JP2002121198A - METHOD FOR PRODUCING 2'-DEOXY-beta-ADENOSINE DERIVATIVE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing a 2'-deoxyadenosine derivative without restriction of a feeding amount by eliminating the conventional defect. SOLUTION: This method for producing the 2'-deoxy-β-adenosine derivative by which the derivative is easily isolated and purified is established by discovering that when the condensing reaction of a compound of formula [1] with an adenine salt is carried out in 2-butanone or 4-methyl-2-pentanone, the 2'-deoxy-β-adenosine derivative [2] is formed in a high β-selectivity (in the formulas, R is a phenyl group which may be substituted).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 2'-deoxy-β-
The present invention relates to a method for producing an adenosine derivative. 2'-deoxy-
β-adenosines are useful as raw materials for pharmaceuticals such as anticancer agents and antiviral agents, and are also useful as raw materials for producing antisense DNA and the like, which have been recently developed.

[0002]

2. Description of the Related Art As a method for producing 2'-deoxyadenosine, for example, the following is known. (1) Naturally occurring DNA is enzymatically degraded and 2′-
A method for obtaining deoxyadenosine. (2) converting the silylated nucleobase to 1-O-acetyl-2-
A method in which a deoxyribose derivative is reacted with potassium iodide in the presence of a crown ether, and then the protecting group is eliminated to obtain 2'-deoxyadenosine [Tetrahe
drone Lett. , 31 (31), 4437-44
40 (1990)]. (2) A method of reacting a silylated nucleobase with a 1-chloro-2-deoxyribose derivative and then removing a protecting group to obtain 2′-deoxyadenosine [Chem. Le
tt. 1365-1368 (1989);
160799]. (3) Adenine is converted to a sodium salt, and 1-chloro-2-
A method for obtaining 2'-deoxyadenosine by condensing with a deoxyribose derivative and then removing the protecting group [Chem.
Lett. , 235-238 (1989);
17199].

[0003] Of the above methods, naturally occurring DNA
In the method (1) for enzymatically decomposing the compound, there is a limitation in mass supply due to restrictions on the availability of raw materials, and the method cannot be applied to any method other than the production of a natural D-isomer.

According to the method (2), the ratio of the desired β-isomer to the α-isomer (β- / α-isomer ratio) is as low as 62/38, and it is difficult to obtain the β-isomer by purification. It is.

It has been reported that the methods (3) and (4) have improved β selectivity. In the method of (3), β
The isomer / α-isomer ratio is 89/11, and the combined yield of β- and α-isomer is described as 46%. In the method (4),
Condensation in acetone solvent gives the maximum yield, β-form /
The α-form ratio is 83/17, and the combined yield of β-form and α-form is described as 50%. However, β-selectivity cannot be said to be sufficiently high in any of the methods, and isolation and purification by an industrially applicable purification method such as recrystallization is difficult.

[0006]

As described above, heretofore, there has been no method for producing a 2'-deoxyadenosine derivative which can be supplied efficiently and in large quantities. The present invention provides a production method for producing a 2′-deoxyadenosine derivative efficiently and without restriction on the supply amount.

[0007]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the condensation reaction of compound [1] with an adenine salt can be carried out with 2-butanone or 4-methyl-2-methyl-2-butanone. When performed in pentanone, 2'-deoxy-β-
The present inventors have found that the adenosine derivative [2] is produced with high β selectivity, established a method for producing a 2′-deoxy-β-adenosine derivative which can be easily isolated and purified, and completed the present invention.
That is, the present invention relates to [1] a general formula [1] [formula 3]

[0008]

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(Wherein R represents a phenyl group which may be substituted, and X represents a halogen atom), and a 2′-deoxyribose derivative represented by the following formula:
-Condensation in butanone or 4-methyl-2-pentanone; general formula [2]

[0010]

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(Wherein R represents a phenyl group which may be substituted), a method for producing a 2′-deoxy-β-adenosine derivative represented by the formula: [2] wherein R is a 4-methylphenyl group or The method for producing a 2′-deoxy-β-adenosine derivative according to [1], wherein X is a chlorine atom in a 4-chlorophenyl group.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The phenyl group of R in the 2′-deoxyribose derivative represented by the general formula [1] may be an unsubstituted phenyl group or a substituent at any of the 2-, 3-, and 4-positions on the phenyl group. There may be. Further, a substituent may be present at a plurality of positions. Examples of the substituent include an alkyl group such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a butyl group and a t-butyl group, a hydroxyl group, a methoxy group, an ethoxy group and an alkyloxy group such as a propyloxy group; Group, chloro group, bromo group, halogeno group such as iodine group, acyl group such as acetyl group, propionyl group, alkylamino group such as methylamino group, ethylamino group, propylamino group, dimethylamino group, unsubstituted amino Group, nitro group, cyano group and the like.

Specifically, a phenyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group,
4-methoxyphenyl group, 3-methoxyphenyl group, 2
-Methoxyphenyl group, 4-chlorophenyl group, 3-chlorophenyl group, 2-chlorophenyl group, 4-bromophenyl group, 3-bromophenyl group, 2-bromophenyl group, 4-acetylphenyl group, 3-acetylphenyl group, 2-acetylphenyl group, 4-nitrophenyl group,
Examples thereof include a 3-nitrophenyl group, a 2-nitrophenyl group, a 4-cyanophenyl group, a 3-cyanophenyl group, and a 2-cyanophenyl group. Preferably a 4-methylphenyl group, a 4-chlorophenyl group, a 4-bromophenyl group,
A 4-nitrophenyl group and a 4-cyanophenyl group.

