CS204214B1 - Method of preparing 5'-deoxy derivatives of nucleosides - Google Patents

Description

The invention relates to a process for preparing 5'-deoxyderivátů nucleosides, which comes from the 5-chloro-2 ^', 3 * -sulfinylderivátů nucleosides by MS. These deoxy derivatives (AO 204 212 and AO 204 213) form an important group of analogues which are important as potential antimetabolites of nucleic acids with possible cancerostatic and virostatic potency.

Existing methods for the preparation of 5 ' -deoxy nucleoside derivatives (Collect. Czech. Chem. Commun.

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

These drawbacks are overcome by the process for the preparation of the 5'-deoxy derivatives of the nucleosides of formula I (I)

HO OH where R = uracil, 5-fluorouracil, cytosine or adenine, which is based on the fact that N-chloro-2 *, 3 ^, -sulphinyl derivatives of nucleosides of the general formula II

AND

2042.4

(II) wherein R = uracil, 5-fluorouracil, cytosine or adenine are converted by hydrolysis and the effect of tributyltin hydride on the resulting product. It is also a feature of the invention that the hydrolysis is carried out with sodium methylate or a basic ion exchanger in a carbonate cycle.

The advantages of the present invention are simple reactions, high yields and low technical 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 be used instead of 5-chloro-2‘, 3-sulfinyl nucleoside derivatives. The 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 number of new analogs, such as 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-halo-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.

He did

The uridine 5-chloro-2 ', 3'-sulfinyl derivative (309 mg) was dissolved in 0.1 M methanolic sodium methoxide (10 mL) and allowed to react for 15 min. at 20 ° C. The solution was neutralized with an acidic ion exchanger (Dowex 50, H ⁺ ) previously washed with methanol and the filtrate evaporated in vacuo. The residue was crystallized from 2-propanol to give 223 mg (84.5%) of 5-chloro-5-deoxyuridine, mp 176 DEG -78 DEG C. (.alpha.) @ + 4.0 DEG (.delta. = 0.35, water).

To a solution of 5‘-chloro-5‘-deoxyuridine in methanol (6 mL) was added under reflux over 25 h.

1M benzene solution of tributyltin hydride (12x3 mL) and 2,2'-azobis (2-methylpropionitrile) (4x10 mg). The reaction mixture was evaporated in vacuo, the residue was stirred in petroleum ether (10 ml) and shaken with water (25 ml). The aqueous layer was washed with petroleum ether (2 x 10 mL) and evaporated in vacuo. After chromatography on silica gel and crystallization from 2-propanol, 5-deoxyuridine is obtained in a yield of 79%, mp, 81-183 ° C. >

Example 2

In a similar manner to Example 1, 5'-chloro-2 ', 3'-sulfinyl derivative of 5-fluorouridine (327 mg) afforded 5'-chloro-5'-deoxy-5-fluorouridine (240 mg, 85.5%) mp 18-182 ° C; (alpha) p + 8.8 ° (c = 0.48, water), and 5'-deoxy-5-fluorouridine, mp 186-88 ° C.

Example 3

To a solution of 5'-chloro-2 ', 3'-sulfinyl derivative of cytidine (280 mg) in water (8 mL) was added strongly basic ion exchanger (Dowex 1, CO 2 ^- ) (6 mL) and the mixture was stirred for 5 min. at 20 ° C. The ion exchanger is filtered off and washed with 100 ml of water. The combined filtrates were evaporated in vacuo. Crystallization of the residue from water gave 210 mg (80%) of 5'-chloro-5'-deoxycytidine, mp 170-177 ° C (dec.).

To a solution of 5'-chloro-5'-deoxycytidine in dimethylsulfoxide (5 mL) heated to 110 ° C was added sequentially over 6 h a 1M solution of tributyltin hydride in benzene (6x2 mL) and 2,2'-azo 3 bis (2-methylpropionitrile) (6x7 mL). After cooling, ether (5 ml) and water (15 mlf) were added. After shaking, the aqueous layer was separated, washed with ether (2x5 ml) and evaporated in vacuo to crystallize the residue from water to give 100 mg (51%) of 5'-deoxycytidine. m.p. 209-211 ° C.

Example4

To a solution of 5 * -chloro-2 *, 3 ^from adenosine sulfinyl derivative (184 mg) in water (4 mL) was added strongly basic ion exchanger in a carbonate cycle (5 mL) and the mixture was stirred for 20 min. at room temperature. Then the ion exchanger is filtered off and washed with water until the UV absorption (200 ml) disappears. The combined filtrates were evaporated in vacuo and crystallization of the residue from water gave 121 mg (84.5%) of 5'-chloro-5'-deoxyadenosine, mp 114-115 ° C.

To a solution of 5'-chloroadenosine (286 mg) in dimethylsulfoxide (4 mL) heated to 100 ° C was added within 14 h a 1M solution of tributyltin hydride in benzene (14x2 mL) and 2,2'-azobis (2-methylpropionitrile) (14x7). mg). The mixture was partially evaporated in vacuo, diluted with water (30 mL) and washed with ether (3 x 20 mL). The aqueous solution was evaporated first in a water pump vacuum and then at 2 Torr. The residue is chromatographed on a silica gel column (100 g) in an ethyl acetate system. TOT-acetone-ethanol-water (15: 3: 4: 3). Crystallization from water gave 127 mg (50.5% of 5'-deoxyadenosine, mp 133-134 ° C; (α) ^{5 5} -44 ° (c = 0.51, water).

Claims (2)

A process for the preparation of 5'-deoxy derivatives of the nucleosides of the general formula I, wherein R = uracil, 5-fluorouracil, cytosine or adenine, characterized in that the 5'-chloro-2 ', 3'-sulfinyl derivatives of the nucleosides of the general formula II (II) wherein R = uracil, 5-fluorouracil, cytosine or adenine are converted by hydrolysis and the effect of tributyltin hydride on the resulting product. 2. The process according to claim 1, wherein the carbonate cycle is a basic ion exchanger. that the hydrolysis is carried out with sodium mathylate; or