JPS638394A - Fluorine-containing ribofuranoside derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The 3,5-dideoxy-3-fluoro-D-ribofuranoside derivative of formula I [R is halogen, -OX (X is H, alkyl or protective group) or residue of nucleic acid salt, etc.; R<1> is H or protective group]. EXAMPLE:Methyl 3,5-dideoxy-3-fluoro-2-O-benzoyl-beta-D-ribofuranoside. USE:Intermediate for antiviral agent and antitumor agent. PREPARATION:The furanoside derivative of formula II (R<2> is alkoxyl, protected OH or halogen; R<3> is protective group) (e.g. methyl 2-O-benzyl-3-deoxy-3-fluoro-beta- D-ribofuranoside) is converted to 5-deoxy derivative by reducing its 5-hydroxyl group and, if necessary, subjected to deprotection, introduction of nucleic acid base, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel fluorine-containing ribofuranoside derivative and a method for producing the same.

Sugars containing fluorine atoms are used in a wide variety of fields as important constituent units of pharmaceuticals, and due to their high physiological activity. For example, nucleosides containing fluorine-containing sugars are known as antiviral agents and antitumor agents. Specifically, 2-thioxy-2,2-difluororibofuranoside derivatives (see JP-A-59-175498)
and 3-thioxy-3-fluoro-α-D-xylofuranoside derivatives (J. A. Wright et al., Carboh
ydrateResearch, 18.345-347
(1971), and Y., Fouron et al., rog.
,che+*,, 39.1564-1570 (197
4)), 5'-deoxy-5-fluorocytidine or monouridine (see JP-A-53-95982)
etc. are known.

Fluorine atoms have an extremely strong binding force to carbon atoms compared to hydroxyl groups, are inert and hydrophobic, and have an atomic size similar to that of hydroxyl groups. Therefore, replacing the hydroxyl group of sugar with a fluorine atom can be expected to have excellent effects in terms of antimetabolism and the like. On the other hand, as sugars, lipose and 2-deoxy lipose, which are constituent units of nucleosides, have a wide range of applications. However, the above-mentioned known fluorinated sugars are
The fluorine atom is not substituted only at the steric position of the hydroxyl group of lipose or 2-deoxy lipose, for example, 2-deoxy lipose.
In deoxy-2,2-difluororibofuranoside derivatives, fluorine atoms are present even in positions where hydroxyl groups were not originally present, and in 3-thioxy-3-fluoro-β-D-xylofuranoside derivatives, A fluorine atom is not present in the position of a hydroxyl group in lipoose, and the sugar moiety of the above deoxynucleoside does not have a fluorine atom.

As a result of research and study on the removal of the 5-position hydroxyl group in order to introduce a fluorine atom into the steric position of the 3-position hydroxyl group of Ripose, the present inventor discovered a novel 3,5-dideoxy-3-fluoro-D-ribofuranoside. The present invention, which has led to the discovery of the derivative, is the following new ribofuranoside derivative that accommodates the fluorine atom and a method for producing the same.

3,5-dideoxy-3 represented by the following formula [I]
-Fluoro-D-ribofuranoside derivative.

However, R: a halogen atom, -0X (X is a hydrogen atom, an alkyl group, or a protective group), or a residue of a nucleobase.

R1: hydrogen atom or protective group.

The above method is characterized in that the hydroxyl group at the 5-position of the furanoside derivative represented by the following formula [11] is reduced to form a 5-deoxy compound, and then, if necessary, deprotection, introduction of a nucleic acid base, etc. A method for producing a 3,5-dideoxy-3-fluoro-D-ribofuranoside derivative represented by formula [I].

However, R2: an alkoxy group, a hydroxyl group protected with a protective group, or a halogen atom.

R3: Protecting group.

