JPH0717670B2 - Method for producing nucleoside derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides a novel method for producing a nucleoside derivative having an acyloxy group and a halogen atom at the 2 ′: 3 ′ position (or 3 ′ position, 2 ′ position). And a method of further converting it to a dideoxynucleoside through the above derivative, if necessary.

A nucleoside derivative having an acyloxy group and a halogen atom at the 2'-position, 3'-position (or 3'-position, 2'-position) is an important intermediate for the production of various pharmacologically active substances.

Further, although dideoxynucleoside is a known compound, it is expected to be applied to the pharmaceutical field because of its antiviral activity (for example, H. Mitsuya and S. Broader,
Proc.Natl.Acad.Soi.USA, Vol.83, 1911, 1986).

[Conventional technology]

Regarding the method for producing a nucleoside derivative such as dideoxynucleoside using nucleoside as a raw material, some are already known, or any of its important production intermediates are:
It is a compound of formula (I) or formula (II).

However, Base = purine base or pyrimidine base X = Cl, Br, IR ¹ = H, or a protecting group that can be easily removed.

R ² = acyl group The compounds of formula (I) and formula (II) can be converted into dideoxynucleosides by a known method of reducing with Pd / C under a hydrogen stream, and further hydrolyzing or transesterifying if necessary. Can lead to.

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

(1) The method of John. G. Moffatt et al. In which a nucleoside and 2-acetoxyisobutyric acid bromide are reacted. (J.Am.C
hem.Soc., Vol.95, 4025, 1973 US Patent 3658787) (2) 2 ', 3'-O- (1-methoxyethylidene)-
A method of Morris J. Robins et al. In which a nucleoside is reacted with bivalic acid chloride in the presence of sodium iodide.
(J. Am. Chem. Soc. Vol. 98, 8213, 1976) (3) 2 ', 3'-O- (1-ethoxyethylidene)-
A method of Engels et al. In which an adenosine derivative is reacted with sodium iodide in the presence of a trifluoroboron-diethyl ether complex. (Tetrahedron Letters, Vol.
21,4339, 1980) (4) 2 ', 3'-O- (1-ethoxyethylidene)-
An alternative method of John G. Moffatt et al. In which adenosine is reacted with lithium bromide in the presence of trifluoroboron-diethyl ether complex in acetonitrile. (J.Org.Ch
em., Vol.39, 30, 1974) (5) 2 ', 3'-O- (1-ethoxyethylidene)-
The method of Colin B. Reese et al., In which adenosine is reacted with acetyl bromide in dichloroethane. (Synthesis, 304,198
3 years) The method for producing the compound of formula (I) and formula (II), which is an important intermediate for producing a nucleoside derivative, is known as described in the previous section. There are problems as described in.

(1) The reaction proceeds with a high yield only when an expensive reaction reagent is used.

(2) Many products are produced.

(3) In some cases, it is necessary to protect functional groups that do not participate in the reaction.

All of these problems have been a cause of high cost when considered as an industrial process for producing nucleoside derivatives such as dideoxynucleosides.

[Problems to be Solved by the Invention]

In order to solve the above problems, the 2'position, the 3'position (or the 3'position,
It is desired to develop an industrially advantageous process for producing a nucleoside derivative having an acyloxy group and a halogen atom at the 2'-position) and a dideoxynucleoside. The present invention provides a novel industrially practical method for producing a nucleoside intermediate having a pharmacological action such as antiviral activity and a dideoxynucleoside.

[Means for Solving the Problems]

The present inventors retested all the known methods described in the section of the prior art, evaluated the reaction yield, operability, and economical efficiency,
As a result of further new studies, a manufacturing method superior to the known method was found here, and the present invention was completed.

That is, the present invention relates to a nucleoside whose 2'-position and 3'-position are 1-alkoxyalkylidene-ized or 1-alkoxyarylalkylidene-ized in an organic solvent containing an organic acid, and (1) an acyl halide; , (2) React an acyloxy group and a halogen atom to 2 ′ by reacting with an organic acid anhydride and hydrogen halide.
Position, 3'-position (or 3'-position, 2'-position) is introduced.

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, an organic solvent such as acetonitrile, dioxane, trimethyl phosphate, or dichloromethane.

In the 1-alkoxyalkylidene or 1-alkoxyarylalkylidene, the alkoxy group has 1 to 12 carbon atoms. For example, a methoxy or ethoxy group is adopted.

