JP2005132767A - Method for producing purine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a purine compound of formula(3) ( wherein, X is a halogen atom; Y is H, a halogen atom or amino; R<SP>2</SP>is an acyl or alkoxycarbonyl; and R<SP>3</SP>and R<SP>4</SP>are each a protecting group ) in higher yield without using any reagents of large environmental burden. <P>SOLUTION: The method for producing the purine compound of formula(3) comprises carrying out a reaction between a purine compound of formula(1)( wherein, X is a halogen atom; and Y is H, a halogen atom or amino ) and a compound of formula(2)( wherein, R<SP>1</SP>is an acyl or alkoxycarbonyl; and R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each the same as mentioned above ) in a nitrile-based solvent or ester-based solvent in the presence of a silylating agent and a Lewis acid. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing a purine compound.

（式中、Ｘはハロゲン原子を表わし、Ｙは水素原子、ハロゲン原子またはアミノ基を表わし、Ｒ²はアシル基またはアルコキシカルボニル基を表わし、Ｒ³およびＲ⁴はそれぞれ同一または相異なって、保護基を表わす。）
で示されるプリン化合物は、医薬中間体として重要な化合物であり（例えば非特許文献１参照。）、その製造方法としては、例えばグアノシンを出発原料とする方法が知られている（例えば非特許文献１参照。）。しかしながら、多段階の反応であり、収率の面で必ずしも十分満足し得るものではなく、しかも、例えば四塩化炭素や亜硝酸ｎ−ペンチル等の環境負荷の大きい試剤を大過剰量用いており、労働衛生面や環境面からも改善が望まれていた。 Formula (3)

(In the formula, X represents a halogen atom, Y represents a hydrogen atom, a halogen atom or an amino group, R ² represents an acyl group or an alkoxycarbonyl group, and R ³ and R ⁴ are the same or different, Represents a group.)
Is an important compound as a pharmaceutical intermediate (see, for example, Non-patent Document 1), and as its production method, for example, a method using guanosine as a starting material is known (for example, Non-patent Document 1). 1). However, it is a multi-stage reaction, which is not always satisfactory in terms of yield, and uses a large excess of a reagent with a large environmental load, such as carbon tetrachloride and n-pentyl nitrite, Improvements were also desired in terms of occupational health and the environment.

Synthesis, 670 (1982)

（式中、Ｘはハロゲン原子を表わし、Ｙは水素原子、ハロゲン原子またはアミノ基を表わす。）
で示されるプリン類を原料とし、かかるプリン類と式（２）

（式中、Ｒ¹およびＲ²はそれぞれ同一または相異なって、アシル基またはアルコキシカルボニル基を表わし、Ｒ³およびＲ⁴はそれぞれ同一または相異なって、保護基を表わす。）
で示される化合物とを、ニトリル系溶媒またはエステル系溶媒中、シリル化剤およびルイス酸の存在下に反応させることにより、目的とする上記式（３）で示されるプリン化合物が収率よく得られることを見出し、本発明に至った。 Under such circumstances, the present inventors have developed a method for producing the target purine compound represented by the above formula (3) without using a reagent with a higher yield and a larger environmental load. As soon as possible, formula (1) is easy to obtain

(In the formula, X represents a halogen atom, and Y represents a hydrogen atom, a halogen atom or an amino group.)
And the puddings represented by formula (2)

(In the formula, R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group, and R ³ and R ⁴ are the same or different and each represents a protecting group.)
Is reacted in the presence of a silylating agent and a Lewis acid in a nitrile solvent or an ester solvent to obtain the target purine compound represented by the above formula (3) in a high yield. As a result, they have reached the present invention.

