JPH01224390A - Production of nucleoside derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound of high purity where an acyl group and a halogea atom. are introduced in 2'- and 3'-positions (or 3'- and 2'-positions) in high yield, by reaction of a specific nucleoside with an acryl halide in an organic solvent containing an organic acid. CONSTITUTION:In the organic solvent containing a 6-12C organic acid such as formic or acetic acid, a nucleoside whose 2'- and 3'-position are 1- alkoxyalkylidenized or 1-alkoxyarylalkylidenized (bases are purine or pyrimidine) is combined with 3-4 fold molar equivalents of acyl halide, organic acid anhydride and hydrogen halide to effect the reaction, preferably at 0-20 deg.C to give the subject compound into which a halogen atom.and an acyloxy group are introduced in the 2'- and 3'-positions or 3'- or 2'-positions.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention provides a novel method for producing nucleoside derivatives having an acyloxy group and a halogen atom attached to the 2' and 3' positions (or the 3' and 2' positions). It also relates to a method of further converting the above derivatives into dideoxynucleosides, if necessary.

Nucleoside derivatives having an acyloxy group and a halogen atom attached to the 2' and 3' positions (or 3' and 2' positions) are important as intermediates for the production of various substances exhibiting pharmacological activity.

In addition, dideoxynucleosides are also known compounds, but because they have antiviral activity, they are expected to be applied in the pharmaceutical field (for example, H6 Mitsuya and
S, Broader, Proc, Natl.
Acad.

Soi, USA, Vol, 83, 1911.198
(see Year 6).

[Conventional technology]

Several methods for producing nucleoside derivatives such as dideoxynucleosides using nucleosides as raw materials are already known, but in all of them, the important production intermediate is a compound of formula (1) or formula (It). .

(() (II) However, Ba5e = purine base or pyrimidine base X =
Cj! , Br, 1 R'=H or an easily removable protecting group.

RZ=Acyl group Compounds of formula (1) and formula (II) are reduced to dideoxynucleoside by a known method of reducing with Pd/C in a hydrogen stream and then, if necessary, hydrolyzing or transesterifying. can lead.

Currently known methods for producing compounds of formula (I) or formula (II) are as follows.

(1) Reacting nucleosides with 2-acetoxyisobutyric acid bromide, John, G. Moffatt
etc. method.

(■J, Am, Chem, Soc,, Vol.
95.4025.1973■US Patent
3658787) (212',3'-0-(1-methoxyethylidene)-nucleoside is reacted with pivalic chloride in the presence of sodium iodide, Morris
J.

The method of Robins et al. (J, Am, Chem,
Soc, Vol.

98, 8213.1976) +31 2',3'-0-(1-ethoxyethylidene)
- The method of Engels et al., in which an adenosine derivative is reacted with sodium iodide in the presence of trifluoroboron diethyl ether combresox.

(Tetrahedron Letters, Vol.
, 21, 4339. 1980) Reacting c41 2',3'-0-(1-ethoxyethylidene)-adenosine with lithium bromide in acetonitrile in the presence of trifluoroboron diethyl ether combination, John G. .

An alternative method of Moffatt et al. (J, Org, Chem
, Vol. 39+30.1974) (5) The method of Co11n B, Reese et al., in which 2',3'-0-(1-ethoxyethylidene)-adenosine is reacted with acetyl bromide in dichloroethane.

(Synthesis, 304, 1983) Formula (I) is an important intermediate for the production of nucleoside derivatives.
The method for producing the compound of formula (II) is known as described in the previous section, but when considered as an industrial production method, it has the following problems.

+1) The reaction proceeds in high yield only when expensive reaction reagents are used.

(2) Many (products) are produced.

(3) It may be necessary to protect functional groups that do not participate in the reaction.

Both of these problems result in high costs when considered as an industrial method for producing nucleoside derivatives such as dideoxynucleosides.

[Problem to be solved by the invention]

2' position, 3' position (or 3' position, 2' position) that solves the above problem
There is a desire to develop an industrially advantageous method for producing nucleoside derivatives and dideoxy nucleosides having an acyloxy group or a halogen atom at the position (').

The present invention provides a new industrially practical method for producing nucleoside intermediates and dideoxynucleosides that have pharmacological effects such as antiviral activity.

