JP2770357B2 - Method for producing nucleoside derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a nucleoside derivative using inosine as a raw material, and more particularly to 2 ′, 3′-didehydro-
The present invention relates to a method for producing 2 ', 3'-dideoxy-5'-0-acylinosine and 2', 3'-dideoxyinosine.

2 ', 3'-didehydro-2', 3'-dideoxy-5 '
-O-Acyl inosine is important as an intermediate for producing various substances having pharmacological activity.

In addition, since 2 ', 3'-dideoxyinosine has antiviral activity, it is expected to be applied to pharmaceuticals.

[Conventional technology]

Among the methods for synthesizing 2 ', 3'-dideoxy nucleosides using nucleosides as raw materials, the following three examples are known as those which take means close to the method according to the present invention.

1) MJRobius et al., Tetrahedron Lett. 25 .367 (1
984), 2) B. Samuelsson et al., Acta Chem. Scand., B36 , 251
(1982), 3) J. Chattopadhyaya et al., Acta Chem. Scand., B4
0, 251 (1982).

However, these all use adenosine or protected adenosine as a substrate, and there is no report of producing 2 ', 3'-dideoxynucleoside using inosine.

The reason is considered to be that the zinc complex not only acts as a catalyst poison during catalytic hydrogenation, but also hinders the isolation and purification of the product, so that there was no efficient removal method.

Another reason is that 2 ', 3'-didehydro-2', 3 '
-The dideoxyinosine derivative (III) causes decomposition of the substrate in a solvent containing water during catalytic hydrogenation, and there is no method for effectively preventing this.

[Problems to be solved by the invention]

An object of the present invention is to use a low-cost inosine as a raw material, establish an efficient method for removing a zinc complex generated in the course of the reaction, and provide a method for catalytic hydrogenation with less byproduct of hypoxanthine which is a decomposition product. It has been found that 2 ', 3'-didehydro-2', 3'-dideoxyinosine which is important as an intermediate of a pharmacologically active substance and 2 ', 3'-dideoxyinosine having antiviral activity can be industrially advantageously produced. It is to provide a method that can be used.

[Means for solving the problem]

The present inventors studied the application of a conventional method for producing 2 ', 3'-dideoxyadenosine from adenosine to a method using inosine as a raw material. The present inventors have found an excellent method for producing 2 ', 3'-dideoxyinosine and completed the present invention.

That is, the general formula of the present invention The method for producing the 2 ', 3'-didehydro-2', 3'-dideoxynucleoside derivative represented by the general formula (1) (Where H _X is hypoxanthine linked to the sugar moiety at the 9-position, X is Cl, Br or I, R ³ is H or a readily removable protecting group, and R ⁴ is an acyl group. Wherein the inosine derivative represented by the following formula is reacted in an organic solvent in the presence of zinc powder and acetic acid, and then the zinc complex is removed.

The catalytic hydrogenation of the 2 ', 3'-didehydro-2', 3'-dideoxynucleoside (III) in the presence of a Pd catalyst as described in claim 7, followed by hydrolysis or transesterification. By adding to the general formula 2 ′, 3′-dideoxynucleoside derivative (IV)

This 2 ', 3'-dideoxynucleoside derivative (IV)
Can be continuously and industrially advantageously produced from inosine by following the steps described in claim 10.

In the formula, R ¹ represents an alkyl group, R ² represents an alkyl group or an aryl group, and R ³ , R ⁴ , H _X , and X each have the same meaning as described above.

The first step is the method of Mengel et al. (R. Mengel et al., Lieb
ig Anm. Chem., 1585 (1977) was improved, and inosine and trialkyl orthoacetate were reacted in dimethylformamide (DMF) to form 1-alkoxyalkylidene or 1-alkylaryl at the 2 ′ and 3 ′ positions. This is a step of obtaining an alkylidinated inosine derivative [I]. Here, trichloroacetic acid, p-toluenesulfone, or the like is used as the organic acid.

