CN1057092C - Preparation of Anranofin - Google Patents

Abstract

The present invention relates to a method for preparing auranofin, which takes 2-S-(2, 3, 4, 6-4-O-acetyl-beta-D-glucopyranosyl)-2-thiopseudourea hydrobromate (I), monochlorizate (triethylphosphine) alloy (IV) and potassium carbonate (II) as raw materials. The present invention is characterized in that the methanol-aqueous solution of the 2-S-(2, 3, 4, 6-4-O-acetyl-beta-D-glucopyranosyl)-2-thiopseudourea hydrobromate (I) is mixed with the methanol solution of the monochlorizate (triethylphosphine) alloy (IV); the mixed solution is stirred at 0 to 5 DEG C and the aqueous solution of the potassium carbonate (II) is dropped in the mixed solution for reaction for 60 to 90 minutes and 30 to 40 minutes at a room temperature; the obtained crystal auranofin is recrystallized and purified by the methanol-aqueous solution to obtain a pure auranofin product. The method of the present invention is used for preparing good drugs resisting rheumatoid diseases, namely auranofin.

Description

The preparation method of auranofin

The present invention relates to the preparation method of gold compound, particularly gold compound (2,3,4, the preparation method of (triethyl phosphine) alloy of 6-four-O-ethanoyl-1-sulfo--β-D-glucopyranosyl-S), this compound claims auranofin (Auranofin) again.

Gold salt has the resisting rheumatoid disease activity and is used for the treatment of the rheumatoid arthritis history of existing decades as goldinjection, as sodium aurothiomalate (Myocrisin) and aurothioglucose (Solganol) etc.Use by influence because toxic side effect is big for this type of non-enteron aisle gold medicine

The organophosphite ligand compound auranofin of gold is the oral golden medicine of a kind of novel resisting rheumatoid disease (US3635945), compare with goldinjection, it has safe in utilization, convenient and toxic side effect features of smaller, and be used for clinically, become the oral prescription drug of a new generation treatment rheumatoid arthritis.

In the whole bag of tricks of preparation auranofin, the disclosed method of US 3635945 (1972.1.18) is a kind of by top-priority method.This method is with 2-S-(2; 3; 4; 6-four-O-ethanoyl-β-D-glucopyranosyl)-2-sulfo-isourea halogen acid salt (I) is a raw material, through the solution-treated of alkali metals carbonate (II), generates intermediate (2 earlier; 3; 4,6-four-O-ethanoyl-β-D-Glucopyranose) derivative (III), react with a halogen (triethyl phosphine) alloy (IV) again; obtain auranofin; product productive rate 90% (J.Med.Chem., 1972,15; 1095); in building-up process, make solvent with ethanol, temperature of reaction-20～-10 ℃.It is brief that this method has flow process, the characteristics that the product productive rate is higher, and raw material (I) chemical stability is good, makes easily,

Therefore, has higher Practical significance.But, this method is in (I) and intermediate formation reaction (II), the process of its hydrolysis reaction can't be judged, the intermediate that is generated (III) is extremely unstable again, generate the back if the untimely reaction that generates auranofin, in alkali solution, multiple unmanageable side reaction will take place, cause the productive rate of product to reduce.Product is difficult for purifying; And this method operational condition is harsh, carries out below requiring to be reflected at low temperature-10 ℃, solvent for use ethanol is to raw material (I), (IV) and the solubleness of auranofin less, be difficult to guarantee to be reflected in the liquid phase of homogeneous and carry out, influence the stable of auranofin productive rate, also bring difficulty to operation; Simultaneously, this method does not relate to the purification of auranofin, has reduced its Practical significance to a certain extent.

US 4125710 (1978.11.14) discloses the another kind of method for preparing auranofin.This method with a kind of general formula is:

Compound (in the formula M be a kind of stable positively charged ion from basic metal, ammonium, lead, silver or copper positively charged ion, selected or (wherein Ac is an acetyl)), with a kind of general formula be:

(Et ₃P) ₂The compound reaction (X is a kind of stable negatively charged ion of selecting from halogenide, nitrate, thiocyanate-, perchlorate, tetrafluoride boron or trifluoroacetate in the formula) of AuX is reflected in methyl alcohol or the ethanol and carries out, about 0 ℃ of temperature of reaction or room temperature.But, the gold complex [(Et that this method will be formed with two triethyl phosphines in building-up process ₃P) ₂AuX, cost is higher; And, with the highest ability 42% of auranofin productive rate of this method acquisition.

