JPH05170746A - Production of 2-thioacyclopyrimidine nucleoside derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an antiviral agent, an anticancer agent, an antibacterial agent or their synthetic intermediate by treating a pyrimidine sat with a silylation agent and subsequently reacting the reaction product with a halogenomethyl ether compound. CONSTITUTION:A pyrimidine salt of formula I (R' is H, 1-5C alkyl, 3-6C cycloalkyl, halogen, 2-6C alkenyl) is reacted with a silylation agent (e.g. bistrimethylsilylacetoamide) in a solvent such as acetonitrile, and the reaction product is reacted with a halogenomethyl ether compound of formula R<2>OCH2X (R<2> is 1-5C alkyl, 3-8C cycloalkyl, 7-12C aralkyl, etc.; X is halogen) to provide the subject compound of formula II. The side chain can selectively be introduced to the 1-position of the 2-thiopyrimidine base in a short time in high yield to provide the acyclonucleoside.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing a 2-thioacyclopyrimidine nucleoside derivative, and specifically to 2-thioa which is useful as an antiviral agent, an anticancer agent, an antibacterial agent or a synthetic intermediate thereof. The present invention relates to a novel method for producing a cyclopyrimidine nucleoside derivative.

[0002]

2. Prior Art and Problems to be Solved by the Invention 2-
The thioacyclopyrimidine nucleoside derivative is important as an antiviral agent, an anticancer agent, an antibacterial agent, or a synthetic intermediate thereof, and many methods for producing acyclopyrimidine nucleoside as described below have been studied. -There are few methods applicable to the synthesis of thiopyrimidine derivatives. (1) A pyrimidine base represented by the following general formula (IV) is converted to a bistrimethylsilylpyrimidine derivative (V) with an appropriate silylating agent, and an alkylating reagent such as 2-acetoxyethylacetoxymethyl ether is used in the presence of various catalysts. Various methods for obtaining a compound represented by the following general formula (VI) are known.

[0003]

[Chemical 4]

(In the above formula, Y represents an oxygen atom or a sulfur atom, and R represents a hydrogen atom, an alkyl group, a halogen atom, etc.) As a catalyst used in the above reaction, 1) a method using tin tetrachloride ( J. Med. Chem.,
1981, 24 , 1177) This method has various problems such as high hygroscopicity of tin tetrachloride and easy decomposition, and that it is difficult to handle due to the formation of a poorly soluble tin hydroxide after the reaction. .. 2 in the same document
-Thiopyrimidine derivative (in the above formula, a compound of Y = S)
However, when the present inventors attempted to synthesize a 2-thiopyrimidine derivative according to the method described in the literature,
The reaction was in low yield (see Comparative Example 1).

2) Method using mercury (II) cyanide (J. Med. Chem., 1985, 28 , 356) This method has a significantly low yield (about 23%), and also has a mercury (II) cyanide ) Is toxic to the human body and is considered to be difficult to industrialize due to the danger of environmental pollution. Further, the same document does not describe a 2-thiopyrimidine derivative (Y = S).

3) Method using cesium iodide (Che
(Mistry Letters, 1988, 1045) According to this method, the target compound can be obtained in good yield even in the case of a 2-thiopyrimidine base (a compound of Y = S in the above formula), which is low in yield by other methods. However, in order to obtain the bistrimethylsilyl derivative (V), the base (IV) must be refluxed with hexamethyldisilazane in the presence of ammonium sulfate for several hours, and after the silylation is completed, the excess silylating agent must be distilled off.
This is not a practical method because it requires a large amount of reaction solution to be completely concentrated in the reactor upon industrialization. As another method of this silylation method, a method using bistrimethylsilylacetamide in a suitable solvent has been investigated (J. Med. Chem., 1981, 24 , 1).
177). This method can be used for the next reaction after silylation without concentrating the reaction solution, but the acyclo side chain introduction reaction using cesium iodide does not proceed in this reaction (see Comparative Example 2). .. (2) A method in which a bistrimethylsilyl derivative (V) is reacted with acetoxyethyl bromomethyl ether without addition of an equivalent amount to obtain a compound represented by the following general formula (VI) has been reported (Can. J. Chem. , 1982, 6
0 , 547).

