarthritlsches drug for treatment is usable [J.Med.Chem. 15, 1095 (1972), US-PS Nr.3, 635.945]. In the reaction according to invention the Seitenkette Y is a reactive nucleofuger remainder, i.e. halogen, e.g. Brem, chlorine or aryl or low Alkylsulfonyloxy, like Tosyloxy (Toluolsulfonyloxy), Brosyloxy (p-Bromphenylsulfonyloxy), Trlfluormethansulfonyloxy or Mesyloxy (Methansulfonyloxy): AC is acetyl. Y preferably means “- bromine or s-chlorine. The Konfignration in the 1-Stellung of the Zuckerausgan£skomponenten is either “or B. It is evidently that the displacement one “- substituents (for example “- halogen) under SN2-Bedingungen the desired 8-Konfiguratlon results in, which in the Auranofin is present. On the other hand the displacement of a B-substituent (for example B-Tosyloxy) takes place via a SNi mechanism, due to a participation from the 2-Acetoxygruppe, which leads to a retention of the configuration after the conversion to the production of the Auranofins. With the reaction according to invention a so-called is displaced “leaving group” by a nukleophile group, which is in this case the Goldthiotriäthylphosphingruppe (Organic Chemistry, Morrison and Boyd, 3.Auflage! 973). “Leaving group” thus the set free Halogenidoder is Sulfonyloxy ion. The reactive ones preferably becomes with approximately äquimolaren quantities of the reacting 2,3,4,6-Tetra-Oh-acetyl “- D-glucopyranosylesters (I), and the reacting Goldtriäthylphosphinhalegenlds accomplished, with Natriumoder Kaliumsulfid in a solvent system, in which the reagents can be brought in contact. For example an inert system with two layers (organic solvent and water) can be used. The mostly used organic solvent is a halogenierter hydrocarbon, like carbon tetrachloride, chloroform, dichloromethane, 24thylentetrachlorid or o-Dichlorbenzol. Other organic solvents unmischhare with water can be used also, like aromatic hydrocarbons, e.g. benzene, toluol or xylene, or hydrocarbons, like Gyclohexan. In the comparison with the halogenierten hydrocarbons these have a small advantage. Another possible solution consists in the additive of a Katalysator-0hertragungsphase of an Crown ether. The reaction is accomplished at ambient temperature with agitating during 1/2 to 6 h and/or to would usually eat reaction is complete. Warming up can take place up to the bending river temperature, however without noticeable advantage, and in case of of high-boiling solvents the reaction temperature on for instance 75°C can be limited. The output components for the reaction are well-known, e.g. a 2,3,4,6-Tetra-O-auetyl - - is D-glucopyranosylhalogenid, like bromide, in Carbohydrate Chemlstry, 2.Band, page 434 (1963), B.L. Whistler et el., described. Others are in the same way manufactured. Typical Tosyl, Brosyl, Trifluormethansulfonylund Mesylester is made e.g. of 2,3,4,6-Tetraacetyl-B-glucose with i0 the general reaction methods descriptive in the same volume (pages 244-245). The gold Tertiary period pho fit halides are et in B.M. Sutton el., J.Med.Ghem. 15, 1095 (1972) described. The reaction product is separated with standard methods, z, B. are separated, washed and evaporated the organic layer, in order to supply the desired Bohauranofin, which can be cleaned on it by chromatography or recrystallization. It is assumed that the alkali metal sulfide reacts first with the gold Tertiary period pho fit halide, in order to form the sodium salt Goldthiol tertißr phosphins, which reacts with the sugar remainder. Until today no proof for this reaction rim, created on experience, exists. In the following examples all temperatures are indicated in centigrades. Example 1: A mixture of 1,2 g (5 mMol) sodium sulfide mono hydrate in 20 ml water was given to 1.7 g to a mixture of 2,0 g (5 mMol) 2, S, 4,6-Tetra-O-acetyl “- D-glucopyranosylbromid and {5 mMol) gold tri ethyl pho fit chloride in 20 ml chloroform and 20 ml water. According to agitating at ambient temperature during 1 h the layers were separated. The chloroform-laminated was dried washed, over magnesium sulfate, evaporated filtered and the filtrate under decreased pressure, in order to supply an oily Rohauranofin. This material was chromatographiert on a A12 OS column (Woelm) with chloroform to result in order to supply firm Auranofin, which was recrystallized afterwards from ethanol/water, in order a white, firm product. Fp.: 99 to 102°C; Cl methanol) = -52,4°. With Kaliumsulfid and/or 2,3,4,6-Tetra-Oh-acetyl “- D-glucopyranesylchlorid a homogenous product is won. Dichloromethane can replace chloroform. Example 21 a mixture of 3,4 g (10 mMol) Goldtriäthylphosphinahlorid with 10 mMol l - Tosyloxy-2.3, 4,6-tetra-O-aeetylglucese and I0 mMol Kaliumsulfid in 80 ml dichloromethane and ml water are agitated afterwards with 0QC during I h and at ambient temperature during 5 h. The organic laminates is separated, washed, filtered and the filtrate evaporated, in order to receive Rohauranofin, which as with example 1 is cleaned. If one uses the Mesyloxyoder Brosyloxyester in äquimolaren quantities, the same product is received.