JPH0368879B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-substituted uracil nucleosides. Lithiation of organic compounds has become recognized as an important means for carbon-carbon bond forming reactions. However, in the field of nucleoside chemistry, there are not many examples of applications of this lithiation reaction. This is related to the fact that the results reported so far have been impractical from a manufacturing standpoint. The present inventors previously studied the lithiation of uridine derivatives and found that when 2',3'-O-isopropylidene-5'-O-methoxymethyl uridine was reacted with lithium diisopropylamide (LDA),
The C-6 position is regioselectively lithiated, and N ³ ,
It was found that the 6-dilithio form was obtained (Nucleic Acids Symposium Series No. 8, 33
(1980)). By reacting the N ^3,6 -dilithio form with various electrophilic reagents, we succeeded in introducing various substituents at the C-6 position via a carbon-carbon bond (Nucleic Acids Symposium).
Series No. 10, 1 (1981)). The present invention was completed with the object of providing a method capable of regioselectively introducing various substituents into the C-5 position of uracil nucleoside via a carbon-carbon bond. That is, the present inventors lithiated 5,6-dihydrouracil nucleoside obtained by catalytic reduction of uracil nucleoside using a reduction catalyst such as rhodium/alumina using a lithiation agent, and the lithiated product was It has been found that 5-acyluracil nucleoside can be selectively obtained by reacting with an acid halide as an electronic reagent and further unsaturating the 5-6 bond with phenylselenenyl chloride-pyridine. Therefore, from the chemical reaction point of view, the lithiated product of 5,6-dihydrouracil nucleoside is N ³ ,5-
It was identified as dilithio-5,6-dihydrouracil nucleoside, which can be easily substituted at the C-5 position via a carbon-carbon bond by reaction with various electrophilic reagents. It was found to be extremely useful as a raw material compound for uracil nucleoside. Raw material compound N ³ ,5-dilithio-5,6
-Dihydrouracil nucleoside is represented by the following general formula []. In this formula, R represents a sugar residue having a protecting group. Specific examples of sugar residues include furanosyl groups, such as β
-D-ribofuranosyl group, β-D-2-deoxyribofuranosyl group, β-D-3-deoxyribofuranosyl group, β-D-arabinofuranosyl group and the like. As the protecting group for sugar residues, those applicable in nucleoside chemistry may be appropriately selected depending on the position of the sugar hydroxyl group that requires protection. Specifically, those that can be easily eliminated by acid treatment are preferred, such as methoxymethyl groups,
Alkoxyalkyl groups such as ethoxyethyl groups,
For simultaneous protection of aralkyl groups such as trityl group and benzyl group, and when the sugar residue is β-D-ribofuranosyl group, alkylidene groups such as isopropylidene group and ethylidene group are used for simultaneous protection of hydroxyl groups at the 2′ and 3′ positions. Examples include alkoxyalkylidene groups such as methoxymethylene groups, ethoxymethylene groups, and ethoxyethylene groups. The raw material compound can be prepared by reacting 5,6-dihydrouracil nucleoside with a lithiation agent. 5,6-dihydrouracil nucleoside is represented by the following formula. In the formula, R corresponds to that of the desired starting compound. This compound can be produced by a known method such as a method of catalytic reduction of uracil nucleoside using rhodium/alumina as a reduction catalyst (for example, J. Chem. Soc. (1970)).
2444). The lithiation agents used in the lithiation reaction include LDA, n-butyllithium, phenyllithium, lithium-n-propylamide,
Examples include tetramethylpiperidinyllithium. The reaction is usually carried out in an ether solvent, and examples of the reaction solvent include tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diethylene glycol dimethyl ether, and the like. Tertiary amines such as triethylamine, N,N,N',N'-tetramethylethylenediamine can also be present in the solvent to enhance the nucleophilicity of the lithiation agent. The reaction conditions are anhydrous conditions and low temperature conditions of -78 to 0°C to prevent side reactions. The reaction is completed in several tens of minutes to several hours. Since the raw material compound thus obtained is unstable, it is directly subjected to the following reaction without being isolated from the synthesis reaction solution. The reaction step for obtaining 5-substituted uracil nucleoside involves a substitution reaction of the C-5 lithium atom with an electrophilic reagent, and a C-
It consists of a step of performing a desaturation reaction of the bond between carbon atoms at the 5th and 6th positions. Electrophilic reagents used in the C-5 substitution reaction include acid halides, aldehydes, formate esters, ketones,
It may be selected from disulfides and alkyl halides. The reaction is carried out by adding an electrophilic reagent to the synthesis reaction solution of the raw material compound (Nucleic Acids Research
Symposium Series No. 10 1-4 (1981)) The unsaturation reaction of the bond between carbon atoms at the C-5 and 6 positions is the thermal decomposition reaction of selenoxide ("New Experimental Chemistry Course 14, Synthesis and Reactions of Organic Compounds"). )” page 151~
This can be done by applying the method (see page 154, published by Maruzen Co., Ltd. in 1978). Specifically, in the presence of a phenylselenenyl chloride-pyridine complex in a solvent such as dichloromethane, it is reacted at 0°C to room temperature for more than ten hours to form phenylselenenylation, and after distilling off the pyridine, it is converted into phenylselenenyl in dichloromethane. 30 at 0℃
% hydrogen peroxide to oxidatively eliminate the phenylselenenyl group. Also,
Depending on the type of electrophilic reagent such as an alkyl halide, the C-5 position may be phenylselenenylated, followed by a substitution reaction of the electrophilic reagent, and then the phenylselenenyl group is oxidatively eliminated. Adopt a method that allows Example: To 15 ml of a tetrahydrofuran solution containing 11.65 mmol of LDA, add 2′,3′-O to 18 ml of tetrahydrofuran.
