JPH01151542A - Cyclopentane derivative, production and use thereof - Google Patents

Abstract

NEW MATERIAL:A 1-substituted-3-fluoro-4-hydroxymethylpentane derivative shown by formula I (R<1> is residue of nucleic acid bases which may be protected, azido, amino or protected amino; R<2> is H or hydroxyl protecting group). EXAMPLE:9-[3alpha-Fluoro-4beta-hydroxymethyl-1beta-cyclopentyl]-6-amin opurine. USE:An antitumor agent or antiviral agent. PREPARATION:A compound shown by formula II (R<3> is residue of nucleic acid bases, azido, protected amino, etc.; R<4> is hydroxyl-protecting group; X is H or activated group) is reacted with a reducing agent such as triphenyltin hydride in an inert solvent such as benzene at room temperature-120 deg.C and the OX group is reduced into H to give a compound shown by formula I. N,N- Azobisisobutyronitrile is preferably used as a reaction initiator.

Description

Detailed Description of the Invention] Industrial Application Field 1 The present invention relates to fluorine-containing C-click type nucleosides, their synthetic intermediates, their production methods, and their uses.

[Prior art l Nucleosides, nucleotides and their various derivatives are
It is used as a so-called antimetabolite substance that antagonizes essential metabolic substances such as malignant tumor cells and suppresses cell growth and proliferation, and as a 1< NΔ synthesis ■ pharmaceutical agent, including antitumor agents and antiviral agents. Widely used in agriculture and other applications.

In particular, fluorine-containing nucleosides, especially nucleosides having fluorine in the sugar moiety, have attracted particular attention in recent years as antitumor and antiviral agents. This is because fluorine atoms have electronic equivalence compared to hydroxyl groups, have a much larger bond to carbon atoms than hydroxyl groups, are inert, and have an atomic size similar to hydroxyl groups. Therefore, replacing the hydroxyl group with a fluorine atom can be expected to have excellent effects in terms of antimetabolism and the like.

However, there are few known examples of nucleosides that correspond to fluorine-containing deoxybenfuranoside, such as 2',3'-dideoxy-3'-fluorothymidine (1).

Langen et al., TcLrahcdron
1. eLLcrs,, 27 2463 (+1)
71), 2', 3'-dideoxy-3''-fluoroadenosine (DP 209.I'171.2', 3-dideoxy-3'-fluoroadenosine (Dr 151), 90
3), 2″, 3′, 5′-1-lysooxy-3′,
5'-difluorodemidine (1', Langen et al., AcLa 13io1.Mod, Gcrm, 2
3. 19+1969).

On the other hand, carbocyclic nucleosides are known as nucleoside analogs.

Carbocyclic nucleosides are those in which the oxygen atom in the ether moiety of sugar is replaced with a carbon atom, and this substitution stabilizes the glycosidic bond and improves chemical stability in vivo. It can be expected that the stability of phosphoribosyltransferases and the like against oxygen will be improved. Although alisteromycin, nebulisin, and the like are known as carbocyclic nucleosides, no fluorine-containing carbocyclic nucleosides are known to date.

[Means for Solving the Problems] The present invention relates to fluorine-containing carbocyclic nucleosides corresponding to nucleosides having a fluorine-containing deoxybento flood, synthetic intermediates thereof, and methods for producing them. The following invention relates to the invention and its use as an antitumor agent.

1-substituted-3-fluoro- represented by the following formula [1]
4-Hydroxymethylcyclopentane derivative.

R' = Optionally protected nucleobase residues, azide groups, amino groups, Or a protected amino group.

R2: hydrogen atom or hydroxyl group retention Protector.

The following formula is characterized by converting the OX group of the I-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula [II] into a hydrogen atom, and deprotecting the protecting group if necessary. A method for producing a 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by [1].

Hi R1, optionally protected nucleobase residues, azide groups, amino groups.

Or a protected amino group.

R2: hydrogen atom or hydroxyl group retention Protector.

R″: Residues of nucleobases (however, anti- If it has a reactive functional group, use a protective group. Protected items) Ajitono, (, Or protected Amitsuno, L.

1 (4: Protecting group for hydroxyl group.

X: hydrogen atom or activating group.

An antitumor agent containing as an active ingredient a 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula ti1) or a pharmaceutically acceptable salt thereof.

to B: Remains of nucleobases, (.

Among the derivatives represented by the above formula [1] of the present invention, 1 (
If the compound in which 1 is a residue of a nucleobase and 1 (2 is a hydrogen atom) is a fluorine-containing carbocyclic!91!nucleoside Xn, and R' and R2 are other groups, the synthesis It is an intermediate. R1 and -CIl□OR, corresponding to normal nucleosides, must be on the same side of the cyclobencune ring (referred to as the β-face side). Even if the fluorine atom is present on the 0-face side, , the opposite side (hereinafter referred to as the α side)
may exist in However, more preferably, it is present on the 0-face side corresponding to the 3' hydroxyl group (usually present on the 0-face side) of normal nucleosides. Derivatives in which the fluorine atom is on the α-plane side can be regarded as carbocyclic nucleosides corresponding to 2″, 3′-dideoxy-3′-fluoro-β-〇-ribonucleosides, and the fluorine atom is on the β-plane side. The derivative is 2',3'-dideoxy-
It can be considered as a carbocyclic !-linucleoside corresponding to 3″-fluoro-β-D-xylonucleoside.

