JPH0778044B2 - Fluorocyclopentane derivative and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a fluorocyclopentane derivative and a process for producing the same.

Nucleosides having a fluorine-containing sugar are known as antitumor agents and antiviral agents. Specifically, 3-deoxy-3-fluoro-furanoside derivative (JP 59-175498 discloses, JAWright other, Carbohydrate Research, 18, 345-
347 (1971)) and the like are known. However, in many cases, there is a decrease in in vivo activity as compared with in vitro. The present inventors concluded that this cause was due to the chemical instability of the above compound in vivo, and investigated the synthesis of carbocyclic derivative. Carbocyclic derivatives are those in which the oxygen atom of the ether part of the sugar is replaced with a carbon atom, and this substitution stabilizes the glycosidic bond, improving chemical stability in vivo, and further improving phosphoribosyl transferase. It can be expected that the stability to the enzyme is improved. As carbocyclic derivatives, alisteromycin, teplanocin, etc. are known, but no fluorine-containing carbocyclic derivatives have been known so far.

The present inventor conducted research and study to introduce a fluorine atom into the steric position of the hydroxyl group at the 3-position of xylose (also at the 3-position in the carbocyclic form) of the fluorine-containing derivative of the carbocyclic derivative of xylose. Have found a novel fluorine-containing carbocyclic nucleoside derivative that can be used as an antiviral agent such as an antitumor agent or an anti-AIDS agent.

The present invention is the following invention relating to the novel carbocyclic nucleoside derivative having a fluorine atom, a synthetic intermediate thereof and a method for producing the same.

A 3-fluoro-2-hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative represented by the following formula [I].

R ¹ : a residue of a nucleic acid base which may have a protecting group, an azide group, an amino group, or a protected amino group R ² , R ³ : a hydrogen atom or a protecting group of a hydroxyl group, the following formula [II] 2,3-epoxy-1-substituted represented by
3-Fluoro-2-hydroxy-1-substituted-4 represented by the following formula [I], characterized in that the 4-hydroxymethylcyclopentane derivative is fluorinated with a fluorinating agent, and if necessary, then deprotected. -Process for producing hydroxymethylpentane derivatives.

R ¹ : Residue of nucleobase which may have a protecting group, azido group, amino group, or protected amino group R ² , R ³ : hydrogen atom or hydroxyl protecting group in formula [I] , R ¹ , -CH ₂ OR ² , and a fluorine atom are present on the same side of the cyclopentane ring surface (hereinafter referred to as β surface side), and -OR ³ is on the opposite surface side (hereinafter referred to as α surface side).
Exists in. The oxygen atom of the epoxy group in the formula [II] described below exists on the α-face side. R ¹ represents a residue of a nucleobase as described below, an azide group (—N ₃ ), an amino group (—NH ₂ ), or an amino group protected by a protecting group. When R ¹ is a residue of a nucleobase, when the residue has a highly reactive functional group such as an amino group, the functional group may be protected with a protecting group. The carbocyclic nucleoside derivative in the present invention is represented by the above formula [I] in which R ¹ is a residue of a nucleobase having no protective group and both R ² and R ³ are hydrogen atoms. Refers to a derivative. This carbocyclic nucleoside derivative is
It is useful not only as a drug itself but also as an intermediate for leading to other derivatives. Further, when R ¹ is a residue of a nucleobase having a protecting group,
When it is an azido group, an amino group, or a protected amino group, or when at least one of R ² and R ³ is a hydroxyl-protecting group, the derivative represented by the formula [I] is
It is useful as an intermediate for synthesizing the above carbocyclic nucleoside derivative and other compounds.

In the present invention, the nucleobases mean purines and pyrimidines which may have a substituent, and the residue (B) thereof means a 9-purinyl group which may have a substituent and 1- Refers to a pyrimidinyl group. As the substituent, not only amino group, oxo group and methyl group but also other substituents such as halogen atom, alkyl group, haloalkyl group, halovinyl group, alkoxy group, hydroxyalkyl group, alkylamino group, dialkylamino group, acylamino group. It may be a group, a mercapto group, an alkylthio group, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyl group and the like. The bonding position of these substituents is 2 in purines.
At least one of the positions 6, 6 and 8 and at least one of the positions 2, 4 and 5 in the pyrimidines.
Examples of purines having a specific substituent include, for example,
Adenine, guanine, hypoxanthine, xanthine, 6
-Halopurine, 2-halopurine, 2,6-dihalopurine,
There are 6-alkylaminopurines, 6-acylaminopurines and the like, and examples of pyrimidines having a substituent include uracil, cytosine, thymine, 5-halouracil,
There are 5-halomethyluracil, 5-halothymine, 5-halomethylthymine, 5-β-bromovinylthymine and the like.
Preferred nucleic acid bases is a 2- and / or 6-substituted purine, especially adenine, 2-Haroadenin, N ⁶ -
Substituted adenine, 6-halopurine, 2,6-dihalopurine and the like are preferable.

