JPS5943550B2 - Process for producing unsaturated nucleosides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is represented by the general formula R'U(I) (where B represents a nucleobase, and R1 represents a hydroxyl group, an acyloxy group, or an azido group).

) relates to a method for producing a 2', 3' monounsaturated nucleoside compound.

5 Conventionally, as a method for producing 2', 3' monounsaturated nucleoside compounds, for example, 2'-deoxy-3'-0
- Mesyl (or monotosyl) - 3' from nucleosides
A method in which the 0-mesyl group (or tosyl group) at the position is removed by alkali treatment to produce a 3',5'-oxetane derivative 0 conductor, and then this is reacted with an alkali reagent [J, Org.
, Chem, , U, 205 (1966) ■ J, A, C,
S,, ± and, 1549 (1966)], 2', 3'-
A method for causing zinc to act on G-O-mesyl ribonucleoside [J, Org, Chem, 1, 12835 (1
973)], a method of reacting an alkyl phosphite with a nucleoside 2', 3'-0 monothionocarbonate (
Special Publication No. 45-40531), 2'-0-acetyl
3'-deoxy-3'-halogeno nucleoside is treated with chromas acetate [J, Org
, Chem, Chu, 30 (1974)], etc. are known.

However, these methods are not satisfactory as industrial production methods because they have drawbacks such as difficulty in synthesis of starting materials and preparation of reagents and low yields of the target compound. 15 As a result of various studies, the present inventors have found that the nucleoside derivative represented by the following general formula [■], which is easily derived from inexpensive ribonucleosides, is used as a starting material, and by simple reaction operations such as electrolytic reduction. It has been found that the 2',3' monounsaturated nucleoside compound represented by the above general formula can be produced in high yield.

That is, according to the present invention, the target compound pile has the general formula (wherein B and R have the same meanings as above, and R2
and R3 are both halogen atoms, or one of them is a halogen atom and the other is an acyloxy group.

) can be produced by electrolytically reducing the nucleoside derivatives shown.

In the present invention, a preferable example of the raw material compound is the symbol R
The group represented by 1 is, for example, an acetyloxy group, a propionyloxy group, a butyryloxy group, a benzoyloxy group,
an aliphatic or aromatic acyloxy group such as a phenylacetyloxy group, a hydroxyl group, an azide group, etc., and the groups or atoms represented by the symbols R2 and R3 are both halogen atoms such as bromine and chromium, or the symbols R2 and Either one of R3 is the above halogen atom, the other is an aliphatic or aromatic acyloxy group similar to the above symbol R1, and the nucleobase represented by symbol B is, for example, uracil, thymine, cytosine, methylcytosine, etc. Nutaleoside derivatives such as pyrimidine bases and purine bases such as adenine and guanine can be mentioned.

These raw materials have two stereoisomers, cis and trans, depending on the coordination of the halogen atom at the 27,3' position and the acyloxy group, but the method of the present invention can be used to detect either isomer. Similarly, it is possible to guide the target compound to the corresponding target compound pile. The electrolytic reduction reaction of the present invention is preferably carried out using an ordinary electrolytic reaction apparatus in which cathode and cathode chambers are separated by a porous membrane such as an unglazed or glass filter. For example, mercury,
Lead, nickel, carbon plates, platinum, etc., and as the anode, for example, carbon rods, platinum, etc. can be suitably used.

Polar solvents are suitable as the electrolytic solvent, and examples of such solvents include methanol, acetonitrile, dioxane, dimethylformamide, and mixed solvents of these and water. In addition, in this electrolytic reaction, the electrolytic solvent may be a tetraalkylammonium salt such as tetraethylammonium chloride or tetrabutylammonium bromide, a chlorate such as potassium chlorate or sodium chlorate, or a lower fatty acid salt such as potassium acetate or sodium acetate. A supporting electrolyte such as sodium chloride, hydrochloric acid, etc. may be present. This electrolytic reduction reaction using the electrolytic apparatus as described above can be suitably carried out by charging the raw material compound into the catholyte and applying electricity while keeping the cathode potential constant. The reaction proceeds suitably at -30 to 50°C, particularly around 0 to 30°C, in a stream of inert gas such as nitrogen gas. The target compound mountain thus generated can be easily isolated by conventional purification operations such as recrystallization extraction from the residue obtained by distilling off the solvent from the catholyte.

The target compounds of the present invention are not only useful compounds having antitumor and antiviral effects, but also important compounds as intermediates for the synthesis of nucleoside pharmaceutical compounds.

Example 1 Tetrabutylammonium bromide 400 was added as a catholyte to a glass electrolytic cell with an inner diameter of 5CTIL equipped with a mercury cathode.
Add 30me of dimethylformamide solution containing mq.

