JPH0156A - Cyclopentane derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

] Industrial Application Field 1 The present invention relates to a cyclopentane derivative and a method for producing the same. E. Prior Art Nucleosides having fluorine-containing sugars are known as antitumor agents and antiviral agents. Specifically, 3-deoxy-3-fluorofuranoside derivatives (Japanese Unexamined Patent Publication No. 59-17
Publication No. 5498, J, ^, ■right et al., Carbo
hydrate research, 18.345-
347 (see +971)), etc. are known. but,
In many cases, a decrease in in vivo activity is observed compared to in vitro. The present inventors concluded that the cause of this was due to the chemical instability of the above compound in vivo, and as a result of extensive investigation, they were able to synthesize a carbocyclic derivative. Carbocyclic derivatives are those in which the oxygen atom in the ether moiety of sugar is replaced with a carbon atom.This substitution stabilizes the glycosidic bond, improves chemical stability in vivo, and improves enzymes such as phosphoribosyltransferase. It can be expected that the stability against Although alisteromycin, nebranocin, and the like are known as carbocyclic derivatives, no fluorine-containing carbocyclic derivatives are known to date.

Problem to be Solved by the Invention 1 The present invention solves the problem in that the steric position of the hydroxyl group at the 3-position of ribose (also the 3-position in the carbocyclic form) in a fluorine-containing derivative of a carbocyclic analog of ribose is As a result of research and study aimed at introducing fluorine atoms, a new fluorine-containing carbocyclic nucleoside derivative was discovered. The present invention hereinafter relates to this novel fluorine atom-containing carbocyclic nucleoside derivative, its synthetic intermediate, and its production method. [Means for Solving the Problems] A 3-fluoro-2-hydroxyato-substituted-4-hydroxymethylcyclopentane derivative represented by the following formula [N]. However, B: Nucleic acid base residues, azide groups, amino groups,
Or an amino group with a protecting group. 11, ill, hydrogen atom, or protective group. The following formula [11] is characterized by fluorinating the epoxide represented by the following formula [11] with a fluorinating agent to introduce a fluorine atom at the 3-position.1 Next, if necessary, deprotection, formation of nucleic acid bases, etc. 3-fluoro-2 represented by
-Production method of hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative. However, i: Nucleic acid base residue, azide group, amino group,
Amino group with a protecting group. RI, 11: hydrogen atom or protective group. However, RI: hydrogen atom or protective group. R3 Niacyto group, amino group, or amino group with a protecting group. The compound represented by the above formula [11] includes both fluorine-containing carbocyclic nucleosides and synthetic intermediates thereof. The latter is a case where B is a part of a residue of a nucleobase skeleton or a precursor thereof. In this case, B is particularly preferably an amino group or an amino group attached with a protecting group. As protecting groups for amino groups, benzyl group,
Acetyl group, benzoyl group, pivaloyl group are preferred,
Since the stereochemistry of the substituent of the carbocyclic nucleoside matches that of the arabinofuranosyl nucleoside, the position B is located between the hydroxymethyl group at the 4-position and the cis,
In other words, it must be in the β position. Similarly, the hydroxyl group at the 2nd position is at the β position, and the fluorine atom at the 3rd position is at the α position. When -R1 and R2 are hydroxyl group-protecting groups, known hydroxyl group-protecting groups are suitable. Examples include triorganosilyl groups (organic groups include alkyl, aryl, or aralkyl), aralkyl groups, etc. The aromatic group of the aryl group or the 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 of the triorganosilyl group may be the same or different from each other. It's okay. Specifically, for example, trimethylsilyl group, triethylsilyl group, t
