DD209197A1 - PROCESS FOR PREPARING 3'-FLUOR-2 ', 3'-DIDESOXYGUANOSINE - Google Patents

Abstract

The invention relates to a process for the preparation of 3'-fluoro-2 ', 3'-dideoxyguanosine. The method is applicable in the pharmaceutical industry and the product produced can be used as an antiviral and cancerostatic agent. According to the invention, in a transglycosidation reaction, the sugar residue of 5'-O-acetyl-3'-fluoro-3'-deoxythymidine is transferred to the tristrimethylsilyl derivative of N-high 2-palmitoylguanine under the catalytic action of trimethylsilyl triflate in acetonitrile.

Description

23196 1 8

G. Saizeva

G. Kowollik

P. Langen

I. Mikhailopulo

"Process for the preparation of 3'-Plaor-2 ', 3'-dideoxyguano-

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Field of application of the invention;

The invention relates to a process for the preparation of 3 ^T - fluoro-2 ^f, 3'-dideoxyguanosine. The method is applicable in the pharmaceutical industry, wherein the product produced can be used in medicine as antiviral and cancerostatic.

Characteristic of the known technical solutions 3'-fluoro-2 ', 3'-dideosyguanosine is not yet known. This compound belongs to the purine sucucides with modified sugar residue, which show biological activity in several cases, eg. Cordycepin, arabinosyladenine, xylosyladenine and others (Sohadolnik, RJ, nucleotide · Antibiotics, Wiley Interscience, Hew York, Έ. Υ, 1970). It is known that antimetabolites act as cytostatic agents by inhibiting synthesis of hiccinsin. Mercaptopurine (Mashkovskij MD., Arzneimittel, Kishin-ov, 1962, p. 594), which is also considered to be a widely used antimetabolite in medical practice for the treatment of malignant lesions. analogues of 3'-iTuor-2 ¹ , 3'-dideocadenosine. A major disadvantage of mercaptopurine, however, is its low water lability, which does not allow its application via injections. In addition, appear over time Resistenzerscheinongen the body against this compound over time.

231951 b

In DD 158 903 'it has already been proposed to separate out the analogous compound 3'-fluoro-2''-dideosyadenosine by transglycosidation. In this case, 5'-0-acetyl-3'-fluoro-2 ^1, 3 'didesoixyuridin understood and implemented with the Bistrimethylsilylderivat of I -benzoyladenine, a transfer of this process to the corresponding guanine

Derivative is because of the extreme. Poor solubility of the Έ -

Benaoylguanine or short-chain Ef acylguanine not possible.

Aim of the invention;

The invention aims to find a novel purine-lfueleoside with virostatic and cancerostatic properties. Your ¹ is the object of developing a process for the preparation of 3'-fluoro-2 ^f , 3'-dideozyguanosine.

Explanation of the essence of the invention

The preparation of 3'-fluoro-2 ', 3'-didesos: yguanosine (III) according to the invention by a transglycosidation reaction of 5' -O-acetyl ^ '- fluoro' 'desozy-thymidine (I) on tris-trimethylsilyl U -palmitoylguanine (II) under the catalytic action of trifluoromethanesulfonic acid trimethylsilyl ester (= triaethylsilyltriflate).

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2319 6 1 8. ₃ .

The process starts from readily available starting compounds and gives the target product with a yield of about 25%. 3 ⁱ -5 ^! lnor-2 ', 3'-d ± cleso: s: yguanosine shows surprisingly high biological activity, it inhibits the propagation of murine Ehrlich ascitic tumor cells in vitro. This biological activity allows application in medical precision, including as antiviral and cancerostatic. The invention will be explained in more detail below using an exemplary embodiment.

embodiment

13 ml Hexamethyldisilaaan and 0.7 ml of trimethylchlorosilane are added 1.6 g (4 mmol) of Pal -Palmitoylguanin, the mixture is heated to boiling and after each one hour and 4 hours per 0.5 ml of added trimethylchlorosilane, after 5 hours, gives a clear solution , which is evaporated down iV and distilled several times with dry toluene. is

2 remains a syrupy residue (tris-trimethylsilyi-H palmitoylguanine), which is dissolved in 15 ml of anhydrous acetonitrile. Is added with stirring 0.68 g (2.4 mfflol) 5'-0-acetyl-3 ^{f-fluoro-3'-desosythymidin} and thereafter, 0.55 ml (3.22 mMöl) Trifluormethansülfonsäuretrimethylsilylester (as a catalyst) was added. The reaction mixture is heated under exclusion of moisture for 3 hours to boiling. The mixture is then allowed to cool to room temperature, the solution is poured into a mixture of 150 nil sat, aq. KHCO -, - Etnylacetat and shakes well, lach separation of both layers is the aq. Layer 2mai washed with 50 ml of ethyl acetate. The organic phases are combined and the unreacted

2

Έ -Palmitoylguanine filtered off (0.4 g) .. The solution is iV

concentrated under repeated Kodestiilieren with anhydrous benzene to dryness. The oily residue is dissolved in a little chloroform and separated on a Kieselgelsäuie (120 g). First, it is eluted with pure chloroform and later added increasing amounts of methanol. Man receives 320 mg (24.S %) 9-

23196 1 8

(5-0-Aoetyl-3-fluoro-2,3-clidesoxy-β-D-ribofQranosyl) -] Sr palmitoylguanine which is treated with saturated methanol as ammonia to deprotect in a conventional manner. After 24 hours, concentrate to a small volume. The crystals formed are filtered off with suction and washed with methanol. This gives 120 mg (81%) of 3'-fluoro-2 ^r , 3'-dideoxyguano sin vom Schaip. 265 ⁰ C (for "T. to 290 ⁰ C melting.) UY (methanol); X _MQV 255 nm, with shoulders / L 275 and 208mn Mass Spectrum:. MoIpeak m / e 269th.

Inhibition of the compound on the propagation of Ehrlich ascitic tumor cells in vitro:

Concentration 7 (/AROUND) 33 1 46 3 53rd 6 82 10 100 30 50

Claims (1)

23196 1 Erfindunffsanspruch Process for the preparation of 3'-fluoro-2 ', 3'-dideoxyguanosine of the formula ., characterized in that in a transglycosidation reaction the Zackerrest of 5'-O-acetyl-3 ^f -fluor-3'-desosy- thymidine is transferred to the tris-trimethylsilyl derivative of U -palmitoylguanine under the catalytic action of trimethylsilyl triflate in acetonitrile .