The alkylidene group of the 1-alkoxyalkylidene group is, for example, a methylidene group or an 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 and benzoyl.

The organic acid that constitutes the organic acid anhydride has a carbon number of 2 to 12, such as acetic acid and propionic acid. Acetic anhydride is preferred as the organic acid anhydride.

Examples of the hydrogen halide include hydrogen chloride, hydrogen bromide,
Hydrogen iodide is adopted.

The base that constitutes the nucleoside is, for example, a purine base or a pyrimidine base, and examples of the purine base include adenine, hypoxanthine, guanine, xanthine and the like.
As the pyrimidine base, uracil, thymine, cytosine and the like are adopted.

According to the method of the present invention, the acyloxy group and the bromine atom are 2 '.
The nucleoside derivative introduced at the 3'-position (or 3'-position, 2'-position) is further subjected to, for example, a hydrogenation reaction, and then subjected to a hydrolysis or transesterification reaction step to obtain a deacyloxy and Dideoxynucleosides can be produced by debromination. The acyloxy group is an acetoxy group, a benzoyloxy group or the like and has 2 to 2 carbon atoms.
About 12 are adopted.

Further, the base constituting the nucleoside derivative is a purine base, and in this case, adenine, hypoxanthine, guanine,
Xanthine etc. are adopted.

The starting material of the present invention may be a nucleoside obtained by subjecting a ribonucleoside to a 1-alkoxyalkylideneation reaction or a 1-alkoxyarylalkylideneation reaction. Those alkylideneation reactions are per se conventional methods (eg HPMFromageot et al, Tetrahedron,
Vol.23, 2315, 1967) should be adopted. Further, in the case of producing a dideoxynucleoside, the above-mentioned ribonucleoside has a purine base as its constituent base, and adenine, hypoxanthine, guanine, xanthine and the like are adopted.

The present invention described above will be described in more detail below.

That is, regarding the production of the nucleoside derivative having the acyloxy group and the halogen atom described above at the 2'position, 3'position (or 3'position, 2'position), the carbon number of the organic acid to be contained in the organic solvent Is acetic acid within the range of 1 to 12,
Any of propionic acid, butyric acid, etc. may be used. Among them, formic acid and acetic acid are more preferably used.

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

Furthermore, 1-alkoxyalkylidene-ized or 1-alkoxyarylalkylidene-ized nucleosides are known substances and can be easily produced.
The carbon number of the alkoxy group is not particularly limited as long as it is in the range of 1 to 12. That is, there are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Of these, methoxy and ethoxy are particularly preferable from the economical point of view. Further, as the alkylidene group of the alkoxyalkylidene group, a methylidene or ethylidene group is preferably used from the viewpoint of practical use. Furthermore, in the case of an arylalkylidene group, a benzylidene group is practical.

The base constituting the nucleoside of the starting material may be either a purine base or a pyrimidine base. Of these, apurine bases may be any of adenine, hypoxanthine, guanine, and xanthine, and pyrimidine bases are preferably uracil, thymine, and cytosine.

Next, the halogen atom of the acyl halide used as one of the reaction reagents may be chlorine, bromine or iodine. The acyl group of the acyl halide is not particularly limited as long as it has 2 to 12 carbon atoms. For example, acetyl, propionyl, oxalyl, malonyl,
Examples include benzoyl and trioil. Of these, an acetyl group and a benzoyl group are most preferable.

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

Further, as the hydrogen halide serving as a reaction reagent, any of hydrogen chloride, hydrogen bromide or hydrogen iodide is used. In this case, the hydrogen halide may be used as a gas or may be produced in the system.

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

The reaction temperature used here can be generally in the range of 0 ° C to 75 ° C, but is most preferably 0 ° C to 20 ° C.

Also, the reaction time varies depending on the temperature, but it is 15 ℃ to 20 ℃.
In the above, 0.5 to 3.0 hours are preferable.

Based on the above conditions, the 1-alkoxyalkylidene-ized or 1-alkoxyarylalkylidene-ized nucleoside as a starting material, by performing the above reaction,
It is possible to produce a nucleoside derivative in which an alkyloxy group and a halogen atom are bonded in a high yield and a high purity, which has never been considered before.

The following is a specific example. That is, 2 ', 3'-O- (1-methoxyethylidene) -adenosine (starting material) (formula (III)) is added to acetic acid containing acetyl bromide and reacted to give the desired nucleoside derivative. A mixture containing the compounds of formula (IV) and formula (V) as the main products was obtained.

