JPH10130244A - Method for producing acyclonucleoside - Google Patents

Abstract

(57) Abstract: General formula (1) embedded image W—CH ₂ —OR (1) (wherein W is a 1-pyrimidinyl group or a 1-pyrimidinyl group which may have a substituent) Represents a 9-purinyl group, wherein R has 1 to 5 carbon atoms;
The present invention provides a new method for producing an acyclonucleoside represented by the following formula: SOLUTION: After silylating a base represented by the general formula (2): W—H (2) (wherein W is the same as in the formula (1)), iodotrimethylsilane or bromotrimethylsilane is used. Or acetoxymethyl alkyl ether or dialkoxymethane in the presence of chlorotrimethylsilane and a metal iodide compound or a metal bromide compound. Instead of the silylation in advance, the reaction may be carried out in the presence of a silylating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing acyclonucleoside, and in particular,
The present invention relates to a method for producing an acyclonucleoside useful as an antiviral agent, an anticancer agent, an antibacterial agent or a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Numerous methods have been studied for producing acyclonucleosides. For example, a pyrimidine base represented by the following formula (3) is silylated with a suitable silylating agent to give a bis (trimethylsilyl) derivative (4), which is reacted with a halogenomethylalkyl ether (5) to give an acyclonucleoside (6). ) Are known.

[0003]

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(In the above formulas (3) to (6), X represents an oxygen atom or a sulfur atom, R ′ represents a hydrogen atom or a substituent such as an alkyl group or a halogen atom, R represents an alkyl group, and Y represents Represents a halogen atom.)

However, it has been pointed out that the halogenomethylalkyl ether represented by the formula (5) has a carcinogenic potential, which is a problem when the above reaction is carried out industrially. In order to avoid this point, a method has been disclosed in which dialkoxymethane is reacted with (4) in the presence of trimethylsilyl triflate to obtain (6) (Synthesi).
s, 934-936 (1995)), since trimethylsilyl triflate is expensive, it is considered to be difficult to synthesize it on an industrial scale.

[0006]

As described above, the processes for producing acyclonucleosides which have been reported so far are as follows.
It is hard to say that it is suitable for industrial implementation. Accordingly, an object of the present invention is to provide a safe, inexpensive and industrially feasible method for producing an acyclonucleoside.

[0007]

The present inventors have found that the reaction of a silylated product of a pyrimidine base or a purine base with acetoxymethyl alkyl ether or dialkoxymethane can be easily carried out in the presence of iodotrimethylsilane or bromotrimethylsilane. It has been found that progress has been made to give acyclonucleosides corresponding to these bases. It has also been found that this reaction proceeds similarly when chlorotrimethylsilane and a metal iodide compound or a metal bromide compound are used instead of iodotrimethylsilane or bromotrimethylsilane.

Further, instead of preliminarily silylizing a pyrimidine base or a purine base, a silylating agent and iodotrimethylsilane or bromotrimethylsilane, or a silylating agent, chlorotrimethylsilane and a metal iodide compound are added to the reaction system. Alternatively, it has been found that in the presence of a metal bromide compound, a pyrimidine base or a purine base reacts with acetoxymethyl alkyl ether or dialkoxymethane to generate an acyclonucleoside corresponding to these bases.

The present invention has been accomplished based on such findings, and is characterized by reacting a pyrimidine base or a purine base or a silylated product thereof with acetoxymethyl alkyl ether or dialkoxymethane. When introducing an alkoxymethyl group at the 1-position of the pyrimidine base or the 9-position of the purine base, the reaction is carried out in the presence of iodotrimethylsilane or bromotrimethylsilane, or chlorotrimethylsilane and a metal iodide compound or a metal bromide compound. In the presence of
It is to provide an inexpensive method for synthesizing acyclonucleoside.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In more detail, the present invention uses a compound represented by the formula (1) as a pyrimidine base or a purine base.

[0011]

## STR6 ## WH (1)

(Wherein W may have a substituent,
(Indicating a 1-pyrimidinyl group or a 9-purinyl group) Preferably, a pyrimidine base represented by the formula (7) or a purine base represented by the formula (8) is used.