A glass cylinder with an inner diameter of 2.5cm and a glass filter at the bottom was placed perpendicularly to the mercury cathode as a passive anode chamber.
It was fixed so that the distance between its bottom and the mercury surface was 0.5 cm. A platinum wire was used as the anode, and the anolyte had the same supporting electrolyte-solvent composition as the catholyte, and the liquid height was the same as that of the catholyte. A calomel electrode (S.C.E.) was used as the reference electrode, fixed so that the salt bridge part was located one corner above the mercury surface, and the voltage was 1.0A-55V.
connected to a potentiostat. The cathode potential is -1.4
5V vs S. C. E. 15 under nitrogen gas flow.
9-(2',57-di-0-acetyl-3 at ~25°C
420 m9 of 7-bromo-3'-deoxy-β-D-xylofuranosyl)-adenine are slowly added to the catholyte. The current value during that time was 0.4 to 0.5A. After the reaction is completed, the catholyte is neutralized with a small amount of acetic acid, and the solvent is distilled off under reduced pressure. 40 Tne. of ethyl acetate was added to the residue. Add and leave in the refrigerator overnight. The precipitated white crystals are removed from the mouth and the oral fluid is concentrated. The resulting residue was subjected to silica gel column chromatography (developing solvent: chloroformrimethanol = 85:15
), 9-(5'0-acetyl-27,37-dideoxy-β-D glyceropento-2'-enofuranosyl)adenine 214W! was obtained as white crystals. F7
get. Yield 7J MoV00mp. 74-76℃ (Dec)
When this product is recrystallized from isopropanol, the Mp. 83
The result is colorless needle crystals (containing 1 molecule of isopropanol as a crystal solvent) at ~85°C (Dec).

Example 2 In Example 1, instead of the dimethylformamide solution containing tetrabutylammonium bromide as the catholyte, 40 d of methanol solution containing 820 ml of anhydrous sodium acetate was used as the catholyte; 40 d of methanol solution containing 570 ml of concentrated hydrochloric acid was used as the anolyte. using a cathode potential of -1.3V vs. S
．． C. 9-15℃ at 10-15℃ under nitrogen gas flow.
(27,51-di-10-acetyl-3'-bromo-3'
-deoxy-β-D-xylofuranosyl)adenine 82
8mv electrolytic reduction was performed.

After the electrolytic reduction reaction is completed, the catholyte is concentrated and the resulting residue is extracted using hot ethyl acetate (50d). After drying the extract, the solvent was distilled off and the resulting residue was recrystallized with isopropanol to give 9-(57-0
-acetyl 2/,37-dideoxy-β-D-glyceropent-27-enofuranosyl)adenine (contains one molecule of isopropanol as crystallization solvent) 483T
Get 1ff. The physical and chemical properties of this product were consistent with those of the specimen obtained in Example 1.

Example 3 In Example 2, the catholyte was anhydrous sodium acetate 820
Anhydrous sodium acetate 6 in place of the methanol solution containing
Using 40 d of methanol solution containing 97%, the cathode potential was set to -1.1V vs. S. C. E. 9-(27-0-acetyl-57-azido-3'-bromo-3',5'-dideoxy-β-D-
Electrolytic reduction of 675m9 of xylofuranosino(c)adenine was carried out.

After the electrolytic reduction reaction, the catholyte was treated in the same manner as in Example 2 to produce 9-(5'-azide-2/
, 3/, 5'-trideoxy-β-D-glyceropento-2L enofuranosyl) adenine (234 mg) is obtained.

Yield 54,700 Example 4 In Example 1, dimethylformamide solution 3 containing 400 mσ of tetrabutylammonium bromide as catholyte
Tetrabutylammonium bromide 19 instead of 0me
Using 50d of dimethylformamide solution containing S. C. E. Then, in the same manner as in Example 1, I-(2',5'-di-10-acetyl-3'-bromo-31-deoxy-β-D-xylofuranosino(c)-N4-acetyl-cytosine 1 .299
electrolytic reduction was carried out.

After the electrolytic reduction reaction is completed, the solvent is distilled off from the catholyte under reduced pressure, and 50 g of ethyl acetate is added to the resulting residue, which is left in a refrigerator overnight.

The precipitated crystals are removed and the oral liquid is concentrated, and the resulting residue is dissolved in 50 ml of water and extracted with chloroform. After drying this extract, the solvent is distilled off.

The resulting residue was subjected to silica gel column chromatography (
When applied to chloroformrimethanol (developing solvent: 85:15), l-(5/-
0-acetyl-2',37-dideoxy-β-D-glyceropent-2L enofuranosino(ha)-N4-acetyl-cytosine 1917119 is obtained. Example 5 In Example 1, 20 ml of tetrahydrofuran-0.1N hydrochloric acid (1:1) was used instead of the dimethylformamide solution containing tetrabutylammonium bromide, which is the negative and positive polar solution. , and set the cathode potential to -1.25V vs. S. C. E. 1-(37
,5Ldi-0-propionyl-2'-bromo-2'-deoxy-β-D-xylofuranosyl)uracil 420T
II! electrolytic reduction was carried out.

After electrolytic reduction, the catholyte is neutralized with sodium hydrogen carbonate and then concentrated under reduced pressure. The resulting residue is extracted with chloroform, the extract is dried, and the solvent is distilled off. The resulting residue [1-(5'-0-propionyl-2',3'-
dideoxy-β-D-glyceropent-2'-enofuranosino(c)uracil] was added to Diamond SA-11B.
Pass through a column packed with (0H-)10i and wash with water.
2N acetic acid is passed through the column and the effluent is concentrated.

By recrystallizing the resulting residue from methanol,
l-(2',3-dideoxy-β-D) as colorless needle crystals
-glyceropent-2/-enofuranosyl) uracil) uracil 130 is obtained. Yield 62,700mp. 15
5-156℃ (Dec)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▲Mathematical formulas, chemical formulas, tables, etc. are ▼ (However, B and R^1 have the same meanings as above.) A method for producing a 2',3'-unsaturated nucleoside compound.