JPH01203399A - Thymine derivative - Google Patents

Abstract

NEW MATERIAL:The derivative of formula I (R is H or group of formula II). EXAMPLE:1-(2'-O-phenoxythiocarbonyl-3', 5'-O-isopropylidene-beta-D-xylofuranosyl) thymidine. USE:An intermediate for the synthesis of 3'-azido-3'-deoxythymidine useful as a remedy for AIDS. PREPARATION:The objective derivative can be produced by reacting (A) a tetraacetylxylofuranose of formula II (Ac is acetyl) with (B) bis(trimethylsilyl) thymine in an organic solvent in the presence of (C) anhydrous stannic chloride, hydrolyzing the reaction product in the presence of a base, reacting the hydro lyzed product with (D) acetone in the presence of an acid and finally reacting the reaction product in (E) acetonitrile in the presence of (F) phenyl chlorothionocarbonate and (G) 4-dimethylaminopyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to 3--
The present invention relates to a novel compound not described in conventional literature that is useful as an intermediate for the synthesis of azido-3-deoxythymidine, and a method for producing the compound.

More specifically, the present invention provides a novel compound of the following formula useful as an intermediate in the synthesis of 3'-azido-3'-deoxythymidine represented by the following formula (A), which is used as a therapeutic agent for AIDS. It relates to a thymine derivative represented by

(Prior Art) Conventionally, as a method for synthesizing 3noazido-3'-deoxythymidine of the above formula (A), for example, thymidine is used as a raw material, and the compound is reacted with trityl chloride to synthesize 5''-
0-) Lythyl thymicin was synthesized and this trityl derivative was treated with mesyl chloride to form 5''-0-)cutyl 3'-
〇-mesylthymidine, the compound is then reacted with phthalimide potassium salt to form 5''-0-) lythyl-2゜3'-anhydrothymidine, and this thymidine is further reacted with sodium azide to form the azide derivative. It is known to form and hydrolyze with acetic acid to give compounds of linear formula (A) (J, Org, Chem, V
o 138. No, 25.1973.4299-430
(see 5).

Thymidine, which is a starting material used in this method, is a type of rimidine deoxyribonucleoside when present in living organisms, is contained as a nucleoside in deoxypentose nucleic acids, and is widely distributed in the living world. Industrially, thymidine is generally extracted from salmon milt or cow thymus, hydrolyzed with acid or enzyme, and collected from the hydrolyzate. However, the yield of thymidine obtained here is very small, its price is extremely expensive, and it is not easily available. Therefore, the 3'-azide of the above formula (A) synthesized from thymidine Since -3-1-deoxythymidine is extremely expensive as a therapeutic agent for AIDS, there is a strong desire to develop a method for producing the compound of linear formula (A) that can be obtained at low cost.

(Problems to be Solved by the Invention) The purpose of the present invention is to solve the above-mentioned formula (
When synthesizing the compound of A), the compound of the above formula (
The object of the present invention is to provide an intermediate useful in the synthesis of the compound A) and a method for producing the same.

(Means for Solving the Problems) The present inventors have conducted extensive research on a method for producing 3-azido-3-deoxythymidine without using the expensive thymidine in the conventional method described above. the result,
The compound of the above formula (1) of the present invention, which can be easily synthesized from xylose that is inexpensive and easily available on the market, or manually synthesized from tetraacetyl xylofuranose [formula (6) below], which has not been described in any prior literature. If you use
The present invention has been completed by discovering that the compound of formula (A) above can be advantageously synthesized with good purity and yield, and by industrially simple operations.

Therefore, according to the present invention, (a) tetraacetyl xylofuranose represented by the following formula (6), where Ac represents an acetyl group (the same applies hereinafter), for example, in the presence of anhydrous tin chloride. was reacted with bis(trimethylsilyl)thymine represented by the following formula (5) in an organic solvent, where Me represents a methyl group (the same applies hereinafter) to form the following formula (
4) Form tri-acetylxylosylthymine represented by the formula (b) Hydrolyze the compound of the linear formula (4) in the presence of a base to form l-β- represented by the following formula (3) D-xylofuranosylthymidine is synthesized, and (c) the compound of the linear formula (3) is reacted with acetone in the presence of an acid to form 1-(3', 5'-0 expressed by the following formula (2)). -Isopropylidene-β-D-xylofuranosyl)thymidine was synthesized and (
d) Next, by reacting the compound of linear formula (2) in acetonitrile in the presence of phenyl chlorothionocarbonate and 4-dimethylaminopyridine, the compound of the present invention useful as a synthetic intermediate for the compound of formula (A) above is obtained. 1-(2'-0-phenoxythiocarbonyl-3',5'-0-isopropylidene-β-D-xylofuranosyl)thymidine represented by the following formula (1)- included in formula (1) is provided be done.