In the compound represented by the general formula [2], R
Has the same meaning as R in the general formula [1]. X represents a halogen atom. Specific examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a chlorine atom and a bromine atom.

Examples of the adenine salt include inorganic salts such as lithium salt, sodium salt, potassium salt, rubidium salt, cesium salt, magnesium salt and calcium salt of adenine and ammonium salts, triethylammonium salt, tetraethylammonium salt and tetrabutylammonium salt. And ammonium salts such as benzyltrimethylammonium salt.

As the salt-forming operation, for example, the following method is used. Dissolve or suspend adenine in a solvent, add a base such as sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium methoxide, potassium methoxide, tetraethylammonium hydroxide, benzyltrimethylammonium hydroxide, and stir, The solvent can be obtained by evaporating the solvent under reduced pressure and drying.

Examples of the solvent used for salt formation include water, methanol, ethanol, propanol, 2-propanol, acetonitrile, dioxane, THF and the like. The temperature for salt formation can be any temperature, but is preferably from 0 ° C to 150 ° C.

The amount of the solvent, 2-butanone or 4-methyl-2-pentanone, used in the condensation reaction between the compound [1] and the adenine salt is 3 to 1 times the amount of the compound [1].
It is 00 times, preferably 10 times to 50 times. The reaction temperature is from -30 ° C to 150 ° C, preferably 0 ° C
To 50 ° C. The reaction time is between 15 minutes and 24 hours.

The 2'-deoxyadenosine derivative [2] obtained by the present invention can be purified by a commonly used method such as a recrystallization method to obtain a higher purity 2'-deoxyadenosine derivative [2]. Can be.

According to the present invention, the 2′-deoxyadenosine derivative [2] can be produced more efficiently.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 15 ml of methanol and 139 mg of sodium hydroxide were added to 493 mg of adenine, and the mixture was heated under reflux for 1 hour. After dissolution, the mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Toluene was added to the concentrated residue, and the solvent was distilled off under reduced pressure. This operation was repeated twice. Of the white powder obtained here, 7
3.1 mg was suspended in 2 mL of 2-butanone, and
100 mg of 5-di (4-chlorobenzoyl) -1-chloro-2-deoxyribose was added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate, diluted with water three times, and saturated brine with water.
Washed twice. The organic layer was dried over magnesium sulfate and concentrated. After adding 20 mL of toluene to the concentrated residue and dissolving by heating, the mixture was stirred at room temperature. After the precipitate was filtered off, the filtrate was concentrated to dryness and 3 ′, 5′-bis (4-chlorobenzoyl)
72.3 mg of -2'-deoxy-β-adenosine was obtained. The yield was 59%, and the ratio of β-form / α-form was 98/2. ¹ H NMR (DMSO-d ₆ , 270 MHz) d 8.32 (s, 1 H), 8.2 7.
9 (m, 5 H), 7.7 7.5 (m, 4 H), 7.29 (s, 2 H, D ₂ O e
xchangeable), 6.53 (dd, J = 8.9 & 6.3 Hz, 1H), 5.8
5 (m, 1 H), 4.68 (m, 1 H), 4.56 (m, 2 H), 3.41
(m, 1 H), 2.75 (m, 1 H): FT-IR (cm ^-1 , KBr) 3336, 32
00, 1715, 1664, 1594, 1508, 1488, 1402, 1269, 1173,
1093, 1016: MS (APCI) m / z 528 (M + 1).

Example 2 To 1.38 g of adenine, 80 mL of methanol and 389 mg of sodium hydroxide were added, and suspended under ultrasonic waves. After dissolution, the solvent was distilled off under reduced pressure. Toluene was added to the concentrated residue, and the solvent was distilled off under reduced pressure. This operation was repeated twice. The obtained white powder was treated with 4-methyl-2-pentanone 4
Suspended in 2 mL, 2.05 g of 3,5-di (4-chlorobenzoyl) -1-chloro-2-deoxyribose at room temperature
Was added. After stirring at room temperature for 5 hours, the insolubles were filtered through silica gel and washed with 4-methyl-2-pentanone. The organic layer was washed three times with water and once with saturated saline. The organic layer was dried over magnesium sulfate, concentrated to dryness, and 3 ', 5'-
Bis (4-chlorobenzoyl) -2′-deoxy-β-
1.41 g of adenosine were obtained. The yield is 55%, β-form / α
The body ratio was 97/3.

[0024]

According to the present invention, a 2'-deoxyadenosine derivative can be efficiently produced in a higher yield and more efficiently than a conventional method.

Claims (2)

[Claims] [Claim 1] A compound represented by the general formula [1] (Wherein, R represents a phenyl group which may be substituted,
X represents a halogen atom. Wherein the 2'-deoxyribose derivative represented by the formula (1) and an adenine salt are condensed in 2-butanone or 4-methyl-2-pentanone. ] (In the formula, R represents a phenyl group which may be substituted.) A method for producing a 2′-deoxy-β-adenosine derivative represented by the formula: 2. The method for producing a 2′-deoxy-β-adenosine derivative according to claim 1, wherein R is a 4-methylphenyl group or a 4-chlorophenyl group, and X is a chlorine atom.