（式中、Ｘはハロゲン原子を表わし、Ｙは水素原子、ハロゲン原子またはアミノ基を表わす。）
で示されるプリン類と式（２）

（式中、Ｒ¹およびＲ²はそれぞれ同一または相異なって、アシル基またはアルコキシカルボニル基を表わし、Ｒ³およびＲ⁴はそれぞれ同一または相異なって、保護基を表わす。）
で示される化合物とを、ニトリル系溶媒またはエステル系溶媒中、シリル化剤およびルイス酸の存在下に反応させることを特徴とする式（３）

（式中、Ｘ、Ｙ、Ｒ²、Ｒ³およびＲ⁴は上記と同一の意味を表わす。）
で示されるプリン化合物の製造方法を提供するものである。 That is, the present invention provides the formula (1)

(In the formula, X represents a halogen atom, and Y represents a hydrogen atom, a halogen atom or an amino group.)
Purines and formula (2)

(In the formula, R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group, and R ³ and R ⁴ are the same or different and each represents a protecting group.)
The compound represented by formula (3) is reacted in a nitrile solvent or ester solvent in the presence of a silylating agent and a Lewis acid.

(In the formula, X, Y, R ² , R ³ and R ⁴ have the same meaning as described above.)
The purine compound shown by these is provided.

  According to the present invention, a purine compound can be produced with higher yield without using a reagent having a large environmental load, which is industrially advantageous.

で示されるプリン類（以下、プリン類（１）と略記する。）の式中、Ｘはハロゲン原子を表わし、Ｙは水素原子、ハロゲン原子またはアミノ基を表わす。ハロゲン原子としては、例えばフッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。 Formula (1)

In the formula of purines (hereinafter abbreviated as purines (1)), X represents a halogen atom, and Y represents a hydrogen atom, a halogen atom or an amino group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of such purines (1) include 6-fluoropurine, 6-chloropurine, 2,6-dichloropurine, 2-amino-6-chloropurine, 2-amino-6-iodopurine and the like. As the puddings (1), commercially available ones may be used. For example, JP-A-5-170766, JP-A-6-157530, JP-A-11-60575, JP-A-2002-88082. You may use what was manufactured according to well-known methods, such as gazette.

で示される化合物（以下、化合物（２）と略記する。）の式中、Ｒ¹およびＲ²はそれぞれ同一または相異なって、アシル基またはアルコキシカルボニル基を表わす。アシル基としては、例えばアセチル基等の脂肪族アシル基、例えばベンゾイル基等の芳香族アシル基等が挙げられる。アルコキシカルボニル基としては、例えばメトキシカルボニル基、エトキシカルボニル基、ｎ−プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基等の炭素数１〜４の低級アルコキシ基とカルボニル基とから構成される基等が挙げられる。また、Ｒ³およびＲ⁴はそれぞれ同一または相異なって、保護基を表わす。保護基としては、水酸基の保護基として使用可能なものであればよく、例えばベンジル基等のアラルキル基、例えばアセチル基等の脂肪族アシル基、例えばベンゾイル基等の芳香族アシル基、例えばメトキシカルボニル基等のアルコキシカルボニル基、例えばトリメチルシリル基等の三置換シリル基、例えばメトキシメチル基等のアルコキシアルキル基等が挙げられ、アラルキル基、脂肪族アシル基、芳香族アシル基が好ましい。 Formula (2)

In the formula (hereinafter abbreviated as compound (2)), R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group. Examples of the acyl group include an aliphatic acyl group such as an acetyl group, and an aromatic acyl group such as a benzoyl group. Examples of the alkoxycarbonyl group include lower alkoxy groups having 1 to 4 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, tert-butoxycarbonyl group, and carbonyl. And a group composed of a group. R ³ and R ⁴ are the same or different and each represents a protecting group. The protecting group is not particularly limited as long as it can be used as a protecting group for a hydroxyl group. For example, an aralkyl group such as a benzyl group, an aliphatic acyl group such as an acetyl group, an aromatic acyl group such as a benzoyl group, for example, methoxycarbonyl, etc. An alkoxycarbonyl group such as a trimethylsilyl group, an alkoxyalkyl group such as a methoxymethyl group, and the like, and an aralkyl group, an aliphatic acyl group, and an aromatic acyl group are preferred.