[Means to solve the problem]

The present inventors tried all the known methods described in the prior art section, evaluated their reaction yield, operability, and economical efficiency, and then
Further, as a result of new studies, a manufacturing method superior to known methods was discovered, and the present invention was completed.

That is, the present invention provides: a nucleoside whose 2'-position and 3'-position are 1-alkoxyalkylidened or 1-alkoxyarylalkylidened in an organic solvent containing an organic acid; (1) an acyl halide; or (2) A nucleoside characterized by reacting an organic acid anhydride and hydrogen halide to introduce an acyloxy group and a halogen atom at the 2'-position and 3'-position (or 3'-position and 2'-position). A method for producing a derivative.

The organic acid contained in the organic solvent is an organic acid having 1 to 12 carbon atoms, such as formic acid, acetic acid, and propionic acid.

The organic solvent used is, for example, acetonitrile, dioxane, trimethyl phosphate or dichloromethane.

The alkoxy group in the 1-alkoxyalkylidene or 1-alkoxyarylalkylidene has 1 to 12 carbon atoms. For example, methoxy or ethoxy groups are employed.

The alkylidene group of the 1-alkoxyalkylidene group is, for example, a methylidene or ethylidene group. The arylalkylidene group of the 1-alkoxyarylalkylidene group is
For example, benzylidene.

The halogen atom of the acyl halide is, for example, chlorine, bromine or iodine.

The acyl group of the acyl halide has 2 to 12 carbon atoms, such as acetyl or benzoyl.

The organic acid constituting the organic acid anhydride has 2 to 12 carbon atoms, such as acetic acid and propionic acid. Acetic anhydride is suitable as the organic acid anhydride.

Examples of hydrogen halides include hydrogen chloride, hydrogen bromide,
Hydrogen iodide is used.

Bases constituting nucleosides are, for example, purine bases and pyrimidine bases, and examples of purine bases include adenine, hypoxanthine, guanine, and xanthine.

As the pyrimidine base, uracil, thymine, cytosine, etc. are employed.

By the method of the present invention, the acyloxy group and the bromine atom are
The nucleoside derivative introduced at the 3'-position or the 3'-position (or the 3'-position or the 2'-position) is further subjected to, for example, a hydrogenation reaction and then to a hydrolysis or transesterification reaction step to remove acyloxy and Dideoxynucleosides can be produced by debromination. Acyloxy groups are acetoxy groups, hexyloxy groups, etc. and have 2 to 1 carbon atoms.
Approximately 2 will be adopted.

The base constituting the nucleoside derivative is a purine base, and in this case, adenine, hypoxanthine, guanine, xanthine, etc. are employed.

The starting material of the present invention may be a nucleoside obtained by subjecting a ribonucleoside to a 1-alkoxyalkylidene reaction or a 1-alkoxyaryl alkylidene reaction. These alkylidene reactions can be carried out using conventional methods (for example, H, P, M, Fromageote
tal, Tetrahedron, Vol, 23
+2315, 1967). Furthermore, in the case of producing dideoxynucleosides, the bases of the ribonucleosides are purine bases, and adenine, hypoxanthine, guanine, xanthine, etc. are employed.

The above-mentioned present invention will be explained in more detail as follows.

In other words, regarding the production of nucleoside derivatives having an acyloxy group and a halogen atom attached to the 2'-position, 3'-position (or 3'-position, 2'-position) as described above, the number of carbon atoms in the organic acid contained in the organic solvent may be any of acetic acid, propionic acid, butyric acid, etc. as long as it is within the range of 1 to 12. Among them, it is more preferable to use formic acid and acetic acid.

Moreover, as for the organic solvent, acetonitrile, dioxane, trimethyl phosphate, etc. are preferable. In addition, in the solution containing the above-mentioned solvent, for example, an acid catalyst used in the production of 2',3'-O-(1-methoxyethylidene)-adenosine, such as p-toluenesulfonic acid, methanesulfonic acid, trichloro Even if acetic acid or the like remains, it does not affect the reaction for introducing acyloxy groups and halogen atoms.

