CS204212B1 - Method of preparing 5-deoxyarabinosyl derivatives of nucleosides - Google Patents

Description

The invention relates to a process for the preparation of 5'-deoxyarabinosyl derivatives of nucleosides starting from the 5'-chloro-2 ', 3'-sulfinyl derivative of nucleosides of AO 199 949. These derivatives (see also AO. 204 213 and AO 204 214) are important. a group of analogues which are of interest as potential antimetabolites of nucleic acids with possible cancerostatic and virostatiotic efficacy.

Existing methods for the preparation of 5'-deoxyarabinosyl derivatives of nucleosides (Collect. Czech.

Chem. Commun. 41 2110 (1976), Nucleic Acids Res. J, 1125 (1976)) have the particular disadvantage that they must be based on specifically substituted nucleoside derivatives, since their methods of preparation are multi-step syntheses and provide lower yields, calculated on the starting unsubstituted nucleoside. j,

Said drawbacks are overcome by the process according to the invention which is based on a process for the preparation of 5'-deoxyarabinosyl derivatives of the nucleosides of the formula I wherein R is uracil, 5-fluorouracil or the nucleoside derivatives of the formula

OH cytosine characterized by the fact that 5'-chloro-2 ', 3´-sulfinyl-

(II) where R is uracil, 5-fluorouracil or cytosine, converted by heating in dimethylformamide at 65 to 150 ° C and alkaline cleavage to 5'-chloro-5'-deoxyarabinosyl derivatives which are further reduced with tributyltin hydride to the final product. It is a further feature of the invention that the alkaline cleavage to give 5'-chloro-5'-deoxyarabinosyl derivatives is preferably carried out by the action of a self-basic ion exchanger in the carbonate cycle.

The advantages of the present invention are simple reactions, high yields, low demands on laboratory equipment. A further advantage of the invention is that said processes can be carried out with all natural nucleosides and analogues thereof and that 5'-bromo-2 ', 3'-sulfinyl derivatives can also be used as starting material instead of 5'-chloro-2', 3'- sulfinyl derivatives of nucleosides.

Starting materials, 5'-halo-2 ', 3'-sulfinyl nucleoside derivatives, prepared from unsubstituted nucleosides in one reaction step in high yield, can serve for the preparation of a wide variety of new analogs, eg: 5'-halogen-5'-deoxy derivatives 2 ', 5'-dihalo-2', 5'-dideoxy derivatives, 5'-halo-2 ', 5-dideoxy derivatives, 5'-deoxyribosyl derivatives, 2', 5'-dideoxy derivatives, 5'-halogen-5 '- deoxy-2,2'-anhydroderivatives, 5'-halogen-5'-deoxyarabinosyl derivatives and 5'-deoxyarabinosyl derivatives.

In the following, the invention is explained in more detail in the examples without being limited thereto.

Example 1

A solution of 5-chloro-2 ', 3-sulfinyl derivatives of 5-fluorouridine (1.1 g) and imidazole (250 mg) in dimethylformamide (18 mL) was heated at 150 ° C for 15 min. and the solution was evaporated in vacuo. Crystallization of the residue from ethanol and chromatography of the mother liquors on silica gel afforded 786 mg (90%) of 2,2'-anhydro-1- (5-chloro-3-D-arabinofuranosyl) 5-fluorouracil m.p. Mp 194-195 ° C.

A solution of the 2,2'-anhydride in 0.1 M sodium hydroxide solution (31.5 mL) was stirred at room temperature for 1.5 hours and then neutralized with an acidic ion exchanger (Dowex 50,

H ⁺ ). After filtration of the ion exchanger and evaporation of the filtrate in vacuo, the residue is crystallized from 2-propanol. 756 mg (90%) of 5'-chlorarabinofuranosyl-5-fluorouracil of mp 211-214 ° C are obtained; (alpha) i ⁵ + 116.1 ° (c »0.50, methanol).

Example 2

To a boiling solution of 5'-chlorarabinosyl-5-fluorouracil (256 mg) in methanol (18 mL) was added within 20 hours a 1M solution of tributyltin hydride in benzene (5x9 mL) and 2,2'-azobis (2-methylpropionitrile) (5x30 mg). ). After evaporation in vacuo and extraction of the residue with water (90 ml) and petroleum ether (3 x 30 ml), the aqueous layer was evaporated and the residue was chromatographed on silica gel. Crystallization of the main fraction residue from 2-propanol gave 5'-deoxyerabinofuranosyl-5-fluorouracil in 41% yield, mp 188-191 ° C.