[0013]

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(In the above formulas (7) and (8), R ¹ and R ² are each independently a hydrogen atom; a methyl group;
Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, s-butyl group, n
A C ₁ -C ₅ alkyl group such as a pentyl group; a vinyl group,
Allyl group, 1-propenyl group, 2-butenyl group, 1,3
R _{2 represents} a C ₂ -C ₆ alkenyl group such as a butadienyl group, a 2-pentenyl group or a 2-hexenyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a benzyl group; ³ and R ⁴ are
Each independently represents a hydrogen atom, a hydroxyl group or an amino group, X represents an oxygen atom or a sulfur atom,
Y represents a hydroxyl group or an amino group. )

Further, in the present invention, W is a 5-alkyluracil such as 5-ethyluracil, 5-n-propyluracil, 5-i-propyluracil, 5-butyluracil and the like; Arylthio derivatives are preferred, and particularly preferred compounds are 6-benzyl derivatives of 5-i-propyluracil. In addition, as a preferable compound produced by the method of the present invention, in the above formula (2),
1- (ethoxymethyl) wherein W is 5-i-propyluracil or a benzyl derivative at the 6-position and R is an ethyl group
-5-isopropyluracil or 6-benzyl-1-
(Ethoxymethyl) -5-isopropyluracil. In the compound of the above formula (7) or (8), when Y or R ³ represents a hydroxyl group,
There are two isomers due to keto-enol tautomerism as shown in the following formulas (9) and (10), and the present invention includes such tautomers.

[0016]

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In one embodiment of the present invention, these pyrimidine bases or purine bases are first silylated by a suitable method. The silylation can be easily carried out, for example, by reacting these bases with a large amount of hexamethyldisilazane under reflux in the presence of a catalytic amount of ammonium sulfate or chlorotrimethylsilane. Since a large amount of unreacted hexamethyldisilazane remains in the reaction mixture, this is removed by distillation, and the remaining silylated product is dissolved in a solvent such as acetonitrile, dimethylformamide, dichloromethane, dichloroethane, or tetrahydrofuran. For the next reaction.

Alternatively, a pyrimidine base or a purine base and 2 to 2
6 mol times of bistrimethylsilyl acetamide is added and stirred at room temperature for 10 minutes to several hours to silylate or
Or 0.5 instead of bistrimethylsilylacetamide
Silylation can also be carried out using hexamethyldisilazane up to 3 mole times and a catalytic amount of ammonium sulfate or chlorotrimethylsilane. Further, silylation can also be carried out by reacting with chlorotrimethylsilane in the presence of a base such as triethylamine. In the case of using such a silylation method, the reaction mixture can be directly used for the next reaction.

The solution containing the silylated product thus obtained is mixed with acetoxymethyl alkyl ether or dialkoxymethane in an amount of 1 to 3 moles per mole of the silylated product, and 0.1 to 1 mol of the silylated product.
When 1 to 3 mole times of iodotrimethylsilane or bromotrimethylsilane is added, and the mixture is reacted under stirring at -40 ° C or the reflux temperature of the solvent for about 1 hour to 4 days, the desired product is produced in good yield. . It should be noted that even if chlorotrimethylsilane and a metal iodide compound or a metal bromide compound which are inexpensive and easy to handle are used instead of iodotrimethylsilane or bromotrimethylsilane, the desired product is similarly produced at a good yield. In this case, iodotrimethylsilane or bromotrimethylsilane is generated from chlorotrimethylsilane and a metal iodide compound or a metal bromide compound, and this is considered to act as a catalyst.
As the metal iodide compound, potassium iodide, sodium iodide, iodides of alkali metals such as cesium iodide are usually used, and as the metal bromide compound, potassium bromide, sodium bromide, cesium bromide and the like Alkali metal bromides are commonly used. The ratio of chlorotrimethylsilane to the metal iodide compound or the metal bromide compound to the silylated product is usually 0.1 to 3 times by mole of the chlorotrimethylsilane to the base subjected to the silylation, and the metal iodide compound or the metal bromide is used. The compound may be 0.1 to 3 molar times.

