DD247266A1 - Process for the preparation of E2-substituted vinylpyrimidines - Google Patents

Abstract

The invention relates to a process for preparing E 2 -substituted vinylpyrimidines of the general formula I. According to the invention, these compounds are prepared by brominating thymidine in carbon tetrachloride under free-radical conditions in a one-pot process. After the solvent has been evaporated in vacuo, the residue is mixed with 90% aqueous pyridine and partially azeotroped with sodium acetate, 1,3-dicarbonyl compounds such as malonic acid, piperidine and benzene. Subsequently, it is mixed with halogenated, interhalogenated or pseudohalogen compounds and heated to the end of the CO2 evolution. Optionally, the resulting acid or the Saheederivat is isolated. Formula I

Description

Field of application of the invention

The invention relates to a process for the preparation of E2-substituted vinylpyrimidines of the general formula I 0 U

in the R = halogen or pseudohalogen and Z = 2'-deoxyribose, ribose, arabinose and its halogen and amino derivatives, alkyl, alkyl ethers and

Alkyl ether alcohols mean. Field of application is the pharmaceutical industry.

Characteristic of the hitherto known technical solutions

The 5- (2-bromovinyl) 2'-deoxyuridine, which has a high antiviral index (Nucleic Acid Research, Special Publication No. 4,103), is already known. However, the synthesis of this compound from the nucleobase 5- (2-bromovinyl) uracil and the 2'-deoxyribose requires 9 synthesis or separation steps (Tetrahedron 32, 2795 [1976]).

Another method for preparing the 5- (2-bromovinyl) 2'-deoxyuridine has been described in WP C07 D / 214788, which results in the final product in 3 stages.

In addition, WP C07 D / 217293 a process for the preparation of 5-vinylpyrimidines (R = CN, COCH ₃ , COOH, NC ₂ ) has been described, which are important starting compounds for the production of E2-substituted vinylpyrimidines and also show even surprising virustatic activity ,

Object of the invention

The invention aims to develop a technically simple process for the preparation of compounds of formula I.

Explanation of the essence of the invention

According to the invention, the compounds of the formula I are prepared by brominating thymidine in carbon tetrachloride under free-radical conditions in a one-pot process. After the solvent was evaporated in vacuo, the residue is treated with 90% aqueous pyridine and partially azeotroped with sodium acetate, 1,3-dicarbonyl compounds such as malonic acid, piperidine and benzene.

The mixture is then mixed with halogenated, interhalogenated or pseudohalogenated compounds and heated until the CO ₂ evolution has ended.

Optionally, the resulting acid or acid derivative is isolated.

It is advantageous to protect the OH groups present in the Z radical, preferably by acetyl groups. These acetyl groups may, for. B. introduced by reaction with acetic anhydride and easily removed after the reaction by ammoniacal methanol.

The compounds according to the invention have a high virostatic activity. The simplicity of the manufacturing process provides good opportunities for therapeutic use.

embodiment

1. One-Pot Method 5- (2-Bromovinyl) -2'-deoxyuridine

6.5 g of 3 ', 5'-diacetylthymidine are dissolved in 1200 ml carbon tetrachloride under reflux. Thereafter, 2.5 ml Br _{2 are} blown with dry nitrogen into the stirred, boiling solution under the action of light (500 A / V photolamp). (3-4 hrs.) After addition of all bromine, the solvent is evaporated to dryness in vacuo and the residue in 200 ml of pyridine with ice cooling 20 ml of H ₂ O added. After 20 hours, 2 g of anhydrous sodium acetate, 5 g of malonic acid, 10 ml of piperidine and 200 ml of benzene are added and the whole is heated on the boiling H ₂ O bath with descending condenser. About 200ml are distilled off azeotropically, finally in a low vacuum (2-3h). 1.1 ml of bromine are added to the residue and the mixture is further heated until the end of CO ₂ evolution (about 2 h). Thereafter, pyridine is distilled off in vacuo, the residue optionally after acid extraction of the chloroform extract, deacetylated with 200 ml of ammoniacal methanol and the residue optionally after a column chromatography on silica gel (chloroform / methanol 9/1) recrystallized from alcohol. Yield: 3 g = 36% F _p : 145-155 ° (decomp.)

UV _max 295nm

UV _min 252nm

2. Although the resulting acid was isolated, it is then treated with 0.6 ml of bromine and boiled to decolorization on a 500W radiator under reflux. It is then heated briefly with 2 ml of triethylamine, concentrated by rotary evaporation and the residue is deacetylated with ammoniacal methanol. After evaporation of the solvent, the residue is optionally recrystallized after chromatography on silica gel from alcohol.

Yield 2.9 g = 70% F145-155 (dec.) UV _max 295nm UV _min 252nm

Claims (1)

Process for the preparation of E2-substituted vinylpyrimidines of the formula I 0 и θ ' where R = halogen or pseudohalogen Z = 2'-deoxyribose, ribose, arabinose and its halogen and amino derivatives, alkyl, alkyl ethers and alkyl ether alcohols mean characterized in that brominated thymidine in CCI ₄ under free-radical conditions, the solvent evaporated in vacuo, the residue mixed with 90% aqueous pyridine, then partially azeotroped with sodium acetate, 1,3-dicarbonyl compounds such as malonic acid, piperidine and benzene, the If appropriate, the resulting acid or the acid derivative is isolated, mixed with halogen, interhalogen or pseudohalogen compounds and heated until the evolution of CO.sub.2 has ended.