GB1586996A - Method for preparing auranofin - Google Patents

Description

(54) METHOD FOR PREPARING AURANOFIN (71) We, SMITHKLINE CORPORATION of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organised under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to process for preparing (2,3,4,6 - tetra - O - acetyl - I thio - A - D - glucopyranosato - S)(triethyl phosphine gold) referred to in this specification as auranofin.

Auranofin is an orally active anti-arthritic agent and has been disclosed in J. Med.

Chem., 15, 1095, (1972) and disclosed and claimed in British Patent Specification 1270776. These references describe inter alia a preparation of auranofin in which an alkali-metal salt of 1 - thio - p - D glucopyranose is reacted with a triethylphosphine gold halide. We have now found that auranofin can be prepared from certain tetra - 0 - acetylglucopyranosyl derivatives by reaction with certain triethylphosphine gold(I) halides and sodium or potassium sulfide.

Accordingly the present invention provides a process for preparing auranofin which comprises reacting a compound of structure (I):-

where Y is tosyloxy (p-toluenesulfonyloxy), brosyloxy (p-bromophenylsulfonyloxy), trifluoromethanesulfonyloxy, mesyloxy (methanesulfonyloxy), chloro, bromo or iodo, with triethylphosphine gold(I) chloride, bromide or iodide and sodium or potassium sulfide.

Preferably Y is a-chloro or a-bromo Preferably the reaction is with triethylphosphinegold(I) chloride or bromide.

Preferably triethylphosphinegold(I) chloride is reacted with 2,3,4,6 - tetra - 0 acetyl - a - D - glucopyranosyl bromide in a biphase solvent system as described below comprising a halogenated hydrocarbon organic solvent and water until the reaction is complete.

The configuration at the l-position of the sugar starting materials is indicated to be either cr or A. Those skilled in the art will recognize that displacement under SN2 conditions of an a-substituent (for example ce-halo) will give the desired A-configuration which is present in auranofin. On the other hand, displacement of a p-substituent (for example p-tosyloxy) proceeds by an SN mechanism which results in retention of configuration upon reaction to give auranofin.

The reaction can be carried out most conveniently by reacting approximately equimolar quantities of a reactive 2,3,4,6 tetra -O-acetyl-a - D - glucopyranosyl derivative, a triethylphosphine gold(I) halide and either sodium or potassium sulfide in a solvent system in which the reactants can be brought into contact. For example most conveniently an inert biphasic system of organic solvent is halogenated hydrocarbon solvent e.g.

carbon tetrachloride, chloroform, methylene dichloride, ethylene tetrachloride or o-dichlorobenzene. Other water-immiscible organic solvents may also be used: these include benzenoid solvents, for example, benzene, toluene or xylene, or hydrocarbon solvents, for example, cyclohexane. These give little advantage over the halogenated hydrocarbons.

An alternative which may be used is the addition of a phase transfer catalyst such as a Crown ether.

The conditions of the reaction may be varied but most usefully the reaction is carried out at about room temperature with stirring for from 1/2-6 hours or until the reaction is complete. Heating up to the reflux temperature of the reaction may be used but with no marked advantage and in the case of high boiling solvents the reaction temperature may be limited to about 75"C.

The starting materials for the reaction are known for example a representative 2,3,4,6 - tetra 0 - acetyl - a - D - glucopyranosyl halide, the bromide, is reported in Methods in Carbohydrate Chemistry, Vol. 2, page 434 (1963) R. L.

Whistler et al. Others can be prepared similarly. Representative tosyl, brosyl, trifluoromethane sulfonyl and mesyl esters can be prepared for example from 2,3,4,6 tetraacetyl- p- glucose by the general reaction methods disclosed in the same volume pages 244-245. The tertiaryphosphinegold halides are reported in B. M. Sutton et al. J. Med. Chem. 15, 1095 (1972).

The reaction product can be isolated by standard methods. For example the organic layer is separated washed and evaporated to give the desired crude auranofin which then may be purified by chromatography or fractional crystallization.

The following Examples illustrate the invention. All temperatures are Centigrade.

EXAMPLE 1 A mixture of 1.2 g (5 mmole) of sodium sulfide monohydrate in 20 ml of water was added to a mixture of 2.0 g (5 mmole) of 2,3,4,6 - tetra - 0 - acetyl - a - D - glucopyranosyl bromide and 1.7 g (5 mmole) of triethylphosphinegold(I) chloride in 20 ml of chloroform and 20 ml of water. After stirring at room temperature for 1 hour, the layers were separated. The chloroform layer was washed, dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give oily crude auronofin. This material was passed over an alumina (Woelm) column using chloroform to give solid auranofin which was then recrystallized from ethanol-water to give a white solid, m.p. 99-1020C. [ t]DS (1% methanol) =52.4o.

Substituting potassium sulfide and/or 2,3,4,6 - tetra - 0 - acetyl - a - D - glucopyranosyl chloride gives similar product. Methylene chloride may be substituted for chloroform.

EXAMPLE 2 A mixture of 3.4 g (10 mmole) of triethylphosphinegold(I) chloride with 10 mmole of 1 - p - tosyloxy - 2,3,4,6 tetra - O - acetylglucose and 10 mmole of potassium sulfide in 80 ml of methylene chloride - 30 ml of water is stirred at OOC.

for 1 hour and then at room temperature for 5 hours. The organic layer is separated, washed, filtered and the filtrate evaporated to give crude auranofin which is purified as in Example 1.

