JPH0798778B2 - Cyclopentane derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a cyclopentane derivative.

[Prior Art] Nucleosides having a fluorine-containing sugar are known as antitumor agents and antiviral agents. Specifically, a 3-deoxy-3-fluorofuranoside derivative (JP 59-175498 A, JA Wright et al., Carbohydrate Research, 18 , 345-3).
47 (1971)) and the like are known. However, in many cases there is a decrease in activity in vivo compared to in vitro.

The present inventors have concluded that the cause of this is due to the chemical instability of the above compound in vivo, and conducted extensive studies, resulting in the synthesis of a carbocyclic derivative.

Carbocyclic derivatives are those in which the oxygen atom in the ether part of the sugar is replaced with a carbon atom, and this substitution stabilizes the glycosidic bond, improving the chemical stability in vivo and further improving the oxygen content of phosphoribosyl transferase. It can be expected that the stability against is improved. As carbocyclic derivatives, alisteromycin, neplanocin, etc. are known, but no fluorine-containing carbocyclic derivatives have been known so far.

[Problems to be Solved by the Invention] In the present invention, in the fluorine-containing derivative of the carbocyclic analog of ribose, fluorine is present at the three-dimensional position of the hydroxyl group at the 3-position of ribose (also at the 3-position in the carbocyclic body). As a result of research and study to introduce an atom, a novel fluorine-containing cyclopentane derivative has been found. This compound is useful as a synthetic intermediate for a fluorine-containing carbocyclic nucleoside derivative.

[Means for Solving Problems] The present invention is the following novel fluorine-containing cyclopentane derivative.

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

However, B: an amino group or an acetamide group.

R ¹ : hydrogen atom or acetyl group.

R ² : hydrogen atom.

The compound represented by the above formula [I] is useful as a synthetic intermediate for fluorine-containing carbocyclic nucleosides. That is, it is easy to convert B into a residue of nucleobases to form fluorine-containing carbocyclic nucleosides. The B position must be at the cis, or β position, with the hydroxymethyl group at position 4 in order for the stereochemistry of the substituents of the carbocyclic nucleosides to match that of the arabinofuranosyl nucleoside. Similarly,
The hydroxyl group at the 2-position is at the β-position, and the fluorine atom at the 3-position is at the α-position.

The cyclopentane derivative represented by the formula [I] is preferably produced from the cyclopentane polyol derivative represented by the following formula [II] through a fluorination step.

However, R ^{1 is a} hydrogen atom or an acetamide group.

R ³ : an amino group with a protecting group.

In the formula [II], R ¹ is a hydrogen atom or an acetamido group, and when it is a hydrogen atom, it is preferably exchanged with a protecting group prior to the reaction. The protecting group is preferably an acetamide group, but is not necessarily limited to this. When a protecting group other than an acetamide group is used, it can be deprotected after completion of the reaction to give a compound in which R ¹ is a hydrogen atom, and then converted to an acetamide group. R ³ is an amino group or an amino group with a protecting group, and particularly preferably an amino group with a protecting group. Most preferably, it is an acetamide group. The steric position should be β.

As the amino-protecting group, a benzyl group, an acetyl group, a benzoyl group and a pivaloyl group are preferable. Particularly, an acetyl group is preferable. The protective group for the hydroxyl group is preferably an alkyl group, an aralkyl group, an acetyl group, a benzoyl group or a pivaloyl group, and may be a silyl group such as a t-butyldimethylsilyl group. A particularly preferred hydroxyl protecting group is an acetyl group.

The fluorination is preferably performed by a ring-opening reaction of the epoxide of compound [II]. 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. In addition, cyclic amines such as pyrrolidine, piberazine and morpholine, aniline, N, N-dimethylaniline, m-phenylenediamine, pyridine, melamine, 1,3,5-triazine, cyanuric acid, cyanuric chloride, 2,4, 6-triphenyl 1,
Aromatic compounds such as 3,5-triazine are also used.
The equivalent ratio of organic base to anhydrous hydrogen fluoride is 0% to 10
It can be arbitrarily used up to 0%. Preferably 1% to 50% is used.