-isopropylidene-5'-O-methoxymethyl-
A solution containing 1.54 g (4.66 mmol) of 5,6-dihydrouridine was heated under dry argon gas pressure.
The mixture was added while not exceeding 70°C, and the reaction was allowed to proceed for 1 hour with stirring. (=Preparation of raw material compound) Add 1.09 ml of benzoyl chloride to the synthesis reaction solution of this raw material compound while keeping the temperature below -70℃.
(9.32 mmol) was added dropwise little by little and reacted for 1 hour. After stopping the reaction with acetic acid and returning the temperature to room temperature, the mixture was concentrated to dryness and the residue was subjected to silica gel column chromatography. Elute with 1% ethanol-chloroform solution, and concentrate the eluate to dryness to give 5-benzoyl-2',3'-O-isopropylidene-5'-O-
Methoxymethyl-5,6-dihydrouridine
1.61g (yield 79.6%) was obtained. Mass spectrometry spectrum: M ⁺ m/z: 434 0.26 g of phenylselenenyl chloride was dissolved in 25 ml of dichloromethane, cooled to 0° C., and 0.12 g of pyridine was added to prepare a phenylselenenyl chloride-pyridine complex. A solution of 510 mg of 5-benzoyl-2',3'-O-isopropylidene-5'-O-methoxymethyl-5,6-dihydrouridine in 7 ml of dichloromethane was heated at 0°C.
The mixture was added to 25 ml of the above complex and stirred overnight. The reaction solution was concentrated to dryness, pyridine was completely removed by azeotroping with ethanol, and the residue was dissolved in dichloromethane.
Dissolve in 10ml, cool to 7℃, and add 30% hydrogen peroxide.
0.1 ml was added and stirred at 0°C for 1 hour. 30 more
% hydrogen peroxide was added and stirring was continued for 1 hour at 0°C. 10 ml of water was added to the reaction solution, and the organic solvent layer was separated, dried over sodium sulfate, filtered, and concentrated to dryness. 5-benzoyl-2',3'-O-isopropylidene-5'-O-methoxymethyluridine was separated and purified by silica gel column chromatography (eluent: 1% ethanol chloroform solution).
456 mg (yield 89.7%) was obtained. Mass spectrometry spectrum: M + 1m/z: 433 PMR spectrum: δ8.39sH-6 5-benzoyl-2',3'-O-isopropylidene-5'-O-methoxymethyluridine 360mg
Add 8 ml of % trifluoroacetic acid aqueous solution and stir at room temperature.
The mixture was stirred for several days. The reaction solution was concentrated to dryness, and the residue was subjected to silica gel column chromatography (eluent: 5%
Separate with ethanol-chloroform solution) and 5-
245 mg (yield 84.3%) of benzoyl uridine was obtained. Melting point 210-211℃ Elemental analysis Calculated value C, 15.17 H, 4.63 N, 8.04 Actual value C, 55.23 H, 4.63 N, 7.85 PMR spectrum: (D ₂ O, DSS) δ 5.93 H-1' 8.52 H-6 7.45 ~7.79 Phenyl The reaction route of the above example is illustrated as follows. Note that R represents a phenyl group. The results of reacting various acid halides with the compounds of the present invention in place of benzoyl chloride are shown in the following table. 【table】

Claims (1)

[Scope of Claims] 1. A method for producing 5-substituted uracil nucleosides, which comprises the general formula () as a raw material compound. (In the formula, R represents a furanosyl group having a protecting group.) Using N ³ ,5-dilithio-5,6-dihydrouracil nucleoside, the compound can be added to acid halides, aldehydes, formate esters, ketones, etc. , a substitution reaction to react with an electrophilic reagent selected from disulfides and alkyl halides, and a thermal decomposition reaction of selenoxide to unsaturate the bonds between the carbon atoms at the 5- and 6-positions of the base moiety,
If necessary, the protecting group of the furanosyl group is removed and 5
- A method for producing a 5-substituted uracil nucleoside, characterized by obtaining a substituted uracil nucleoside.