JPS5982396A - N3,5-dilithio-5,6-dihydrouracil nucleoside - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is a saccharide residue having a protecting group). EXAMPLE:The compound of formula II. USE:A synthetic intermediate for 5-substituted uracil uncleosides. PROCESS:A 5,6-dihydrouracil uncleoside of formula III is reacted with a lithiating agent, e.g. lithium diisopropylamide, in a reaction solvent, e.g. tetrahydrofuran, under anhydrous conditions at -78-0 deg.C for several tens of minutes - several hours.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel and useful synthetic intermediate, N8゜5-
This invention relates to dilithio-5,6-sihydrouracil nucleoside and its production method.

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 poor in practicality from a manufacturing standpoint.

The present inventors previously studied the lithium theta conversion of uridine derivatives, and converted 2',8'-1-isopropylidene 5'--methoxymethyl uridine into lithium diisopropylamide (LDA). When the reaction starts,
It was found that the C-6 position was regioselectively lithiated, resulting in a monodilithio form at N3,6 (Hu4icA).
cids3ymposition3eriesNa8.
88 (1980)) and by reacting the N8,6-dilithio form with various electrophilic reagents, C-
We succeeded in introducing various substituents into the 6-position via a carbon-carbon bond (Nuckic, 4cids 3y
mposium 3eries N(110,1(19
81)).

The present invention was completed with the object of providing a synthetic intermediate capable of selectively introducing various substituents into the C-5 position of uracil nucleoside via a carbon-carbon bond.

That is, the present inventors lithiated 5,6-dihydrouranyl nucleoside obtained by catalytic reduction of uracil nucleoside using a reduction catalyst such as rhodium/alumina using a lithiation agent, and removed the lithium. The reaction product is reacted with an acid halide as an electrophilic reagent, and the 5-6 bond is further converted into phenylselenenyl chloride-
It has been found that 5-anluuracil nucleoside can be selectively obtained by unsaturation with pyridine. Therefore, from the chemical reaction point of view, the lithium compound of 5,6-dihydrouranyl nucleoside is N3゜5-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, resulting in 5-substituted uracil nucleoside. It was found to be extremely useful as an intermediate in the synthesis of nucleosides.

N8,5-dilithio-5,6-sihydrouracil nucleoside, which is a compound of the present invention, has the following general formula % Formula % In the formula, R represents a sugar residue having a protecting group. Specific examples of sugar residues include furanosyl groups, such as β-D-ribofuranonor group, β-D-2-deoquine ribofuranonol group, and β-D-ribofuranonor group.
-1) Examples include -8-deoxoliphofuranosyl group and β-D-arabinofuranosyl group. The protecting group for the sugar residue may be selected as appropriate depending on the position of the sugar hydroxyl group that requires protection, depending on the nucleoside chemical number.

Specifically, those that can be easily eliminated by acid treatment are preferred, such as alkoxyalkyl groups such as methoxymethyl groups and ethoxyethyl groups, aralkyl groups such as tridel groups and benzyl groups, and sugar residues. When the group is a β-D-ribofuranosyl group, for the simultaneous protection of the 2'- and 8'-position hydroxyl groups, the alkylated compound of the present invention with an inpropylidene group or an ethylidene group can be 5,6-sihydrouracil. It can be prepared by reacting screoside with a rhidium-forming agent.

The compound 5,6-dihi]-lourasol nucleondo of Gen 14 is represented by the following general formula (III).

In the formula, R corresponds to that of the target compound of the present invention. This raw material compound is rukotocatekyl (Ritoeva 1.r, □heIq, 3oc(1,970) 244), which is produced by a known method such as the method of catalytic reduction of uracil nucleoside using rhodium/alumina as a reduction catalyst.
(see 4).

Lidium forming agents used in the lithiation reaction include LDA, n-butyllithium, phenyllithium,
Examples include lithium-n-propino+/amide and tetramethylpiperidinyllithium. The reaction is generally carried out in an ether solvent, and examples of the reaction solvent include tetrahydrofuran, dioxane, diethyl ether, dimethoquinoethane, and diethyl glycol dimethyl ether.A tertiary amine such as ethylenediamine may also be present in the solvent. Ru. Reaction conditions and 1. In this case, low temperature conditions of -78 to 0°C are set under anhydrous conditions to prevent side reactions. The reaction is completed in several tens of minutes to several hours.

Since the compound of the present invention is unstable, it is directly subjected to the next reaction without being isolated from the synthesis reaction solution.

The reaction step for obtaining the 5-substituted uracil nucleond includes: (1) a substitution reaction between the lithium atom at the -5 position and an electrophilic reagent, and (2) an unsubstituted bond between the carbon atoms at the C-5 and 6 positions on the compound of the present invention. Carry out a saturation reaction] It consists of two steps.