  Examples of the compound (2) include tetra-O-acetyl-D-ribofuranose, tetra-O-benzoyl-D-ribofuranose, tetra-O- (methoxycarbonyl) -D-ribofuranose, tetra-O- ( tert-butoxycarbonyloxy) -D-ribofuranose, 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, 1,2-di-O-acetyl-3,5-di -O-benzyl-D-ribofuranose, tetra-O-acetyl-L-ribofuranose, tetra-O-benzoyl-L-ribofuranose, tetra-O- (methoxycarbonyl) -L-ribofuranose, tetra-O- (Tert-butoxycarbonyl) -L-ribofuranose and the like. As the compound (2), a commercially available product may be used, or a compound produced according to a known method may be used.

  In this reaction, compound (2) may be used in an amount of 1 mol or more with respect to purine (1), or purine (1) may be used in an amount of 1 mol or more with respect to compound (2). The amount used may be determined in consideration of the cost and availability of the purines (1) and the compound (2), the post-treatment surface, and the like.

  Examples of the silylating agent include N, O-bis (trimethylsilyl) acetamide, hexamethyldisilazane, trimethylsilyl chloride and the like, and N, O-bis (trimethylsilyl) acetamide is preferable. The usage-amount of this silylating agent is 0.8-5 mole times normally with respect to purines (1).

  Examples of the Lewis acid include trimethylsilyl trifluoromethanesulfonate and trimethylsilyl iodide, and trimethylsilyl trifluoromethanesulfonate is preferable. As such Lewis acid, a commercially available product is used, and if the amount used is too large, the amount of impurities by-product increases, so that the amount of the purine (1) and the compound (2) used is less than the amount used. The amount is usually 0.005 to 1 mol times, preferably 0.01 to 0.5 mol times with respect to the smaller one.

（式中、Ｘ、Ｙ、Ｒ²、Ｒ³およびＲ⁴は上記と同一の意味を表わす。）
で示されるプリン化合物（以下、プリン化合物（３）と略記する。）を製造することができる。 In the present invention, the purines (1) and the compound (2) are reacted in a nitrile solvent or an ester solvent (hereinafter abbreviated as a solvent) in the presence of a silylating agent and a Lewis acid. Thereby, the formula (3) can be obtained with good yield.

(In the formula, X, Y, R ² , R ³ and R ⁴ have the same meaning as described above.)
Can be produced (hereinafter abbreviated as purine compound (3)).

  Examples of the nitrile solvent include hydrophilic nitrile solvents such as acetonitrile and propionitrile, and examples of the ester solvent include ethyl acetate and propyl acetate. A hydrophilic nitrile solvent is preferable in that the treatment after the reaction is easy and the target purine compound (3) can be easily taken out as crystals, and acetonitrile is particularly preferable.

  The usage-amount of a solvent is 1-20 weight times normally with respect to purines (1).

  This reaction is usually carried out by mixing purines (1), compound (2), silylating agent and Lewis acid in a solvent, and the mixing order is not particularly limited. For example, purines (1), Compound (2), silylating agent, Lewis acid and solvent may be mixed together, or after purine (1), silylating agent and solvent are mixed, compound (2) and Lewis acid may be added. . Further, after mixing the purines (1), the silylating agent, the compound (2) and the solvent, a Lewis acid may be added, or after the purines (1), the silylating agent, the Lewis acid and the solvent are mixed. Compound (2) may be added. From the viewpoint of yield and stability of the compound (2), it is preferable to add the compound (2) and Lewis acid after mixing the purines (1), the silylating agent and the solvent.

  This reaction may be carried out under normal pressure conditions or under pressurized conditions. Moreover, in order to suppress decomposition | disassembly of a silylating agent etc., it is preferable to implement in inert gas atmosphere, such as nitrogen gas, for example. Moreover, reaction temperature is 0-150 degreeC normally, Preferably it is 50-150 degreeC.