However, what should be emphasized here is that the reaction using acetic acid as the reaction solvent not only proceeds in a high yield of 82%, but also the purity of the product is higher than that of the conventional product. It means that it is expensive. The by-product, 2 ', 3', 5'-O-triacetyl-adenosine, is produced in only 5 to 10%. This is the above Mo
Since the number of products is smaller than that of the method such as ffatt, it is extremely advantageous as an industrial production method. Further, the main products of formula (IV) and formula (V) can be extracted with an organic solvent (for example, acetonitrile, ethyl acetate, etc.) without loss. And, as will be described later, this extract contains almost no hydrophilic impurities which are problematic when the main products of formula (IV) and formula (V) are converted into dideoxyadenosine (abbreviated as DDA) in the next step. It has advantages.

Further, when 2'3'-O- (1-ethoxyethylidene) -adenosine was reacted in acetic acid containing acetyl bromide, the yield and purity similar to those of the above-mentioned specific examples were obtained. However, the method of Reese et al. (Synthesis, 304, 1983) -reaction conditions; heating under reflux in dichloroethane for 15 minutes-has a low yield (formula (IV) 53%) and a low purity, which makes it difficult to control the reaction. The novelty of the present invention is clear from the fact that it exists. But,
From the point of view of the prior art, it is considered surprising to carry out the reaction of the nucleoside derivative in an acidic solvent such as acetic acid.

Next, the nucleoside derivative having an acyloxy group and a halogen atom introduced at the 2'-position, 3'-position (or 3'-position, 2'-position) is subjected to a hydrogenation reaction using the above-mentioned novel production method,
Next, a method for producing a deacyloxylated and dehalogenated dideoxynucleoside characterized by hydrolysis or transesterification 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 should be an aqueous solution of sodium hydrogen carbonate, sodium carbonate or the like, or a weak base such as aqueous ammonia. As the organic solvent for extraction, acetonitrile, ethyl acetate or the like can be used. The solvent of the product extract was distilled off under reduced pressure,
Dissolve the residue in methanol. This solution is subjected to catalytic hydrogenation in the presence of Pd / C and triethylamine in a hydrogen stream, and after removing the catalyst, the reaction solution is directly added with a methanol solution of sodium methoxide for transesterification to obtain a dideoxynucleoside. it can.

Further, the base constituting the nucleoside derivative used in the above reaction is preferably a purine base. And among 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-alkoxyalkylideneation reaction or a 1-alkoxyarylalkylideneation reaction can be adopted. For these alkylidene-forming reactions, the method of Fromageot et al. May be adopted, as described in Examples below. When producing a dideoxynucleoside, the ribonucleoside preferably has a purine base as its constituent base, and adenine, hypoxanthine, guanine, xanthine or the like is used.

Specifically, for example, as described in the Examples below, 2 ', 3'-O- (1-methoxyethylidene) -adenosine is produced from adenosine by a known method, and without isolation, Alternatively, the compound of formula (IV) and the compound of formula (V) can be obtained in high yield by a method of isolation and reaction with acetyl bromide in an organic solvent containing acetic acid, or a method of reacting with hydrogen bromide in acetic anhydride. It has been found that a mixture of compounds of). In this case, the reaction solvent is a mixed system of acetic acid and the organic solvent used in the production of 2 ', 3'-O- (1-methoxyethylidene) -adenosine. Further, if necessary, DDA, which is a dideoxynucleoside, can be obtained by the above-mentioned method in which the compounds of formula (IV) and formula (V) are subjected to hydrogenation reaction and then hydrolyzed or transesterified.

〔Example〕

 Hereinafter, the present invention will be described based on examples.

Example 1 (1) To a solution prepared by dissolving 0.27 ml (4 mmol) of acetyl bromide in 2 ml of acetic acid, 323 mg (1 mmol) of 2 ', 3'-O- (1-methoxyethylidene) adenosine was gradually added. After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The organic layer was quantified by high performance liquid chromatography (hereinafter, abbreviated as HPLC) to give 9-{(3'-bromo-3'-deoxy-2 ', 5'.
-Di-O-acetyl) -β-D-xylofuranosyl}-
Adenine and 9- {2'-bromo-2'-deoxy-
A mixture of 3'-5'-di-O-acetyl) -β-D-xylofuranosyl} -adenine (hereinafter abbreviated as Br-AcO-AR) was produced in a yield of 341 mg (0.824 mmol) and 82%. The 300 MHz nuclear magnetic resonance absorption spectrum of the isolated product supported the structure of the product.