The compound represented by the above formula [I] includes both fluorine-containing nucleosides of type 1 and fluorine-containing ribofuranosides useful as synthetic intermediates thereof, and the latter is a compound in which R is a group excluding nucleobases. be. In this case, R is a chlorine atom,
It is preferably a bromine atom or an iodine atom, or the above -Ox is an alkoxy group, particularly a bromine atom or a lower alkoxy group (referring to one having 4 or less carbon atoms),
A methoxy group is particularly preferred, and the R position is at the β position (the above formula [
11) is appropriate, but in the middle of the reaction route it may be at the α position or a mixture of the β and α positions.
In fluorine-containing nucleosides, R is at the β position.

When RIJ2 and X are hydroxyl-protecting groups, known hydroxyl-protecting groups are suitable.

Examples include tri(alkyl, aryl, or aralkyl)silyl groups, acyl groups, and aralkyl groups. The aromatic nucleus of the aryl group or aralkyl group may have a substituent such as an alkyl group or an alkoxy group, and the three organic groups bonded to the silicon atom may be the same or different from each other. Specifically, for example, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, phenyldimethylsilyl group, acetyl group, benzoyl group, benzyl group, trityl group, tris(P
-methoxyphenyl)methyl group. Furthermore, in some cases an alkyl group may be used as a protecting group. Suitable examples of this alkyl group include lower alkyl groups, particularly methyl groups.

When R is a nucleobase, it consists of purine residues, pyrimidine residues, and purine or pyrimidine residues having halogen atoms, haloalkyl groups, alkyl groups, or other substituents. For example, adenine, guanine, cytosine, thymine, uracil, 5-fluorouracil, 5-fluorocytosine, 2-fluoroadenine, 5
- It is a residue obtained by removing the hydrogen atom bonded to the nitrogen atom of the ring from a compound such as trifluoromethyluracil or 5-iodouracil. Preferably, the above-mentioned five types of nucleobases having no A substituent or residues of 5-fluorouracil and 5-fluorocytosine are preferable.

The fluorine-containing sugar represented by the above formula [I] is the fluorine-containing sugar represented by the above formula [I]
Desirably, the hydroxyl group at the 5-position is produced by reducing the hydroxyl group at the 5-position from a furanoside derivative represented by I]. For the reduction of the hydroxyl group at the 5-position, the hydroxyl group is acetylated and then reduced with triphenylsilane. After that, it is reduced with tributyltin hydride or triphenyltin hydride, or it is iodinated with triphenylphosphite methiodite or triphenylphosphine-iodine, and then triethylamine is reduced in alcohol using a noble metal catalyst such as palladium-carbon. It is desirable to adopt a reduction method such as a reduction method using Liraney nickel which is catalytically hydrogenated by adding an organic base such as A method of catalytic hydrogenation using palladium-carbon in the presence of triethylamine is adopted. In the compound represented by the above formula [R1, R2 must be inactive against reducing action. Therefore, unprotected hydroxyl groups and nucleobase residues of R in formula [I] cannot be used as R2.
A compound represented by formula [I] in which is one of these groups is converted or introduced into one of these groups after reduction of a compound represented by formula [11]. Preferred R2 is a lower alkoxy group and a halogen atom, most preferably a methoxy group, and its position is preferably at the β position.Similarly, the hydroxyl group at the 2nd position is also protected by a protective group R3
R3 is particularly preferably a benzyl group, but is not limited to this and may be any other protecting group as mentioned above. If R3 is a benzyl group, this is protected during the above reduction reaction. The benzyl group is deprotected,
The product becomes a compound in which the 2-position hydroxyl group is not protected. However, the reduction of the 5-position hydroxyl group and the deprotection of the 2-position hydroxyl group may be carried out in separate steps. Protecting group R3 of the 2-position hydroxyl group
Desorption is performed by hydrogenation or the like. For example R3
When is a benzyl group, it is eliminated by hydrogenation using palladium-carbon or the like as a catalyst. When a nucleobase residue is introduced into a compound represented by formula [I] in which R is not a nucleobase residue, it is usually necessary to protect the 2-position hydroxyl group again. As this protecting group, an acyl group such as an acetyl group or a benzoyl group can be employed.