Furthermore, 1-alkoxyalkylidened or 1-alkoxyarylalkylidened nucleosides are known substances and can be easily produced, but here,
The number of carbon atoms in the alkoxy group is not particularly limited as long as it is in the range of 1 to 12. That is, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

Among these, methoxy and ethoxy are particularly preferred from an economic point of view. Furthermore, from a practical standpoint, a methylidene or ethylidene group is preferably used as the alkylidene group of the alkoxyalkylidene group. Furthermore, in the case of aryl alkylidene groups, benzylidene groups are practical.

stomach. Among these, purine bases may be adenine, hypoxanthine, guanine, or xanthine, and pyrimidine bases are preferably uracil, thymine, or cytosine.

Next, the halogen atom of the acyl halide used as one of the reaction reagents may be chlorine, bromine or iodine. Further, the acyl group of the acyl halide is not particularly limited as long as the number of carbon atoms is within the range of 2 to 12. For example, acetyl, propionyl, oxalyl, malonyl,
There are benzoyl, tri-oil, etc. Among these, acetyl group and benzoyl group are most preferred.

Similarly, regarding organic acid anhydride, which is one of the reaction reagents, acetic anhydride, propionic anhydride, butyric anhydride, etc. can be used, but among these, acetic anhydride is more preferable because it is easily available and has good reaction efficiency. .

Furthermore, the hydrogen halide used as a reaction reagent is either hydrogen chloride, hydrogen bromide, or hydrogen iodide. In this case, the hydrogen halide may be used in the form of a gas or may be produced in-system.

The required amount of acyl halide or organic acid anhydride and hydrogen halide used in the present invention is 1 to 5 times the amount of the 1-alkoxyalkylidene or 1-alkoxyaryl alkylidene nucleoside used as the initial starting material. Use molar equivalents. Most preferably, it is 3 to 4 times the molar equivalent.

The reaction temperature used here is generally 75° from Q'C.
It can be used within the range of C, but most preferably 0°C.
to 20°C.

The reaction time varies depending on the temperature, but the reaction time ranges from 15°C to 2°C.
At 0°C, 0.5 to 3.0 hours is preferred.

Based on the above conditions, by carrying out the above reaction using a 1-alkoxyalkylidene or 1-alkoxyarylalkylidene nucleoside as a starting material,
Nucleoside derivatives in which an alkyloxy group and a halogen atom are bonded can be produced with high yield and high purity, which has not been possible in the past.

A specific example will be described below. That is, the starting material 2',3'-〇-(1-methoxyethylidene)-adenosine (formula (■)) is added to acetic acid containing acetyl bromide and reacted to produce the desired nucleoside derivative. A mixture containing compounds of formulas (IV) and (V) as main products was obtained.

However, it should be emphasized that this reaction using acetic acid as the reaction solvent not only proceeds with a high yield of 82% (but also has a higher purity of the product than before). This is relatively high. Only about 5 to 10% of the by-product 2', 3', 5'-triacetyl-adenosine is produced.
This method is extremely advantageous as an industrial production method because it produces fewer products than the method of Moffatt et al.

Furthermore, the main products, formula (rV) and formula (V), can be easily processed in organic solvents (e.g., acetonitrile, ethyl acetate, etc.) without loss.
is extracted. As described below, this extract contains almost no hydrophilic impurities that become a problem when it is converted into the main products formula (■) and formula (V) di-deoxyadenosine (abbreviated as DDA) in the next step. This has the advantage that there is no

Also, 2',3'-0-(1-ethoxyethylidene)
- When adenosine was reacted in acetic acid containing acetyl bromide, the same yield and purity as in the above-mentioned example were obtained.

However, the method of Reese et al. (Synthesis,
304.1983) - Reaction conditions; in dichloroethane,
The novelty of the present invention is evident from the fact that heating under reflux for 15 minutes results in low yield (53% for formula (IV)) and low purity, making it difficult to control the reaction.

Furthermore, from the perspective of the prior art, it is surprising that the reaction of nucleoside derivatives is carried out in an acidic solvent such as acetic acid.
It is regarded as something that should be done.

Next, using the new production method described above, a nucleoside derivative in which an acyloxy group and a halogen atom were introduced at the 2'-position and 3'-position (or 3'-position and 2'-position) was converted into a nucleoside derivative and dehalogenated dideoxy A method for producing nucleosides will be described.