Examples of electrophilic reagents used in the C-5 substitution reaction include acid halides, aldehydes, formic acid esters, ketones, epoxides, and 710 saponified alkyls. The reaction is carried out by adding an electrophilic reagent to a reaction solution for synthesizing the compound of the present invention. 0 °C in the presence of C-5 and 6-position pyridine complex
~ React at room temperature for more than ten hours to form phenylselenenylation,
After distilling off the pyridine, at 00C in dichloromethane,
% hydrogen peroxide to oxidatively eliminate the phenylselenenyl group. Further, depending on the type of electrophilic reagent such as /S halogenated alkyl, a method of oxidative elimination of the ru group is adopted.

Examples of the synthesis of the compounds of the present invention and their applied reactions will be shown below.

Example J, D A 11. Tetrahydrofradi-5,6-hydrouridine containing 65 nnnnoll 1.5
A solution in which 49 (4,66+nmol) was dissolved was added to the dry alcon cass under pressure while not exceeding -70°C, and reacted with stirring for 1 hour.

(=Preparation of the compound of the present invention) In the following, for the purpose of proving the production of the compound of the present invention, the reaction of the compound of the present invention with an acid halide using an electrophilic-r-reagent, and the reaction of the compound at the C5-6 position will be described. A saturation reaction was performed to obtain various acyl-substituted uridines.

That is, -709C is added to the reaction solution for synthesis of the compound of the present invention.
Penn Soil Chloride while maintaining the temperature below],,
Add 09 ml (9,82rnmol@l) to a small amount
1 dropwise and allowed to react for 1 hour. The reaction was stopped with acetic acid, and after returning to room temperature, it was concentrated to dryness, and the residue was applied to a silica gel column. 1% ethane
The eluate was eluted with a dichloroform solution, and the eluate was concentrated to obtain 5.6-7hydrouridine 1.61'/(yield 796%).

Quality rJ' analysis spectrum: M+ mlz: 43
Dissolve 0.269 of 4 phenyl selenenyl chloride in 25 ml of dichloromethane, cool to 0°C, and add Bi'J
A phenylselenenyl chloride-pyridine complex was prepared by adding 0.12 g of Schiff.

5-benzoyl-2',8'-11-impropyritino 5'--methoxymedyl-5,6-cyhydrourin 510 m (/ of dichloromethane 7 vtt solution to 0
The reaction mixture was added to the above complex 25 at 0° C. and stirred overnight. The reaction solution was concentrated to dryness, the bidine was completely removed by azeotroping with ethanol, and the residue was dissolved in dichloromethane 10 FIt. Cool to 0.1 m of 30% hydrogen peroxide.
1 was added and stirred at 0°C for 1 hour. Further, 0.1 ml of 30% hydrogen peroxide was added, and stirring was continued at 0°C for 1 hour. 10 tnf of water was added to the reaction solution, and the organic solvent layer was separated, dried over sodium sulfate, filtered, and concentrated to dryness.

Separation and purification by gel chromatography (eluent = 1% ethanol-chloroform solution) yielded 5-hensoyl-2',3'Q-11-impropylidene-5'-1-methoxy. 456 mg (yield: 897%) of methyluridine was obtained.

Mass spectrometry spectrum: M+1 +n/z +
488PMR spectrum δ8.89 S H-6
5-pensoyl-2', 8'-1-inpropylideno-5'-1-meI-xymethyluridine 860 mg
8 ml of 50% trifluoroacetic acid aqueous solution was added to the mixture, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated to dryness, and the residue was separated by silica gel column chromatography (eluent: 5% ethanol-chloroform solution) to obtain 246 mg of 5-benzoyl uridine (yield: 84.3%).

Melting point 210-211°C Elemental analysis calculated value C, 55,17H, 4,68N, 8.04 Actual value C, 55,28H, 4,68N, 7.85PM
R spectrum: (D20. DSS) δ5, 98
H-1' 8.52 H-6 745-7.79 Phenyl The reaction route of this example is illustrated as follows. Note that R represents a phenyl group.

(1a) (2a) (8a) The results of reacting various acid nitrides with the compounds of the present invention in place of benzoyl chloride are shown in the following table.

The production of these 5-anyl-substituted urinones confirms the production and usefulness of the compounds of the present invention.

Claims (1)

[Claims] 1) General formula (1) In formula 1, R represents a sugar residue having a protecting group. ] N3,5-dilithio-5,6-sihydrouracil nucleoside. 2) General formula (II) ○ [In the formula, R does not represent a sugar residue having a protecting group. , ] is reacted with a rhidium-forming agent to form N3,5-dilithio represented by the general formula [1] (wherein R has the same meaning as above. -5,
A method for producing N8゜5-dilithio-5,6-sihydrouracil nucleoside, which is characterized in that 6-sihydrouracil nucleoside is obtained.