JP2001031691A - Production of 9-(2-phosphonylmethoxyalkyl)adenine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject 9-(2-phosphonylmethoxyalkyl)adenine in high yield by subjecting an adenine derivative to condensation reaction with chloromethylphosphinylidenebismorpholine, followed by hydrolysis of the reaction product, dimorpholidate derivative. SOLUTION: A compound of formula I (R1 is H, benzoyl; R2 is H, methyl) and 4,4'-[(chloromethyl)phosphinylidene]bismorpholine are subjected to condensation reaction, preferably in a solvent (for example, dimethyformamide, dioxane, acetonitrile or the like in the presence of a base (for example, sodium hydride) at room temperature to the boiling point of the solvent to form a dimorpholidate derivative of formula III [for example, 2-dimorpholinophosphonylmethoxyethyl) adenine]. Then, the product is hydrolyzed, preferably in a solvent of an amide, for example, dimethylformamide or the like at 0 deg.C to room temperature to give the compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing 9- (2-phosphonylmethoxyalkyl) adenine useful as an antiviral agent, and more particularly to a method for producing a compound using a dimorpholidate derivative as an intermediate.

[0002]

2. Description of the Related Art Conventionally, various methods for producing 9- (2-phosphonylmethoxyalkyl) adenine are known (for example, Japanese Patent Application Laid-Open No. 61-275218,
Nos. 61-275289 and 63-45289, Collect. Czech. Chem. Comm
un. 1987 52 2801, Collect. C
zech. Chem. Commun. 1988 53
2753, Nucleosides Nucleoti
des 1995 14 607, Collect. C
zech. Chem. Commun. 1995 60
1196, US 5,514,798, Nucleos
Ides Nucleotides 1996 15
1771, etc.). These methods all use a compound represented by the following formula 5 (wherein R represents a methyl group or an ethyl group, and R2 represents a hydrogen atom or a methyl group) as an intermediate, and this is deprotected. Converted to the target.

[0003]

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[0004]

However, when a lower alkyl group is used as a protecting group for a phosphonic acid derivative, deprotection requires a special reagent such as trimethylbromosilane or trimethyliodosilane, and the yield is low. In addition to the deprotection reaction, the purine ring and the like are trimethylsilylated, which consumes reagents, and thus requires a large excess of reagents.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to find a production method free of such disadvantages, and as a result, have found that a dimorpholidate derivative can be easily produced in good yield as an intermediate, and that the dimorpholidate derivative has a mild It was found that hydrolysis was carried out without side reactions under the conditions, and the product was converted into the desired product in good yield, and the present invention was completed. That is, the present invention provides a novel production method of 9- (2-phosphonylmethoxyalkyl) adenine, particularly a production method using a dimorpholidate derivative as an intermediate.

Hereinafter, the present invention will be described in detail. The dimorpholidate derivative represented by the formula (6) (wherein R1 represents a hydrogen atom or a benzoyl group and R2 represents a hydrogen atom or a methyl group), which is an intermediate of the present invention, is a compound represented by the following formula (7).
Represents a hydrogen atom or a benzoyl group, and R2 represents a hydrogen atom or a methyl group. )) And 4,4 ′-{(chloromethyl) phosphinylidene} bismorpholine represented by Chemical Formula 8.

[0007]

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[0008]

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[0009]

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The starting compounds of the present invention represented by the above formulas (7) and (8) are all known compounds which can be easily prepared (for example, J. Chem. Soc. P
erkin I 1977 1266; Am. Che
m. Soc. 1982 104 1316, Colle
ct. Czech. Chem. Commun. 1987
52 2801, Chem. Lett. 1973 9
67, etc., and, for example,
doc. 1976 VINITI 2739,
etc. ).

The compound represented by the formula (7) and the compound represented by the formula (8) are condensed in the presence of a solvent. The reaction solvent may be any solvent that does not inhibit the reaction, for example,
Examples thereof include ethers such as dioxane, nitriles such as acetonitrile, amides such as dimethylformamide, and dimethylsulfoxide. Of these, amides such as dimethylformamide are preferred. The reaction is performed in the presence of a base. Examples of the base used include sodium hydride, potassium hydroxide, sodium hydroxide and the like, and preferably sodium hydride is preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent, preferably at room temperature to 100 ° C. Although the reaction time varies depending on the reaction conditions, the reaction is carried out for 1 hour to several days. After completion of the reaction, the product is easily isolated by concentrating the reaction solution, directly or after extracting with an organic solvent, and then crystallizing with an appropriate solvent. be able to.