As the solvent, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogen solvents such as dichloromethane, chloroform carbon tetrachloride and 1,1,2-trichloro-1,2,2-trifluoroethane are used. A halogen-based solvent is preferably used.

The reaction temperature is -100 ° C to the solvent reflux temperature, and is preferably 0 ° C to about room temperature.

The above formula [II] is a known compound, and (S. Daluge, R. Vinc
e, J. Org. Chem., 43 , 2311 (1978), which can be stereospecifically synthesized.

As described above, B of the compound represented by the formula [I] of the present invention
Can be converted into residues of nucleobases to give fluorine-containing carbocyclic nucleosides. The nucleobases refer to nucleobases or their derivatives or nucleobase analogs. Nucleic acid base or its derivative refers to purines and pyridimines which may have a substituent,
The residue means a 9-purinyl group and 1-pyrimidinyl which may have a substituent.

As the substituent, an amino group, an oxo group, a methyl group, as well as other substituents, for example, a halogen atom, an alkoxy group, a fodoxyalkyl group, an alkylamino group, a dialkylamino group, an acylamino group, a mercapto group, an alkylthio group, It may be a cycloalkyl group, an aryl group, an aryloxy group, an aralkyl group, or the like. In addition, here, halogen means fluorine, chlorine, bromine, and iodine, and the same applies below unless otherwise specified. The bonding positions of these substituents are 2-position and 6-position in purines.
Position, and at least one of the 8 positions, pyrimidines,
At least one of the second, fourth, and fifth positions. Further, aninoxide in which an oxygen atom is bonded to the ring nitrogen atom is also useful.

Examples of purines having a specific substituent include, for example,
Adenine, guanine, hypoxanthine, xanthine, 2,
There are 6-diaminopurine, 6-halopurine, 2-halopurine, 2,6-dihalopurine, 6-alkylmethylaminopurine, 6-acylaminopurine, adenine-1-oxide, adenine-7-oxide, etc. Examples of the pyrimidines include uracil, cytosine, thymine, 5-halomethyluracil, 5-halothymine, 6-halomethylthymine, 5-β-bromovinylthymine and the like. Preferred nucleobase or derivatives thereof are 2- and / or 6-substituted purine, adenine, guanine, hypoxanthine, xanthine, 2-Haroadenin, N ⁶ - substituted adenine, 2,6-diaminopurine,
Particularly preferred are 6-halopurine, 2,6-dihalopurine, uracil, cytosine, thymine, 5-halouracil and the like.

The nucleobase analog in the present invention means a heterocyclic compound having a ring corresponding to purines or pyrimidines or a derivative thereof, and the residue means 9 of purines.
Position, a residue having a bond at the position corresponding to position 1 of the pyrimidines. As such a heterocyclic compound, those known as analogs of nucleic acid bases are preferable. Specifically, at least one of the ring nitrogen atoms of purines or pyrimidines is converted to a carbon atom or a hetero atom other than the nitrogen atom, or at least one of the ring carbon atoms is a nitrogen atom or another hetero atom. And a heterocyclic compound obtained by performing both of these conversions. More preferably, one nitrogen atom in the ring of purines (particularly the nitrogen atom at the 1st, 3rd or 7th position)
A heterocyclic compound obtained by converting to a carbon atom or an oxygen atom, one carbon atom of the ring of purines (particularly the 2-position,
A heterocyclic compound obtained by converting the 5- or 8-position carbon atom into a nitrogen atom, and a heterocyclic compound obtained by performing both of these conversions (that is, one nitrogen atom is converted into a carbon atom or an oxygen atom, and one carbon atom is obtained). Heterocyclic compounds obtained by converting atoms into nitrogen atoms) are preferred.