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

Thus, the inosine derivative (I) in which the 2'-position and the 3'-position are 1-alkoxyalkylidene- or 1-alkoxyarylalkylidene-modified from inosine is obtained.

In the second step, the inosine derivative (I) is reacted with an acyl halide or an organic acid anhydride and hydrogen halide in an organic solvent in the presence or absence of an organic acid to form an acyloxy group and a halogen atom in an organic solvent. This is a step of producing an inosine derivative [II] introduced at the 'position, 3'position (or 3'position, 2'position).

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, dichloromethane, or DMF
And other organic solvents.

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

As the hydrogen halide, for example, hydrogen chloride, hydrogen bromide, and hydrogen iodide are employed.

In the third step, as described above, an inosine derivative [II] in which an acyloxy group and a halogen atom have been introduced at the 2'-position or 3'-position (or 3'-position or 2'-position) is prepared in an organic solvent in the presence of acetic acid. A zinc powder is reacted, and after completion of the reaction, the generated zinc complex is efficiently removed to produce and purify 2 ', 3'-didehydro-2', 3'-dideoxy-5-O-acylinosine [III]. It is a process.

The organic solvents used here are methanol, ethanol,
Acetonitrile, THF, DMF or a mixed solvent thereof.

Removal of the zinc complex can be achieved by using an ion exchange resin, an adsorption resin or a chelating resin, or by partitioning the organic solvent with water or an aqueous solution of a chelating agent. Examples of the chelating agent include acids such as ethylenediaminetetraacetic acid, oxalic acid, citric acid, glycolic acid, and polyphosphoric acid, and inorganic salts thereof, but are not limited thereto. Chloroform, dichloromethane, acetonitrile, ethyl acetate and the like are used as the organic solvent at the time of distribution.

In the fourth step, the above 2 ′, 3′-didehydro-
2 ', 3'-dideoxy-5'-0-acylinosine [II
I) in an organic solvent in the presence of a Pa-catalyst to minimize the decomposition of the reaction substrate and hydrogenate the catalyst to give the 2 ', 3'-dideoxyinosine derivative [IV] for the hydrolysis or ester conversion reaction. This is the step of obtaining.

As the organic solvent, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate or the like is employed.

Pd-catalysts for catalytic hydrogenation include Pd carbon, Pd-BaCO ₃ ,
Pd-CaCO ₃ or the like is employed.

The present invention will be described more specifically as follows. For the 1-alkoxyalkylidation reaction using isosine, the above-mentioned method of Mengel et al. Using hydrogen chloride in DMF is known. However, these conditions require anhydrous conditions, and there are difficulties in terms of industrial practicability such as using hydrogen chloride.

The present inventors have studied the reaction conditions, as a result, in DMF solvent,
By using an organic acid, the 2'- and 3'-positions are 1-
They have found that an alkoxyalkylidene or 1-alkoxyarylalkylidinated inosine derivative [I] can be obtained.

As the organic acid contained in DMF, carboxylic acids such as trichloroacetic acid or sulfonic acids such as paratoluenesulfonic acid are preferable. In the case of trichloroacetic acid and paratoluenesulfonic acid, the reaction proceeds with a catalyst amount of 10 mol% or less.

These organic acids can be removed by filtration after distilling off DMF under reduced pressure and adding an organic solvent such as ethyl acetate, since the product is hardly soluble, and can be removed by filtration.
An inosine derivative [I] which is -alkoxyalkylidinated or 1-alkoxyarylalkylidinated can be easily obtained.

Here, the number of carbon atoms 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 preferred from the economical point of view. As the alkylidene group of the alkoxyalkylidene group, a methylidene or ethylidene group is preferably used from a practical viewpoint. Further, in the case of an arylalkylidene group or the like, benzylidene or the like is practical.