Its method of preparation method that US 4125711 also discloses a kind of auranofin is to make 1-β-D-sulfo--2,3,4, and 6-four-O-ethanoyl Glucopyranose and a kind of general formula are:

(C ₂H ₅) ₃The compound reaction of PAuS-R, R is the alkyl of 1～8 carbon in the formula, phenyl or Et ₃PAuS-; Being reflected at a kind of organic solvent for example carries out in the chloroform.Yet, this method finally will under-23 ℃ in 3: 5 methanol aqueous solution recrystallization obtain auranofin, after perhaps purifying earlier, carry out twice recrystallization with methanol-water again and obtain auranofin, its productive rate only 55% with column chromatography.

The objective of the invention is to overcome the deficiency that prior art exists, a kind of improved auranofin preparation method is provided,, improve the purity of product, and make to be reflected under the relatively mild condition and carry out, thereby reduce preparation cost to improve the productive rate of auranofin.

Technical scheme of the present invention is: (1) changes the raw material interpolation order of 2-S-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl)-2-sulfo-isourea hydrobromate (I), a chlorine (triethyl phosphine) alloy (IV) and salt of wormwood (II); (2) methyl alcohol replaces ethanol, does reaction solvent with methanol-water; (3) improve temperature of reaction, make to be reflected under the mild conditions that taps into 0～20 ℃ of room temperature and carry out; (4) auranofin that makes is purified at the room temperature recrystallization.

The inventive method comprises that a chlorine (triethyl phosphine) alloy (IV) and salt of wormwood (II) are raw material, it is characterized in that synthesis procedure is as follows with 2-S-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl)-2-sulfo-isourea hydrobromate (I):

A. (I) is dissolved in methyl alcohol: water=1.5～2: in the solution of 1 (volume ratio), obtain A liquid;

B. (IV) is dissolved in the methyl alcohol, obtains B liquid;

C. (II) is soluble in water, obtain C liquid;

D.A liquid mixes with B liquid, is cooled to 0～5 ℃, under 0～5 ℃ of stirring to mixed solution and dripping C liquid, add C liquid, reacted 90～100 minutes, and continued reaction 30～40 minutes again under room temperature, heating in water bath is to the solid dissolving that generates, filter, adding distil water to precipitation occurs in the filtrate, and cooling is filtered, leach thing methyl alcohol: the solution washing of water=0.4: 1 (volume ratio), room temperature vacuum-drying get white auranofin crystal.

Resulting auranofin crystal is carried out methanol-water solution weight crystallization and purification again under room temperature, vacuum-drying gets pure product.

In aforesaid method, input starting raw material should satisfy the measuring requirement of chemical reaction, under the principle of not wasting, by near waiting mole or suitably excessive (I), (II) for well; Institute's solubilizing agent should guarantee that the starting raw material that drops into dissolves fully, under the principle of not wasting, and can be suitably excessive.

Compare with prior art, the present invention has following advantage:

1, improve the temperature of building-up reactions, reaction can be carried out under near the mild conditions of room temperature, operated the simple and easy little energy that expends, with low cost.

2, the productive rate height of auranofin product, the auranofin product productive rate that obtains with the inventive method is not less than 94.0%, and the product yield that recrystallization is purified is not less than 89.5%.

3, flow process is short, and the time of consumption is few.

4, the reliable easily row of recrystallization method of purification.

Therefore, in known each preparation method, the present invention has very high Practical significance.

Embodiment 1

Get 5.0 gram (10.3mmol) 2-S-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl)-2-sulfo-isourea hydrobromates (I) and be dissolved in 15ml water and the 30ml methanol solution, obtain A liquid; 3.4 gram (9.7mmol) chlorine (triethyl phosphine) alloy (IV) is dissolved in the 50ml methyl alcohol, obtains B liquid; 1.6 gram (11.6mmol) salt of wormwood (II) is dissolved in the 15ml water, obtains C liquid.

A liquid mixes with B liquid, is cooled to 0～5 ℃, in this temperature range, in mixed liquid, drip C liquid, add C liquid, continue reaction 60 minutes, continue reaction 30 minutes again under room temperature, heating in water bath filters to the solid dissolving that generates, adding distil water to precipitation occurs in the filtrate, cooling is filtered, and leach thing methyl alcohol: the solution washing of water=0.4: 1 (volume ratio) leaches thing, room temperature vacuum-drying gets white crystal product 6.2 grams, productive rate 94.0%.Through the methanol-water recrystallization, room temperature vacuum-drying gets pure product 5.5 grams of auranofin, recrystallization product yield 89.5% to products therefrom under room temperature.

