JPS5928558B2 - Method for producing carbon nucleoside derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing nucleoside derivatives.

More specifically, the present invention relates to the following general formula R1-C
-NC=511(1) (herein, R1 represents a group of the following formula OAOAOAOA 5III1 AOCH2-CH-CH-CH-CH-CH, and A represents an acetyl group as a protecting group for a hydroxyl group). A sugar acid compound having a nato group has the following general formula (wherein
A diamino compound represented by the following general formula (wherein R1, R2 and R3 have the same meanings as above), characterized by reacting a diamino compound represented by C-N-C-N- (representing C-N-C-N-) The present invention relates to a method for producing nucleoside derivatives.

The present inventors have conventionally conducted research on the synthesis of various nucleosides. The present invention was completed based on the discovery that a nucleoside compound represented by the formula () can be obtained in one step by reacting a diamino compound having the following.

The method of the present invention involves combining the compound of formula (1) and the compound of formula () under anhydrous conditions, such as hydrocarbons such as benzene, toluene, xylene or a mixed solvent thereof, ethers such as tetrahydrofuran, and acids such as dimethylacetamide. It is preferable to carry out the reaction by dissolving the amide in a solvent.

When the compound of formula (1) or formula () is difficult to dissolve in the above solvent, dimethylformamide, diethylamine, triethylamine, piperidine, morpholine pyridine, quinoline, or other secondary or tertiary amine is added to the compound in the presence of these. It is also possible to cause a reaction to occur. Raw material compounds used (
It is sufficient to carry out a dehydration condensation reaction between 1) and the reactant compound () in equimolar amounts, and the reaction temperature is suitably 50 to 150°C.

Refluxing is usually carried out on a water bath, with heating or on an oil bath. The reaction time varies depending on the substance to be reacted, but may take from 10 minutes to 2 days. Thin layer chromatography is suitably used to determine the end point of the reaction. The sugar acid isothiocyanate compound represented by the general formula (1) in It can be a sugar acid compound having an isothiocyanate group, including isothiocyanate derivatives of pyranosyl type or furanosyl type or chain type compounds of sugar acids corresponding to sugars.

In this method, this sugar acid compound is used in the form of a protected form in which the hydroxyl group is protected with an acetyl group. The present inventors named the isothiocyanate compound represented by the general formula (1) a carbon nucleoside synthesis reagent. It is desirable to store this synthetic reagent in a cool, dark place. These carbon nucleoside reaction reagents, that is, the compounds of the general formula (), are all new compounds. It can be prepared by chlorinating with silver thiocyanate and then reacting with silver thiocyanate. Further, as the diamino compound represented by the general formula (), 4...5-diaminopyrimidine, 4,5-diamino-2,6-mercaptopyrimidine, 5,6-diamino-2-mercaptopyrimidine,
Examples include 5,6-diamino-1,3-dimethyluracil.

After the reaction is completed, recrystallization is performed using an organic solvent such as methanol or ethanol to obtain a purified product. The acetyl group protecting the hydroxyl moiety of the sugar of the compound represented by the general formula () can be removed by a conventional method if necessary after the completion of this method. The nucleoside compounds represented by the general formula () obtained in this way are all new substances that have not been described in literature, and exhibit pharmacological activities such as antibacterial, antiviral, and psychotropic effects, and are useful as pharmaceuticals. .

Next, the desired product obtained by the present invention ( ) * However, in the above table, the RaCO group is represented by the following formula As shown in Table 1 below.

(In the formula, Ac is an acetyl group) 2, 3, 4.5,
6-bender 0-acetyl-D-gluconyl group.

Next, the present invention will be illustrated by examples, but the present invention is not limited thereto.

Example 1 4-5-diaminopyrimidine and 2,3,4,5,-6-
Reaction with bender 0-acetyl-D-gluconyl isothiocyanate in 10 ml of anhydrous tetrahydrofuran.
450 m9 of 3,4,5,6-bender 0-acetyl-D-gluconyl isothiocyanate and 4,5-diamino-pyrimidine 110Tn9 (0.001 mol) were added and heated under reflux on a water bath for 5 hours.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developed with benzene-acetone) to give the colorless needle crystals shown in the table above from a benzene-acetone (85:15) fraction. The desired product shown in 1 was obtained. Mp. l39-140° (uncorrected), yield 400Tf1f7 (75%), engineering R: νKBr (
CTfL-1):3350(-NH)Maxl74O(
ester).

Example 2 4,5-diamino-2-6-mercaptopyrimidine and 2,3,4,5,6-bender 0-acetyl-D
450 m9 (0.001 mol) of 2,3,4,5,6-bender 0-acetyl-D-gluconyl isothiocyanate and 4-5-diamino in 5 mi of dimethylacetamide. -2/6-dimercaptopyrimidine 174m
9 (0.001 mol) and 1 on a water bath (604).
．． Heated for 5 hours.

Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developed with chloroform-acetone) in the same manner as in Example 1.
The product shown in Table 1 above was obtained as colorless needles from a fraction of 0:30). Recrystallized from benzene.
Mp. l2O-121be (uncorrected), yield 492~(8
2%). IR: νKBr((IV7l-1); 3350
, 3200max (-NH) 1740 (ester) 16
30) 1540) Elemental analysis value: C2lH2OlON5
S3 theoretical value C4l. 79H4. l7Nll. 6O% measurement value C4l. 57H4. O8Nll. 42% example
35,6-diamino-2-mercaptopyrimidine and 2.
Reaction with 3,4,5,6-bender O-acetyl-D-gluconyl isothiocyanate 2,3,4-5,6-bender O-acetyl-D-gluconyl isothiocyanate in 10 ml of anhydrous tetrahydrofuran 45
0 to (0.001 mol) and 5,6-diamino-2-
Mercaptopyrimidine 142mf7 (0.001 mol) was added thereto, and the mixture was heated under reflux on a water bath for 3 hours.

Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography in the same manner as in Example 1. The desired products shown in Table 1 were obtained. Yield 485~(85
%). IR: νKBr(儂-1); 3350, 3200
max(-NH) 1740 (ester).

Elemental analysis value: C2lH27OlON5S2 theoretical value C4
4. l3H4.4lNl2.25% Measured value C44. O
4H4.38Nl2.28% Example 45,6-diamino-1,3-dimethyluracil and 2,3,4,5,6
- Bender O - Reaction with acetyl-D-gluconyl isothiocyanate in 10 ml of anhydrous benzene 2.3.
4.5.6-penta-1 O-acetyl-D-gluconyl isothiocyanate 450-(0.001 mol) and 5.6
-diamino-1.3-dimethyluracil 170~(
0.001 mol) and heated under reflux on a water bath for 24 hours.

Claims (1)

[Claims] 1. The following general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (here R
_1 represents the group of the following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and A represents an acetyl group as a protecting group for the hydroxyl group), and the following general formula is added to the sugar oxide having an isothiocyanate group. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼
(II) (Here, R_2 and R_3 are combined to form one group -N=CH-N=CH-, group ▲ mathematical formula, chemical formula, table, etc. ▼, group ▲ mathematical formula, chemical formula, There are tables, etc. ▼, or the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
III) A method for producing a nucleoside derivative represented by (herein, R_1, R_2 and R_3 have the same meanings as above).