In another embodiment of the present invention, a pyrimidine base or a purine base is not preliminarily silylated, but is used in the presence of a silylating agent and iodotrimethylsilane or bromotrimethylsilane in the presence of an acetoxymethyl alkyl ether or dibromotrimethylsilane. React with alkoxymethane. For example, in an organic solvent such as acetonitrile, dimethylformamide, dichloromethane, dichloroethane, tetrahydrofuran,
Pyrimidine bases or purine bases and 0.1 to
3 mole times hexamethyldisilazane, 0.1 to 3 mole times iodotrimethylsilane or bromotrimethylsilane, and 1 to 3 mole times acetoxymethylalkyl ether or dialkoxymethane are added, and the mixture is added at -40 ° C or a solvent. When the reaction is carried out at a reflux temperature of 1 hour to several days, the desired product is produced in a good yield. The reaction appears to go through a process in which the base is first silylated, which then reacts with the acetoxymethyl alkyl ether or dialkoxymethane. Also in this reaction, a combination of chlorotrimethylsilane and a metal iodide compound or a metal bromide compound can be used instead of iodotrimethylsilane or bromotrimethylsilane. Also in this case, the chlorotrimethylsilane and the metal iodide compound or the metal bromide compound may be used in a ratio of 0.1 to 3 times by mole to the base in a ratio of 0.1 to 3 times by mole.

The above two embodiments are represented by the following reaction formulas (11) and (12), respectively.

[0022]

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(In the above formula, R represents an alkyl group having 1 to 5 carbon atoms.) Separation and purification of the target product from the reaction product solution include extraction, silica gel column chromatography, crystallization from an appropriate solvent, and the like. Conventional methods for purifying organic compounds can be used.

[0024]

According to the production method of the present invention, acyclonucleoside can be produced safely, inexpensively, easily and efficiently.

[0025]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil 154 mg (1 mmol) of 5-isopropyluracil was suspended in 10 ml of hexamethyldisilazane, and ammonium sulfate 10 m
g was added and heated at reflux for 6 hours. Excess hexamethyldisilazane was distilled off under reduced pressure, and the residue was dissolved in 10 ml of acetonitrile. To this, 0.142 g (1.2 mmol) of acetoxymethyl ethyl ether and 0.014 ml (0.1 mmol) of iodotrimethylsilane were added,
Stir at room temperature for 3 hours. After evaporating the solvent, saturated aqueous sodium bicarbonate 10
The operation of adding ml and extracting with 10 ml of chloroform was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained is dichloromethane-
The crystals were dissolved in n-heptane, and the desired crystals were obtained therefrom. Yield: 0.182 g (86% yield) Melting point: 78.4 ° C. UV (MeOH): λmax 263 nm ¹ H-NMR (CDCl ₃ , δ): 1.17 (d, J =
6.9 Hz, 6H), 1.23 (t, J = 7.0 Hz,
3H), 2.91 (dqq, J = 0.8 Hz, 6.9H
z, 1H), 3.61 (q, J = 7.0 Hz, 2H),
5.14 (s, 2H), 7.04 (d, J = 0.8H)
z, 1H), 8.24 (bs, 1H)

Example 2 1- (2-ethoxymethyl)-
Synthesis of 5-isopropyluracil 154 mg (1 mmol) of 5-isopropyluracil was suspended in 10 ml of acetonitrile, 0.54 ml (2.2 mmol) of bis (trimethylsilyl) acetamide was added, and the mixture was stirred at room temperature for 30 minutes. 0.142 g of acetoxymethyl ethyl ether was added to the obtained homogeneous solution.
(1.2 mmol), iodotrimethylsilane 0.01
4 ml (0.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent, 10 ml of saturated aqueous sodium hydrogen carbonate was added, and 10 m
The operation of extracting with 1 l of chloroform was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was dissolved in dichloromethane-n-heptane to obtain a desired crystal.

Example 3 1- (ethoxymethyl) -5
Synthesis of isopropyluracil In Example 1, 0.127 ml (1.0 mmol) of chlorotrimethylsilane was used instead of iodotrimethylsilane.
Using l) and 166 mg (1.0 mmol) of potassium iodide, the desired product was obtained in the same manner except that the reaction was carried out at room temperature for 3 hours. Example 4 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 3, 150 mg (1.0 mmol) of sodium iodide was used in place of potassium iodide, and in all other respects the target product was obtained. .