-Protecting groups include a butyldimethylsilyl group, a phenyldimethylsilyl group, an acetyl group, a benzoyl group, a benzyl group, a trityl group, a dimethoxytrityl group, and a monomethoxytrityl group. Additionally, alkyl groups may be used as protecting groups in some cases. Suitable examples of this alkyl group include lower alkyl groups, particularly methyl groups. In the present invention, nucleobases refer to nucleobases, derivatives thereof, or nucleobase analogs. Nucleobases or derivatives thereof refer to purines and pyridimines that may have substituents, and their residues ( B) refers to a 9-purinyl group and 1-pyrimidinyl which may have a substituent. Examples of substituents include amino groups, oxo groups, and methyl groups, as well as other substituents such as halogen atoms, alkoxy groups, hydroxyalkyl groups, alkylamino groups,
dialkylamino group, acylamino group, mercapto group,
It may be an alkylthio group, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyl group, or the like. In addition, here, halogen refers to fluorine, chlorine, bromine,
It refers to iodine, and the same applies hereinafter unless otherwise specified. The bonding position i of these substituents is at least one of the 2-position, 6-position, and 8-position for purines, and at least one of the 2-position, 4-position, and 5-position for rimicins. Also useful are aminoxides in which an oxygen atom is bonded to the nitrogen atom of the ring. Examples of purines having specific substituents include azothone, guanine, hypoxanthine, xanthine, 2,6-cyamitsupurine, 6-herobulin, 2-halopurine, 2,6-cyhalopurine, 6-alkylmethylapurine, etc. Examples include monopurine, 6-acylaminopurine, adenine l-oxyto, adenine-7-oxide, and examples of pyrimidines having substituents include uracil, cytosine, thymine, 5-halomethyluracil,
Examples include 5-halothymine, 5-halomethylthymine, and 5-β-bromovinylthymine. Preferred nucleobases or derivatives thereof are ν
In particular, azonine, guanine, hypoxanthine, xanthine, 2-haloadenine, N6-substituted adenine, 2゜6-cyamitsupurine, 6-herobulin, 2,6-dihatalobulin, uracil, cytosine, thymine, 5-herouracil. etc. are preferable. In the present invention, the above-mentioned nucleobase analogs refer to heterocyclic compounds or derivatives thereof having a ring corresponding to purines or pyrimidines, and the residue (B) is the 9-position of purines or the 1-position of pyridimines. As such a heterocyclic compound, which refers to a residue having a bond at a position corresponding to the position, those known as analogs of nucleobases are preferable. Specifically, at least one nitrogen atom in the ring of purines or pyrimidines is converted to a carbon atom or a heteroatom other than a nitrogen atom, or at least one carbon atom in the ring is converted to a nitrogen atom or another atom. Heterocyclic compounds obtained by converting to a telo atom or both of these conversions are preferred, and more preferably, one of the purine rings is
Heterocyclic compounds obtained by converting one nitrogen atom (especially the nitrogen atom at the 1st, 3rd or 7th position) into a carbon atom or an oxygen atom, and one carbon atom (especially the 2nd nitrogen atom) in the ring of purines.
Heterocyclic compounds obtained by converting a carbon atom at position, 5 or 8 into a nitrogen atom, and heterocyclic compounds obtained by performing both of these conversions (i.e., converting one nitrogen atom into a carbon atom or an oxygen atom, and Heterocyclic compounds (obtained by converting one carbon atom to a nitrogen atom) are preferable; in the case of pyrimidines, the nitrogen atom at the 3rd position is similarly converted to a carbon atom, or the carbon atom at the 5th or 6th position is converted to a carbon atom. Heterocyclic compounds obtained by converting into a nitrogen atom are more preferable. Derivatives of these heterocyclic compounds are compounds into which the same substituents as above are introduced, and the substituents include in particular an amino group, an oxo group, a halogen atom, Specific compounds in which a methyl group is preferable include, for example, 5-amino-3,6, which is an analog of guanine.
-Sihydro7)1-1.2.3- Triazine [4,
5,-dlpyrimidin-7-one (see structural formula 1 below). Furthermore, specific examples of residues of nucleobase analogs are shown below, but are not limited to these.
