KR820000202B1 - Method for preparing auranofin - Google Patents

Abstract

Auranofin(I; Ac = acetyl; Y = Bromo, Chloro, tosyloxy, trifluoromethane sulfonyloxy or mesyloxy), useful for treatment of arthritis, was prepd. by reacting compd.(II) with Na2S(or K2S) and XAuP(C2H5)3 (X = halogen). Thus, 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 2.0 g was dissolved in water 20 ml and chloroform 20 ml. The soln. and ClAuP(C2H5)3 1.7 g was added in water 20 ml soln. of Na2SH2O 1.2 g, stirred at room temp. for 1 hr and then chloroform layer was separated. The chloroform layer was washed, dried, filtered, evaporated, and then recrystallized to give auranofin (m.p. 99-102≰C).

Description

New manufacturing method of oranopine

The present invention provides a novel chemical for the production of auranofin by reacting a 2,3,4,6, tetra-0-acetylglucopyranosyl reaction ester with triethylphosphine gold chromide in the presence of a monovalent alkali metal sulfide. It is about a method.

Oranopine is an active therapeutic agent in humans, like anti-arthritis. [J.Med.chem 15 1095 (1972): United States Patent No. 3,635,945]

The synthesis process is represented by the formula:

In the above scheme, Y is a reactive halogen residue such as bromine or chlorine or tosyloxy (toluenesulfonyloxy) brosyloxy (P-bromophenylsulfonyloxy) trifluoromethane sulfonyl Aryl or lower alkyl sulfonyloxy, such as oxy or mesyloxy (methanesulfonyloxy), Ac is acetyl, M is a monovalent alkali metal such as potassium or sodium, X is the remaining group defined in Y, preferably chlorine, bromine It is iodine.

Preferably, at least Y is chlorine or bromine and X is also chlorine, bromine or iodine. The arrangement in the 1-position of the sugar starting material (I) represents either α or β. Those skilled in the art will recognize that the substitution of α-halo will represent the desired β-configuration seen in oranopine.

Sulfur containing ester starting materials, such as tosyloxy, on the other hand would be β-arrays, as experts can expect the array to be invariant in oranopine production (SN1).

A "leaving group" is defined in the art as a weakly basic ionic group substituted with a nucleophilic group which is a triethylphosphinegoldthio group. See Morrison and Boyd, Third Edition Organic Chemistry (1973). As defined above, the remaining group is the reactive halo or sulfonyloxy moiety generated during the nucleophilic substitution.

The reaction was carried out in approximately equimolar amounts of reactions 2, 3, 4, 6-tetra-0-acetyl-α-D-glucopyranosyl ester (I), reaction triethylphosphine gold (I) halide (II) and sodium, The potassium sulfide (III) can be conveniently carried out by reacting in a solvent system capable of contacting the reactant. For example, the inert ideal system of organic / water can be most conveniently mapped. The most commonly used organic solvents are halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform, methylene dichloride, ethylene tetrachloride or 0-dichlorobenzene. Organic solvents that cannot be mixed with other water, such as benzene, solvent benzene, such as benzene, toluene xylene, hydrocarbon solvents, such as cyclohexane, can also be used. This is less advantageous than halogenated hydrocarbons.

Meanwhile, a phase transfer catalyst such as crown ether can be added and used.

시간 동안 혹은 반응이 완성될 때까지 교반하여 반응을 진행시킨다. 반응도중 환류온도까지 가열할 수 있으나 잇점은 없으며 고비등 용매를 사용할 경우 반응온도는 약 75℃로 제한된다.The reaction conditions may be changed by those skilled in the art, but preferably at room temperature

The reaction proceeds by stirring for a time or until the reaction is completed. It can be heated to the reflux temperature during the reaction, but there is no advantage, the reaction temperature is limited to about 75 ℃ when using high boiling solvent.

The starting materials to react are 2, 3, 4, 6-tetra-0-acetyl-α-D-glucopyranosyl, recorded in the field of RL Whistler's co-carbohydrate chemistry, Vol. 2, page 434 (1963). Halides, bromine are known to be representative. Others are made similarly. Representative tosyl, brosyl, trifluoromethanesulfonyl and mesyl esters were prepared, for example, from 2, 3, 4, 6-tetracetyl-β-glucos by the general reaction method developed on pages 244-245 of the book. .

The third postingold halide is B.M. A number of introductory publications are described in co-author J. Med.chem 15, 1097 (1972).

The reaction product was isolated by standard methods. For example, the organic layer was separated, washed and evaporated to obtain the desired John Moranovine, which can be purified by chromatography or fractional crystallization.

Alkali metal sulfides are believed to first produce sodium salts of tert-phosphine cold thiols which react with tert-phosphine gold halides and, conversely, sugar esters. At this stage, no mechanism for the reaction process is obtained.

The following examples are intended to illustrate the practice of the invention and do not limit the scope of the invention. All temperatures are in degrees Celsius.

Example 1

20 g of chloroform and 2.0 g (5 mmol) of 2, 3, 4, 6-tetra-0 dissolved in 20 ml of chloroform and 20 ml of water in a mixture of 1.2 g (5 mmol) of monohydrate sodium sulfide dissolved in 20 ml of water. -Acetyl-α-D-glucopyranosylbromide and 1.7 g (5 mmol) of tetraethylphosphine gold (I) chloride were added. After stirring for 1 hour at room temperature the layers were separated. The chloroform layer was washed, dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to yield an oily crude auraanoin. This material was passed through a woelm tube using chromoform to obtain a solid oranopine, and then recrystallized from ethanol-water to obtain a white solid.

(1%메탄올)=－52.4℃Melting Point 99-102 ° C

(1% methanol) = -52.4 degrees Celsius

Similar products were obtained by substituting potassium sulfide and 2, 3, 4, 6-tetra-0-acetyl-α-D-glucopyranosyl corrolide. Methylene chloride can also be substituted with chloroform.

Example 2

10 mmol of 1-β-tosyloxy 2, 3, 4, 6-tetra-0- dissolved in 3.4 g (10 mmol) of triethylphosphine gold (I) chromide and 80 ml of methylene chloride-30 ml of water. A mixture of acetylglucose and 10 mmol potassium sulfide was stirred at 0 ° C. for 1 hour and at room temperature for 5 hours. The organic layer was separated, washed, filtered and the filtrate was evaporated to give crude oranopine which was purified as in Example 1.

Example 3

1.0 g (1.5 mmol) bis [(triethylphosphine)] orus] sulfide [Asut. J. chem 19, 547 (1966) chromoform, prepared by reacting sodium sulfide with 2 molar equivalents of triethylphosphine chloride in water; and 0.6 g (1.5 mmol) of 2,3,4,6- The chloroform solution of tetra-0-acetyl-α-D-glucopyranosyl bromide was stirred for 48 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by benzene-ether (0 → 50%) on silica gel.

The product was purified to give oranopine.

(1%메탄올)=－53.3℃Melting point 109-111 degrees Celsius

(1% methanol) = -53.3 ° C

On the other hand, bromine dissolved in chromoform can be added to the used chromoform-water mixture to produce bis sulfide without isolating sulfides.

Claims (1)

A method of preparing oranopine by reacting a compound of the following structural formula with sodium sulfide or potassium sulfide and triethyl phosphine gold (I), triethyl phosphine gold (I) or triethyl phosphide gold (I).

Wherein Ac is acetyl and Y is bromo, chloro, tosyloxy, brosyloxy, trifluoromethane sulfonyloxy or mesyloxy.