JPH10168068A - 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)), acetyl iodide and acetyl bromide are obtained. Alternatively, it is reacted with dialkoxymethane in the presence of acetyl chloride.

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]

Embedded image

(In the above formulas (3) to (6), X represents an oxygen atom or a sulfur atom, and R ′ represents a hydrogen atom, an alkyl group,
R represents an alkyl group, and Y 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 in handling the above reaction when it is industrially carried out. 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).
synthesis, 934-936 (1995)), because trimethylsilyl triflate is expensive, it is considered that there is a difficulty in the synthesis 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 between a silylated product of a pyrimidine base or a purine base and a dialkoxymethane easily proceeds in the presence of acetyl iodide, acetyl bromide or acetyl chloride. Have been found to give acyclonucleosides 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 a dialkoxymethane to form a pyrimidine base. Of 1
In introducing an alkoxymethyl group at the ninth position of the thiol or purine base, the reaction is carried out in the presence of acetyl iodide, acetyl bromide or acetyl chloride to provide an inexpensive method for synthesizing acyclonucleoside.

[0009]

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.

[0010]

Embedded image 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.

[0012]

Embedded image

(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 mentioned as preferred, and particularly preferred compounds are 5-i-propyluracil or 5-
and a 6-benzyl derivative of i-propyluracil. In addition, as a preferable compound produced by the method of the present invention, in the above formula (2), W is 5-i-propyluracil or a 6-benzyl derivative thereof, 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), Y or R
^{When 3} represents a hydroxyl group, the following formula (9):
By the keto-enol tautomerism as shown in the formula (10), 2
There are various types of isomers, and the present invention includes such tautomers.

[0015]

Embedded image

In one embodiment of the present invention, these pyrimidine 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.

As an alternative, a pyrimidine base or a purine base and two to two
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 added to the alkoxylated methane in an amount of 1 to 3 times by mole, and acetyl iodide, acetyl bromide or acetyl chloride in an amount of 0.1 to 3 times the amount of the silylated product. 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 to produce the desired product in a good yield. When acetyl chloride is used, the target product is produced in a good yield when a metal iodide compound or a metal bromide compound is further added to the reaction system. In this case, acetyl chloride or acetyl iodide or acetyl bromide is generated from acetyl chloride and the metal iodide compound or metal bromide compound, and it is considered that this acts 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 use ratio of acetyl chloride to a metal iodide compound or a metal bromide compound with respect to the silylated product is usually 0.1 to 3 times the acetyl chloride to the base subjected to silylation, and the metal iodide compound or the metal bromide compound is used. May be 0.1 to 3 molar times.

The separation and purification of the target substance from the reaction product solution is performed as follows.
Conventional methods for purifying organic compounds, such as extraction, silica gel column chromatography, and crystallization from an appropriate solvent, can be used.

[0020]

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

[0021]

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. Add 0.14 of diethoxymethane
9 ml (1.2 mmol), acetyl bromide 0.089 m
l (1.2 mmol) was added, and the mixture was stirred at room temperature for 6 hours.
After evaporating the solvent, an operation of adding 10 ml of saturated aqueous sodium hydrogen carbonate 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 obtained residue was dissolved in dichloromethane-n-heptane,
From this, the target crystal was obtained. 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. 0.149 ml of diethoxymethane (1.2 mmo) was added to the obtained homogeneous solution.
l), 0.089 ml (1.2 mmol) of acetyl bromide
Was added and stirred at room temperature for 6 hours. After evaporating the solvent, an operation of adding 10 ml of saturated aqueous sodium hydrogen carbonate 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 obtained residue was dissolved in dichloromethane-n-heptane to obtain a desired crystal.

Example 3 1- (ethoxymethyl) -5
Synthesis of Isopropyluracil In Example 2, 0.086 ml (1.2 mmol) of acetyl chloride and potassium iodide 1 were used instead of acetyl bromide.
The desired product was obtained in the same manner except that 99 mg (1.2 mmol) was used and reacted at room temperature for 3 hours. Example 4 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil In Example 3, 180 mg (1.2 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 The desired product was obtained in the same manner as in Example 3 except that potassium bromide was used instead of potassium iodide (143 mg, 1.2 mmol) and the reaction temperature was heated to reflux. Example 6 Synthesis of 1- (ethoxymethyl) -5-isopropyluracil Same as Example 3 except that potassium iodide was replaced with 123 mg (1.2 mmol) of sodium bromide and the reaction temperature was heated to reflux. To obtain the desired product.

Example 7 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. 0.149 of diethoxymethane was added to the obtained homogeneous solution.
ml (1.2 mmol), acetyl bromide 0.089 ml
(1.2 mmol) and stirred at room temperature for 6 hours.
After evaporating the solvent, an operation of adding 10 ml of saturated aqueous sodium hydrogen carbonate 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 obtained residue was dissolved in ethanol, from which crystals of the desired product were obtained.

Yield: 251 mg (83% 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 8 Synthesis of 6-benzyl-1- (2-ethoxymethyl) -5-isopropyluracil In Example 7, instead of acetyl bromide, 0.086 ml (1.2 mmol) of acetyl chloride and potassium iodide were used. 1
The desired product was obtained in the same manner except that 99 mg (1.2 mmol) was used and reacted at room temperature for 3 hours.

Example 9 Synthesis of 6-benzyl-1- (2-ethoxymethyl) -5-isopropyluracil In Example 8, sodium iodide (180 mg, 1.2 mmol) was used in place of potassium iodide. In the same manner, the desired product was obtained.

Example 10 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 8, 143 mg (1.2 mmol) of potassium bromide was used in place of potassium iodide, and the reaction temperature was heated to reflux. In all other respects, the desired product was obtained. Example 11 6-benzyl-1- (ethoxymethyl)-
Synthesis of 5-isopropyluracil The target compound was obtained in the same manner as in Example 8 except that 123 mg (1.2 mmol) of sodium bromide was used instead of potassium iodide, and the reaction temperature was heated to reflux.

Example 12 1- (ethoxymethyl) -5
Synthesis of -Isopropyluracil In Example 2, 0.086 ml (1.2 mmol) of acetyl chloride was used in place of acetyl bromide, and the reaction time was heated to reflux temperature and stirred for 1 day.
The desired product was obtained.

Example 13 Synthesis of 6-benzyl-1- (ethoxymethyl) -5-isopropyluracil In Example 7, 0.086 ml (1.2 mmol) of acetyl chloride was used in place of acetyl bromide, and the reaction temperature was refluxed. The desired product was obtained in the same manner except that the mixture was heated to a temperature and stirred for one day.

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. After the compound was silylated to the presence of iodide acetyl, acetyl bromide or acetyl chloride, and wherein the reaction with dialkoxymethane, formula (2) ## STR2 ## W-CH ₂ -O-R ... (2) (wherein, W is the same as defined in the formula (1), R represents an alkyl group of C ₁ -C ₅₎ represented by the manufacturing method of the acyclo nucleosides. 2. The method according to claim 1, wherein the reaction with the dialkoxymethane is carried out in the presence of acetyl chloride in the presence of a metal iodide compound or a metal bromide compound. 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. 3. The method according to claim 2, wherein the method is selected from: 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.