The corresponding nucleobase is shown in parentheses under the chemical formula. The cyclopentane derivative represented by the formula [11] is
Preferably, it is produced from the cyclopentane polyol derivative represented by the above formula [rll through a fluorination step. R3 is preferably an amino group or an amino group with a protecting group attached. As the protecting group for the amino group, Benzyl group, acetyl group, benzoyl group, pivaloyl group are preferred, and the steric position must be β-position,
R' is the same hydroxyl-protecting group as mentioned above, and is preferably an alkyl group, an aralkyl group, an acetyl group, a benzoyl group, or a pivaloyl group, and may also be a silyl group such as t-butyldimethylsilyl group. The fluorination is preferably carried out by a ring-opening reaction of the epoxide of the compound [rll. As the fluorinating agent, an anhydrous hydrogen fluoride-organic base system or anhydrous hydrogen fluoride alone is used. Examples of organic bases include primary alkyl amines, secondary alkyl amines, and tertiary alkyl amines, and the alkyl group has carbon atoms ranging from 1 to 10
Straight or branched chains up to are preferred. In addition, cyclic amines such as pyrrolidine, perazine, and morpholine, aniline, N,N-dimethylaniline, m-phenylenediamine, pyridine, melamine, 1.3.5-triazine, cyanuric acid, cyanuric chloride, 2.4 .6-
Aromatic compounds such as triphenyl-1,3,5-triazine are also used. The equivalent ratio of the organic base to anhydrous hydrogen fluoride can be arbitrarily set from 0% to 100%. Preferably 1% to 50% is used. Solvents include aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents,
Dichloromethane, chloroform, carbon tetrachloride, 1,1.
A halogen solvent such as 2-trichloro-1,2,2-trifluoroethane is used. Preferably, a halogen solvent is used. The temperature range used is from -100°C to the solvent reflux temperature, but preferably from 0°C to around room temperature. The above formula [11] is a known compound, (S. Daluge, R, Vince, J, Org,
Chem, 43.2311 (1978), can be stereospecifically synthesized. The formation of a skeleton of nucleobase residues can be accomplished in a variety of ways. For example, in the literature (S, Daluge et al., J, 0'r
g,Chem,, 43.2311 (+978),
Y., F., Shealy, et al., J. Am., Chem., So.
c,, 91, 3075 (1969), Y, F. 5healy et al., J. Heterocyclic ch.
Em., +3.1015 (1976)). For example, in the case of adenosine, this method uses 5-amino-4,6-dichloropyrimidine and the formula [1]
(When R' and R2 are hydrogen atoms and B is an amane group) are reacted in the presence of triethylamine to form a diaminopyrimidine derivative, and then a purine skeleton is formed using ethyl orthoformate. The chlorine atom at position 6 of the purine ring can be converted to adenosine by treatment with ammonia. [Real stream side 1 Example 1 4β-acetamido-3β-hydroxy-2a-fluoro-1β-cyclopentane methyl acetate 1 formula [
Synthesis of a compound in which R' is an acetyl group, R2 is a hydrogen atom, and B is an acetamido group in Il. 4β-acetamido-2β,3β-epoxycyclobentane-1β-methylacetate [Compound in which R' is an acetyl group and R3 is an acetamide group in formula [111] 7
．． Og (32, Ommol) 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 potassium carbonate aqueous malt and extracted with dichloromethane. Purified by column chromatography to obtain 5.87 g of the title α-fluoroalcohol (
A yield of 77% was obtained. 'H-NMR (CDCl2): δ 1.4-1.6 (
m, Il, 2.00 (8,3 old, 2.07 (s,
3 old, 2.1-2.4 (m, 2 old, 4.07 (d
, J = 6.8Hz, 2 old, 4. l-5,1,
(m, 4 old, 6.52 (d, JT= 7.2Hz
, IHI. "F-NMR (CDC!3): (CFCl, group?l
) -179,9 (ddd, J・5θ, 3.27.8
