RU961355C - Method of producing 9-beta-d-ribofuranozyl-6- mercaptopurine - Google Patents

Abstract

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Description

An improved process for the preparation of 9-D-ribofuranosyl-bmercaptopurin (thioinosin) is provided. Thioinosine. Along with other derivatives of 6-mercaptopurine, it exhibits an inhibitory effect on the growth of tumor and leukemia cells and can be used to treat malignant neoplasms and leukemia, as well as an intermediate for the synthesis of compounds with diverse biological activity.

A known method of producing thioinosine is that the sugar derivative 23-5-tri-0-benzoyl-9 D-ribofuranosylhypoxanthine in a mixture of chloroform and dimethylformamide is treated with boiling thionyl chloride to form the chlorine derivative 235-tri-0-benzoyl- 9- D-ribofuranosyl6-chloropurine - is treated with thiourea while boiling in alcohol, followed by the interaction of the resulting 2,3,5-tri-0-benzoylthioinosine with a solution of sodium methylate in methanol while boiling and thioinosine is added by adding water to the reaction mixture, extract chlorination of this mixture, acidification of the aqueous layer of acetic acid to pH 4 and crystallization of the target product at 20 ° C. The total yield of the target product is 50% based on the starting 2,3.5-tri-0-benzoyl9- / 3-0-ribofuraiosylhypoxanthine.

A drawback of this method is the use of a benzoyl group to protect the inosine hydroxyl groups. Being stable to the action of acidic and relatively weakly basic agents, it requires severe conditions (such as boiling in a solution of sodium methylate in methanol with a pH of 9 in this case) to completely remove it, which can lead to the formation of by-products. The resultant refractory methyl ester of benzoic acid also makes it difficult to isolate the desired product.

An object of the invention is to increase the yield of thioinosine.

The present object is achieved by the described method for the preparation of 9- / 3-D-ribofuranosyl-b-mercaptopurine (thioinosine), which consists in the following. that tri-0-acetylinosine is used as the sugar tri-0-acyl derivative, the peracetate derivative in a mixture of chloroform and dimethylformamide is reacted by boiling with thionyl chloride, the resulting chloro derivative is treated with thiourea when boiled in alcohol, and

Subsequent reaction of the obtained thioderivative with a solution of sodium methylate in methanol was carried out at room temperature and the target product was isolated from the reaction mixture at pH 5-6 at 0-5 ° C. The total yield of the target product is 64% based on the starting inosine.

0 A difference of the proposed method is the use of a tri-0-acyl derivative of tri-0-acetylinosine as a sugar. The use of β-acetyl protecting groups allows them to be carried out

5 removal under mild conditions (treatment with sodium methylate in methanol at room temperature) and the desired product is isolated from the reaction mixture at a pH of 5-6 and a temperature of 0-5 ° C.

0 EXAMPLE 9 - / 3-0-Ribofuranosyl-6-mercaptopurine (thioinosine).

A suspension of 56 g (0.20 mol) of inosine in a mixture of 350 ml of acetic anhydride and 15 ml of pyridine is stirred at room

temperature to complete dissolution and leave to stand for 10-12 hours. The precipitate formed is filtered off, washed with alcohol and ether. The mother liquor and washings are combined and evaporated to dryness. The remainder

0 is treated with 300 ml of ether, the precipitate is filtered off and washed with ether. The precipitates were combined to give 80 g of 2.3.5-tri-0-acetyl-9-y-D-ribofuranosylhypoxanthine, yield 93%. 50 g (| 0.13 mol)

5 obtained inosine triacetate without additional. purifications are dissolved in 1 L of chloroform, 33 ml of dimethylformamide, 100 ml of thionyl chloride are added and boiled for 2 hours. The solution is cooled to room temperature.

temperature and with stirring, pour into 700 ml of a mixture of ice and water. The organic layer was separated, the aqueous layer was washed with 200 ml of chloroform, and the combined chloroform solutions were washed with 250 ml of water, 2x250 ml of saturated sodium bicarbonate solution and dried with anhydrous sodium sulfate. Chloroform was evaporated, the residue was dissolved in 500 ml of absolute alcohol, 14.5 g (0.19) were added.

mol) of thiourea, the solution is boiled for 1 hour and the mixture is left to stand at room temperature for 10-12 hours. The precipitated precipitate is filtered off, washed with cold alcohol and ether. Receive (after drying)

36.5 g of a white powder of 2,3.5-tri-0-thioinosia acetate, yield 70% based on 2,3.5tri-0-inosine acetate. To a suspension of 36.5 g of thioinosine triacetate in 400 ml of methanol, a solution of 2.1 g of sodium metal in 100 ml of methanol was added, the solution was stirred at room temperature for 1 h, acidified with 5 N. a solution of acetic acid to pH 5-6 and kept at 1 h. The precipitate formed is filtered off, washed with cold methanol, ether and dried. 25.8 g (99%) of thioinosinast. Mp are obtained. 217218 ° C. The total yield of thioinosia based on the starting inosine is 64%. UV spectrum, A max °: 324 nm {e 21200). SUMMARY OF THE INVENTION METHOD FOR PRODUCING 9- / -O-RIBOFURANOZYL-6-MERCAPTOPURINE, comprising reacting a "tri-aacyl derivative of sugar in a mixture of chloroform and dimethylformamide by boiling with thionyl chloride. processing the obtained chloro derivative with thiourea while boiling in alcohol, followed by the interaction of the obtained

Found,%: 042.30; H 4.30; N19.60: S 11.20,

C10H12N40.) S

Calculated,%; C, 42.25; H, 4.26; N, 19.71; 311.26,

(56) Ikehara M., Uno N ,, ishikawa F. Study of nucleosides and nucleotides XXIII, a widely applicable method for replacing the 6-hydroxyl group of purine nucleoside. Chem. Pharm, Bull, 1964,12.267-271. a thio derivative with a solution of sodium methylate in methanol and isolation of the target product, characterized in that what. in order to increase the yield of the target product., tri-o-acetylinosine is used as the sugar tri-o-acyl derivative, the thio-derivative is reacted with a solution of sodium methylate in methanol at room temperature, and the target product is isolated from the reaction mixture at pH 5- 6 at O - 5C,.