Next, the inosine derivative [I] is reacted with an acyl halide, or an organic acid anhydride and hydrogen halide in an organic solvent in the presence of an organic acid, to thereby convert the acyloxy group and the halogen atom to the 2′-position. 3 'position (or 3' position, 2 '
) Introduced into the inosine derivative [II].

Here, as the organic solvent, acetonitrile, dioxane, trimethyl phosphate and the like are preferable. If the carbon number of the organic acid to be contained in the organic solvent is in the range of 1 to 12, acetic acid,
Any of propionic acid and butyric acid may be used. Among them, use of formic acid and acetic acid is more preferable. At this time, the reaction proceeds in good yield even if no organic acid is present, but requires a longer reaction time.

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

Similarly, as the organic acid anhydride which is one of the reaction reagents, acetic anhydride, propionic anhydride, butyric anhydride and the like can be used, and among them, acetic anhydride which is easily available and has high reaction efficiency is more preferable.

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

The required amount of the acyl halide or organic acid anhydride and the hydrogen halide used in the present invention is 1 to 5 times as much as that of the starting 1-alkoxyalkylidene or 1-alkoxyarylalkylidinated inosine derivative [I]. Use twice molar equivalents. Most preferably, three to four times
Double molar equivalents.

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

The reaction time varies depending on the temperature, but from 15 ° C. to 20 ° C., preferably 0.5 hour and 3.0 hours.

Next, the alkyloxy group and the halogen atom are located at the 2'-position and 3'-position.
The inosine derivative [II] introduced at the 3rd position (or 3 'position, 2' position) is reacted with zinc powder in an organic solvent in the presence of acetic acid to react with 2 ', 3'-didehydro-2', 3'-. Dideoxy-
A method for producing the 5'-O-acylinosine derivative [III] and a method for removing the zinc complex after the reaction will be described. In the case of the catalytic hydrogenation reaction described later, the mixture of the zinc complex significantly inhibits the hydrogenation reaction, and when the zinc complex is treated with water, the zinc complex becomes gelled zinc hydroxide, making purification of the product extremely difficult. Efficient removal of zinc complexes is essential.

As the organic solvent for the reaction, methanol, ethanol acetonitrile, THF, DMF and the like can be used. Also, a zinc-copper reagent can be used instead of zinc powder and acetic acid. It is desirable to use 2 to 3 equivalents of zinc powder and 2 to 3 equivalents of acetic acid, and the reaction is completed in 15 minutes to 2 hours at room temperature.

After the completion of the reaction, several methods described below can be used for purifying the residue obtained by removing the organic solvent.

The residue is dissolved in aqueous ammonium and the adsorption resin (eg, SP
-207 manufactured by Mitsubishi Kasei Co., Ltd.) and eluted with ammonium water-methanol to purify. In this case 5 '
-2 ', 3'-didehydro-2', 3 'from which the acyl group has been removed
-Dideoxyinosine can also be subjected to purification.

The residue is dissolved in methanol, and a chelating resin (for example, CR
-10 (manufactured by Mitsubishi Kasei Corporation) and eluted with methanol for purification. As a method using a chelate resin, a batch type method is also possible.

As a simpler method, purification can be performed by partitioning with an organic solvent and water. Suitable organic solvents include chloroform, dichloromethane and the like. As an extraction method, a method using a solvent such as acetonitrile, THF, or ethyl acetate as an organic solvent and an aqueous solution of a chelating agent as an aqueous layer is excellent. According to this method, 2 ', 3'-didehydro-2', 3'-dideoxyinosine [III] containing no zinc complex in the organic layer is quantitatively recovered. As a chelating agent, for example, an aqueous solution of EDTA-2Na is used before use.
It is desirable to prepare from DTA and a base such as sodium hydroxide immediately before use, and use it from neutral to acidic.

2 ', 3'-didehydro-2', 3 'thus obtained
A process for obtaining 2 ', 3'-dideoxyinosine [IV] by catalytic hydrogenation of -dideoxy-5'-O-acylinosine [III] will be described.