[0007]

[Chemical 5]

(In the above formula, R and Y have the same meanings as above.) In the same document, a 2-thiopyrimidine derivative (wherein Y =
Although the compound of S) is not described, when the present inventors tried to synthesize a 2-thiopyrimidine derivative according to the method described in the same document, the reaction showed a low yield (see Comparative Example 3). .. (3)

Embedded image HCHO, HCl R′—OH ───── → R′-O—CH ₂ —Cl (VII) (wherein R ′ represents an acyloxyalkyl group etc.) Formaldehyde and hydrochloric acid in alcohol Chloromethyl ether (VII) obtained by reacting with is a substance useful as an acyclo side chain introducing reagent. It has been reported that a compound represented by the following general formula (VI) is obtained by reacting this with a bistrimethylsilylpyrimidine derivative (V) in an equivalent amount.

[0009]

[Chemical 7]

(In the above formula, R, R'and Y have the same meanings as above.) The above reaction proceeds even without a catalyst, but the reaction is slow and the yield is 50% or less (Y: O in the above formula). Compound) and low (J. Med. Chem., 1985, 28 , 97).
1). On the other hand, methods using various catalysts in the same reaction have been investigated.

1) Method using p-toluenesulfonic acid (J. Med. Chem., 1981, 24 , 472) Although the literature only exemplifies the compound in the above formula where Y = O. This method requires a reaction time of about 3 days under heating under reflux. 2) Method using mercury cyanide (Can. J. Che
m. , 1984, 62 , 16) In the above formula, there are only examples of compounds in the case of Y = O,
The reaction proceeds under heating under reflux for 2 to 3 hours, but the above (1)
Similar to the method 2) of 2), since mercury cyanide is used, there is concern about toxicity to the human body, and it is considered to be a method with difficulty in industrialization such as environmental pollution.

3) Method using tetrabutylammonium iodide (Can. J. Chem., 1984, 62 ,
16) In the same document, there is only an example of a compound in the case of Y = O in the above formula, the reaction time is as short as about 1.5 hours under reflux in dichloromethane, and the yield is relatively good at 60%. However, when the present inventors attempted to synthesize a 2-thiopyrimidine derivative (a compound of Y = S in the above formula) according to this method,
The reaction was as low as 50% or less (see Comparative Example 4).

4) Method using cesium iodide (Che
(Mistry Letters, 1988, 1048) In this document, a method suitable for obtaining a 2-thiopyrimidine derivative is reported, but the present inventors have attempted to synthesize a 2-thiopyrimidine derivative according to such a method. However, the reaction was a low yield of 50% or less (see Comparative Example 5).

As described above, various studies have been conducted on methods for introducing an acyclo side chain into a pyrimidine base.
At present, the method for industrially producing a thiopyrimidine derivative has not been established.

[0015]

Means for Solving the Problems As a result of repeated studies in view of the above problems, the present inventors have easily synthesized side chain moieties having various structures as an alkylating agent for introducing an acyclo side chain into a pyrimidine base. By using the halogenomethyl ethers that can be produced, 2-
The present invention was completed for the first time by discovering that a side chain can be introduced at the 1-position of a thiopyrimidine base.

That is, the gist of the present invention is the following general formula (I)

[0017]

[Chemical 8]

(In the above general formula (I), R ¹ is a hydrogen atom,
A pyrimidine salt represented by a C ₁ -C ₅ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom or a C ₂ -C ₆ alkenyl group) is treated with a silylating agent, and then the following general Formula (II)

Embedded image R ² OCH ₂ X (II) (In the general formula (II), R ² is a C _{1 to} C ₅ alkyl group, a C _{3 to} C ₈ cycloalkyl group, or a C _{7 to} C ₁₂ aralkyl. Group, a C _{3 to} C ₇ acyloxyalkyl group or a C _{8 to} C ₁₈ aralkyloxyalkyl group, and X represents a halogen atom), and the above pyrimidine treated with a silylating agent. The following general formula (III) is characterized in that 1.7 to 3.0 equivalents are reacted with the salt.

[0019]

[Chemical 10]

A method for producing a 2-thioacyclopyrimidine nucleoside derivative represented by the general formula (III), wherein R ¹ and R ² have the same meanings as above, is present. Hereinafter, the present invention will be described in detail. The C ₁ -C ₅ alkyl group defined by R ¹ in the above general formula (III) is a methyl group,
Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, s-butyl group, n
—Pentyl group and the like, examples of the C _{3 to} C ₆ cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group, and examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine. And the like. Examples of the C _{2 to} C ₆ alkenyl group include vinyl group, allyl group, 1-propenyl group, 2-butenyl group, 1,3-butadienyl group, 2-pentenyl group,
2-hexenyl group etc. are mentioned.

