DD147774A3 - PROCESS FOR THE PREPARATION OF 2'-HALOGEN-2'-DESOXY-5-FLUORURIDINES AND THEIR 3 ', 5'-DI-O-BENZOYL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 2'-halo-2'-deoxy-5-fluorouridines and their 3 ', 5'-di-O-benzoylderivaten of the general formula I, where X = Cl or Br and R = H or C & ind6! H & ind5! CO means. Nucleosides derived from fluorinated pyrimidine bases, particularly 2'-deoxy-5-fluorouridine, are of interest for their bacteriostatic and virostatic activity and are used as cancerostatics. The process according to the invention is characterized in that a solution of the 2'-halo-2'-deoxyuridines or their 3 ', 5'-di-O-benzoyl derivatives of the general formula II in which X and R have the same meaning as in formula I. have, added in chloroform or acetic acid with a defined content of fluorine at room temperature, the products obtained with triaethyamine heated to boiling and then recrystallized.

Description

19 1 395-1-

Process for the preparation of 2'-halo-2'-deoxy-5-fluorouridines and their 3 ', 5'-di-O-benzoyl derivatives

The invention relates to novel 2'-halo-2'-deoxy-5-fluorouronium · dines and their 3 ', 5 ^f -Dl-0-benzoyl derivatives of the general formula I.

(KO

ro ¹ k

AO χ

where X is β Cl or Br and R = H or C ₁ -H ₁ -CO, and you

if

Production method.

Nucleosides derived from fluorinated bases of the pyrimidines, especially 2 * -deoxy-5-fluorouridine, are of interest for their bacteriostatic and virostatic efficacy and are used as cancerostatics in some forms of cancer. (P. Langen in "Antimetabolites of the Nucleic Acid Metabolism", Akademie Verlag Berlin 1968. Roy.-Burman in "Analogues of Nucleic Acid Components." Mechanisms of Action., Springer Verlag, Berlin-Heidelberg-New York 1970). Compared with corresponding heterocyclic bases, these nucleosides are not only more effective, but have significantly decreased toxicity.

In principle, 5-fluoro-substituted pyrimidine nucleosides have hitherto been prepared in two ways: a) by synthesizing the nucleosides from fluorinated pyrimidine base by enzymatic or chemical nucleosidation or b) by direct fluorination of the preformed nucleoside (D. Cech, H. Meinert, G. Etzold, P. Langen, 3. Prakt. Chem 315, 149 (1973).) The latter of either method employs either elemental / nitrogen-diluted / J, fluoro or trifluoromethyl hypofluorite ^f make its acetyl derivatives and 2-deoxy-5-fluorouridine, in high yield and sufficient purity without coming for fluorination vatyiZuckerrest of the nucleoside. despite the simplicity and in spite of high yields of this method is the high price of the starting 2 ^f -Desoxyuridine limited Recently, the process, which was the production

of 2'-deoxyribonucleosides of the pyrimidine releases from the

2 2 '

speaking ribonucleosides, specifically via O 'anhydronucleoside and their 3', 5'-dibenzoyl derivatives, developed (A.Holy, Collect. Czech Chem. Commun 37, 4072 (1972)). By etereospecific opening of the anhydrobinding in both groups of these compounds under the action of hydrogen halide, 2'-deoxy-2-halo-ribonucleosides (A.Holy, D.Chech, Collect .Chem.Chem.Commun. 39, 3157 (1974)), or their 3 *, 5 ^§ -Di-0-benzene derivatives prepared, which then pass by reduction with tri-n-butyltin hydride in high yields in 2-deoxyribonucleosides or their 3 ¹ , 5 '~ di-0-benzoyl derivatives. Debenzoylation of the compounds listed last also produces corresponding 2 * -deoxyribonucleosides. By this method one can produce different derivatives of uracil nucleosides. From 5-fluorouridine, 2'-deoxy-5-fluorouridine was synthesized in such a manner in high yield and high purity. Although this method is favorable, its limitation lies again in the accessibility of the starting ribonucleoside, which sometimes needs to be synthesized. Therefore, it is convenient to prepare O ² ' ² anhydrouridine and some of its substituted derivatives, which are the key intermediates of the above synthesis, either from ribonucleosides or, better, by total synthesis from 2'

19 13 9 5

Amino-β-D-arabinofuro (1 *, 2 ': 4,5) oxazoline esters of β-alkoxyacrylic acid (A.Holy, Collect. Czech Chem. Commun. 39, 3177 (1974)), from esters of substituted β -Halogenacrylsäuren or from acetylene monocarboxylic acid, or their alkyl esters, forth deliver. In this way one can easily come from simple starting compounds to 2'-deoxyuridine and its substituted derivatives.

The purpose of this invention is to reduce costs in the synthesis of 2'-deoxy-5-fluorouridine, to simplify the manufacturing process and to achieve higher purity of the product, by elaborating a new manufacturing process of readily available and cheap

Jt M V

Starting intermediates which can be converted according to the invention y2 * -halogen-2 * -deoxy-5-fluorouridine and their 3 * 5 * -The-0-benzoyl derivatives of the general formula I.