After tested, 113～114.5 ℃ of the fusing points of the pure product of gained auranofin, [α] _D ²⁰=-59.01 (1% methyl alcohol); Ultimate analysis (weight %) measured value (calculated value): C35.33 (35.40), H5.06 (5.06), S5.01 (4.73), Au 28.95 (29.02); UV: λ _Shoulder=220, ε ₂₂₀=2900 (95% methyl alcohol); IR:(cm ^-1); KBr pressed disc method: ν _CH3(2956,2884), ν _CH2(2922,2855), ν _C=O(1746), δ _CH2(1450), δ _CH3(1370), ν _C-O-C(1230), ν _C-O-C(1090,1052,1032), pyranose ring vibration (910), ρ _CH2(770), ν _P-C(738,604); Valelinum Liquidum pressed disc method: ν _P-Au(380), ν _S-Au(270).

Embodiment 2

Get 44.0 gram (0.090mol) 2-S-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl)-2-sulfo-isourea hydrobromates (I) and be dissolved in 120ml water and the 234ml methanol solution, obtain A liquid; 30.0 gram (0.086mol) chlorine (triethyl phosphine) alloy (IV) is dissolved in the 400ml methyl alcohol, obtains B liquid; 14.0 gram (0.101mol) salt of wormwood (II) is dissolved in the 115ml water, obtains C liquid.

A liquid mixes with B liquid, is cooled in 0～5 ℃ of scope, drips C liquid in mixed liquid, add C liquid, continue reaction 90 minutes, under room temperature, continue reaction 40 minutes again, heating in water bath is to the solid dissolving that generates, filter, adding distil water to precipitation occurs in the filtrate, cooling, filter, leach thing methyl alcohol: the solution washing of water=0.4: 1 (volume ratio) leaches thing, and room temperature vacuum-drying gets white crystal product 55.2 grams, productive rate 95.0%.Through the methanol-water recrystallization, room temperature vacuum-drying gets pure product 49.6 grams of auranofin, recrystallization product yield 90.0% to products therefrom under room temperature.

After tested, 112～114 ℃ of the fusing points of the pure product of gained auranofin, [α] _D ²⁰=-54.40 (1% methyl alcohol); Ultimate analysis (weight %) measured value (calculated value): C 35.32 (35.40), H 5.09 (5.06), S4.68 (4.73), Au29.25 (29.02); UV: λ _Shoulder=220, ε ₂₂₀=5900 (95% methyl alcohol); IR:(cm ^-1), KBr pressed disc method: ν _CH3(2954,2878), ν _CH2(2930,2854), ν _C=O(1748), δ _CH2(1450), δ _CH3(1372), ν _C-O-C(1233), ν _C-O-C(1092,1052,1033), pyranose ring vibration (910), ρ _CH2(771), ν _P-C(738,604); Valelinum Liquidum pressed disc method: ν _P-Au(380), ν _S-Au(270).

Claims (2)

1, a kind of preparation method of auranofin comprises with 2-S-(2,3; 4; 6-four-O-ethanoyl-β-D-glucopyranosyl)-and 2-sulfo-isourea hydrobromate (I), a chlorine (triethyl phosphine) alloy (IV) and salt of wormwood (II) they are raw material, it is characterized in that synthesis procedure is as follows:

A. (I) is dissolved in methyl alcohol: water=1.5～2: in the solution of 1 (volume ratio), obtain A liquid;

B. (IV) is dissolved in the methyl alcohol, obtains B liquid;

C. (II) is soluble in water, obtain C liquid;

D.A liquid mixes with B liquid, is cooled to 0～5 ℃, under 0～5 ℃ of stirring to mixed solution and dripping C liquid, add C liquid, reacted 90～100 minutes, and continued reaction 30～40 minutes again under room temperature, heating in water bath is to the solid dissolving that generates, filter, adding distil water to precipitation occurs in the filtrate, and cooling is filtered, leach thing methyl alcohol: the solution washing of water=0.4: 1 (volume ratio), room temperature vacuum-drying get white auranofin crystal.

2, according to the method for claim 1, it is characterized in that the auranofin crystal that is obtained by claim 1 is carried out the methanol-water recrystallization again purifies under room temperature, vacuum-drying gets pure product.