Example 5 1- (ethoxymethyl) -5
Synthesis of isopropyluracil 0.127 ml (1.0 mmol) of chlorotrimethylsilane instead of iodotrimethylsilane in Example 2
And 166 mg (1.0 mmol) of potassium iodide. Example 6 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 5, 150 mg (1.0 mmol) of sodium iodide was used in place of potassium iodide, and the other steps were repeated to obtain the desired product. Was.

Example 7 1- (ethoxymethyl) -5
Synthesis of isopropyluracil In Example 1, 0.149 ml (1.2 mmol) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours. Example 8 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 2, instead of acetoxymethyl ethyl ether, 0.149 ml of diethoxymethane (1.2 mmol) was used.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours.

Example 9 1- (ethoxymethyl) -5
Synthesis of Isopropyluracil Instead of acetoxymethyl ethyl ether in Example 3, 0.149 ml of diethoxymethane (1.2 mmo) was used.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours. Example 10 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil Instead of acetoxymethyl ethyl ether in Example 4, 0.149 ml of diethoxymethane (1.2 mmol) was used.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours.

Example 11 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil Instead of acetoxymethyl ethyl ether in Example 5, 0.149 ml (1.2 mmol) of diethoxymethane was used.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours. Example 12 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil Instead of acetoxymethylethyl ether in Example 6, 0.149 ml of diethoxymethane (1.2 mmol) was used.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 9 hours.

Example 13 1- (ethoxymethyl) -5
Synthesis of -isopropyluracil 154 mg (1 mmol) of 5-isopropyluracil was suspended in 10 ml of acetonitrile, 0.148 ml (0.7 mmol) of hexamethyldisilazane, 0.127 ml (1.0 mmol) of chlorotrimethylsilane, and acetoxymethyl ethyl ether 0 .142 mg (1.2 mm
ol) and 166 mg (1 mmol) of potassium iodide, and the mixture was heated to reflux temperature and stirred for 1 hour. After evaporating the solvent, the operation of adding 50 ml of saturated aqueous sodium hydrogen carbonate and extracting with 50 ml of chloroform was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane-n-heptane to obtain a desired crystal. Yield: 0.184 g (87% yield)

Example 14 1- (ethoxymethyl) -5
Synthesis of Isopropyluracil The target compound was obtained in the same manner as in Example 13 except that 150 mg (1 mmol) of sodium iodide was used instead of potassium iodide. Example 15 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 13, 0.26 g (1 mmol) of cesium iodide was used in place of potassium iodide, and the other conditions were the same to obtain the desired product. .

Example 16 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil In Example 13, 0.149 ml (1.2 mmol) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
The desired product was obtained in the same manner as in 1) except for using l). Example 17 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 13, 0.149 ml of diethoxymethane (1.2 mmol) was used in place of acetoxymethyl ethyl ether.
l) is replaced with sodium iodide 15 instead of potassium iodide.
0 mg (1 mmol) was used, and in the same manner as in the other cases, the desired product was obtained.

Example 18 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil In Example 13, 0.149 ml (1.2 mmol) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
l) is replaced by cesium iodide 0.2 instead of potassium iodide
6 g (1 mmol) was used, and the other conditions were the same as above to obtain the desired product.

Example 19 1- (2-ethoxymethyl)
Synthesis of -5-isopropyluracil In Example 2, 153 mg (1 mmol) of trimethylsilane bromide was used in place of iodotrimethylsilane,
In all other respects, the desired product was obtained. Example 20 Synthesis of 1- (2-ethoxymethyl) -5-isopropyluracil In Example 5, 119 mg (1.0 mmol) of potassium bromide was used in place of potassium iodide, and the other procedures were repeated except that the target compound was used. Obtained.