In the case of pyrimidines, similarly, a heterocyclic compound obtained by converting the nitrogen atom at the 3-position into a carbon atom or converting the carbon atom at the 5- or 6-position into a nitrogen atom is more preferable. Derivatives of these heterocyclic compounds are compounds in which the same substituents as described above are introduced, and as the substituents, an amino group, an oxo group, a halogen atom and a methyl group are particularly preferable. Specific compounds include, for example, 5-amino-3,6-dihydro-7H-1,2,3-triazine [4,5-
d] Pyrimidin-7-one and the like.

Introduction of residues of nucleobases can be performed by various methods. For example, the literature (S. Daluge et al., J. Org. Chem., 43 , 2311 (197
8), YF Shealy et al., J. Am. Chem. Soc., 91 , 3075 (1969),
YF Shealy et al., J. Heterocyclic Chem., 13 , 1015 (1976)
The described method can be adopted. In this method, for example, in the case of adenosine, 5-amino-4,6-dichloropyrimidine is reacted with the formula [I] (when R ¹ and R ² are hydrogen atoms and B is an amino group) in the presence of triethylamine to give a diaminopyrimidine derivative. Then, the purine skeleton is formed using ethyl orthoformate. The chlorine atom at the 6-position of the purine ring can be converted to adenosine by treating with ammonia.

[Examples] Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples. Further, the reference examples below show examples in which fluorine-containing carbocyclic nucleosides were produced from the compound of the present invention.

Example 1 Synthesis of 4β-acetamido-3β-hydroxy-2α-fluoro-1β-cyclopentanemethylacetate.

4β-acetamido-2β, 3β-epoxycyclopentane-1β-methylacetate [a compound of the formula [II] in which R ¹ is an acetyl group and R ³ is an acetamide group] 7.0 g (32.0 mmo
l) was dissolved in dichloromethane (100 ml) and cooled to 0 ° C. 70% Hydrogen fluoride-pyridine (18 ml) was added dropwise over 5 minutes. After 2 hours, the reaction mixture was added to saturated aqueous potassium carbonate solution and extracted with dichloromethane. Purification by column chromatography gave 5.87 g (yield 77%) of the title 4β-acetamido-3β-hydroxy-2α-fluoro-1β-cyclopentanemethyl acetate. ¹ H-NMR (CDCl ₃ ): δ 1.4-1.6 (m, 1H), 2.00 (s, 3
H), 2.07 (s, 3H), 2.1-2,4 (m, 2H), 4.07 (d, J = 6.
8Hz, SH), 4.1-5.1 (m, 4H), 6.52 (d, J = 7.2Hz, 1
H). ¹⁹ F-NMR (CDCl ₃ ): (CFCl ₃ standard) -179.9 (ddd, J = 5)
0.3,27.8,11.7Hz).

Example 2 Synthesis of 3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentylamine.

4.87 g (26.3 mmol) of 4β-acetamido-3β-hydroxy-2α-fluoro-1β-cyclopentanemethylacetate synthesized in Example 1 was dissolved in methanol (142 ml), 2N-HCl (142 ml) was added, and 1 Deprotection was performed by heating under reflux for an hour. Distilled off metamole, Diaion SA-21A O
The mixture was neutralized with H ^- type (300 ml), and the solvent was distilled off to obtain 3.6 g (yield 92%) of the title compound (hereinafter referred to as aminodiol). _{^{19 F-NMR (D 2 0}} ) :( CCl 3 F standard) -181.0 (ddd, J = 15 .
2,28.8,51.8Hz).

Reference Example 1 Synthesis of 9- [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentylamine] -6-aminopurine.

0.73 g (4.9 mmol) of the aminodiol obtained in Example 2 was added to 1-
Dissolve in butanol (60 ml), 5-amino-4,6-dichloropyridine 2.0 g (12.2 mmol), toluethylamine 3.5 m
l was added and the mixture was heated under reflux for 2 days. The solvent was distilled off, and the mixture was extracted with chloroform-water (1: 1), and the aqueous layer was Amberlite CG-120.
(H ⁺ type) (10 ml) was adsorbed and eluted with 0.3% -ammonia water (about 300 ml), diaminopyridine 0,97 g (yield 97
%) Was obtained. ¹⁹ F-NMR (CD ₃ OD): (CCl ₃ F standard) -179.1 (ddd, J = 1)
6.1,27.2,41.5Hz).