2 ', 3'-didehydro-2', 3'-dideoxy-5 '
-O-acylinosine [III] and 2 ',
3'-dideoxy-5'-O-acetylinosine [IV]
Is extremely acid-labile, so the reaction system must always be kept from neutral to basic. Furthermore, it has been found that the incorporation of water into the reaction solvent significantly accelerates the decomposition of the substrate during catalytic hydrogenation with a Pd-catalyst.

Therefore, as the organic solvent used in the reaction, methanol, ethanol, isopropanol, acetonitrile,
Alternatively, it is desirable to use a non-aqueous solvent such as ethyl acetate.

Pd-catalysts include PdP carbon, and Pd-BaCO, which is generally considered to have low activity for hydrogenation of double bonds.
₃ , Pd-CaCO _{3 and the} like are suitable. When these were used, it became clear that the contamination of water into the system was smaller than in the case of Pd-carbon. When performing industrial large-scale operations
It is desirable to use a catalyst such as Pd-BaCO ₃ and Pd-CaCO _{3 which} does not cause ignition.

The reaction rate varies depending on the activity of the catalyst, but when the Pd content is 5 to 30 mol% (based on the substrate [II]), the catalyst is added.
The reaction is completed at room temperature under a stream of hydrogen for 1 to 6 hours.

Next, Table 1 shows the experimental results on the amount of hypoxanthine produced in this reaction when various Pd catalysts were used and water was mixed. It can be seen that non-aqueous conditions suppress the formation of hypoxanthine.

The reaction was carried out in 2 ml of ethanol using 15.0 mg of the produced 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O-acetylinosine and, by liquid chromatography, the starting materials 2 ', 3' - didehydro-2 ', 3'-dideoxy-5'-O-acetyl-inosine product 2', 3'-dideoxyinosine (III) and hypoxanthine [H _X]
Was measured.

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

Example 1 (1) Inosine 20.0 g (74.6 mmol) was suspended in DMF 70 ml and trimethyl orthoacetate 14.2 ml (1.5 equivalents, 11 equivalents)
1.8 mmol) and 18.3 g of trichloroacetic acid (1.5 equivalents, 111.8 mmol)
l) was added. After stirring at room temperature for 12 hours, the reaction solution is
The mixture was concentrated to 1 l, 150 ml of ethyl acetate was added, and the mixture was stirred. The insoluble solid was collected by filtration to obtain 23.4 g (72.2 mmol, yield 96.8%) of 2 ', 3'-O- (1-methoxyethylidene) -inosine as a white powder. The 300 MHz NMR and FAB-MS spectra of the product supported the structure.

(2) 10.0 g (37.3 mmol) of inosine was suspended in 25 ml of DMF, and 7.1 ml of trimethyl orthoacetate (1.5 equivalents, 55.
9 mmol) and p-toluenesulfonic acid monohydrate 710 mg (0.1
(Equivalent, 3.7 mmol). After stirring at room temperature for 12 hours,
The reaction solution was concentrated to about 10 ml, and 100 ml of ethyl acetate was added.
Stirred. The insoluble solid was collected by filtration and 2 ', 3'-O- (1-
Methoxyethylidene) -inosine (11.4 g, 35.1 mmol, yield 94.0%) was obtained.