  After completion of the reaction, for example, the reaction solution and water are mixed, and if necessary, an organic solvent insoluble in water is added, followed by liquid separation treatment, and concentration of the resulting organic layer to extract the purine compound (3). be able to. When the raw material purine (1) remains in the reaction solution, it is preferable to perform a liquid separation treatment after mixing the reaction solution with water and neutralizing. The neutralization treatment is usually performed by mixing the reaction solution and water, and then adding an aqueous alkali solution such as aqueous ammonia or sodium hydrogen carbonate solution in such an amount that the pH of the treatment solution after the neutralization treatment is usually in the range of 7-9. Is implemented. For example, when a hydrophilic nitrile solvent such as acetonitrile is used, since the purine compound (3) of interest is usually precipitated as a crystal by mixing the reaction solution and water after the completion of the reaction, it is precipitated. The crystal can be easily taken out by means such as filtration. Also in this case, when the raw material purine (1) remains in the reaction liquid, the reaction liquid and water are mixed, neutralized, and then filtered to obtain the purine compound (3). From the point of purity, it is preferable. The extracted purine compound (3) may be further purified by ordinary purification means such as recrystallization. Examples of the organic solvent insoluble in water include aromatic hydrocarbon solvents such as toluene and xylene, and aliphatic hydrocarbon solvents such as hexane and heptane.

  In this reaction, the reaction proceeds by steric retention. For example, when 2,6-dichloropurine is used as the purine (1) and tetra-O-acetyl-D-ribofuranose is used as the compound (2), 2,6-dichloro-9β- (2 ′, 3 ′ , 5'-tri-O-acetyl) -D-ribofuranosylpurine, 2,6-dichloropurine as purine (1), and tetra-O-acetyl-L-ribofuranose as compound (2) Is used, 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -L-ribofuranosylpurine is obtained.

  Examples of the purine compound (3) thus obtained include 6-fluoro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine, 6-chloro-9β- (2 ', 3', 5'-tri-O-acetyl) -D-ribofuranosylpurine, 2,6-dichloro-9β- (2 ', 3', 5'-tri-O-acetyl) -D-ribo Furanosylpurine, 2-amino-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine, 2-amino-6-iodo-9β- (2 ', 3', 5'-tri-O-acetyl) -D-ribofuranosylpurine, 2-bromo-6-chloro-9β- (2 ', 3', 5'-tri-O-acetyl) -D Ribofuranosylpurine, 2-iodo-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O— Cetyl) -D-ribofuranosylpurine, 6-fluoro-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -D-ribofuranosylpurine, 6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -D-ribofuranosylpurine, 2-fluoro-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribo Furanosylpurine, 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -D-ribofuranosylpurine, 2-amino-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -D-ribofuranosylpurine, 2-amino-6-iodo-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -D-ribo Furanosylpurine, 2-bromo-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-be Benzoyl)-D-ribofuranosyl purines, 2-iodo-6-chloro -9β- (2 ', 3', 5'- tri -O- benzoyl)-D-ribofuranosyl purines,

6-Fluoro-9β- (2 ′, 3 ′, 5′-tri-O-methoxycarbonyl) -D-ribofuranosylpurine, 6-chloro-9β- (2 ′, 3 ′, 5′-tri-O -Methoxycarbonyl) -D-ribofuranosylpurine, 2,6-dichloro-9β- (2 ', 3', 5'-tri-O-methoxycarbonyl) -D-ribofuranosylpurine, 2-amino-6 -Chloro-9β- (2 ', 3', 5'-tri-O-methoxycarbonyl) -D-ribofuranosylpurine, 2-amino-6-iodo-9β- (2 ', 3', 5'- Tri-O-methoxycarbonyl) -D-ribofuranosylpurine, 6-fluoro-9β- (2 ′, 3 ′, 5′-tri-O-tert-butoxycarbonyl) -D-ribofuranosylpurine, 6- Chloro-9β- (2 ′, 3 ′, 5′-tri-Ot rt-butoxycarbonyl) -D-ribofuranosylpurine, 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-tert-butoxycarbonyl) -D-ribofuranosylpurine, 2- Amino-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-tert-butoxycarbonyl) -D-ribofuranosylpurine, 2-amino-6-iodo-9β- (2 ′, 3 ', 5'-tri-O-tert-butoxycarbonyl) -D-ribofuranosylpurine, 2-bromo-6-chloro-9β- (2', 3 ', 5'-tri-O-tert-butoxycarbonyl) ) -D-ribofuranosylpurine, 2-iodo-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-tert-butoxycarbonyl) -D-ribofuranosylpurine, 2,6- Dichloro-9β- (2′- O-acetyl-3 ′, 5′-di-O-benzyl) -D-ribofuranosylpurine, 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-benzoyl) -L Ribofuranosylpurine, 2-amino-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -L-ribofuranosylpurine, 2-iodo-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -L-ribofuranosylpurine and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Example 1
To a reaction vessel, 50 mL of acetonitrile, 1.9 g of 2,6-dichloropurine, 3.5 g of tetra-O-acetyl-D-ribofuranose and 2 g of N, O-bis (trimethylsilyl) acetamide were added, and the reaction was performed for 1 hour under a nitrogen atmosphere. Refluxed. After cooling to room temperature, 0.1 g of trimethylsilyl trifluoromethanesulfonate was added, and the mixture was refluxed and reacted for 6 hours. The reaction mixture was cooled to room temperature, extracted with 20 mL of saturated aqueous sodium bicarbonate and 50 mL of ethyl acetate. The obtained organic layer was washed twice with 30 mL of saturated brine and then dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure, and 8 mL of ethyl acetate was added to the resulting concentrated residue for recrystallization, and 2,6-dichloro-9β- (2 ′, 3 ′, 5′- 3.9 g of tri-O-acetyl) -D-ribofuranosylpurine was obtained. Yield: 88%.