Example 21 1- (2-ethoxymethyl)
Synthesis of -5-isopropyluracil In Example 13, 119 mg (1.0 mmol) of potassium bromide was used in place of potassium iodide, and in all other respects the desired product was obtained. Example 22 Synthesis of 1- (2-ethoxymethyl) -5-isopropyluracil In Example 17, 103 mg (1.0 mmol) of sodium bromide was used in place of sodium iodide. Obtained.

Example 23 Synthesis of 6-benzyl-1- (2-ethoxymethyl) -5-isopropyluracil 244 mg of 6-benzyl-5-isopropyluracil
(1 mmol) was suspended in 10 ml of acetonitrile, and 0.54 ml of bis (trimethylsilyl) acetamide was suspended.
(2.2 mmol) and stirred at room temperature for 30 minutes. To the obtained homogeneous solution, 284 mg (2.4 mmol) of acetoxymethyl ethyl ether, 0.127 ml (1.0 mmol) of chlorotrimethylsilane, and 166 mg (1 mmol) of potassium iodide were added, and the mixture was stirred at 0 ° C for 3 hours. After evaporating the solvent, 10 ml of saturated aqueous sodium hydrogen carbonate was added,
The operation of extracting with 10 ml of chloroform was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol, from which crystals of the desired product were obtained.

Yield: 281 mg (93% yield) Melting point: 109-110 ° C. (EtOH) UV (MeOH): λmax 268 nm ¹ H-NMR (CDCl ₃ ) δ: 1.19 (t, J =
7.0 Hz, 3H, OCH ₂ Me), 1.29 (d, J
= 6.9Hz, 6H, 5-CHMe 2), 2.87 (q
q, J = 6.9 Hz, 1H, 5-CHMe ₂ ), 3.6
3. 2 (q, J = 7.0 Hz, 2H, OCH ₂ Me);
18 (s, 2H, CH ₂ Ph), 5.12 (s, 2H,
_{NCH 2 O), 7.10-7.37 (m} , 5H, P
h), 8.40 (br, 1H, NH).

Example 24 Synthesis of 6-benzyl-1- (2-ethoxymethyl) -5-isopropyluracil In Example 23, 153 mg of trimethylsilane bromide (1 mg) was used in place of chlorotrimethylsilane and potassium iodide.
mmol), and the procedure was carried out in the same manner for all other steps to obtain the desired product.

Example 25 Synthesis of 6-benzyl-1- (2-ethoxymethyl) -5-isopropyluracil In Example 23, 0.298 ml (2.4 mm) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
ol) and the reaction time was changed to 24 hours to obtain the desired product in the same manner.

Example 26 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil 244 mg of 6-benzyl-5-isopropyluracil
(1 mmol) was suspended in 10 ml of acetonitrile, and 0.148 ml (0.7 mmol) of hexamethyldisilazane was suspended.
l), 0.127 ml of chlorotrimethylsilane (1.0
mmol), acetoxymethyl ethyl ether 284m
g (2.4 mmol), 166 mg of potassium iodide (1
mmol) and stirred at 0 ° C. for 9 hours. After evaporating the solvent, the operation of adding 50 ml of saturated aqueous sodium hydrogen carbonate and extracting with 50 ml of chloroform was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane-n-heptane to obtain a desired crystal. Yield: 0.281 g (93% yield)

Example 27 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 26, sodium iodide (150 mg, 1 mmol) was used in place of potassium iodide, and all other conditions were the same. The desired product was obtained. Example 28 6-benzyl-1- (ethoxymethyl)-
Synthesis of 5-isopropyluracil The desired product was obtained in the same manner as in Example 26 except that 119 mg (1 mmol) of potassium bromide was used instead of potassium iodide.

Example 29 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 26, 0.298 ml (2.4 mmol) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
The desired product was obtained in the same manner as in 1) except that the reaction time was changed to 48 hours.

Example 30 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 29, 150 mg (1 mmol) of sodium iodide was used in place of potassium iodide, and the other conditions were the same. I got something. Example 31 6-benzyl-1- (ethoxymethyl)-
Synthesis of 5-isopropyluracil The desired product was obtained in the same manner as in Example 29 except that 103 mg (1 mmol) of sodium bromide was used instead of potassium iodide.

