JPH02209886A - Production of erythroxetanosylnucceoside derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an antiviral agent and carcinostatic agent by reacting a protected erythroxetanose derivative with a purine base or pyrimidine base, which functional group is protected, followed by elimination of the protecting group, as necessary. CONSTITUTION:A compound expressed by formula I (R1 and R2 represent acyl; R3 represents H or lower alkyl) is reacted with a purine base or pyrimidine base, which amino or oxy is protected, preferably expressed by formulae II or III [R4 and R7 represent protecting group; R5, R6 and R8 represent O-R10 (R10 represents protecting group) or NH-R11 (R11 represents protecting group); R9 represents H, halogen or lower alkyl] preferably in an anhydrous solvent (example; acetonitrile) at 0-30 deg.C in the presence of a condensing agent (example; Lewis' acid) and the resultant compound is deprotected with an acid or base, as necessary, to afford the objective compound expressed by formula IV (B represents purine type base or pyrimidine type base).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing erythrooxetanosyl nucleoside derivatives having purine bases and pyrimidine bases that are expected to be used as pharmaceuticals.

[Conventional technology]

Recently, an unusual nucleoside, oxetanosine (formula below), which has an oxetane ring as a sugar moiety, was isolated for the first time as a natural product (N., Shimada, et al.).

J' Antibiotics, 1J-1623+
(1986).

By reacting the protected erythrooxetanose compound represented by (shown) with a purine base or pyrimidine base with a protected functional group, and then removing the protective group as necessary, the compound a of the general formula (It) can be obtained with antibacterial and antibacterial properties. It has 1' fils action and antitumor action, and is expected to be used as a drug.

However, the 2'-nor form, ie, the erythrooxetanosyl form, is difficult to derive from this substance, and no method for its production is known at all.

[Problem to be solved by the invention]

It is desired to develop a method for producing various erythrooxe and tanosyl nucleoside derivatives.

[Means to solve the problem]

As a result of various studies, the present inventors found that the general formula (1) (wherein,
R+ and Rz may be the same or different, and R3 is hydrogen or a lower alkyl group (in the formula, B represents a purine base and a pyrimidine base). I found out what I can get.

The present invention was completed based on the above findings.

In the present invention, examples of the acyl group include C1 to C4 lower alkyl acyl groups such as acetyl, globionyl, butyroyl, oxalate ester type noalkoxylponyl acyl group, malonate ester type alkoxycarbonylmethylacyl group, benzoyl, substituted benzoyl, etc. Examples include aromatic acyl groups.

Examples of lower alkyl groups include methyl, ethyl, propyl, and butyl groups.

The compound of the present invention can be produced as follows.

is usually prepared with a pyrimidine base in an inert organic solvent, preferably an anhydrous solvent, at a temperature usually from 0°C to about 100°C, preferably from about 0°C to 30'C, in the presence of a condensing agent such as a Lewis acid. The reaction is carried out, and the resulting compound is deprotected with an acid or a base as necessary (. is a base) to give the general formula (Il
A compound represented by l is produced.

Examples of the anhydrous solvent include, but are not particularly limited to, ace-1-nitrile, halogenoalkane (eg, dichloroethane), xylene, nitrobenzene, dichlorobenzene, and the like.

Lewis acids are used as condensing agents, such as tin tetrahalides (tin tetrachloride, tin tetrabromide, etc.), mercuric or mercuric halides (preferably mercuric or mercuric bromide, mercuric or diiodide), etc. mercury, etc.), tri-lower alkyl (C+~C4
) Acid conjugates of silyl (for example, trimethylsilyl trifluoromethanesulfone), trimethylsilyl halochenomethanesulfonate, trimethylsilyl perhalogenoic acid such as trimethylsilyl perchloric acid), and the like.

Purine bases and pyrimidine bases with protected functional groups include, for example, compounds with protected amine groups and oxy groups, preferably represented by the following general formula (wherein R4 and 1 (7 is a protecting group, Rs, Ra and ns is -ORho (11 (+o is a protecting group) or -NH-R,.

(Rh is a protecting group) and R9 is hydrogen, halogen, or a lower alkyl group) Functionally protected purine bases and pyrimidine bases are mentioned. Protecting groups for R4y Ry and Rho include acyl groups, silyl protecting groups (lower allylsilyl, such as trimethydisilyl, lower alkylarylsilyl,
Examples include isopropyldiphenylsilyl, t-7'' tyldiphenylsilyl, t-butyldimethylsilyl).

There are no particular restrictions on the protecting group for Ro that can be used to protect the amine group, and examples include acyl groups (for example, substituted or unsubstituted lower alkyl carbonyls such as acetyl, globionyl, and halogenoacetyl, and aromatic carbonyls such as benzoyl). can give.