Introduction of nucleobase residues can be carried out in various ways. For example, in the literature (Wright, Carbohydrate
Research, 18.345 (1971), etc. may be employed. This method is a method in which the hydroxyl group at the 1-position or its 4-group is substituted with a bromine atom, and the bromine atom is substituted with a residue of a nucleic acid base. Specifically, the alkoxy group of a compound represented by the above formula [I] in which R is an alkoxy group (wherein R1 is a protecting group) is converted to a bromine atom with a hydrobromic acid-acetic acid solution, and then the alkoxy group is converted to a bromine atom. Bromide and a reactive purine derivative such as 6-benzaminopurine are reacted in nitromethane in the presence of mercuric cyanide to replace the bromine atom with a purine residue. Introduction of pyrimidine residues can be carried out in a similar manner. By removing the protective symbol after @, a nucleoside containing a fluorine atom at the 3-position can be obtained.

The furanoside derivative represented by the above formula [1] is a novel chemical compound. This compound and its manufacturing method are described in a previous application (Japanese Patent Application No. 80-220188) related to the invention by the present inventors. The outline will be explained below.

The furanoside derivative represented by the formula [fl] is produced by fluorinating a compound represented by the following formula [ml] with a fluorinating agent.

However, l12a, alkoxy group, protected hydroxyl group,
or a halogen atom; R5, R6: the same or different protecting group; Y: a hydrogen atom or a leaving group. In particular, R4 is preferably the same group as the above R2, and R5 is preferably the same group as the above R group; however, The invention is not necessarily limited to this, and different groups may be employed to form R2 and R, respectively, before reduction.
3. R4 is preferably a lower alkoxy group, particularly a methoxy group.

R4 may be a halogen atom, but it is preferably an alkoxy group during fluorination, and its position is preferably at the β position. 1li4 and R5 are both hydroxyl protecting groups as described above. R5 is preferably an alkyl group or an aralkyl group, particularly a furfurkyl group such as a benzyl group. R6 is a protective group other than an alkyl group.

For example, a trialkylsilyl group or an aralkyl group is preferable, and a t-butyldimethylsilyl group is particularly preferable.
may be a hydrogen atom, but fluorination of the hydroxyl group bonded to the 3-position is not necessarily easy, and it is preferable to use a leaving group (
After the introduction of Y'), fluorination is carried out. This leaving group is a group that facilitates fluorination after activating the 3-position hydroxyl group, and examples include methanesulfonyl group, trifluoromethanesulfonyl group, p-toluenesulfonyl group, imidazoylsulfonyl group, acetyl group, and trimethylsilyl group. There are bases etc. In particular, a trifluoromethanesulfonyl group has a high activation effect and is preferably used as a leaving group.

As the fluorinating agent, known fluorinating agents can be used, but in particular tetraalkyl fluoride (or aralkyl fluoride)
Ammonium is suitable. As the alkyl group, a lower alkyl group is suitable, and as the aralkyl group, a benzyl group is suitable, and the four alkyl groups and aralkyl groups may be different, or may consist of both an alkyl group and a full alkyl group. Preferably, tetrabutylammonium fluoride is used. These fluorinating agents are usually used dissolved in an inert solvent such as tetrahydrofuran. The fluorination reaction is usually carried out in an inert solvent at a temperature of several tens of degrees Celsius or less, and preferably at about 0'C to room temperature.

The compound represented by the formula [ml needs to be stereospecifically synthesized. In addition, the hydroxyl groups other than the 3-position hydroxyl group must be selectively protected so as not to undergo the fluorination reaction.For these reasons, the compound represented by the formula [ml] was synthesized by the following route. It is preferable that R4 is an alkoxy group.