Another feature of the invention lies in the preparation of compounds of the general formula I, which is characterized in that 2 * -deoxy-2 * -halogenated derivatives or their 3 *, 5 * -di-O-benzoyl derivatives of the general formula II

RO ^{1 1} X

where X and R is the same as in formula I, in the solution of chloroform or acetic acid with saturated fluorine solution in acetic acid or chloroform and crystallized after heating the recovered product to boiling with triethylamine from ethanol or methanol.

The above-mentioned manufacturing method is easy to carry out on a large scale. Unlike common methods, fluorine is not introduced directly into the solution of the starting material, but its previously prepared saturated solution in the appropriate solvent, advantageously in chloroform or in acetic acid, is added to the solution of the reactant. The advantage of this method lies in the fact that the amount of fluorine can be precisely metered (its content in the solution is determined iodometrically) and not an excess used, and further that one can work without danger in glassware. While preserving v «-«. Also, experimental conditions do not produce by-products to any substantial extent and there is no replacement of the halogen for fluorine in the sugar residue.

As the product of this fluorination carried out in such a way only compounds which are substituted in the 5-position of the uracil, before, namely 2-halo-2 * -deoxy-5-fluorouridine of the formula I, where X = chlorine or bromine and R "H, and 3 *, 5'-di-O-benzoyl-2'-deoxy-2 'halo-5-fluorouridines of general formula I, where X = chlorine or bromine and R is the group C ₆ H ₅ CO means.

All the products listed are characterized in that they can easily convert them into the relevant 2 * -deoxy-5-fluorouridine, which is gradually reduced by the action of reducing agents, for. B. tri-n-butyltin hydride and dibenzoyl derivatives can continue to achieve by methanolysis. Physical properties of the intermediates allow their easy purification by crystallization. Because the starting materials are easily accessible from inexpensive raw materials by simple processes and in high yields, and also because this invention their simple Oberführung in 5-fluoro derivatives, which are easily convertible in high yield and in simple processes on 5-fluoro-2 * - deoxyuridine , in the practical conclusion of the invention in question, it is possible to considerably reduce the price of 2 "-deoxy-5-fluorouridine, to simplify its manufacture and to greatly increase the possibility of its production,

- 5-19 13

Furthermore, the invention in the embodiments of the preparation of 2 * -halo-2'-deoxy-5-fluorouridines and their 3 ', 5 * -Dibenzoaten is explained in detail without being limited thereby.

Example 1

Preparation of 3 ', 5 * -di-O-benzoyl-2'-deoxy-2'-chloro-5-fluorouridine. To the solution of 940 mg (2 mmol) of 3 ', 5'-di-O-benzoyl-2'-deoxy-2'-chlorouridine and 50 ml of acetic acid is added a saturated solution of 76 mg (2 mmol) of fluorine in acetic acid. After one hour at room temperature, the mixture is evaporated at 40 ° C / l5 Torr. The residue is codistilled gradually with acetic acid and with toluene and dissolved in 50 ml of triethylamine. The mixture is boiled under reflux for one hour, evaporated in vacuo, codistilled repeatedly with toluene and crystallized from ethanol. Yield 710 mg (73%) of melting point 224 ° C.

Example 2

Preparation of 3 ', 5'-di-O-benzoyl-2'-deoxy-5-fluorouridine. To solve 1.03 g (2 mmol) of 3 ', 5'-di-O-benzoyl-2'-bromo- -2 ^f -deoxyuridine in 200 ml of acetic acid, a solution of 76 mg of fluorine in acetic acid is added and after a Hour at room temperature, the mixture is evaporated to dryness and the residue is codistilled in vacuo gradually with acetic acid and toluene. The residue is refluxed with 100 ml of triethylamine, excess triethylamine evaporated in vacuo and the residue crystallized from ethanol. Yield 725 mg (69%) of the compound of mp 240 ° C,

Example 3

Preparation of 2 ^I -chloro-2'-deoxy-5-fluorouridine.

To dissolve 786 mg (3 mmol) of 2'-chloro-2-deoxyuridine in 100 ml of acetic acid, a saturated solution of 114 mg (3 mmol) of fluorine in acetic acid is added and the mixture is after

if 1395

Stired for one hour at room temperature in vacuo to dryness dry. The residue is codistilled in stages with acetic acid and a few times with toluene in vacuo and the residue is boiled under reflux for 30 minutes in a small amount of triethylamine. After evaporation in vacuo, the residue is codistilled with toluene and placed on the column of 100 g (100 χ 6 cm ) Silica gel in a mixture of chloroform and ethanol (95: 5). Product containing fractions are combined, evaporated in vacuo and the residue crystallized from ethanol. Yield 675 mg (80%) 'mp. 183 ⁰ C.

Claims (1)

19 13 95 - ^ - Erfindungsaηspruch Process for the preparation of 2'-halo-2'-deoxy-5-fluorouridines and their 3 ', 5'-di-O-benzoyl derivatives of the general formula I 0 I. , -J Ά where X is Cl or Br and R is H or C ₆ H ₅ CO, characterized in that a solution of the 2'-halo-2- ^i- desoxyuri-dines or their 3 *, 5 * -di-O-benzoyl derivatives of general formula II II in the X and R have the same meaning as in formula T, in chloroform or acetic acid with a solution of fluorine in chloroform or acetic acid with a defined content of fluorine at room temperature, the recovered products are heated to boiling with triethylamine and then recrystallized.