DD280763A1 - PROCESS FOR PREPARING 5- (2-BROMVINYL) URACIL NUCLEOSIDES - Google Patents

Abstract

The invention relates to a process for the preparation of 5- (2-bromovinyl) uracil nucleosides of general formula I in which R 1 is a sugar residue such as ribose, arabinose, deoxyribose and their halogen derivatives or alkoxy, R 2 and R 3 H, alkyl, Nitrile or carboxyl mean. Field of application is the pharmaceutical industry. The aim of the invention is the development of an economically advantageous preparation process for the compounds I. 5- (2-Bromovinyl) 2-deoxyuridine (I, R2R3H) is inventively by reacting in the sugar moiety by benzoyl, p-chlorobenzoyl or p-Nitrobenzoylreste protected 5-ethyl-2-deoxyuridine in chlorinated hydrocarbons, preferably CHCl3 or CH2Cl2. Formula I

Description

in which R 1, R ₂ and R _{3 have} the abovementioned meaning, after protection of existing OH groups in the sugar moiety by acyl radicals, preferably the benzoyl, p-chlorobenzoyl or p-nitrobenzoyl radical, are reacted in esters, acetic acid, aromatics or chlorinated hydrocarbons , 2. The method according to claim 1, characterized in that the protection of the sugar residue is carried out with the p-chlorobenzoyl and the reaction in CHCl ₃ or CH ₂ CI _{2 is} performed.

Field of application of the invention

The invention relates to a process for the preparation of 5- {2-bromovinyl) -uracil nucleosides of general formula I,

in which R _{1 is} a sugar residue, such as ribose, arabinose, deoxyribose and their halogen derivatives or alkoxy, R ₂ and R _{3 are} H, alkyl, nitrile or carboxyl.

 Field of application of the invention is the pharmaceutical industry.

Characteristic of the known state of the art

Of the compounds of the general formula I, only 5- (2-bromovinyl) 2'-deoxyuridine (I, R ₂ = R ₃ = H) is known hitherto, which has a high antiviral index (Nucleic Acid Research, Special Publication no. 4.103). However, the synthesis of this compound from the nucleobase 5- (2-bromovinyl) uracil and 2'-deoxyuribose requires 9 synthesis or separation steps (Tetrahedron 32 2795 [1976]).

Another process for the preparation of 5- (2-bromovinyl) 2'-deoxyuridine has been proposed in DD 247663, which leads to the final product in 3 stages. This process has the disadvantage that the resulting intermediates difficult

crystallize and must be partially purified by column chromatography.

Object of the invention

The invention aims to develop an economically advantageous process for the preparation of compounds I.

Explanation of the essence of the invention

The process according to the invention for the preparation of the compounds I is characterized in that compounds of the formula II,

in which R _n , R ₂ and R _{3 have} the abovementioned meaning, after protection of the OH groups in the sugar moiety by acyl radicals, preferably by the benzoyl, the p-nitrobenzoyl and the p-chlorobenzoyl radical in esters, acetic acid, aromatics or chlorinated hydrocarbons with bromine or N-bromosuccinimide reacted under the conditions known per se

become. \

Of essential importance for the smooth implementation of the method is the protection of the sugar residues by the substituted benzoyl radicals, because after elimination with NaOAc, alkoxide, amines, preferably triethylamine, the resulting compounds in the concentration of the solvent, preferably the chlorinated hydrocarbons crystalline and thus very pure. A preferred combination for the technical realization of the process is protection with a p-chlorobenzoyl radical and the reaction in CHCl 3 or CH 2 Cl 2.

The invention will be explained in more detail below by exemplary embodiments.

Embodiments.

1. 1.07 g (2 mM) of 5-ethyl- (3 ', 5'-di-p-chlorobenzoyl) -2'-β-deoxyruidine are dissolved in 25 ml of abs. Dissolved chloroform and added dropwise on a 500 W phototube with 0.11 ml of bromine in 5 ml of chloroform. The resulting HBr will be fumed with N ₂ . After addition of the bromine, 0.6 ml of triethylamine are added and the mixture is heated for a further 10 min. The solvent is evaporated in a rotary evaporator, triethylammonium bromide optionally previously removed by aqueous extraction, and the residue is recrystallized from ethanol. Yield: 0.8 g = 66% 5-E-5- (2-bromovinyl) O'B'-di-p-chlorobenzoyl) -2'-β-deoxyuridine. The protecting groups are removed by methanolysis

Yield: 0.4 g = 60% of theory of melting point 17O ⁰ C.

3.98 g (10 μmol) of 1- (2,3,5-tri-O-acetyl-β-D-arabinofuranosyl) -5-ethyluracil are dissolved in 200 ml of abs. (anhydrous) 1,2-dichloroethane and heated to boiling on the IR lamp. To the boiling solution, a solution of 1.2 ml (about 24mMol) of bromine in 20 ml of abs. Added dropwise 1,2-dichloroethane. During the bromine addition, a weak, dry Ni stream is passed through to remove the resulting HBr. The added bromine decolorized quickly.

After completion of the bromine addition, a small sample is taken, mixed with a few drops of triethylamine and boiled briefly. In the thin-layer chromatogram (eluent: ethyl acetate-hexane 6: 4) bromovinyl was detectable as the main product.

8 ml of triethylamine are added to the reaction solution and 5 min. heated to reflux.

The yellow solution is concentrated, codistilled first with ethanol and then with chloroform. The brownish residue is taken up in 200 ml of chloroform and extracted by shaking with 3 x 100 ml of water to remove the triethylammonium salts. The chloroform phase is dried over Na ₂ SO ₄ , the desiccant is filtered off, washed with chloroform and the filtrate is concentrated.

The brown syrupy residue is dissolved in a little chloroform, absorbed on silica gel and purified over a silica gel column (eluent: chloroform). -.

Concentration of the appropriate fractions left 3.34 g (70.2%) of foamy product, which crystallized on co-distilling with EtOH

It was recrystallized from ethanol 2.67 g = 56.2% Yield F: 126-8 ⁰ C (EtOH) UV: A _max (MeOH): 253 and 293 nm X _{m! N} (MeOH): 271 nm

3. (E) -1- (β-D-arabinofuranosyl) -5- (2-bromovinyl) -uracil 475g (1 mmol) (EM-teAS-Tri-O-acetyl-β-D-arabinofuranosy O-S-te Bromviny O-uracil is dissolved in 30 ml of 0.1 M sodium methylate solution After 3 hours, the elimination of the acetyl groups (thin-layer chromatogram: eluent chloroform-methanol 9: 1) is complete The solution is neutralized with DOWEX 50 WX8 (H ⁺ form) , filtered, washed with methanol and the filtrate was concentrated, and the crystalline residue was recrystallized from ethanol Yield: 303 mg = 86.8% F .: 182-5 ° C. (decomp.) UV: X _max (MeOH): 253 and 293 nm X _min (MeOH): 271 nm

Claims (1)

-1-280 763 Claim:
1. A process for the preparation of 5- (2-bromovinyl) uracil nucleosides of general formula I _; in the R ₁ a sugar residue, such as ribose, arabinose, deoxyribose and their halogen derivatives or alkoxy, in which R ₂ and R _{3 are} H, alkyl, nitrile or carboxyl, by bromination of nucleosides with bromine or N-bromosuccinimide in organic solvents under free-radical conditions, characterized in that nucleosides of the general formula II,