The C ₁ -C ₅ alkyl group defined by R ² includes a methyl group, an ethyl group, an n-propyl group, and an i-group.
Propyl group, n-butyl group, i-butyl group, t-butyl group, s-butyl group, n-pentyl group and the like, C ₃
To C ₈ cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, and C _{7 to} C ₁₂ aralkyl groups include benzyl group, phenethyl group, Phenylpropyl group, naphthylmethyl group,
Examples of the C ₃ -C ₇ acyloxyalkyl group include a naphthylethyl group, and examples of the C ₃ -C ₇ acyloxyalkyl group include an acetoxymethyl group, an acetoxyethyl group, an acetoxypropyl group, a propionyloxymethyl group, a propionyloxyethyl group, a propionyloxypropyl group, and a butyryloxy group. Examples thereof include a methyl group, a butyryloxyethyl group and a butyryloxypropyl group. Examples of the C _{8 to} C ₁₈ aralkyloxyalkyl group include a benzyloxymethyl group, a benzyloxyethyl group, a benzyloxypropyl group and a phenethyloxymethyl group. , Phenethyloxyethyl group, phenethyloxypropyl group, naphthylmethyloxymethyl group, naphthylmethyloxyethyl group, 1,3-dibenzyloxypropyl group and the like.

X represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the method of the present invention, first, 2-thiopyrimidine base (I) is silylated by a suitable method. As a silylation method, a method of refluxing with hexamethyldisilazane in the presence of ammonium sulfate for several hours may be adopted, but as a simpler method, acetonitrile, DMF, dichloromethane, dichloroethane, THF can be used.
In a suitable organic solvent such as, for example, a method of using 2-3 equivalents of bistrimethylsilylacetamide and stirring at room temperature for about 10 minutes to 2 hours is preferable. Next, 1.7 to 3.0 equivalents, preferably 1.8 to 2.8 equivalents of the halogenomethyl ethers (II) and room temperature to −10 ° C. for 30 minutes to
The object product (III) can be obtained in high yield by stirring for about 3 hours. This reaction gives good results without additives, but when chloromethyl ethers are used as the halogenomethyl ether, 0.5 to 2 equivalents of a metal iodide salt such as sodium iodide, potassium iodide, or cesium iodide is used. Higher yields can be achieved by adding. or,
Good results are obtained when the reaction temperature is in the range of about -10 ° C to 5 ° C. The reaction time is preferably in the range of 30 minutes to 1 hour. When the amount of the halogenomethyl ethers (II) is less than 1.7 equivalents, the raw material remains, so that a high reaction yield cannot be obtained, and when more than 3.0 equivalents are used. It is not preferable because the amount of by-products increases and it becomes difficult to separate and purify the desired main product.

[0023]

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to the following examples unless it exceeds the gist.

Example 1 1- (Ethoxymethyl) -5-
Synthesis of ethyl-2-thiouracil 5-ethyl-2-thiouracil 1.56 g (10 mmo
l) was suspended in 25 ml of acetonitrile, 5.5 ml (22 mmol) of bistrimethylsilylacetamide was added, and the mixture was stirred at room temperature for 30 minutes. The obtained homogeneous solution is
Cool to 5 to 0 ° C, 3.32 g of potassium iodide (20 mm
ol) and then chloromethyl ethyl ether 2.
02 ml (20 mmol) was added dropwise while maintaining the reaction solution temperature at -5 to 0 ° C. After continuing stirring at the same temperature for 1 hour, 13 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with 50 ml of ethyl acetate, the ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in isopropanol and crystallized at 0-4 ° C to obtain 1.71 g (yield 87%) of the desired product. Melting point 111-112 ° C UV (methanol) λmax 280 nm

Example 2 1- (Ethoxymethyl) -5-
Effect of the amount of chloromethyl ethyl ether on the synthesis of ethyl-2-thiouracil The yield of the target substance when the amount of chloromethyl ethyl ether of Example 1 was changed from 1.5 equivalents to 3.2 equivalents with respect to the nucleic acid base. The rate was checked by reverse phase liquid chromatography.
The results are shown in Table-1.

[0026]

[Table 1]

Example 3 1- (Ethoxymethyl) -5-
Effect of iodide on the synthesis of ethyl-2-thiouracil. Reaction in which equimolar amounts of sodium iodide, cesium iodide, and tetrabutylammonium iodide were added instead of potassium iodide of Example 1 and nothing was added. The reaction was carried out, and the yield of the desired product was examined over time by reverse layer liquid chromatography. The results are shown in Table-2.