256 mg (1.0 mmol) of the diaminopyridine obtained above was dissolved in 25 ml of ethyl orthoformate, concentrated hydrochloric acid (0.6 ml) was added, and the mixture was stirred at room temperature for 18 hours. Evaporate the solvent to remove chloropurine body 18
2 mg (68% yield) were obtained. ¹⁹ F-NMR (acrtone-d ₆ ): (CCl ₃ F standard) -175.3 (dd
d, J = 12.3,26.4,50.8Hz). ¹ H-NMR (acrtone-d ₆ ): δ 2.0-2.23 (m, 2H), 2.3
-4.0 (m, 6H), 4.5-5.5 (m, 2H), 8.59 (s, 1H), 8.7
3 (s, 1H).

Ammonia-methanol solution (10 ml) saturated at 1 ° C. was added to 125 mg (0.47 mmol) of the chloropurine compound, and the mixture was heated in an autoclave at 100 ° C. for 18 hours, then cooled and the low boiling point substance was distilled off. 1N-HCl (5 ml) was added, the mixture was stirred at room temperature for 3 hours, the solvent was evaporated, and the residue was purified by reversed-phase C-18 silica gel column chromatography to give 73 mg of the above-mentioned fluoroadenosine (yield 63
%) Was obtained.

Melting point 200-210 ° C (decomposition). ¹⁹ F-NMR (DMSO-d ₆ ): (CCl ₃ F standard) -171.8 (ddd, J
= 12.6,22.2,50.0Hz). ¹ H-NMR (DMSO-d ₆ ): δ 2.0-3.0 (m, 3H), 3.0-5.2
(M, 6H), 5.4-5.6 (m, 1H), 7.16 (brs, 2H), 8.13
(Brs, 2H).

Reference Example 2 Synthesis of 1- [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl] uracil.

300 mg (2.0 mmol) of the aminodiol obtained in Example 2 was added to N, N
-Dissolved in 10 ml of dimethylformamide and cooled to -25 ° C. 3-Ethoxy-2-propenoyl isocyanate (0.4M-benzene solution, 5.0 ml, 2.0 mmol) was added dropwise thereto over 5 minutes. After 10 minutes, return to room temperature, and then the water bath at 30 ℃
The solvent was distilled off. The solvent was completely distilled off with ethanol (5 ml × 3), 2N-hydrochloric acid (10 ml) was added, and the mixture was heated under reflux for 20 minutes. After cooling to 0 ° C, the mixture was neutralized with 2N-sodium hydroxide, and water was distilled off at a hot water temperature of 40 ° C. Purification by silica gel column chromatography gave 340 mg (yield 70%) of the title compound. ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard): -175.3 (ddd, J = 12.
7,28.3,51.0Hz). ¹ H-NMR (CD ₃ OD): δ 1.9-2.8 (m, 3H), 3.6-4.0
(M, 2H), 4.3-5.4 (m, 3H), 5.85 (d, J = 8.6Hz, 1
H), 7.98 (d, J = 8.6Hz, 1H).

Reference Example 3 Synthesis of 1- [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl] thymine.

270 mg (1.8 mmol) of the aminodiol obtained in Example 2 was added to N, N
-Dissolved in 10 ml of dimethylformamide and cooled to -25 ° C. 3-methoxy-2-methyl-2-propanoyl isocyanate (0.4M-benzene solution, 4.5 ml, 1.8 mmo
l) was added dropwise over 5 minutes. After 10 minutes, the temperature was returned to room temperature, and the water bath was set to 30 ° C. to distill off the solvent. Ethanol (5 ml
After completely distilling off the solvent in 3), 10 ml of 2N hydrochloric acid was added, and the mixture was heated under reflux for 20 minutes. After cooling to 0 ° C, the mixture was neutralized with 2N-sodium hydroxide, and water was distilled off at a hot water temperature of 40 ° C. Purify by silica gel column chromatography, 380 mg of the title compound.
(Yield 82%) was obtained. ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard): -175.0 (ddd, J = 12.
7,28.3,51.0Hz). ¹ H-NMR (CD ₃ OD): δ 1.8-2.8 (m + s, δ 2.02 (s, 3
H), totally 6H), 3.7−4.0 (m, 3H), 4.2−4.6 (m, 2
H), 7.80 (br s, 1H).