Unless otherwise specified, the above halogen means fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferable.

When the residue of the above nucleobase has a protecting group, the protected group is an amino group (—NH ₂ ) or a carbonyl group. Examples of the amino group-protecting group include an aralkyl group, an acyl group, a dialkylaminomethylene group, and a triorganosilyl group described later. Of these, the acyl group may be regarded as a group in the above-mentioned nucleic acid base derivative. The protecting group for a carbonyl group is often protected by etherification, and examples thereof include a triorganosilyl group and an acyl group. Preferred protecting groups for amino group are benzyl group, acetyl group, benzoyl group, bivaloyl group,
Dimethylaminomethylene group, trimethylsilyl group, t-
There are a butyldimethylsilyl group, a t-butyldiphenylsilyl group and the like, and a carbonyl protecting group is preferably a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, an acetyl group, a benzoyl group and the like. Further, this amino-group protecting group can be used as a protecting group when R ¹ is an amino group.

When R ² and R ³ are protecting groups, they may be the same protecting group or different protecting groups. As the protecting group, triorganosilyl group, acyl group, aralkyl group and the like are suitable. Examples of the organic group in the triorganosilyl group include an alkyl group, a cycloalkyl group, an aryl group and an aralkyl group, and the three organic groups may be different. Further, the aromatic nucleus of these protecting groups may have a substituent such as an alkyl group or an alkoxy group. Specific protecting groups include, for example, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a phenyldimethylsilyl group, an acetyl group, a benzoyl group, a benzyl group, a trityl group and a dimethoxytrityl group.

Particularly preferred derivatives of formula [I] are those in which R ¹ is a nucleobase residue. This is because it is a carbocyclic nucleoside directly applicable to the purpose of the present invention, and when R ^{1 of the} epoxide represented by the formula [II] described below is a residue of a nucleobase, a deprotection step is required. This is because it can be directly synthesized from the epoxide even if it is.

The fluorocyclopentane derivative represented by the formula [I] is preferably produced from the epoxide represented by the formula [II] through fluorination. Epoxide Corresponds
It can be produced from a 2,3-dihydroxy compound and is described in the literature (JGMoffatt et al., J. Am. Chem. Soc., 95, 402).
5 (1975) can be adopted. For example, alisteromycin, ie 9- [2α, 3α-dihydroxy-4β-hydroxymethyl-1β-cyclopentyl]
Epoxidation of 6-aminopurine gives 9- [2α, 3α
-Epoxy-4β-hydroxymethyl-1β-cyclopentyl] -6-aminopurine can be synthesized.
The same applies when R ¹ is a residue of another nucleobase, an azido group, an amino group, or a protected amino group 2,
It can be easily synthesized from a 3-dihydroxy compound.

In the epoxide represented by the formula [II], R ¹ is particularly preferably a nucleobase residue or a nucleobase residue having a protecting group. This is because, as described above, carbocyclic nucleosides can be directly synthesized from this. R ² in formula [II] may be a hydrogen atom, but is preferably a protecting group. As the protective group, the above-mentioned hydroxyl protective groups can be adopted, and examples thereof include acetyl group, benzoyl group, trimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trityl group, dimethoxytrityl group and benzyl group. , And the like can be used, but a benzyl group is particularly preferable.

As the fluorinating agent, anhydrous hydrogen fluoride-organic base system is used, or anhydrous hydrogen fluoride is used alone. The organic base is a primary alkylamine, a secondary alkylamine or a tertiary alkylamine, and the alkyl group is preferably a linear or branched chain having 1 to 10 carbon atoms. Besides, cyclic amines such as pyrrolidine, piperazine and morpholine, or aniline, N, N-nimethylanine, m-phenyleneamine, pyridine, melamine, 1,3,
5-triazine, cyanuric acid, cyanuric chloride, 2,4,6
Aromatic compounds such as -triphenyl-1,3,4-triazine are also used. The equivalent ratio of the organic base to anhydrous hydrogen fluoride can be arbitrarily used from 0% to 100%. Preferably 15 to 50% is used.