〔Effect of the invention〕

The compound represented by the general formula (Ill) of the present invention is expected to be used as an antiviral agent and an anticancer agent like oxetanosine.

Next, the production examples of the present invention will be specifically explained with reference to Examples.Example 1゜N,N-dibenzoyl-9-<2',4'-di,
Synthetic compound (11 (6.83 mg, 0.018 mmole) of 〇-benzoyl-β-ri-erythrooxetanosyladenine (compound (2))
) was dissolved in dichloroethane (1 ml), Molecuy Sheep 4A (powder 60ff 1 g) was added, and the solution was dissolved at room temperature.
．． After stirring for 5 hours, N-benzoyl-bis-(trimethylsilyl)adeni7 (23 mg, 0.04 mmol
e) and tin chloride (IVI (0,15+++A!,
8.17 X I Q-'mmole) was added and stirred for 45 minutes in an ice water bath. After adding saturated aqueous sodium bicarbonate and stirring for 10 minutes, the reaction solution was filtered, Solution F was concentrated under reduced pressure, and the resulting residue was purified using preparative thin layer chromatography (hexane:ethyl acetate-1:4). The crystalline substance thus obtained was dissolved in methanol CO (0.75 ml) and dissolved in 0.2N sodium methoxide.
ide) (0.25 ml) was added, stirred at room temperature for 1 hour, concentrated under reduced pressure, the resulting residue was dissolved in methane (1 mA'), and pyrimidine 7 (0.25 ml) was added in an ice-water bath.
, 1 ml, 1.236 mmole) and Hensoyl chloride (0.1 ml, 0.862 mmole)
was added and left at 8°C for 15 hours. The reaction solution was diluted with ethyl acetate and washed with 1N hydrochloric acid, and then the organic layer was washed with water and then with saturated aqueous sodium bicarbonate. Wash the organic layer again with water and
After washing with saturated saline, drying with Glauber's salt and concentrating under reduced pressure, the resulting residue was subjected to column chromatography (silica gel 3
N,N-dibenzyl-4-<2',4'-di0-benzoyl-β-D-erythrooxetanoyl adenine (compound ( 2) ) (2,57ff1g) (total yield of 3 steps 22.8%) was obtained.

White crystalline substance 'H-NMR of compound (2) (400M H2, CDCl2. TMS
): δ4556 (IH, dd, J=2.44,11
．． 23Hz), 4.683(lH,dd, J=4
゜88.4.23H2), 5.775 (IH, m), 6
．． 264 (IH, br, s ), 6.473 (IH,
d, J=1.47Hz), 7.335-7.
410 (6H, Complex), 7.451-
7.545 (6H.

Complex), 7.815-7.885 (
4H, Complex).

8.079-8.135 (4H, Complex),
8.405 (IH,s), 8.617 (IH
,s).

Example 2゜■-<2',4'-di-O-benzoyl-α-D-erythrooxetanosyl)uracil (synthesis of compound (41) Compound (3) (9,53■, 0.258 mmole
) to Jiku o.

Dissolved in ethane (1+++A), added Molecular Thief γ 4A (powder, 50 μg) and stirred at room temperature under a hydrogen atmosphere for 80 minutes.
Uracil (excess) and tin chloride (GV) (excess) were added and stirred for 40 minutes.

After adding saturated sodium bicarbonate solution and stirring for 10 minutes, the reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified using preparative thin layer chromatography (hexane: ethyl acetate = 1:3). 1-(2:4-di-0-benzoyl~α-
D-erythrooxetanosyl)uracil (compound (4i)
) (1.85 μm, yield 17.0%) was obtained.

Compound (4) White crystalline substance ca]I) 5-31. ．． 0 < C, 0, 09, CH
Czi) IR (7 (rum): 1730r 169
0.1600 (''”')'H-NMR (400MHz
, CDCl2. TMS): δ4.706-4.
74 1 (2((, Complex), 5.
082 (IH, dd, J=2.93.3.79Hz
), 5.859 (IH, m), 6.047 (IH
, d, J=6.84B(z).

6.195 (IH, d, , J=2.93Hz),
7.372-7.553 (4H, Complex
), 7.573-7.582 (:H-1, Compl
ex), 7.808-7.841 C2H.

('oplex), 7.985-8.006
(2H, Complex).

8.070 (IH, m).

Claims (2)

[Claims] (1) General formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R_1 and R_2 are acyl groups that may be the same or different, and R_3 represents hydrogen or a lower alkyl group.)
Reacting the protected erythrooxetanose derivative represented by with a purine base or pyrimidine base with a protected functional group,
A method for producing an erythrooxetanosyl nucleoside derivative represented by the following general formula (II), which comprises then removing a protecting group if necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, B represents a purine type base and a pyrimidine type base) (2) General formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, B represents a pyrimidine type base) Erythrooxetanosyl nucleoside derivatives and their salts