That is, after neutralizing the reaction solution with an inorganic base, the product is extracted with an organic solvent. In this case, the base used must be an aqueous solution of sodium bicarbonate, sodium carbonate, etc., or a weak base such as aqueous ammonia. As the organic solvent for extraction, acetonitrile, ethyl acetate, etc. can be used.

The solvent of the product extract is distilled off under reduced pressure and the residue is dissolved in methanol. This solution was mixed with Pd/C under a hydrogen stream.
and catalytic hydrogenation in the presence of triethylamine, and after removing the catalyst, a methanol solution of sodium methoxide is directly added to the reaction solution for transesterification to obtain dideoxynucleoside.

Further, the base constituting the nucleoside derivative used in the above reaction is preferably a purine base. Among the purine bases, any one of adenine, hypoxanthine, guanine, and xanthine may be used.

Furthermore, as the starting material of the present invention, a nucleoside obtained by subjecting a ribonucleoside to a 1-alkoxyalkylidene reaction or a 1-alkoxyaryl alkylidene reaction can be employed.

These alkylidene reactions may be carried out by the method of Fromageot et al., as described in Examples below.

Furthermore, when producing dideoxynucleosides, the base of the ribonucleoside is preferably a purine base, and adenine, hypoxanthine, guanine, xanthine, etc. are employed.

Specifically, for example, as described in Examples below, 2',3'-0-(l-
methoxyethylidene)-adenosine and reacting it with acetyl bromide without isolation or in an organic solvent containing acetic acid, or with hydrogen bromide in acetic anhydride. It has been found that a mixture of the compound of formula (IV) and the compound of (V) can be obtained in high yield. In this case, the reaction solvent is a mixed system of acetic acid and the organic solvent used in the production of 2',3'-0-(1-methoxyethylidene)-adenosine. Further, if necessary, DDA, which is a dideoxynucleoside, can be obtained by the previously described method of subjecting the compounds of formula (IV) and formula (V) to hydrogenation reaction, followed by hydrolysis or transesterification.

〔Example〕

The present invention will be explained below based on Examples.

Example 1 (1) 0.27 ml (4 mmol) of acetyl bromide was gradually added. After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. When the organic layer was quantified by high performance liquid chromatography (hereinafter abbreviated as HPLC), it was found that 9-((3
'-bromo-3'-deoxy-2',5'-di○-acetyl)-β-D-xylofuranosyl)-adenine and 9-((2'-bromo-2'-deoxy-3',5
'-di〇-acetyl)-β-D-xylofuranosyl)
-341 mg (0,824 mmo 1) of adenine mixture (hereinafter abbreviated as Br-Ac0-AR), yield 82%
It was generated with . Further isolated product, 300MHz
Nuclear magnetic resonance absorption spectra supported an ice crystal structure.

(2) B r -A c○- in 30 ml of methanol
1 og (0,741 mmol) of AR307 and 0.18 ml of triethylamine were dissolved. 620 mg of 2% palladium on carbon was added, and hydrogen gas was passed through at a flow rate of 40 ml/min while stirring at room temperature.

After the palladium on carbon was filtered off and washed with ethanol, the solvent was distilled off under reduced pressure. Dissolve the residue in 8 ml of methanol and dissolve 0.4 28% sodium methylate (methanol solution).
ml was added and stirred at room temperature for 30 minutes. HPL the reaction solution
As determined by C, 2',3'-dideoxyadenosine 77.8 mg (0.33 mmol) yield 45%, 3
'-Deoxyadenosine 32.4mg (0.30mm
o l) It was produced in a yield of 17%. purified and separated, 2
300 MHz nuclear magnetic resonance absorption spectra of ',3'-deoxyadenosine and 3'-deoxyadenosine supported an ice crystal structure.

Example 2 Acetic anhydride 0. 4'm I (4,2mrr+o
l e) and 11 ml of 25% hydrogen bromide/acetic acid solution to 1 ml of acetic acid.
2',3'-0-(1-methoxyethylidene)adenosine 323 mg (1 mmol)
e) was added gradually. After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. When the organic layer was quantified by HPLC, Br
-Ac0-AR is 330 mg (0,80 mmo
l e) It was produced with a yield of 80%.