Reference Example 4 Synthesis of [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl]-[2,5-diamino-6-chloro-4-pyrimidinyl] amine.

412 mg (2.76 mmol) of the aminodiol obtained in Example 2 was dissolved in 1-butanol (58 ml) to give 2-amino-4,6-
906 mg (5.52 mmol) of dichloropyrimidine and 770 μl (5.52 mmol) of triethylamine were added, and the mixture was heated under reflux for 15 hours. (The reaction solution was ice-cooled, the resulting precipitate was filtered off, and the mother liquor was concentrated under reduced pressure. This residue was suspended in acetic acid (14 ml), sodium acetate trihydrate (5.52 g), 4-chlorobenzenediazonium). Add 6.4 ml (3.2 mmol) of chloride at room temperature for 15
The mixture was stirred for an hour, and the formed precipitate was collected by filtration and dried. Ethanol (2.2 ml) and zinc dust (2.2 g) were added to this precipitate, and the mixture was stirred at 70 ° C. for 1 hour. The reaction solution is filtered, and the mother liquor is decompressed and then water (50
ml) and washed with ether. This aqueous layer was adsorbed on Amberlite CG-120 (H ⁺ type), washed with water and eluted with 5% aqueous ammonia, and the eluate was concentrated under reduced pressure to obtain the title compound (yield 120 mg).

IR (ratio film): 3300 cm ^-1 .

Reference Example 5 Synthesis of 9- [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl] guanine.

300 mg (1.03 mmol) of the pyrimidine compound prepared in Reference Example 4
It was dissolved in N, N-dimethylformamide (2 ml), triethylorthoformate (15 ml) and concentrated hydrochloric acid (0.5 ml) were added, and the mixture was stirred at room temperature for 15 hours. Concentrate the reaction mixture and add 2N to the residue.
Hydrochloric acid (20 ml) was added and the mixture was heated under reflux for 3 hours. This reaction solution was adsorbed on Amberlite CG-120 (H ⁺ type), washed with water, eluted with 5% ammonia water, and concentrated under reduced pressure to obtain the title compound. Yield 126 mg (43%). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard): -174.2 ppm (ddd, J = 1
1.43Hz, 32.57Hz, 52.00Hz). ¹ H-NMR (CD ₃ OD): δ 1.22-1.83 (m, 1H), 2.05-2.9
5 (m, 3H), 3.88 (m, 2H), 4.35-5, 25 (m, 3H), 9.11
(S, 1H).

Reference Example 6 Synthesis of 9- [3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl] -2,6-diaminopurine.

300 mg (1.03 mmol) of the pyrimidine compound prepared in Reference Example 4
It was dissolved in N, N-dimethylformamide (2 ml), triethylorthoformate (15 ml) and concentrated hydrochloric acid (0.5 ml) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, saturated ammonia-methanol solution (10 ml) was added to the residue,
It was left at 70 ° C for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (5 ml), adsorbed on Amberlite CG-120 (H ⁺ type), washed with water and eluted with 5% aqueous ammonia. The eluate was concentrated under reduced pressure to give the title compound. Yield 138 mg (47
%). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard): −189.13 ppm (m).

Claims (1)

[Claims] 1. A 3-fluoro-represented by the following formula [I]:
2-hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative. However, B: an amino group or an acetamide group. R ¹ : hydrogen atom or acetyl group. R ² : hydrogen atom.