Furthermore, the compound of formula (1)-1 above is reacted with n-
) By reacting in the presence of butyltin hydride and azobisisobutyronitrile, the following formula (1) included in the formula (1) of the present invention is useful as a synthetic intermediate for the compound of the above formula (A). ) is provided.

The method for producing the compound of formula (1) of the present invention is shown by a reaction formula:
For example, as follows.

(3) (Note 2J; A
IBN=(Me)2C(CN)NNC(CNXMe)2
The method for producing the compound of formula (1) of the present invention, which is useful as an intermediate for the synthesis of 3'-azido-3'-deoxythymidine of formula (A), will be described in detail below in accordance with the reaction formula above.

First, in step (a), the reaction of synthesizing the compound of formula (4) from the compound of formula (6) is performed by adding the compound of formula (6) to the compound of formula (6) in the presence of anhydrous stannic chloride. (5
) with bis(trimethylsilyl)thymine.

Although the above reaction differs depending on the type of organic solvent used, - for boat fishing, it is necessary to perform approximately 1
This can be done in about 10 hours.

There is no particular restriction on the amount of bis(trimethylsilyl)thymine of formula (5) used in the above reaction, but it is usually about 1 to about 1.0% per mole of the compound of formula (6). It is used in a range of about 5 moles. The amount of anhydrous tin chloride used as a catalyst can also be varied within a wide range; A range of about 5 moles is appropriate. Furthermore, the solvent that can be used may be any solvent as long as it is inert to the reaction, but usually benzene, toluene, 1,2-dichloroethane, dichloromethane, carbon tetrachloride, etc. are often used. used.

The amount of these solvents to be used may be selected as appropriate, for example,
The amount used is preferably about 5 to about 50 times the weight of the compound of linear formula (6). After the reaction is complete,
The product is neutralized and washed according to a conventional method, and if desired, purified by means such as column chromatography to obtain the compound of formula (4).

Next, in step (b), in order to synthesize the compound of the above formula (3) from the compound of the above formula (4), for example, the linear formula (4
This reaction can be easily carried out by reacting a compound of formula (3) with a compound of formula (3) in the presence of a base such as sodium ethylate or sodium methylate. The amount of base used in this reaction is sufficient to be a catalytic amount, but the preferred amount is, for example, about 1/100 to about 1/1 mole of the compound of formula (4). It is in the range of about 10 moles. When using a base as described above, it may be prepared from the corresponding alkaline earth metal sodium in the reaction system. The reaction is carried out at a temperature at which the alcohol used is refluxed, and a reaction time of about 2 hours is usually sufficient. After the reaction is completed, it is neutralized with an acid such as an acidic ion exchange resin and purified by means such as recrystallization to obtain the compound of linear formula (3) with good purity and yield.The next step ( In c), the compound of formula (3) above is reacted with acetone in the presence of an acid to form 1-(3',
It is sufficient to carry out the reaction capable of synthesizing 5'-0-isopropylidene-β-D-xylofuranosyl)thymine at a temperature of about room temperature for about 3 hours. Examples of acids that can be used in this reaction include p-)luenesulfonic acid,
Acids such as hydrochloric acid and sulfuric acid can be used. The amount of these acids used is sufficient to be about a catalytic amount, for example, the above formula (3)
It is sufficient to use about 1/100% by weight of the compound. Further, the amount of acetone to be used may be equal to or more than the equivalent mole, and is preferably in the range of about 1 to about 100 moles per mole of the compound of formula (3). After the reaction is completed, the reaction product is neutralized with an alkali such as barium hydroxide, and the product is further purified by a means such as recrystallization to obtain the compound of linear formula (2) with good purity and good yield. You can get it.