The compound represented by Chemical formula 6 is converted into 9- (2-phosphonylmethoxyalkyl) adenine which is the target compound by hydrolysis. When R1 in Chemical formula 6 is a benzoyl group, morpholidate can be hydrolyzed first by the method described later, but it is preferable to deprotect the benzoyl group first. Deprotection of the benzoyl group can be easily carried out by a conventional method, for example, at a temperature slightly higher than room temperature with a sodium hydroxide solution.

The hydrolysis of the compound in which R 1 is a hydrogen atom is carried out by using an acid. The acid used may be either an inorganic acid or an organic acid, but preferably an inorganic acid such as hydrochloric acid or sulfuric acid. The reaction is performed in the presence of a solvent. The solvent may be selected arbitrarily, but is desirably one that can be uniformly mixed with the acid to be used, and examples thereof include water, alcohol, and amides. In particular, when an amide such as dimethylformamide is used as a solvent, the production method of the present invention can be efficiently carried out in one pot. Reaction temperature is 0 ° C
A reaction time of about 30 minutes to several hours is sufficient.

After completion of the reaction, the desired product can be easily isolated, for example, by concentrating the reaction solution according to a conventional method.

A feature of the present invention is that morpholidate is used as a phosphonic acid protecting group. Monomorpholidate is widely known, for example, as a reaction for activating a phosphoric acid derivative to produce a diphosphoric acid derivative, and for a phosphonic acid derivative, monomorpholidate is used as an activator of such a reaction. (For example, Colle
ct. Czech. Chem. Commun. 1982
47 3447, Collect. Czech. Ch
em. Commun. 1987 52 2801,
etc). In the present invention, the use of dimorpholidate allows the desired reaction to proceed suitably without involvement of phosphonic acid, and sufficiently exerts the role of a protecting group as if a dimorpholidate derivative was obtained in good yield. The fact that hydrolysis corresponding to deprotection is extremely easy is an unexpected result, and the present inventors speculate that this is due to the difference in reactivity between monomorpholidate and dimorpholidate.

[0016]

The present invention will be described in detail with reference to the following examples. Example 1 9- (2-hydroxyethyl) -N ⁶ - benzoyl adenine (of 7, R1 = benzoyl, R2 = hydrogen atom)
1.4 g was dissolved in 30 ml of dimethylformamide by heating and then cooled, and sodium hydride (in oil) 0.1 g was stirred under stirring.
55 g was added, and the mixture was stirred at room temperature for 30 minutes. Then, 1.35 g of 4,4 ′-{(chloromethyl) phosphylidene} bismorpholine (Chem. 8) was added thereto, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, after cooling, adding a small amount of water and stirring,
The solvent was distilled off under reduced pressure, a small amount of water was added to the residue, and this was washed with ethyl acetate, and extracted with chloroform.
The chloroform layer was concentrated under reduced pressure, ethanol residue - by crystallization from ethyl acetate, 9- (2-di-morpholinopropoxy Noho Suho methoxy ethyl) -N 6 ^- benzoyl adenine (of 6, R1 = benzoyl, R2 = 2.2 g (hydrogen atom) were obtained (reconstitution: ethanol-ethyl acetate). Melting point: 172-3 ° C. TLC: Rf = 0.47 (chloroform: methanol =
5: 1) Anal. (As C ₂₃ H ₃₀ N ₇ O ₅ P) Calculated C: 53.59% H: 5.87% N:
19.02% measured value C: 53.4% H: 6.0% N:
19.1% ¹ H-NMR (DMSO-d6) 3.03, 8H; 3.56, 8H; 3.86, 2H:
3.98, 2H: 4.50, 2H: 7.59-8.0
5,6H; 8.78,1H: 9.03,1H