¹ H-NMR (CDCl ₃ , δ / ppm)
2.10 (s, 3H), 2.15 (s, 3H), 2.18 (s, 3H), 4.42 (d, J = 3.6 Hz, 2H), 4.48 (m, 1H) , 5.58 (t, J = 5.6 Hz, 1H), 5.80 (t, J = 5.6 Hz, 1H), 6.22 (d, J = 5.6 Hz, 1H), 8.30 ( s, 1H)

Example 2
To the reaction vessel were added 120 mL of acetonitrile, 5.1 g of 2-amino-6-chloropurine, 9.5 g of tetra-O-acetyl-D-ribofuranose and 13 g of N, O-bis (trimethylsilyl) acetamide, and under a nitrogen atmosphere. Reflux for 1 hour. After cooling to room temperature, 0.3 g of trimethylsilyl trifluoromethanesulfonate was added and reacted by refluxing for 6 hours. The reaction mixture was cooled to room temperature, extracted with 50 mL of saturated aqueous sodium bicarbonate and 100 mL of ethyl acetate. The obtained organic layer was washed twice with 150 mL of saturated saline and then dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and concentrated under reduced pressure. Methanol was added to the resulting concentrated residue for recrystallization, and 2-amino-6-chloro-9β- (2 ′, 3 ′, 5′- 11.9 g of tri-O-acetyl) -D-ribofuranosylpurine was obtained. Yield: 93%.

¹ H-NMR (DMSO-d ₆ , δ / ppm)
2.01 (s, 6H), 2.10 (s, 3H), 4.24-4.41 (m, 3H), 5.52 (d, J = 3.6 Hz, 5.6 Hz, 1H), 5.86 (dd, J = 5.6 Hz, 6.0 Hz, 1H), 6.09 (dd, J = 6.0 Hz, 1H), 7.04 (br, 2H), 8.34 (s, 1H )

Example 3
To the reaction vessel, 50 mL of acetonitrile, 10 g of 2,6-dichloropurine and 11 g of N, O-bis (trimethylsilyl) acetamide were added and refluxed for 2 hours under a nitrogen atmosphere. After cooling to room temperature, 17.5 g of tetra-O-acetyl-D-ribofuranose and 3 g of trimethylsilyl trifluoromethanesulfonate were added and reacted by refluxing for 3 hours. The reaction solution was cooled to room temperature and dropped into 175 mL of water, and then aqueous ammonia was added to adjust the pH to 8-9. The precipitated crystals were collected by filtration and dried, and 2,6-dichloro-9β- (2 22 g of ', 3', 5'-tri-O-acetyl) -D-ribofuranosylpurine was obtained. Yield: 93%.