Example 2 23.4 g (72.2 mmol) of 2 ', 3'-O- (1-methoxyethylidene) -inosine was suspended in 150 ml of acetonitrile, and 26.7 ml (5 equivalents, 361 mmol) of acetyl bromide was added at room temperature for 15 minutes. It fell down. The mixture was further stirred at room temperature for 5 hours to obtain a homogeneous solution. NaHCO ₃ 60.7 g (722 mmol) in water 100
The above reaction solution was added dropwise to the solution suspended in ml over 15 minutes. Extract twice with 100 ml of ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous MgSO ₄ , filtered, concentrated and dried to give 25.9 g (62.4 mmol, yield 86.4%) of a pale yellow powder. Analysis by liquid chromatography showed that 9-
(2 ', 5'-O-diacetyl-3'bromo-3'-deoxy-β-D.xylofuranosyl) hypoxanthine, 9-
About 4% of 2 ', 3'-5'-triacetylinosine besides (3', 5'-O-diacetyl-2'bromo-2'-deoxy-β-D-xylofuranosyl) hypoxanthine There was found. 300 Hz NMR and FAB-MS spectra of the product obtained by recrystallization from ethyl acetate supported the structure of the product.

Example 3 9- (2 ', 5'-O-diacetyl- obtained in Example 2
8.50 g of a mixture of 3′-deoxy-β-D.xylofuranosyl) hypoxanthine and 9- (3 ′, 5′-O-diacetyl-2′-bromo-2′-deoxy-β-D-xylofuranosyl) hypoxanthine (20.5 mmol) was suspended in a mixed solvent of 25 ml of acetonitrile and 25 ml of methanol. 4.01 G (3 equivalents, 610.4 mmol) of zinc powder and 2.58 ml of acetic acid (2,2
(Equivalent, 45.0 mmol) and stirred at room temperature for 1 hour. Unreacted zinc powder was removed by filtration using Celite, and Na was added to the filtrate.
7.75 (4.5 equivalents, 92.3 mmol) of HC ₃ was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of CHCl ₃ , 10 ml of water was added, and the mixture was stirred and then separated. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated.

The residue was subjected to silica gel column chromatography (100 cc, CH
Cl ₃ : MeOH = 10: 1, eluted with v / v) and purified with 5′-O-acetyl-2 ′, 3′-didehydro 2 ′, 3′-dideoxyinosine 1.96 g (7.1 mmol, yield) 34.7%) as a pale yellow powder. The 300 MHz NMR and FAB-MS spectra of the product supported the structure.

Example 4 500 mg (1.81 mmol) of 5'-O-acetyl 2 ', 3'-didehydro-2', 3'-dideoxynone obtained in Example 3 was suspended in 15 ml of ethanol, and 30% Pd-BaCO _{3 was} added. 100 mg was added. After stirring for 2 hours under a hydrogen stream, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was analyzed by liquid chromatography and found to be 5'-O-acetyl-2 ', 3'-
It contained 445 mg of dideoxyinosine (1.60 mmol, yield 88.4%) and 25 g of hypoxanthine (0.8 mmol, 9.9% yield). The resulting 5'-O-acetyl 2 ', 3'-dideoxyinosino 300 MHz NMR and FAB-MS spectra supported the structure of the product.

Example 5 9- (2 ', 5'-O-diacetyl-3'bromo3'-
Deoxy-β-D-xylofuranosyl) hypoxanthin and 9- (3 ′, 5′-O-diacetyl-2′-bromo-
1.0 g (2.41 mmol) of a mixture of 2′-deoxy-β-D-xylofuranosyl) hypoxanthine was added to 5 ml of acetonitrile.
And methanol in a mixed solvent of 5 ml. Zinc powder472
mg (3 equivalents, 7.23 mmol) and acetic acid 0.30 ml (2.2 equivalents, 5.30 mmol)
mol) and stirred at room temperature for 1 hour. Unreacted zinc powder was removed by filtration using Celite, and the filtrate was NaHCO ₃ 912 mg
(4.5 equivalents, 10.85 mmol) was added and the solvent was distilled off under reduced pressure. After 40 ml of CHCl _{3 and 3} ml of water were added to the residue and stirred, insoluble materials were removed by filtration, and the mixture was separated. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. Residue CHCl ₃ -MeOH (10: 1, v /
It was dissolved in 1 ml of the mixed solvent of v) and filtered using a silica gel column (50 cc). Concentrate the filtrate, then EtOH 30ml, 30% Pd
-BaCO _{3 (} 100 mg) was added, and the mixture was stirred under a hydrogen stream for 12 hours. The catalyst was removed by filtration, 2 ml of 2N-NaOH was added, and the mixture was stirred for 30 minutes. As a result of analysis by liquid chromatography, 255 mg of 2 ', 3'-dideoxyinosine (1.08 mmol,
Yield 44.8%) and hypoxanthine 6.9 mg (0.05 mol, yield 2.
1%). NMR and FAB-MS spectra of the isolated 2 ', 3'-dideoxyinosine at 300 MHz supported the structure of the product.