Next, in step (d), from the compound of the above formula (2), 1 of the above formula (1)-1 included in the above formula (1) of the present invention
-(2'-0-phenoxythiocarbonyl-3',5'
-isopropylidene-β-D-xylofuranosyl)thymine is synthesized by reacting a compound of linear formula (2) in acetonitrile in the presence of phenyl chlorothionocarbonate and 4-dimethylaminopyridine. The reaction is carried out at about room temperature for about 2 to about 4 hours. The amount of phenyl chlorothionocarbonate used in this reaction is, for example, about 1
An example of the range is from about 1.5 mol to about 1.5 mol. Furthermore, it is advantageous to use 4-dimethylaminopyridine in excess; for example, it is generally used in an amount of about 1.5 to about 3 moles per mole of the compound of formula (2). be. The amount of acetonitrile to be used is not particularly restricted and can be selected as appropriate, but usually, for example, a range of about 5 to about 100 times the weight of the compound of formula (2) is appropriate. , partition extraction with a solvent such as ethyl acetate, washing the 81M with an aqueous solution of an acid such as hydrochloric acid,
If desired, the product is purified by means such as recrystallization to obtain the above formula (1)-1 of the present invention in good purity and yield.

Furthermore, in order to obtain 1-(2'-deoxy-3,5-0-isopropylidene-β-D-xylofuranosyl)thymine of the above formula (1)-2 of the present invention, a compound of the above formula (1)-1 in an organic solvent in the presence of n-)butyltin hydride and azobisisobutylnitrile. Advantageously, the reaction is carried out under an inert atmosphere, such as nitrogen gas. Although the treatment temperature depends on the organic solvent used, a range of about 0°C to about 150°C is adopted for boat fishing. Although the treatment time can be selected as appropriate, a range of about 2 to about 3 hours is usually selected. The amount of n-)butyltin hydride used in this reaction is preferably in the range of about 2 to about 5 moles per mole of the compound of formula (1)-1. The preferred amount of azobisisobutylnitrile used is, for example, about 175 to about 1,750 moles per mole of the compound of formula (1)-1. Various organic solvents can be used, but preferred examples include toluene and xylene. There are no particular restrictions on the amount of these solvents to be used, and an appropriate range may be selected; for example, a range of about 10 to about 200 times the weight of the compound of formula (1)-1 is exemplified. After completion of the reaction, the reaction product is purified by means such as column chromatography or by means such as recrystallization to obtain the compound of formula (1)-2 of the present invention with good purity and good yield. It will be done.

The compound of formula (1)-2 produced as described above can be converted into 3'-azido-3'-deoxythymidine, which can be used as a therapeutic agent for AIDS, for example, as shown in the reaction formula below. can do.

(X) (Y)(z)(A) The method for producing the compound of formula (A) will be explained below according to the above reaction formula.

First, in order to produce a compound of formula (X) from a compound of formula (1)-2, the compound of formula (1)-2 is hydrolyzed with an acid such as hydrochloric acid to produce a compound of formula (X). The trityl derivative of formula (Y) is synthesized by reacting the compound of formula (Y) with trityl chloride. Then, the compound of linear formula (Y) is mesylated with mesyl chloride,
Next, it is azidated with sodium azide to give a compound of formula (Z). Furthermore, by treating the compound of the linear formula (Z) with an acid such as hydrochloric acid to cause a detritylation reaction, the compound of the formula (A
) can be synthesized.

(Example) The method for producing the compound of formula (1) of the present invention will be described below with reference to Examples.

Example 1 Tri-acetylxylosylthymine [formula (4)% formula%
()] 8.4 g of tetra7-cetyl xylofuranose in a flask
(30 mmol), 8.7 g (32 mmol) of bis(trimethylsilyl)thymine, and 249 ml of 1°2-dichloroethane, and dissolved with stirring.
A solution prepared by dissolving 3.7 ml (31 mmol) of anhydrous tin chloride in 30 ml of 1,2-dichloroethane was added dropwise to the mixture, and the mixture was reacted at 22° C. for 6 hours. After the reaction was completed, 300 ml of chloroform was added to the reaction solution, washed with a saturated aqueous sodium carbonate solution, and the filtrate was dried over sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform: methanol = 100:1).
) to obtain 10.0 g of the title compound. Yield: 99%.