(2) Br-AcO-AR 307 mg (0.741 mmo) in methanol 30 ml
l) and 0.18 ml of triethylamine were dissolved. Add 620 mg of 2% palladium carbon and add 40 m of hydrogen gas while stirring at room temperature.
The flow rate was 1 / min. After the palladium carbon was filtered off and washed with ethanol, the solvent was distilled off under reduced pressure. The residue was dissolved in 8 ml of methanol, 0.4 ml of 28% sodium methylate (methanol solution) was added, and the mixture was stirred at room temperature for 30 minutes. HPL the reaction solution
When quantified by C, 2 ', 3'-dideoxyadenosine 7
7.8 mg (0.33 mmol) yield was 45%, 3'-deoxyadenosine was 32.4 mg (0.30 mmol) yield was 17%. Purified and separated. 2 ', 3'-deoxyadenosine and 3'-
The 300 MHz nuclear magnetic resonance absorption spectrum of deoxyadenosine supported the structure of the product.

Example 2 Acetic anhydride 0.4 ml (4.2 mmole) and 25% hydrogen bromide / acetic acid solution 1
To a solution obtained by adding ml to acetic acid 1 ml, 2 ', 3'-O- (1-methoxyethylidene) adenosine 323 mg (1 mmole) was gradually added. After stirring at room temperature for 2 hours, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. When the organic layer was defined by HPLC, Br-AcO-AR was
It was produced in a yield of 30 mg (0.80 mmole) of 80%.

Example 3 10 g of adenosine (37.4 mmole) was suspended in 70 ml of acetonitrile, and 6.73 g (42 mmole) of trichloroacetic acid was added thereto, and then 6.0 ml (46 mmole) of trimethyl orthoacetate was added thereto. The mixture was heated and stirred at 50 ° C. for 1 hour and 40 minutes.
After the reaction, the solvent was distilled off under reduced pressure until the residual liquid became 35 ml. 72 ml of acetic acid containing 12.3 ml of acetyl bromide
The mixture was slowly added to the mixture at 0 ° C. with stirring. After the addition was completed, the mixture was further stirred at 15-20 ° C for 50 minutes to finally obtain a uniform solution. This was neutralized with 20% aqueous sodium carbonate solution and extracted with 140 ml of acetonitrile.
According to HPLC analysis, this extract contains 9-
{(3'-bromo-3'-deoxy-2 ', 5'-di-
O-acetyl) -β-D-xylofuranosyl} -adenine, and 9-{(2′-bromo-2′-deoxy-
It contained 12.77 g (82.1% yield from adenosine) of a mixture of 3 ', 5'-di-O-acetyl) -β-D-arabinofuranosyl} -adenine.

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

Example 5 (1) Inosine 10 g (37.2 mmole) was suspended in DMF 100 ml, and trimethyl orthoacetate 33.2 ml (260 m)
mole), then p-toluenesulfonic acid monohydrate 1
0.64g (56.0mmole) was added. The mixture at 15-20 ° C
Stir for 30 minutes. After the reaction, the sodium methylate
The mixture was neutralized with a 28% methanol solution, and the solvent was distilled off under reduced pressure. The residue was suspended in 130 ml of acetonitrile, which was
0 in 71 ml of acetic acid containing 11.0 ml (149 mmole) of acetyl bromide
The mixture was slowly added at ℃ under stirring. After the addition was complete, the mixture was further stirred at 15-20 ° C for 30 minutes. The mixture was neutralized with 10% aqueous sodium carbonate solution and extracted with 140 ml of acetonitrile. According to HPLC analysis, this extract was found to contain 9-{(3'-bromo-3'-deoxy-2 ',
5'-di-O-acetyl) -β-D-xylofuranosyl} -hypoxanthine, and 9-{(2'-bromo-
2'-deoxy-3 ', 5'-di-O-acetyl) -β
A mixture of -D-arabinofuranosyl} -hypoxanthine (hereinafter abbreviated as Br-AcO-Hx), 11.60 g (yield from inosine, 75.1%) was contained. The 300 MHz nuclear magnetic resonance absorption spectrum of the isolated product supported the structure of the product.