Example 6 9- (2 ', 5'-O-diacetyl-3'bromo-3'
-Deoxy-β-D-xylofuranosyl) hypoxanthin and 9- (3 ′, 5′-O-diacetyl-2′-bromo-
Using 1.5 g (3.61 mmol) of a mixture of 2'-deoxy-.beta.-D-xylofuranosyl) hypoxanthine, the reaction was carried out in the same manner as in Example 3 and 5'-O-acetyl-2 ', 3'-didehydro-2'. The crude product of 3,3'-dideoxyinone was obtained. This is dissolved in 6 ml of 5% ammonium water, and the adsorbing resin S
1% aqueous ammonium was passed through a column (50 cc) packed with P-207, followed by elution with 50% methanol, and the eluate was concentrated to 50 ml. 5'-O-acetyl- in the solution
2 ', 3'-didehydro-2', 3'-dideoxyinosine and 2 ', 3'-didehydro- with acetyl group deprotected
2 ', 3'-dideoxyinosine was included. 30 ml of methanol, 250 ml of 10% Pd-carbon and 500 mg of NaCO ₃ were added to the solution, and the mixture was reacted under a hydrogen stream for 4 hours. The catalyst was removed by filtration and analyzed by liquid chromatography. As a result, 268 mg (1.13 mmol, yield 31.4%) of 2 ', 3'-dideoxyinosine and 93 mg of hypoxanthine (0.68 mmol, yield 18.8%) were obtained. Generated.

Example 7 9- (2 ', 5'-O-diacetyl-3'-bromo-
200 mg (0.48%) of a mixture of 3'-deoxy-β-D-xylofuranosyl) hypoxanthin and 9- (3 ', 5'-O-diacetyl-2'bromo-2'-deoxy-β-D-xylofuranosyl) hypoxanthine Example 3
Perform the same reaction as. 5'-O-acetyl-2 ', 3'
A crude product of -didehydro-2 ', 3'-dideoxyinone was obtained.

To this, 30 ml of methanol and a small amount of acetic acid were added to obtain a homogeneous solution. After adding 10 cc of the chelate resin CR-10 and stirring for 5 hours, the resin was removed by filtration, 50 mg of 30% Pd.BaCO ₃ was added, and the mixture was reacted for 7 hours under a hydrogen stream. Filter off the catalyst,
2N-NaOH (2 ml) was added and stirred for 30 minutes. Analysis by liquid chromatography showed that 2 ', 3'-dideoxyinosine 73
mg (0.31 mmol, yield 64.0%) was obtained.