．． Il, 7Hz). Example 2 9-[3a-Fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl]-6-aminopurine Formula 1 [Compound 1 in which R1 and R2 are hydrogen atoms and B is an adenosine residue] Synthesis. α-fluoroalcohol shown in Example 1 5.87g
(26.3 mmol) was dissolved in methanol (142 ml), 2N-HCI (142 ml) was added, and the mixture was heated under reflux for 1 hour. Distill off the methanol and use Diaion 5
Neutralize through A-21A OH- type (300ml),
After distilling off the solvent, 3.6 g of aminodiol (yield: 9
2%). "F-NMR (010): (CCISF standard)
-181,0(ddd, J-15,2,28,8,
51.8Hz). 0.73 g (4.9 mmol) of aminodiol obtained on the upper side
)of! -butanol (60 ml) and 2.0 g of 5-amino-4,6-dichloropyridine (+2.2 mm
ol) and 3.5 ml of toluethylamine were added, and the mixture was heated under reflux for 2 days. The solvent was distilled off and chloroform-water (1:I
), and the aqueous layer was extracted with Amberlite CG-120
(H" type) (1 (1 ml) and eluted with 0.3% ammonia water (about 300 ml) to obtain 0.97 g (yield 97%) of diaminopyridine. 1'F-NMR ( CD, +OD): (CC1,F
Standard) -179,1 (ddd, Ji6.l, 27
．． 2.41.5Hz). Diaminopyridine obtained above 256 mg (1,0 mmo
l) in 25 ml of ethyl orthoformate, and concentrated hydrochloric acid (
0.6ml) was added and stirred at room temperature for 18 hours. The solvent was distilled off to obtain 182 mg of chloropurine (yield: 68%). ”F-NMR (acrtone-da): (CCI
aF standard) -175,3 (ddd, Jl112.3.2
6.4.50.8Hz). 'fl-NMR (acrtone-da): δ 2
．． 0-2.23 (m, 2 old, 2, 3-4.0 (m
, 68), 4.5-5.5 (m, 2H), 8
．． 59 (s, +8). 8, 73 (s, IH). 125 mg of chloropurine ((1℃ to 1,47 mmoυ)
An ammonia-methanol solution (10 ml) saturated with water was added thereto, and the mixture was heated in an autoclave at 100°C for 18 hours, cooled, and low-boiling substances were distilled off. IN-HCI (5m
After stirring at room temperature for 3 hours, the solvent was distilled off, and the mixture was purified by reverse phase C-18 silica gel column chromatography to obtain 73 mg of fluoroadenosine (yield: 63%). Melting point 20G-210°C (decomposed). ”F-NMR (DMSO-dal: (CCI2F
Standard) -171,8 (ddd, J wealth 12.6. 22.
2. 50.0+lz). 'H-NMR (DMSO-da): δ 2.0-3
．． 0 (m, 3 old, 3.0-5.2 (m, 6 old,
5.4-5.6 (m, 1 old, 7.16 (brs. 211), 8.13 (brs, 2H). Example 3 1-[3a-fluoro-2β-hydroxy-4β-hydroxymethyl- 1β-Cyclopentyl 1uracil [formula [
Synthesis of the compound in which R1 and R1 are hydrogen atoms and B is a uracil residue in 11]. 300 mg of aminodiol shown in Example 2 (2,0
mmol) was dissolved in 10 ml of N,N-dimethylformamide and cooled to -25°C. Here 3-ethoxy-2
-Burobenoyl isocyanate (0.4M benzene solution, 5.0 ml, 2.0 mmol) was added dropwise over 5 minutes. After 10 minutes, the temperature was returned to room temperature, and the solvent was distilled off in a hot water bath at 30°C. After completely distilling off the solvent with ethanol (5 mL x 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 temperature of 40°C. Purify it using a silica gel column. 340 mg (yield 70%) of the listed compound was obtained. "F-NMR (CD30D, CCl3F standard) Knee 1
75.3 (ddd, J12.7.28.3.5
1.011z). 'H-NMR (CD30D): δ 1.9-2.8
(m, 3) ri, 3.6-4.0 (m, 211), 4.3
-5.4 (m, 3) 11.5.85 (d, J=8.6H
z. IH), 7.98 (d, J・8.6Hz, l
H). Example 4 1-[3 a-Fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl l-thymine [formula [
Synthesis of Compound 1 in which R1 and R1 are hydrogen atoms and B is a thymine residue in 11. 270 mg (1,8 m
mol) was dissolved in 10 ml of N,N-dimethylformamide and cooled to -25°C. Here 3-methoxy-2-
Methyl-2-propanoylisocyanate (0,4M-
A benzene solution (4.5 ml, 1.8 mmol) was added dropwise over 5 minutes. After 10 minutes, return to room temperature and take a hot water bath.