Example 3 10 g (37.4 mmole) of adenosine,
6. Suspend in 70 ml of acetonitrile, add 6.73 g (42 mmol) of trichloroacetic acid, then add trimethyl orthoacetate. Oml (46 mmol
e) was added. The mixture was heated and stirred at 50° C. for 1 hour and 40 minutes. After the reaction, the solvent was removed under reduced pressure, and the remaining liquid was reduced to 35ml.
I stayed away until

This solution was mixed with 72 ml of acetic acid containing 12.3 ml of acetyl bromide.
mI at 0° C. with stirring. After the addition was complete, the mixture was further stirred at 15-20° C. for 50 minutes to finally obtain a homogeneous solution. This is 20
% sodium carbonate aqueous solution, and acetonitrile 1
Extracted with 40 ml.

According to HPLC analysis, this extract contains the target
9-((3'-bromo-3'-deoxy-2', 5'-
di○-acetyl)-β-ri-1xylofuranosyl)-adenine, and 9-((2'-bromo-2'-deoxy-3',5'-di○-acetyl)-β-D-arabinofuranosyl) )-adenine mixture (82.1% yield from adenosine).

Example 4 The reaction was carried out in the same manner as in Example 2, changing the initial reaction solvent from acetonitrile to trimethyl phosphate, and the desired mixture was obtained in a yield of 84.9% from adenosine.

Example 5 (1) Inosine 10g (37.2mm.

le) was suspended in DMFlooml, and 33.2 ml (260 mmol trimethyl orthoacetate) was added to this.
l e), then p-) 10.64 g (56.0 mm) of luenesulfonic acid-hydrate.

le) was added. The mixture was stirred for 30 minutes at 15-20°C. After reaction, 28% of sodium methylate
The mixture was neutralized with a methanol solution, and the solvent was distilled off under reduced pressure. The remaining residue was suspended in 130 ml of acetonitrile, and this was added to 11.0 ml (149 mmole) of acetyl bromide.
The mixture was slowly added to 71 ml of acetic acid containing acetic acid at 0°C with stirring. After the addition is complete, return the mixture to 15-20"C.
The mixture was stirred for 30 minutes. The mixture was neutralized with a 10% aqueous sodium carbonate solution and extracted with 140 ml of acetonitrile. According to HPLC analysis, this extract contains the target 9-((3'-bromo-3'-deoxy-2゛2.5
'-di-0-acetyl)-β-D-xylofuranosyl)
-hypoxanthine, and 9- ((2'-bromo-2'
-deoxy-31,5'-di-O-acetyl)-β-
D-arabinofuranosyl)-hypoxanthine mixture (
Hereinafter, it will be abbreviated as B r -A c 0-Hx. ), 11.
It contained 80 g (yield from inosine, 75.1%). A 300 MHz nuclear magnetic resonance absorption spectrum of the isolated product supported the main island structure.

(2) Br-AcO-Hx 415mg (1.0mm
ole) was dissolved in 30 ml of methanol containing 0.24 ml of triethylamine. 10% palladium on carbon 1
Add 70 mg of hydrogen gas and add 40 mg of hydrogen gas while stirring at room temperature.
The flow rate was ml/min. After the palladium on carbon was filtered off and washed with ethanol, the solvent was distilled off under reduced pressure.

The remaining residue was dissolved in 8 ml of methanol, 0.54 ml of 28% sodium methylate (methanol solution) was added, and the mixture was stirred at room temperature for 30 minutes. When the reaction solution was quantified by HPLC, 63.7 mg of 2',3'-dideoxyinosine (
0.27 mmol e) was produced in a yield of 27%, and 93.2 mg (0.37 mmol e) of 3'-deoxyinosine was produced in a yield of 37%. 30 purified and separated 2', 3'-deoxyinosine and 3'-deoxyinosine
0MH2 nuclear magnetic resonance absorption spectra supported the structure of the main island.