R7 represents an alkylidene group, preferably an alkylidene group having 7 or less carbon atoms, and particularly preferably an impropylidene group. The compound of formula (1) is a β-D compound in which the hydroxyl groups at the 3- and 5-positions are protected by this alkylidene group. -A xylofuranoside derivative represented by the formula (2) by protecting the hydroxyl group at the 2-position of this compound with the above-mentioned R5, especially a benzyl group. Next, R7 is removed and the 3- and 5-position Deprotect the hydroxyl group. This deprotection can be easily carried out in the presence of an acid catalyst. As the acid catalyst, an inorganic acid such as sulfuric acid or hydrochloric acid or an organic acid such as acetic acid can be used, but it is convenient to use fi=acid. At this time, R5 must not be desorbed,
Therefore, protecting groups as described above are employed. The resulting formula (
By selectively protecting the hydroxyl group at the 5-position of the compound represented by 3) with a protecting group R6, particularly a t-butyldimethylsilyl group, a compound represented by the formula 1 (4) can be obtained. A leaving group Y' is introduced into the hydroxyl group to obtain the desired compound represented by formula (5). However, since the compound represented by formula (4) can be directly fluorinated as described above, it is not necessarily necessary to synthesize the compound represented by formula (5).

The reason for adopting this reaction route is that the reactivity of the 2- and 3-position hydroxyl groups is similar, so it is necessary to introduce a protecting group only to the 2-position hydroxyl group, and the 3-position hydroxyl group This is due to the need to maintain the three-dimensional position.

By fluorinating the compound represented by the above formula [ml, that is, the compound represented by the above formula (4) or (5), the fluorine atom is bonded to the sterically opposite side of the OY group, and OY is eliminated. 6 Usually, at the same time as this fluorination, the protecting group for the 5-position hydroxyl group is removed, yielding a furanoside derivative represented by the above formula [II].

[Examples] Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples. Note that the synthesis example is a synthesis example of a compound represented by the above formula [11].

Synthesis example ■ Methyl 2-0-benzyl-3,5-0-impropylidene-β-D-xylofuranoside [In formula (2), R4 is a metquin group, R5 is a benzyl group, and R7 is an impropylidene group synthesis of compounds].

Methyl 3.5-0-Impropylidene-β-D-xylofuranoside 25 g (0.23 mol) and silver oxide (3
Benzyl bromide (42 g) was added to a suspension of N,N-dimethylformamide (0 g) in N,N-dimethylformamide, and the reaction solution was stirred at room temperature for 36 hours. The reaction solution was filtered, water was added, and extracted with chloroform.

The product was purified by column chromatography to obtain 25 g (yield: 70%) of benzyl ether.

'H-N)IR(C:DC13) :δ1.3B(s
, 6H), 3.41(s, 3H).

3.84.5 (m, 5H), 4.59 (s, 2H),
4.98 (s, IH).

7.32 (g, 5H).

(Synthesis of Φ methyl 2-0-benzyl-β-D-xylofuranoside [a compound in which R4 is a methoxy group and R5 is a benzyl group in formula (3)]).

Methyl 2-0-benzyl-3,5-0-inpropylidene-β-D-xylofuranoside Bog (0,2mat
) was dissolved in acetic acid (120m12)-water (50a+I2) and reacted for 1 hour on a 50°C water bath. Warm bath at 50℃
The low boiling point substances were distilled off while maintaining the temperature. The diol was purified by column chromatography to obtain 42 g (yield: 80%) of the diol.

Rr　O, 40 (benzene-ethyl acetate = l:1).

■ Methyl 2-0-benzyl-5-0-t-butyldimethyl-β-D-xylofuranoside [Compound in which R4 is a methoxy group, R5 is a benzyl group, and R6 is a t-butyldimethylsilyl group] synthesis of.