Example 2 9- (2-hydroxyethyl) -adenine (Formula 7, R1
= Hydrogen atom, R2 = hydrogen atom) 0.72 g was dissolved in 20 ml of dimethylformamide by heating and then cooled, and 0.48 g of sodium hydride (in oil) was added with stirring, followed by stirring at room temperature for 15 minutes. Then, 4,4 ′-{(chloromethyl) phosphidene} bismorpholine (Chem. 8)
08 g was added, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, the mixture was cooled, a small amount of water was added, and the mixture was stirred, and then the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, concentrated under reduced pressure, and the residue was crystallized from chloroform-benzene-ether to give 9- (2-dimorpholinophosphonylmethoxyethyl) -adenine (Formula 6, R1 = hydrogen atom) ,
R2 = hydrogen atom (1.1 g) was obtained (reconstitution: ethanol-).
Ethyl acetate). Melting point: 180-3 ° C. TLC: Rf = 0.24 (chloroform: methanol =
5: 1) Anal. _(C 16 _H 26 as _{N 7 0 4 P · 2H 2} O) Calculated C: 42.95% H: 6.76% N:
21.91% measured value C: 42.8% H: 6.8% N:
22.2% ¹ H-NMR (DMSO-d6) 2.82, 8H; 3.36, 8H; 3.83, 2H;
3.86, 2H; 4.34, 2H; 7.22, 2H;
8.11, 1H; 8.13, 1H

Example 3 9- (2-hydroxypropyl) -adenine (Chemical Formula 7, R
0.77 g of (1 = hydrogen atom, R2 = methyl group) was dissolved in 20 ml of dimethylformamide, and 0.48 g of sodium hydride (in oil) was added with stirring, followed by stirring at room temperature for 15 minutes. Then add 4,4 '-｛(chloromethyl)
1.08 g of phosphidene-bismorpholine (Chem. 8) was added, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, the mixture was cooled, a small amount of water was added, and the mixture was stirred, and then the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, concentrated under reduced pressure, and the residue was crystallized from chloroform-benzene-ether to give 9- (2-dimorpholinophosphonylmethoxypropyl) -adenine (Formula 6, R1 = hydrogen atom) , R2 = methyl group) 1.1 g (reconstitution: ethanol). Melting point: 207-8 ° C. TLC: Rf = 0.55 (chloroform: methanol =
2: 1) Anal. (As C ₁₇ H ₂₈ N ₇ O ₄ P · 3 / 2H ₂ O) Calculated C: 45.13% H: 6.91% N:
21.67% measured value C: 45.1% H: 6.8% N:
21.7% ¹ H-NMR (DMSO-d6) 1.14, 3H; 2.73, 4H; 2.91, 4H;
3.33, 4H; 3.47, 4H; 3.70, 1H;
3.87, 1H; 3.98, 1H; 4.13-4.2.
5,2H; 7.20,2H; 8.09,1H; 8.1
4,1H

Example 4 9- (2-Dimorpholinophosphonylmethoxyethyl) -adenine obtained in Example 2 (Formula 6, R 1 = hydrogen atom, R
0.5 g of dimethylformamide-hydrochloric acid-water = 5 ml: 1 ml: 2 ml was added to a mixed solvent of
Stirred at room temperature for 1 hour. After completion of the reaction, Diaion WA
After removing hydrochloric acid with -30, dilute with water and adjust to pH 10 with ammonia water, and Diaion SA11B (acetic acid type)
Applied to the column. After washing with water, elution with an acetic acid solution elutes 9- (2-
The (phosphonylmethoxyethyl) adenine fraction was collected and concentrated under reduced pressure, and acetic acid was removed by repeating addition and concentration of water to the residue. Ethanol and ether were added to the residue, and the crystalline product was collected by filtration to give 9- (2
-Phosphonylmethoxyethyl) adenine was obtained. The structure of this compound was confirmed by comparison of the infrared absorption spectrum with a known compound.

[0020]

As described in detail above, according to the present invention, 9
There is provided a novel process for producing-(2-phosphonylmethoxyalkyl) adenine, particularly a process using a dimorpholide derivative as an intermediate.

Claims (1)

[Claims] (1) wherein R1 represents a hydrogen atom or a benzoyl group, and R2 represents a hydrogen atom or a methyl group.
An adenine derivative represented by the following formula:
-Condensation with-{(chloromethyl) phosphinylidene} bismorpholine to form a dimorpholidate derivative represented by the following formula (3) (wherein R1 and R2 are the same as described above), and hydrolyzing the derivative. 4. A method for producing 9- (2-phosphonylmethoxyalkyl) adenine represented by the formula 4 (wherein R2 is as defined above). Embedded image Embedded image Embedded image Embedded image