Example 8 9- (2 ', 5'-O-diacetyl-3'-bromo-
1.0 mg (2.4%) of a mixture of 3′-deoxy-β-D-xylofuranosyl) hypoxanthine and 9- (3 ′, 5′-O-diacetyl-2′bromo-2′-deoxy-β-D-xylofuranosyl) hypoxanthine Example 3 using
The same reaction is performed. 5'-O-acetyl-2 ', 3'
A crude product of -didehydro-2 ', 3'-dideoxyinone was obtained. This was dissolved in a mixed solvent of 30 ml of acetonitrile and 15 ml of ethyl acetate, and 10 ml of an aqueous solution of EDTA-2-sodium (3
(Equivalent, 7.23 mmol). The aqueous layer is acetonitrile 10ml
After extraction with a mixed solvent of ethyl acetate and 5 ml of ethyl acetate, the obtained organic layer was extracted with 5 ml of an aqueous solution of EDTA-2-sodium (1 equivalent, 2.41 m 2).
mol). After concentrating the organic layer to dryness, the residue was dissolved in 30 ml of methanol, and 200 mg of 30% Pd-CaCO ₃ and NaHCO ₃
100 mg was added and reacted for 6 hours under a hydrogen stream. The catalyst was removed by filtration, 4 ml of 2N-NaOH was added, and the mixture was stirred for 30 minutes.
As a result of analysis by liquid chromatography, 469 mg (1.99 mmol, yield 82.4%) of 2 ', 3'-dideoxyinosine and 51 mg (0.38 mmol, yield 15.6%) of hypoxanthine were obtained.

〔The invention's effect〕

As described above, according to the present invention, 2 ′, 3′-didehydro-2 ′, 3′-dideoxynucleoside derivative and antivirus which are important intermediates for the production of pharmacologically active substances are obtained from inosine as a raw material. Active 2 ', 3'-
The dideoxynucleoside derivative can be industrially advantageously produced with high purity and yield.

Claims (3)

(57) [Claims] (1) General formula (Wherein, H _X is hypoxanthine linked to the sugar moiety at the 9-position, X is Cl, Br or I, R ³ is H or a readily removable protecting group, and R ⁴ is Wherein an acyl group represented by the following formula is reacted in an organic solvent in the presence of zinc powder and acetic acid, and then a zinc complex is removed. (Wherein, H _X and R ³ have the same meanings as described above.) A method for producing a 2 ′, 3′-didehydro-2 ′, 3′-dideoxy-nucleoside derivative represented by the formula: 2. The general formula (Wherein H _X represents hypoxanthine bonded to the sugar moiety at the 9-position, and R ³ represents H or an easily cleavable protecting group, respectively.) 2 ′, 3′-didehydro A general formula, characterized in that a -2 ', 3'-dideoxy-nucleoside derivative is catalytically hydrogenated in an organic solvent in the presence of a Pd catalyst, and then subjected to a hydrolysis or ester conversion reaction. (Wherein H _X has the same meaning as described above.) A method for producing a 2 ′, 3′-dideoxynucleoside derivative represented by the formula: 3. A process for producing a 2 ', 3'-dideoxynucleoside derivative (IV) according to claim 2, wherein (a) reacting a trialkyl orthoacetate with inosine in dimethylformamide containing an organic acid. Wherein the 2′- and 3′-positions are 1-alkoxyalkylidene or 1-alkoxyarylalkylidene (Wherein H _X is a hypoxanthyl group, R ¹ is an alkyl group,
R ² represents an alkyl group or an aryl group, respectively. And (b) converting the inosine derivative (I) with an acyl halide in the presence or absence of an organic acid or an organic acid in an organic solvent. Reacting with anhydride and hydrogen halide,
An acyloxy group and a halogen atom are introduced at the 2'-position and 3'-position (or 3'-position and 2'-position) to form a compound represented by the general formula (Wherein X represents Cl, Br or I, R ³ represents H or an easily cleavable protecting group, and R ⁴ represents an acyl group, respectively). The second step of producing the inosine derivative (II) And (c) the inosine derivative (II) in an organic solvent,
After reacting in the presence of zinc powder and acetic acid, the zinc complex is removed and the general formula A third step of producing a 2 ', 3'-didehydro-2', 3'-dideoxynucleoside (III) represented by the following formula: (d) a 2 ', 3'-didehydro-2', 3'-dideoxynucleoside derivative (III) in an organic solvent, Pd
A catalytic hydrogenation in the presence of a catalyst, followed by hydrolysis or transesterification, followed by a fourth step.