Example 3

Using the same procedure of Example 1, 2-millimoles (618 mg) of 5-chloro-2 ', 3'-sulfinyl derivatives of uridine 2,2'-anhydro-1- (5-chloro-3-D-arabinofuranosyl) uracil (375 mg) were prepared. 77%) mp 199-201 ° C; (alpha) * ⁵ -12.8 ° (c = 0.45, water).

A solution of the 2,2'-anhydride in 0.111 sodium hydroxide solution (15.5 ml) was stirred at room temperature for 1.5 hours and then neutralized with an acidic ion exchanger (dowex 50,

H ⁺ ). After filtration of the ion exchanger and evaporation of the filtrate in vacuo, the residue is crystallized from 2-propanol. 361 mg (90%) of 5'-chlorarabinofuranosyl-uracil of mp 189-191 ° C are obtained.

To a boiling solution of 5'-chlorarabinosyluracin in methanol (9 mL) was added over 20 h. A 1M solution of tributyltin hydride in benzene (5x4 mL) and 2,2'-azobis (2-methylpropionitrile) (5x10 mg). After evaporation in vacuo and extraction of the residue with water (30 ml) and petroleum ether (3x10 ml), the aqueous layer was evaporated and the residue was chromatographed on silica gel. Crystallization of the main fraction residue from 2-propanol gave 218 mg (69%) of 5'-deoxyarabinofuranosyluracil, mp 164-165 ° C; [.alpha.] D @ ²⁰ +16.1 DEG (c = 0.46, water).

Example 4

A solution of 5'-chloro-5'-deoxy-2 ', 3'-O-sulfinylcytidine hydrochloride (3.44 g) in dimethylformamide (30 mL) was heated at 65 ° C for 4 hours. The solution was evaporated in vacuo. Crystallization of the residue from aqueous ethanol gave 2.2 g (78.5%) of 2,2'-anhydro-1- (5-chloro-5-deoxy-3-D-arabinofuranosyl) cytosine hydrochloride, mp 253 ° C (dec.) [.alpha.] D (alpha) @ 4 -14.7 (c = 0.49, water).

To a solution of 2,2'-anhydride derivative in water (50 mL) was added basic ion exchanger (Dowex 1, CO 2 ^- ) (100 mL) and the mixture was stirred at room temperature for 1 h. Reaction. The mixture was poured onto the column and eluted with water until the UV absorption was lost (about 1.5 L of water). The eluate was evaporated in vacuo and the residue crystallized from water. 1.72 g (83.5%) of 5'-chlorarabinosylcytosine, mp 206-208 ° C; [.alpha.] D @ + 149.8 DEG (c = 0.52, water).

Example 5

To a solution of 5'-chlorarabinofuranosylcytosine (262 mg) in dimethylsulfoxide (5 mL) heated to 1.0 ° C was added sequentially over a period of 6 h., A solution of tributyltin hydride in benzene (6x2 mL) and 2,2'-azobis (2 mL). (methylpropionitrile) (6x7 mg). After cooling, ether (5 ml) and water (15 ml) were added. After shaking, the aqueous layer was separated, washed with ether (2 x 5 mL) & evaporated in vacuo. Crystallization of the residue from water gave 25 mg (5%) of 5 ' -deoxyarabinofuranosylcytosine as the monohydrate, m.p. 172-173 [deg.] C.

Claims (2)

A process for the preparation of 5'-deoxyarabinosyl derivatives of nucleosides of the general formula I CH, (I) OH wherein R is uracl, 5-fluorouracil or cytosine, characterized in that the 5'-chloro-2 ', 3'-sulfinyl derivatives of the nucleosides of the formula XI ¹ Cl (II) where S is uracil, 5-fluorouracil or cytosine are converted by heating in dimethylformamide at 65 to 150 ° C and alkaline cleavage to 5'-chloro-5'-deoxyarabinosyl derivatives which are further reduced with tributyltin hydride to the final product. ² 2. Process according to claim 1, characterized in that the alkaline cleavage to give 5'-chloro-5-deoxyarabinosyl derivatives is preferably carried out by the action of a strongly basic ion exchanger in the carbonate cycle.