The temperature was lowered to 0°C and the solvent was distilled off. Ethanol (5ml x 3)
After the solvent was completely distilled off, 10 ml of 2N hydrochloric acid was added, and the mixture was heated under reflux for 20 minutes. After cooling to O'C, it was neutralized with 2N sodium hydroxide, and water was distilled off at a water temperature of 40'C. The product was purified by silica gel column chromatography to obtain 380 mg (yield: 82%) of the listed compound. ' ``F4MR (CDsOD, CC15F standard) knee 175.0 (ddd, J volume 12.7.28.3.51
．． 01(z). Otori) 1-NMR (CDs oo+: δ 1.8-2
．． 8 (mis, δ 2.02 (s, 3 old. total 6 old, 3.7-4.0 (m, 3H)
, 4.2-4.6 (m, 211), 7.80 (
brs, IHI. Example 5 1-[3a-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl]-5-iodouracil [Formula [11, R1 and R* are hydrogen atoms, B-615
-Synthesis of compound 1 which is an iodouracil residue. 820 mg of the uracil derivative produced in Example 3 (3,4
mmol) in anhydrous pyridine (10 ml), 4-
Dimethylaminopyridine (5mg), acetic anhydride (1m
1) was added and stirred at room temperature for 30 minutes. 0.5M reaction solution
The mixture was poured into an aqueous potassium dihydrogen phosphate solution (60 ml) and extracted with chloroform (60 ml). The chloroform layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography. Yield 1.13
g(+00)%. 560 mg (1.7 mmall) of this acetyl compound was added to acetic acid (
220 mg of iodine (0.87 m
mol) was added, and fuming nitric acid was added until the color of iodine disappeared. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), and the solution was diluted with saturated sodium bicarbonate solution (50 ml).
Washed twice. After concentrating the chloroform layer under reduced pressure, it was dissolved in ethanol (30 ml), and 2N-sodium hydroxide (
30 ml) was added and stirred for 20 minutes under water cooling.
was neutralized with 2N-hydrochloric acid, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the listed compound. Yield (35%). ""F-NMR (CDsOD, CC11F standard) knee 192.7ppm (dt, J-20,00Hz,
54.86Hz). 'H-NMR (CD30D): δ1.24-1.96
(m, 3H), 3.92 (bd, Jl14.
63) 1z, 2H), 4.43 (m, IH)
. 4, 50-5.52 (m, 2H), 7.95
(d, J Maro 1.80 Hz, IHI. Example 6 1-[3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentylaminesin [formula [
Synthesis of compound 1 in which R1 and R1 are hydrogen atoms and B is a cytosine residue in 11. Acetyl compound 56 produced in the manufacturing process of Example 5 above
0 mg' (1,7 mmol) in anhydrous acetonitrile (
1.08 g (5.1 mmol) of 2-mesitylenesulfonyl chloride was added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, saturated ammonia-methanol solution (10 ml) was added and stirred at room temperature for 15 hours. This reaction solution was concentrated under reduced pressure, dissolved in 50% methanol water (10 ml), and then Amberlite CG-
120 () l" type), and after washing with water, it was eluted with 5% aqueous ammonia. The eluate was concentrated under reduced pressure to obtain the listed compound. Yield: 310 mg (77%). "F-NMR (CD30D, CC15F standard) knee 174.3ppm (ddd, J=II2.0OHz,
29.71Hz. 52, 57Hz). 'II-NMR (CDsOD): 51.96-2
．． 68 (m, 3H), 3.88 (bd. J□4.97Hz, 2H), 4.28-4.64
(m, III). 5, 00-5.42 (m, 211), 6.08
(d, J snow 5.14Hz, Ill.?, 98 (d, Jl15.14Hz, [1)
. Example 7 Synthesis of [3α-fluoro-20-hydroxy-4β-hydroxymethyl]-[2,5-diamino-6-chloro-4-pyrimidinyl]amine. 3a-Fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentylamine (Example 2) 4
12 mg (2,76 mmol) was dissolved in 1-butanol (58
ml), add 906 mg (5,52 mmall) of 2-amine-4,6-dichloropyrimidine and 77"0 μl (5,52 mmol) of triethylamine, and add 1
The mixture was heated under reflux for 5 hours. The reaction solution was cooled with water, the resulting precipitate was filtered off, and the mother liquor was concentrated under reduced pressure. This residue was dissolved in acetic acid (14
ml). Suspended in water (14 ml), sodium acetate trihydrate (5
, 52 g), 6.4 ml (3.2 mmol) of 4-chloropenzene diazonium chloride was added, and the mixture was stirred at room temperature for 15 min.
The mixture was stirred for an hour, and the resulting 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 was filtered, and the mother liquor was dissolved under reduced pressure in water (50 ml) and washed with ether. This aqueous layer was adsorbed on Amberlite CG-120 ()l'' type), washed with water, eluted with 5% aqueous ammonia, and the eluate was concentrated under reduced pressure to obtain the title compound. Yield: 120 mg. IR ( film) 3300 cm-' Example 8 9-[3a-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentylcoguanine [formula [
Synthesis of compound 1 in which R' and R'' are hydrogen atoms and B is a guanine residue in step 11. 300 mg of the pyrimidine compound (1,0
3 mmol) in N,N-dimethylformamide (2 ml
) and triethyl orthoformate (15 ml).