42 g (0.18 mol) of diol was dissolved in N,N-dimethylformamide (180 mQ), and imidazole (13 g) was added. To this solution was added 25 g of t-butyldimethylsilane chloride in N,N-dimethylformamide (1
20+a12) was added dropwise over 30 minutes at 0°C.

After stirring for 3 hours, post-treatment was carried out according to a conventional method.

The product was purified by column chromatography to obtain 80 g of silyl ether (yield: 100%).

lH-N)IR(CDCh): δ0.10(s,
8H), 0.91 (s, 9H).

3.37 (s, 3H), 3.9-4.1 (m, 3H)
, 4.2-4.4(+w,3)1), 4.81(s
, 2H), 4.93 (s, IH), 7.32 (s,
5B).

■ Methyl 2-0-benzyl-3-deoxy-3-fluoro-β-D-ribofuranoside [formula [in R1,
Synthesis of a compound in which R2 is methoxyl and R3 is a benzyl group].

Methyl 2-0-benzyl-5-〇-t synthesized above
-butyldimethylsilyl β-D-xylofuranoside 2
8 g (0.07 mol) of dichloromethane (18001
12) 23 g of 2.6-lutidine was added to the solution and cooled to 0°C. Here, trifluoromethanesulfonic anhydride (40
g) was added dropwise over 15 minutes, and the reaction was continued for an additional 30 minutes.

Add ice and post-process.

Short column purification was performed to obtain 33 g of a crude product.

This material was dissolved in tetrahydrofuran (120 mQ), and 180 mQ of a solution of tetrabutylammonium fluoride in tetrahydrofuran (f=1.0) was added dropwise at 0°C over 30 minutes. After stirring at room temperature for 12 hours, tetrahydrofuran was distilled off and the mixture was purified by column chromatography to obtain 11 g of the title fluorinated product.

19F-NMR (CDCh): (IL:ChF standard)
-207,1(ddd.

Jl153.7.22.0. 13.4 Hz).

lH-NMR (C:DCh): δ3.47 (sJ
H), 4.0-4.2 (+, 2H).

4.55 (s, 2H), 4.8-5.2 (m, 5H)
, 7.33 (s, 5) 1).

IR (CuCl2) 3300c11-1.

Example 1 Methyl 3,5-dideoxy-3-fluoro-2-0-
Synthesis of benzoyl-β-D-ribofuranoside [a compound in which R is a methoxy group bonded to the β-position and R1 is a benzoyl group].

1.5 g of alcohol synthesized in Synthesis Example ■ (5.9 mm
Dissolve triphenylphosphitemethiodite 2.ol) in 10 mQ of N,N-dimethylformamide at room temperature.
To the reaction mixture, 5 ml of methanol was added and N,N-dimethylformamide was removed with water to obtain a crude product. This product was dissolved in methanol 10+Q and hydrogenated at room temperature and normal pressure in the presence of triethylamine 2+w (!) and 2.0 g of palladium-carbon (5%).The product was fractionated by column chromatography and the 5-deoxy form was 0. .58g was obtained. ゛This deoxy form was dissolved in ethanol 5IIIQ, and 5%
Hydrogenation was carried out at room temperature and normal pressure in the presence of palladium-carbon.

After 48 hours, it was filtered using Celite 545.

The crude product was dissolved in 3 mQ of pyridine, 0.33 g of benzoyl chloride was added at 0°C, and after stirring at 0°C for 18 hours,
Pyridine was distilled off and the residue was purified by column chromatography to obtain 0.64 g of methyl 3,5-dideoxy-3-fluoro-2-0-benzoyl-β-D-ribofuranoside.

19F-NMR (C:DC13): (CCI3F standard) -207,4 (dddd.

j1152.3.20.0.9.3.1.2Hz).

IH-NMR (CDCh): δ1.41 (d, J
-13.8Hz, 3H).

3.44 (s, 3H), 4.2-4.8 (+a, 2H
), 5.10 (brs.

IH), 5.3-5.5 (+a, 1) I), 7.4
-7.8 (m, 3H).