Substituting the mesyloxy or broxyloxy esters in molar equivalent quantities gives the same product.

WHAT WE CLAIM IS: 1. A process of preparing auranofin which comprises reacting a compound of the structure (I):-

where Ac is acetyl and Y is bromo, chloro, iodo, tosyloxy, brosyloxy, trifluoromethanesulfonyloxy or mesyloxy with sodium or potassium sulfide and triethylphosphinegold(I) chloride, bromide or iodide.

2. A process as claimed in claim 1 where Y is a-bromo or a-chloro.

3. A process as claimed in claim 2 where triethylphosphinegold(I) chloride is reacted with 2,3,4,6 - tetra - 0 - acetyl - a - D glucopyranosyl bromide and sodium or potassium sulfide in a biphase solvent comprising a halogenated hydrocarbon organic solvent and water until the reaction is complete.

4. A process as claimed in claim 1 in which the reaction is carried out in the presence of methylene dichloride as a solvent.

5. A process as claimed in claim 3 where methylene dichloride is used as the halogenated organic solvent.

6. A process for preparing auranofin substantially as described in Examples 1 or 2.

7. Auranofin whenever prepared by a process according to any one of claims 1 to 6.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   An alternative which may be used is the addition of a phase transfer catalyst such as a Crown ether.

   The conditions of the reaction may be varied but most usefully the reaction is carried out at about room temperature with stirring for from 1/2-6 hours or until the reaction is complete. Heating up to the reflux temperature of the reaction may be used but with no marked advantage and in the case of high boiling solvents the reaction temperature may be limited to about 75"C.

   The starting materials for the reaction are known for example a representative 2,3,4,6 - tetra 0 - acetyl - a - D - glucopyranosyl halide, the bromide, is reported in Methods in Carbohydrate Chemistry, Vol. 2, page 434 (1963) R. L.

   Whistler et al. Others can be prepared similarly. Representative tosyl, brosyl, trifluoromethane sulfonyl and mesyl esters can be prepared for example from 2,3,4,6 tetraacetyl- p- glucose by the general reaction methods disclosed in the same volume pages 244-245. The tertiaryphosphinegold halides are reported in B. M. Sutton et al. J. Med. Chem. 15,

   1095 (1972).

   The reaction product can be isolated by standard methods. For example the organic layer is separated washed and evaporated to give the desired crude auranofin which then may be purified by chromatography or fractional crystallization.

   The following Examples illustrate the invention. All temperatures are Centigrade.

   EXAMPLE 1 A mixture of 1.2 g (5 mmole) of sodium sulfide monohydrate in 20 ml of water was added to a mixture of 2.0 g (5 mmole) of 2,3,4,6 - tetra - 0 - acetyl - a - D - glucopyranosyl bromide and 1.7 g (5 mmole) of triethylphosphinegold(I) chloride in 20 ml of chloroform and 20 ml of water. After stirring at room temperature for 1 hour, the layers were separated. The chloroform layer was washed, dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give oily crude auronofin. This material was passed over an alumina (Woelm) column using chloroform to give solid auranofin which was then recrystallized from ethanol-water to give a white solid, m.p. 99-1020C. [ t]DS (1% methanol) =52.4o.

   Substituting potassium sulfide and/or 2,3,4,6 - tetra - 0 - acetyl - a - D - glucopyranosyl chloride gives similar product. Methylene chloride may be substituted for chloroform.

   EXAMPLE 2 A mixture of 3.4 g (10 mmole) of triethylphosphinegold(I) chloride with 10 mmole of 1 - p - tosyloxy - 2,3,4,6 tetra - O - acetylglucose and 10 mmole of potassium sulfide in 80 ml of methylene chloride - 30 ml of water is stirred at OOC.

   for 1 hour and then at room temperature for 5 hours. The organic layer is separated, washed, filtered and the filtrate evaporated to give crude auranofin which is purified as in Example 1.

   Substituting the mesyloxy or broxyloxy esters in molar equivalent quantities gives the same product.

   WHAT WE CLAIM IS: 1. A process of preparing auranofin which comprises reacting a compound of the structure (I):-

   where Ac is acetyl and Y is bromo, chloro, iodo, tosyloxy, brosyloxy, trifluoromethanesulfonyloxy or mesyloxy with sodium or potassium sulfide and triethylphosphinegold(I) chloride, bromide or iodide.
2. 2. A process as claimed in claim 1 where Y is a-bromo or a-chloro.
3. 3. A process as claimed in claim 2 where triethylphosphinegold(I) chloride is reacted with 2,3,4,6 - tetra - 0 - acetyl - a - D glucopyranosyl bromide and sodium or potassium sulfide in a biphase solvent comprising a halogenated hydrocarbon organic solvent and water until the reaction is complete.
4. 4. A process as claimed in claim 1 in which the reaction is carried out in the presence of methylene dichloride as a solvent.
5. 5. A process as claimed in claim 3 where methylene dichloride is used as the halogenated organic solvent.
6. 6. A process for preparing auranofin substantially as described in Examples 1 or 2.
7. 7. Auranofin whenever prepared by a process according to any one of claims 1 to 6.