Example 32 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil 244 mg of 6-benzyl-5-isopropylpropyluracil
(1 mmol) was suspended in 10 ml of acetonitrile, and 0.148 ml (0.7 mmol) of hexamethyldisilazane was suspended.
l), 0.09 ml of chlorotrimethylsilane (0.35
mmol), and the mixture was heated and stirred at the reflux temperature for 1 hour. The reaction solution was cooled to 0 ° C., 284 mg (2.4 mmol) of acetoxymethyl ethyl ether, 0.127 ml (1.0 mmol) of chlorotrimethylsilane, and 166 mg (1 mmol) of potassium iodide were added, and the mixture was stirred at 0 ° C. for 2 hours. . After evaporating the solvent, 50 ml of saturated aqueous sodium hydrogen carbonate was added, and 50 ml of sodium bicarbonate was added.
The operation of extracting with chloroform of ml was repeated 5 times. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloroethane-n-heptane, from which crystals of the desired product were obtained. Yield: 0.283 g (94% yield)

Example 33 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 32, 0.298 ml (2.4 mm) of diethoxymethane was used instead of acetoxymethyl ethyl ether.
ol), and the reaction was carried out at 0 ° C. for 9 hours in the same manner as described above to obtain the desired product in a yield of 94%.

Example 34 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil 154 mg (1 mmol) of 5-isopropyluracil was suspended in 10 ml of acetonitrile, and 0.316 ml (1.5 mmol) of hexamethyldisilazane and 10 mg of ammonium sulfate were suspended.
Was added and stirred at reflux temperature for 1 hour. 0.142 mg of acetoxymethyl ethyl ether was added to the obtained homogeneous solution.
(1.2 mmol), chlorotrimethylsilane 0.12
7 ml (1.0 mmol), 166 mg of potassium iodide
(1 mmol) was added and the mixture was stirred at room temperature for 9 hours. 50 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and chloroform (50 ml ×
3 times), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. From the obtained residue, crystals of the target product were obtained using dichloromethane-n-heptane.

Example 35 1- (ethoxymethyl) -5
-Synthesis of isopropyluracil In Example 34, 0.149 ml of diethoxymethane (1.2 mmo) was used in place of acetoxymethyl ethyl ether.
The desired product was obtained in the same manner except for using l). Example 36 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 34, 150 mg (1 mmol) of sodium iodide was used in place of potassium iodide, and in all other respects the desired product was obtained.

Example 37 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil In Example 25, 150 mg (1 mmol) of sodium iodide was used in place of potassium iodide, and in all other respects the target product was obtained.

Claims (4)

[Claims] 1. A compound represented by the formula (1): W—H (1) wherein W represents a 1-pyrimidinyl group or a 9-purinyl group which may have a substituent. Reacting with acetoxymethyl alkyl ether or dialkoxymethane in the presence of iodotrimethylsilane or bromotrimethylsilane, or in the presence of chlorotrimethylsilane and a metal iodide compound or a metal bromide compound, after silylation of the compound to be obtained. wherein the formula (2) ## STR2 ## _{W-CH 2 -O-R ...} (2) ( wherein, W is the same as defined in the formula (1), R is alkyl of C ₁ -C ₅ A process for producing an acyclonucleoside represented by the formula: 2. A compound represented by the formula (1): W—H (1) wherein W represents a 1-pyrimidinyl group or a 9-purinyl group which may have a substituent. Compound in the presence of a silylating agent and iodotrimethylsilane or bromotrimethylsilane, or a silylating agent,
Reacting with acetoxymethyl alkyl ether or dialkoxymethane in the presence of chlorotrimethylsilane and a metal iodide compound or a metal bromide compound, characterized by the following formula (2): W—CH ₂ —O—R ... A method for producing an acyclonucleoside represented by the following formula (2). 3. The metal iodide compound is selected from the group consisting of potassium iodide, sodium iodide, and cesium iodide, and the metal bromide compound is a group consisting of potassium bromide, sodium bromide, and cesium bromide. The method according to claim 1, wherein the method is selected from the group consisting of: 4. W is 5-i-propyluracil or 6
The method according to any one of claims 1 to 3, wherein the compound is -benzyl-5-i-propyluracil, and R is an ethyl group.