Example 6 Uridine (1.0 g, 4.10 mmole) was suspended in acetonitrile (5.0 ml), and to this was added trichloroacetic acid (0.737 g, 4.51 g) and trimethyl orthoacetate (0.63 ml, 4.0 mmole). 92
mmole) was added. The mixture was stirred at 15-20°C for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved again in acetonitrile (5 ml). this,
The mixture was slowly added to acetic acid containing acetyl bromide (1.21 ml, 18.4 mmole) under water cooling and vigorous stirring. After the addition is complete, the mixture is further heated to 15-20°C.
So, 2 o'clock RG! 1 stirred. The mixture was neutralized with a 10% aqueous sodium carbonate solution and extracted with 20 ml of ethyl acetate. According to HPLC analysis, this extract contains the desired 1
-((2'-bromo-2'-deoxy-3',5'-di○-acetyl)-β-D-ribofuranosyl)-uracil was 0.561 g (yield from uridine 35.0%)
) was included.

〔Effect of the invention〕

As is clear from the above, according to the present invention, the yield and purity of the production of nucleoside derivatives have been further improved, making industrialization extremely advantageous. As a result, the present invention facilitates the production of various substances such as dideoxynucleosides that exhibit pharmacological activity, and is highly expected to contribute to the pharmaceutical industry.

Claims (1)

[Claims] 1. In an organic solvent containing an organic acid, the 2' position, 3
A nucleoside whose 1-alkoxyalkylidene or 1-alkoxyarylalkylidene position is reacted with (1) an acyl halide; or (2) an organic acid anhydride and a hydrogen halide to form an acyloxy group and a halogen. atom 2'
A method for producing a nucleoside derivative, which comprises introducing the derivative into the 3'-position or the 3'-position (or the 3'-position or the 2'-position). 2. The method according to claim 1, wherein the organic acid contained in the organic solvent has 1 to 12 carbon atoms. 3. The method according to claim 1, wherein the organic acid contained in the organic solvent is formic acid or acetic acid. 4. The method according to claim 1, wherein the organic solvent is acetonitrile, dioxane, trimethyl phosphate, or dichloromethane. 5. The method according to claim 1, wherein the alkoxy group has 1 to 12 carbon atoms. 6. The method according to claim 1, wherein the alkoxy group is a methoxy or ethoxy group. 2. The method according to claim 1, wherein the alkylidene group of the 7,1-alkoxyalkylidene group is a methylidene or ethylidene group. 2. The method according to claim 1, wherein the arylalkylidene group of the 8,1-alkoxyarylalkylidene group is a benzylidene group. 9. The method according to claim 1, wherein the base constituting the nucleoside is a purine base or a pyrimidine base. 10. The method according to claim 9, wherein the purine base is any one of adenine, hypoxanthine, guanine, and xanthine. 11. The method according to claim 9, wherein the pyrimidine base is any one of uracil, thymine, and cytosine. 12. The method according to claim 1, wherein the halogen atom of the acyl halide is a chlorine, bromine or iodine atom. 13. The acyl group of the acyl halide has 2 to 12 carbon atoms.
The method according to claim 1. 14. The method according to claim 1, wherein the acyl group of the acyl halide is an acetyl group or a benzoyl group. 15. The number of carbon atoms in the organic acid constituting the organic acid anhydride is 2 to 1
2. The method according to claim 1. 16. The method according to claim 1, wherein the organic acid anhydride is acetic anhydride. 17. The method according to claim 1, wherein the hydrogen halide is hydrogen chloride, hydrogen bromide or hydrogen iodide. 18. Acyloxy group and bromine atom at 2' and 3' positions (or 3' and 2' positions)
2. A method for producing dideoxy nucleosides, which comprises subjecting the nucleoside derivative according to claim 1 to a hydrogenation reaction, followed by hydrolysis or transesterification to deacyloxylate and debromate the nucleoside derivative according to claim 1. 19. The method according to claim 18, wherein the base constituting the nucleoside derivative is a purine base. 20. The method according to claim 19, wherein the purine base is any one of adenine, hypoxanthine, guanine and xanthine. 2. The nucleoside having 1-alkoxyalkylidene or 1-alkoxyarylalkylidene at the 21, 2', and 3' positions is obtained by subjecting a ribonucleoside to an alkylidene process at the 2' and 3' positions. the method of. 22. The method according to claim 18, wherein the dideoxy nucleoside is obtained by deacyloxylating and debrominating the nucleoside derivative obtained according to claim 21.