[0028]

[Table 2]

Example 4 1- (Benzyloxymethyl)
Synthesis of 5-methyl-2-thiouracil 5 instead of 5-ethyl-2-thiouracil of Example 1
-Methyl-2-thiouracil 1.42 g (10 mmo
l) was used instead of chloromethyl ethyl ether, and 3.1 ml (20 mmo) of benzyl chloromethyl ether.
l) was used, and otherwise the same as in Example 1, except that the target compound 2.
17 g (yield 83%) was obtained. Melting point 112-114 ° C UV (methanol) λmax 281 nm

Example 5 1- (Benzyloxymethyl)
Synthesis of -5-isopropyl-2-thiouracil Instead of 5-ethyl-2-thiouracil of Example 1, 5
-Isopropyl-2-thiouracil 1.7 g (10 mm
ol) instead of chloromethyl ethyl ether, 2.78 ml (20 mmo) of benzyl chloromethyl ether.
l) was used and otherwise in the same manner as in Example 1 to obtain 1.9 g of the desired product (yield 66%). Melting point 103.5-104.5 ° C UV (methanol) λmax 282nm

Example 6 1- (Ethoxymethyl) -5-
Synthesis of cyclopropyl-2-thiouracil 5 instead of 5-ethyl-2-thiouracil of Example 1
-Cyclopropyl-2-thiouracil 1.68 g (10
was used in the same manner as in Example 1 to obtain 1.78 g of the desired product (yield 79%). Melting point 123-124 ° C UV (methanol) λmax 285 nm

Example 7 1- (Benzyloxymethyl)
Synthesis of -5-ethyl-2-thiouracil Instead of the chloromethyl ethyl ether of Example 1, 2.78 ml of benzyl chloromethyl ether (20 mmo
l) was used, and otherwise the same as in Example 1, except that the target compound 2.
4 g (yield 87%) was obtained. Melting point 92-94 ° C UV (methanol) λmax 282nm

Example 8 Synthesis of 1- (cyclohexyloxymethyl) -5-ethyl-2-thiouracil Instead of the chloromethyl ethyl ether of Example 1, 5.5 ml (20 mm of chloromethyl n-propyl ether) was used.
was used in the same manner as in Example 1 except that 1.5 g (yield: 56%) of the desired product was obtained. Melting point 123-124 ° C UV (methanol) λmax 280 nm

Example 9 Synthesis of 5-ethyl-1- (4-methylbenzyloxymethyl) -2-thiouracil In place of the chloromethylethyl ether of Example 1, 3.41 g (2) of chloromethyl-4-methylbenzyl ether was used.
0 mmol) was used and all the same as in Example 1 to obtain 2.29 g of the desired product (yield 79%). Melting point 110-111 ° C UV (methanol) λmax 281 nm

Example 10 Synthesis of 5-ethyl-1- (4-chlorobenzyloxymethyl) -2-thiouracil 3.82 g (20) of chloromethyl-4-chloromethyl ether in place of the chloromethyl ethyl ether of Example 1
(2.7 mmol) was obtained in the same manner as in Example 1 except that (1 mmol) was used. Melting point 101-102 ° C UV (methanol) λmax 282nm

Example 11 1- (Ethoxymethyl) -5
-Ethyl-2-thiouracil synthesis The amount of potassium iodide in Example 1 was 0.83 g (5 mmo).
The target product was obtained in the same yield as in Example 1 except that the above was changed to l).

Example 12 1- (Ethoxymethyl) -5
Synthesis of isopropyl-2-thiouracil 5 instead of 5-ethyl-2-thiouracil of Example 1
-Isopropyl-2-thiouracil 1.7 g (10 mm
Ol) was used and in the same manner as in Example 1 to obtain 2.03 g of the desired product (yield 89%). Melting point 89.5-90.5 ° C UV (methanol) λmax 280 nm

Example 13 Synthesis of 1- (2-acetoxyethoxymethyl) -5-ethyl-2-thiouracil Instead of the chloromethylethyl ether of Example 1, (2
-Acetoxyethoxy) methyl bromide 2.7 ml (2
0 mmol) and potassium iodide were not added, and 1.8 g (yield 66%) of the desired product was obtained in the same manner as in Example 1 except for the above. Melting point 107-108 ° C UV (methanol) λmax 282nm

Comparative Example 1 1.42 g (10 mmol) of 2-thiothymine was suspended in 25 ml of dichloromethane, 5.5 ml (22 mmol) of bistrimethylsilylacetamide was added, and 2
Stir for hours. The obtained uniform solution was water-cooled, and 2.7 g (15 mmo) of 2-acetoxyethoxymethyl acetate.
l) and 1.3 ml (11 mmol) of tin tetrachloride were added, and the mixture was stirred at room temperature for 2 days and then analyzed by reverse phase liquid chromatography. As a result, the peak area of the target substance was only 34%.