8.00-113(,2H).

Example 2 9-(3,5-deoxy-3-fluoro-β-D-ribofuranosyl)adenine [Compound in which R is an adenine residue bonded to the β-position and R1 is a hydrogen atom in Nimehat] synthesis of.

Methyl glycoside synthesized in Example 1, 0.20 g (0
, 8111 mol) and acetic acid (1.4 m (monoacetic anhydride (
0.04m12). 30% hydrogen bromide here-
Add acetic acid solution (4.5 mQ) and stir at room temperature for 24 hours. After completely distilling off acetic acid, acetic anhydride, etc., tolunine (
Adenine monobenzoate 0
．． In addition to 22 g of nitromethane solution (20 m(2)), 0.33 g of mercuric cyanide was added and heated under reflux for 1 hour. After distilling off nitromethane and toluene, 30% aqueous potassium iodide solution was added and stirred. It was crudely separated using a column and used in the next reaction.

0.20 g of N-glycosylated product was added with methanol (5 m (2
), IM-sodium methoxide-methanol solution (0.87m(2)) was added thereto, and the mixture was heated under reflux for 1 hour. After distilling off the methanol, water (20mQ) was added,
N = Neutralized with aqueous acetic acid solution. The aqueous layer was extracted with chloroform and passed through an ion exchange column to produce the final product, the title fluoroadenosine. IQg was obtained.

19F-NMR (CDCh): (CG13F standard) -
195,4 (ddd.

j=53.7.24.7.23.0Hz).

'H-NMR (CD300): δ1.45(d
, Jeg. 8.8H2, 3H).

3.2-5.5 (m, 8H), 8.00 (d, J=8
．． 2Hz, IH).

8.21 (s, IH), 8.29 (s, 1) 1).

I R3300, 1fi50 cm-1.

Melting point 230'0 (decomposition) Example 3 l-(3,5-deoxy-3-fluoro-β-D-ribofuranosyl)-5-fluorocytosine [5-fluorocytosine in which R is bonded to the β position in formula [I] Synthesis of a compound which is a fluorocytosine residue and R1 is a hydrogen atom].

Similarly to Example 2, 0.20 g of methyl glycoside (0.8
After converting 0 mmol) into glycodylbromide, this was converted into N4-p-toluoyl-5-fluorocytosine (
0.23 g) and mercuric chloride (0.28 g) in nitromethane, and the mixture was heated under reflux for 1 hour. After post-treatment by adding a 30% aqueous potassium iodide solution, the mixture was extracted with chloroform. After rough separation using a short column (silica gel), IN-sodium methoxide-methanol solution was added, and the mixture was reacted in methanol at room temperature for 4 hours. Neutralization was performed with 2N-butyric acid to obtain 0.08 g of the desired product.

19F-NllIR (CD30D): (CChF standard)
-182,5 (ddd.

j-52,2,19,0,12,0Hz) I R330
0,1620 cm-1.

Claims (1)

[Claims] 1. 3,5-dideoxy- represented by the following formula [I]
3-Fluoro-D-ribofuranoside derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] However, R: halogen atom, -OX (X is a hydrogen atom, an alkyl group, or a protecting group), or a residue of a nucleobase. R^1: Hydrogen atom or protective group. 2. The following, which is characterized by reducing the hydroxyl group at the 5-position of the furanoside derivative represented by the following formula [II] to derive a 5-deoxy form, and then performing deprotection, introduction of a nucleic acid base, etc. as necessary. A method for producing a 3,5-dideoxy-3-fluoro-D-ribofuranoside derivative represented by formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] However, R: halogen atom, -OX (X is a hydrogen atom, an alkyl group, or a protecting group), or a residue of a nucleobase. R^1: Hydrogen atom or protective group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] However, R^2: an alkoxy group, a hydroxyl group protected with a protective group, or a halogen atom. R^3: Protecting group.