(2) Br-AcO-Hx 415 mg (1.0 mmole) was dissolved in 30 ml of methanol containing 0.24 ml of triethylamine. 170 mg of 10% palladium carbon was added, and hydrogen gas was passed through at a flow rate of 40 ml / min while stirring at room temperature. After palladium carbon was filtered off and washed with ethanol, the solvent was distilled off under reduced pressure. The 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. The reaction solution was quantified by HPLC. As a result, 2 ', 3'-dideoxyinosine 63.7 mg (0.27mmole) yield 27%, 3'-
Deoxyinosine was produced in a yield of 93.2 mg (0.37 mmole) and 37%. Purified and separated 2 ', 3'-deoxyinosine and 3'-deoxyinosine 300 MHz nuclear magnetic resonance absorption spectra supported the structure of the product.

Example 6 Uridine (1.0 g, 4.10 mmole) was added to acetonitrile (5.0 m
l), and add trichloroacetic acid (0.737g, 4.51
g) and trimethyl orthoacetate (0.63ml, 4.92mm
ole) 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 redissolved in acetonitrile (5 ml). This was slowly added to acetic acid containing acetyl bromide (1.21 ml, 16.4 mmole) under ice cooling and vigorous stirring. After the addition was complete, the mixture was further stirred at 15-20 ° C for 2 hours. The mixture was neutralized with 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-O
-Acetyl) -β-D-ribofuranosyl} -uracil was contained in an amount of 0.561 g (yield from uridine: 35.0%).

〔The invention's effect〕

As is clear from the above, according to the present invention, with respect to the production of nucleoside derivatives, the yield and purity were further improved, and industrialization became very advantageous. As a result, the present invention facilitates the production of various substances having pharmacological activity such as dideoxynucleoside, and is expected to greatly contribute to the pharmaceutical industry.

Claims (22)

[Claims] 1. An organic solvent containing an organic acid, which comprises 2 '
1-alkoxyalkylidene at the 3'-position or 1-
Alkoxyarylalkylideneated nucleosides are reacted with (1) acyl halide; or (2) organic acid anhydride and hydrogen halide to form an acyloxy group and a halogen atom at 2 '.
Position, 3'position (or 3'position, 2'position) is introduced, The manufacturing method of the nucleoside derivative characterized by the above-mentioned. 2. The organic acid contained in the organic solvent has 1 carbon atom.
The method according to claim 1, wherein 3. The method according to claim 1, wherein the organic acid contained in the organic solvent is formic acid or acetic acid. 4. The organic solvent is acetonitrile, dioxane,
The method according to claim 1, which is 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 group or an ethoxy group. 7. The method according to claim 1, wherein the alkylidene group of the 1-alkoxyalkylidene group is a methylidene or ethylidene group. 8. The method according to claim 1, wherein the arylalkylidene group of the 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 of adenine, hypoxanthine, guanine, and xanthine. 11. A pyrimidine base is uracil, thymine,
10. The method according to claim 9, wherein the method is any one of the following: 12. The method according to claim 1, wherein the halogen atom of the acyl halide is a chlorine, bromine or iodine atom. 13. The method according to claim 1, wherein the acyl group of the acyl halide has 2 to 12 carbon atoms. 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 method according to claim 1, wherein the organic acid constituting the organic acid anhydride has 2 to 12 carbon atoms. 16. The organic acid anhydride is acetic anhydride.
The method described. 17. The method according to claim 1, wherein the hydrogen halide is hydrogen chloride, hydrogen bromide or hydrogen iodide. 18. An organic solvent containing an organic acid, wherein the 2'-position and the 3'-position are 1-alkoxyalkylidene, or
The 1-alkoxyarylalkylideneated nucleoside is reacted with (1) acyl bromide; or (2) an organic acid anhydride and hydrogen bromide to form an acyloxy group and a bromine atom at the 2'position,
A nucleoside derivative obtained by introducing at the 3'-position (or 3'-position, 2'-position) is subjected to hydrogenation reaction, and then subjected to hydrolysis or transesterification reaction for deacyloxylation and deodorization and deodorization. A method for producing a dideoxynucleoside, which comprises: 19. The method according to claim 18, wherein the base constituting the nucleoside derivative is a purine base. 20. The purine base is any one of adenine, hypoxanthine, guanine and xanthine.
The method described. 21. A nucleoside having 1-alkoxyalkylidene or 1-alkoxyarylalkylidene at the 2'-position and 3'-position is obtained by subjecting ribonucleoside to the 2'-position, 3'-position alkylideneation step. 1
The method described. 22. The process according to claim 18, wherein the dideoxynucleoside is obtained by deacyloxylating and debrominating the nucleoside derivative obtained according to claim 21.