Example 2 1-β-D-xylofuranosylthymine [formula (3)% formula%
()] A flask was charged with 1.38 g (3,59 mmol) of tri-acetylxylosylthymine of formula (4) and 50 ml of absolute ethanol, and after dissolving, a catalytic amount of metallic sodium pieces was added and the mixture was stirred for 1 hour. After the completion of the reaction, neutralize with ion exchange resin (amberlitlR-120), filter, concentrate the filtrate, add ethyl alcohol:ether (1:1) to the concentrate, perform recrystallization, and obtain the title. 0.19g of the compound was obtained.

Yield: 98%, '# & point: 159.0°C OH) Example 3 1-(3', 5'-0-isopropylidene-β-
Synthesis of D-xylofuranosyl)thymine [Formula (2)] [Step (C) 0.19 g (3,53 mmol) of 1-β-D-xylofuranosylthymine of formula (3) and 50 g of acetone were added to a coffin flask.
m1 and p-') luenesulfonic acid 260 mg
After the reaction was completed, the mixture was stirred at room temperature for 2 hours, neutralized with 0.44 g of barium hydroxide, filtered, and concentrated. 8
The condensed solution I was dissolved in chloroform, and ether was further added to obtain 0.98 g of the title compound in the form of crystals.

Yield: 93%, melting point: 173.1°C [α几2=-27.88°(C=0.33, CHCl3
).

Example 4 l-(2'-0-phenoxythiocarbonyl-β-D-
xylofuranosyl) thymine [formula (1) - 11% formula % (] 1- (3', 5'-〇-isopropylidene-β-D-xylofuranosyl) thymine formula (2) 10
0 mg (0.34 mmol) in anhydrous acetonitrile 1
After the completion of the reaction, 64 mg (0.37 mmol) of phenyl chlorothionocarbonate and 84 mg (0.69 mmol) of 4-dimethylaminopyridine were added with stirring, and the mixture was stirred at room temperature for 2 hours. Partition extraction was carried out with 10 ml of ethyl acetate and 10 ml of water, and the organic layer was sufficiently cooled and washed successively with cold 1-NH4C1/H20, saturated aqueous sodium carbonate solution, and saturated aqueous sodium chloride solution.

Sodium sulfate was added and the mixture was allowed to stand overnight, filtered and concentrated to yield 125 mg of the title compound.

Yield; 85.9% [α]"2=+3.0' (C=0.3 CHCl3
) Example 5 l-(2'-deoxy-3',5'-0-isopropylidene-β-D-xylofuranosyl)thymine [formula (% formula% 1 of formula (1)-1 dried under reduced pressure in a desiccator) -(2'
-0-phenoxythiocarbonyl-3,5-〇-isopropylidene-β-D-xylofuranosyl)thymine 125
11 mg (0.07 mmol) of azobisisobunalnitrile and 29 mg (1.0 mmol) of n-)butyltin hydride.
mmol) was added. 75℃ under nitrogen gas flow for 20 minutes
The mixture was heated to reflux. After the reaction was completed, it was concentrated, and the syrup was purified by silica gel column chromatography (chloroform: ethyl acetate = 1:1). Ethyl acetate: ether = 1:1 was added to the concentrated collected fraction, and -i was left. The title compound in crystalline form was heated to 70 m
I got g.

Yield: 91%, melting point: 168.5°C [α]', 3=+18.09 (C=0.52, C)
(C (Effect of the invention)) The present invention provides 3'-
The object of the present invention is to provide a thymine derivative represented by a novel compound that has not been described in conventional literature and is useful as an intermediate for the synthesis of azido-3'-deoxythymidine.

Conventionally, in the method for producing 3'-azido-3'-deoxythymidine, 3'-azido-3'-deoxythymidine has become extremely expensive because thymidine, which is difficult to handle and expensive, is used as a starting material. Ta. However, according to the present invention, by using the compound of formula (1) as a synthetic intermediate, the compound of linear formula (A) can be produced at low cost.

1 other person

Claims (1)

[Claims] Thymine represented by the following formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) In the formula, R is a hydrogen atom or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ derivative.