Comparative Example 2 142 mg (1 mmol) of 2-thiothymine was suspended in 5 ml of acetonitrile, 0.55 ml (2 mmol) of bistrimethylsilylacetamide was added, and the mixture was stirred at room temperature for 30 minutes. 0.23 ml (1.2 mmol) of 2-acetoxyethoxymethyl acetate in the obtained homogeneous solution.
And 0.26 g (1 mmol) of cesium iodide were added,
After heating and refluxing for 18 hours, the peak of the target substance was not obtained by analysis by reverse layer liquid chromatography.

Comparative Example 3 142 mg (1 mmol) of 2-thiothymine was suspended in 5 ml of acetonitrile, 0.55 ml (2 mmol) of bistrimethylsilylacetamide was added, and the mixture was stirred at room temperature for 1 hour. 2-Acetoxyethoxymethyl bromide (0.14 ml, 1 mmol) was added to the obtained homogeneous solution under ice cooling, and then the mixture was stirred at room temperature for 1 hour and analyzed by reverse phase liquid chromatography to find that 1- (2-acetoxy The peak area of ethoxymethyl) -2-thiothymine is 10%
It was below. After that, the mixture was heated under reflux for 5 hours, but remained unchanged.

Comparative Example 4 128 mg (1 mmol) of 2-thiothymine was suspended in 2.5 ml of dichloromethane, 0.55 ml (2 mmol) of bistrimethylsilylacetamide was added, and 2
Stir for hours. Chloromethyl ethyl ether (0.14 ml, 1.5 mmol) and tetrabutylammonium iodide (3.7 mg, 0.01 mmo) were added to the obtained homogeneous solution.
1) was added and the mixture was heated under reflux for 4 hours and analyzed by reverse phase liquid chromatography to find that 1- (ethoxymethyl) -2-
The peak area of thiothymine was 50% or less.

Comparative Example 5 5-Ethyl-2-thiouracil 468 mg (3 mmo
l) and 30 mg of ammonium sulfate to 10 ml of hexamethyldisilazane
After heating under reflux for 5 hours, the remaining hexamethyldisilazane was distilled off under reduced pressure to obtain a transparent candy-like substance. This is 30
It was dissolved in ml of acetonitrile, 0.33 ml (3.6 mmol) of chloromethyl ethyl ether and 0.78 g (3 mmol) of cesium iodide were added, and the mixture was heated under reflux for 8 hours and analyzed by reverse phase liquid chromatography.
The peak area of-(ethoxymethyl) -5-ethyl-2-thiouracil was 50% or less.

[0044]

EFFECTS OF THE INVENTION According to the method of the present invention, a side chain can be selectively introduced into the 1-position of 2-thiopyrimidine base in a short time and in high yield, and an acyclonucleoside can be obtained.

Claims (1)

[Claims] 1. The following general formula (I): (In the general formula (I), R ¹ represents a hydrogen atom, a C _{1 to} C ₅ alkyl group, a C _{3 to} C ₆ cycloalkyl group, a halogen atom or a C _{2 to} C ₆ alkenyl group) The resulting pyrimidine salt is treated with a silylating agent, and then R ² OCH ₂ X (II) represented by the following general formula (II) (wherein R ² is C ₁ -C ₅ alkyl). Group, a C ₃ -C ₈ cycloalkyl group, a C ₇ -C ₁₂ aralkyl group, a C ₃ -C ₇ acyloxyalkyl group or a C ₈ -C ₁₈ aralkyloxyalkyl group, and X represents a halogen atom. ) Is reacted with the pyrimidine salt treated with the silylating agent in an amount of 1.7 to 3.0 equivalents, and the following general formula (III): (In the general formula (III), R ¹ and R ² have the same meanings as described above), and a method for producing a 2-thioacyclopyrimidine nucleoside derivative.