By the fluorination, the fluorine atom is selectively introduced at the β-position at the 3-position. When the fluorinating agent is the anhydrous hydrogen fluoride-based fluorinating agent as described above, a hydroxyl group is generated at the α-position at the 2-position. When another fluorinating agent is used, an intermediate product may be formed in which the residue of the fluorinating agent is bonded to the hydroxyl group at the 2-position α,
It can be easily converted into a hydroxyl group by hydrolysis or the like. After the fluorination, if a hydroxyl group at the 5-position of the product or a residue of a nucleic acid base has a protecting group, it is preferably subsequently deprotected. However, when R ¹ is a group other than the residue of nucleobases, it can be used in the next reaction without deprotection in order to lead to the final target compound. The next reaction is usually a reaction for introducing a residue of nucleobases into the 1-position.

The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 9- [3β-fluoro-2α-hydroxy-4β-hydroxymethyl-1β-cyclopentyl] -6-aminopurine [in the formula [I], R ² and R ³ are hydrogen atoms, and R ¹ is an adenine residue. Certain compounds].

Alisteromycin (9- [2α, 3α-hydroxy-4
β-Hydroxymethyl-1β-cyclopentyl] -6-
Aminopurine) 200 mg (0.75 mmol) in acetonitrile (1
2-acetoxyisobutyryl bromide
1.4 ml was added, and the mixture was reacted under reflux condition for 1 hour. After distilling off acetonitrile, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The crude product was added to methanol (5m
l) dissolved in sodium methoxide (1M methanol)
The solution (2.0 ml) was added, and the mixture was reacted at room temperature for 1.5 hours. After distilling off the solution, water (10 ml) was added and neutralized with 2N-acetic acid. The crude product was separated by a C-18 reverse phase column, and the epoxy compound represented by the formula [II] (R ² hydrogen atom, R ¹ is an adenine residue) was adjusted to 0.
17g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.0 to 2.8 (m, 3H), 3.7 to 3.9 (m, 2H), 3.9 to 4.2 (m, 2
H), 5.2 to 5.4 (m, 1H), 8.50 (s, 1H), 8.60 (s, 1H). Dissolve the epoxy compound prepared above in 3 ml of tetrahydrofuran, and add 30 mg (0.6 mmo) of sodium hydride (60%).
l) in tetrahydrofuran (3 ml) and added at room temperature.
After stirring for 10 minutes, 0.07 ml (0.6 mmol) of benzyl bromide was added, and the mixture was heated under reflux for 4 hours. After cooling the reaction solution, water was added and the mixture was extracted with dichloromethane. The crude product was dissolved in cyclochloromethane (10 ml) and fluorinated hydrogen-pyridine complex was added.
5 ml was added, and the mixture was stirred at 0 ° C for 45 minutes. The reaction mixture was poured into a saturated potassium carbonate solution and extracted with dichloromethane. The crude product was dissolved in ethanol (5 ml) and chloroform (0.25 ml), palladium-carbon (5%) 50 mg was added, and the mixture was stirred at room temperature.
Added for 18 hours. Purify by column chromatography to obtain the title compound.
Obtained 35 mg. ¹⁹ F-NMR (CDCl ₃ CCl ₃ F standard): -186.3 (m).

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // A61K 31/505 ADU 31/52 ADY

Claims (2)

[Claims] 1. A 3-fluoro-represented by the following formula [I]:
2-hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative. R ¹ : a residue of a nucleic acid base which may have a protecting group, an azido group, an amino group, or a protected amino group R ² , R ³ : a hydrogen atom or a hydroxyl group-protecting group 2. A method of fluorinating a 2,3-epoxy-1-substituted-4-hydroxymethylcyclopentane derivative represented by the following formula [II] with a fluorinating agent and, if necessary, subsequently deprotecting it. 3-fluoro-2-hydroxy-1-substituted-4- represented by the following formula [I]
Process for producing hydroxymethylpentane derivative. R ¹ : a residue of a nucleic acid base which may have a protecting group, an azido group, an amino group, or a protected amino group R ² , R ³ : a hydrogen atom or a hydroxyl group-protecting group