), concentrated hydrochloric acid (0.5ml) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, 2N hydrochloric acid (20 ml) was added to the residue, and the mixture was heated under reflux for 3 hours. This reaction solution was adsorbed on Amberlite CG-120 () I'' type), washed with water, eluted with 5% aqueous ammonia, and concentrated under reduced pressure to obtain the title compound. Yield: 126 mg (43%). F-NMR (CD30D, CCIIF standard) knee 174.2 ppm (ddd, J-11, 4311z, 3
2.57) 1z. 52.00Hz). '11-NMR (CD300): 61.22-1.
83 (m, I)I). 2, 05-2:95 (m, 3 old, 3.88 (m
, 2) 1) , 4.35-5.25 (m, 3) 1
), 9.11 (s, IH) Example 9 9-[3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-cyclopentyl]-2,6-diamitpurine [Formula [11, Ht, Hz is the atom] Synthesis of Compound 1 in which the atom, B, is a 2,6-cyamitubulin residue. 300 mg of pyrimidine produced in Example 7 (1,0
3 mmol) in N,N-dimethylformamide (2 ml
Triethylorthoformate (15 m
l) 1. Concentrated hydrochloric acid (0.5ml) was added and stirred at room temperature for 15 hours. This 9 reaction solution was concentrated under reduced pressure, saturated ammonia-methanol solution (10 ml) was added to the residue, and the mixture was allowed to stand at 70°C for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (
Amberlite CG-120 (HI
After washing with water, it was eluted with 5% aqueous ammonia. The eluate was concentrated under reduced pressure to obtain the title compound. Yield 138 mg (47%). I″F-NMRtct+Loo, CCI, F standard)
: -l 89.13ppm (m) Example 10 5-amino-3,6-sihydro-3-[3α-fluoro-2β-hydroxy-4β-hydroxymethyl-1β-
cyclopentyl] -78-1,2,3-triazolo[
4,5-d ] Synthesis of pyrimidin-7-one 300 mg (1,03 mmol
) was dissolved in IN hydrochloric acid (2.5 ml), sodium nitrite (65 mg) was added, and the mixture was stirred for 1 hour under water cooling. The reaction solution was passed through Diaion 5A-214 (OH type), 2N hydrochloric acid was added thereto, and the mixture was heated under reflux for 3 hours. This reaction solution was adsorbed on Amberlite CG-120 (H" type), washed with water, and eluted with 5% aqueous ammonia. The eluate was concentrated under reduced pressure to obtain the listed compound. Yield: 121 mg. 1"F- NMR (CD20D, CCl3F standard) Nee l? 8.8ppm (ddd, , l'14.291
1z, 32.00) 1z. 54.57Hz). 'H-NMR (CD30D): δ2. l 2-
2.89 (m, 311). 3,82 [d, J116.17Hz, 2H),
4.10-4.38(m, 1)1) ,' 4.6
2-5.54 (m, 2 old. [Effect of the invention] The production method of the present invention enables the stereospecific synthesis of carbocyclic forms of fluorine-containing nucleosides. This makes it possible to improve the low chemical stability of fluorine-containing nucleosides.

Claims (2)

[Claims] (1) 3-fluoro-2- represented by the following formula [I]
Hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] However, B: Residues of nucleobases, azide groups, amino groups, or amino groups with protective groups. R^1, R^2: Hydrogen atom or protective group. (2) It is characterized by fluorinating the epoxide represented by the following formula [II] with a fluorinating agent to introduce a fluorine atom at the 3-position, and then performing deprotection, formation of a nucleobase skeleton, etc. as necessary. A method for producing a 3-fluoro-2-hydroxy-1-substituted-4-hydroxymethylcyclopentane derivative represented by the following formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] However, B: Residues of nucleobases, azide groups, amino groups, or amino groups with protective groups. R^1, R^2: Hydrogen atom or protective group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] However, R^1: Hydrogen atom or protective group. R^3: Azido group, amino group, or amino group with a protecting group.