Example 4
To the reaction vessel, 20 mL of acetonitrile, 3.4 g of 2-amino-6-chloropurine and 9.4 g of N, O-bis (trimethylsilyl) acetamide were added and refluxed for 2 hours under a nitrogen atmosphere. After cooling to room temperature, 6.4 g of tetra-O-acetyl-D-ribofuranose and 0.4 g of trimethylsilyl trifluoromethanesulfonate were added and reacted by refluxing for 3 hours. The reaction solution was cooled to room temperature and added dropwise to 50 mL of water, then aqueous ammonia was added to adjust the pH to 8-9, the precipitated crystals were collected by filtration and dried, and 2-amino-6-chloro-9β- 7 g of (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine was obtained. Yield: 81%.

Examples 5-7
In the presence of N, O-bis (trimethylsilyl) acetamide and trimethylsilyl trifluoromethanesulfonate in acetonitrile solvent, various purines and tetra-O-acetyl-D-ribofuranose were reacted under reflux conditions for 3 hours. A reaction solution containing the purine compound was obtained. The results are shown in Table 1. In the table, the purine compound (%) is an area percentage value (by high performance liquid chromatography analysis) of the purine compound in the obtained reaction solution.

Example 8
In Example 5, 2,6-dichloro-9β- (2 ′, 3 ′) was carried out in the same manner as in Example 5 except that the same volume of ethyl acetate was used instead of acetonitrile and the reaction was refluxed for 5 hours. , 5′-tri-O-acetyl) -D-ribofuranosylpurine was obtained. When the reaction solution was analyzed by high performance liquid chromatography, the area percentage value of 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine was 90. It was 8%.

Example 9
In a reaction vessel, 20 mL of acetonitrile, 1.7 g of 2-amino-6-chloropurine, 4 g of N, O-bis (trimethylsilyl) acetamide, 3.2 g of tetra-O-acetyl-D-ribofuranose and 0.1 g of trimethylsilyl iodide The mixture was refluxed and reacted for 7 hours to obtain a reaction liquid containing 2-amino-6-chloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine. . When the reaction solution was analyzed by high performance liquid chromatography, the area percentage value of 2,6-dichloro-9β- (2 ′, 3 ′, 5′-tri-O-acetyl) -D-ribofuranosylpurine was 62. 2%.

Example 10
In a reaction vessel, 10 mL of acetonitrile, 0.43 g of 2-amino-6-chloropurine, 1 g of 1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose and N, O-bis (Trimethylsilyl) acetamide (1.3 mL) was added, and the mixture was refluxed for 1 hour under a nitrogen atmosphere. After cooling to room temperature, 28 mg of trimethylsilyl trifluoromethanesulfonate was added, and the mixture was refluxed and reacted for 6 hours. The reaction solution is concentrated, and the resulting concentrated residue is subjected to column chromatography to give 2-amino-6-chloro-9β- (2′-O-acetyl-3 ′, 5′-di-O-benzyl) -D. -Ribofuranosylpurine was obtained in 84% yield.

Claims (7)

Formula (1)

(In the formula, X represents a halogen atom, and Y represents a hydrogen atom, a halogen atom or an amino group.)
Purines and formula (2)

(In the formula, R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group, and R ³ and R ⁴ are the same or different and each represents a protecting group.)
The compound represented by formula (3) is reacted in a nitrile solvent or ester solvent in the presence of a silylating agent and a Lewis acid.

(In the formula, X, Y, R ² , R ³ and R ⁴ have the same meaning as described above.)
The manufacturing method of the purine compound shown by these. The method for producing a purine compound according to claim 1, wherein the reaction is carried out in a nitrile solvent. The method for producing a purine compound according to claim 1 or 2, wherein the nitrile solvent is a hydrophilic nitrile solvent. The method for producing a purine compound according to claim 3, wherein the hydrophilic nitrile solvent is acetonitrile. The method for producing a purine compound according to claim 1, wherein the silylating agent is N, O-bis (trimethylsilyl) acetamide. The method for producing a purine compound according to claim 1, wherein the Lewis acid is trimethylsilyl trifluoromethanesulfonate. The method for producing a purine compound according to claim 1, wherein the protecting group is an aralkyl group.