Hl is preferably a residue of nucleobase Z0 as described in 1) (ie, 1i1) and the derivative represented by the formula [1] is preferably a carbocyclic nucleoside).

In the present invention, nucleobase ¥r1 refers to a nucleobase, a derivative thereof, or a nucleobase analog. Nucleic acid bases or derivatives thereof refer to purines and pyridimines which may have a substituent, and the term "residues" refers to 9-purinyl groups which may have a substituent and ! - Refers to pyrimidinyl. 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 groups, acylamino groups, mercapto groups, and alkylthiono groups ( .

It may be a cycloalkyl group, an aryl group, an aryloxy group, an aralkyl group, or the like. In addition, here, halogen refers to fluorine, chlorine, bromine, and iodine, and the same applies to the following unless specifically mentioned. The &1° bonding position of these substituents is at least one of the 2-position, 6-position, and 8-position in purines, and the 2-position, 4-position in pyrimidines.
and at least one of 5th place. Furthermore, aminoxide in which an oxygen atom is bonded to the nitrogen atom of the ring is also used for if. Examples of purines with specific substitutions), (
For example, adenine, guanine, hyboxanthin, xanthine, 2,6-diamitubulin, 6-valobulin, 2
-halopurine, 2,6-cyhalopurine, 6-alkylmethylaminopurine, 6-acylaminopurine, adenine 1-oxyto, adenine-7-oxide, etc.; examples of pyrimidines having substituents include uracil, cytosine , thymine, 5-halomedeluracil, 5-halothymine, 5-halomethylthymine, 5-0-bromovinylthymine, and the like.

Preferred nucleobases or derivatives thereof are in particular adenine, guanine, hypoxanthine, xanthine, 2-haloadenine, N6-substituted adenine, 2,6-diamitubulin, 6-herobulin, 2,6-cyhalopurine, uracil,
Cytosine, thymine, 5-he〇uracil and the like are preferred.

The above-mentioned nucleobase analog in the present invention refers to a heterocyclic compound or a derivative thereof having a ring corresponding to purines or pyrimidines, and the residue (13) is the 9-position of purines or the 1-position of pyrimidines. This refers to a residue that places a bond at the position corresponding to the position. As such a heterocyclic compound, those known as 'ffl derivatives of nucleobases are preferred. 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. Preference is given to those heterocyclic compounds which can be obtained by conversion to a telo atom or both. More preferably, one nitrogen atom in the purine ring (particularly the 1st, 3rd or 7th position)
carbon atom or oxygen Jj;i :f
A heterocyclic compound obtained by converting into -.

Heterocyclic compounds obtained by converting one carbon atom (particularly the carbon atom at the 2nd, 5th or 8th position) in the ring of purines to a nitrogen atom, and those obtained by carrying out both of these conversions (i.e. one nitrogen atom). convert an atom into a carbon atom or an oxygen atom,
and a heterocyclic compound obtained by converting one carbon atom to a nitrogen atom is preferred. Further, among pyrimidines, heterocyclic compounds obtained by similarly converting the nitrogen atom at the 3rd position to a carbon atom, or converting the carbon atom -r at the 5th or 6th position to a nitrogen atom are more preferable. Derivatives of these heterocyclic compounds are compounds into which the same substituents as in +iiJ have been introduced,
As the substituent, particularly preferred are an amino group, an oxo group, a halogen atom, and a methyl group. Specific compounds include, for example, 5-amino-3,6-sihydro71)-1.2.3-1-riazolo[4,5,-d
l-pyrimidin-7-one (see the first structural formula in 1.).Furthermore, specific examples of residues of nucleobase analogs are shown below, but are not limited to these. The corresponding nucleobases are shown in parentheses.

Nil N1)゜1(1 may be a residue of a nucleobase protected with a protecting group as described further below. This protecting group is ultimately deprotected, but 1 - In the case of vines that are considered to be residual derivatives of nucleic acid bases as described above (
For example, 6-acylaminopurine residue), the deprotecting group is not essential. R1 may also be a functional group useful for introducing the residue of a nucleobase, ie, an azido group, an amino group, or a protected amino group. That is, R1
Derivatives having these groups are useful as intermediates for the synthesis of carbocyclic 1%+7 nucleosides In. Of course, the use of this derivative is not limited to only as an intermediate for the synthesis of carbocyclic nucleosides. Also, nm is usually a hydrogen atom, but
The synthetic intermediate may be a hydroxyl group-protecting group, which will be described later.

When the residue of the nucleobase has a reactive group such as an amino group or a hydroxyl group (including a tautomer of a compound having a keto group), the reactive group may be temporarily protected. As the protecting group for an amino group or the protecting group when R' is a protected amino group, a benzyl group, an acelyl group, a benzoyl group, a pivaloyl group, a dialkylmethyl group, etc. are preferable. Known hydroxyl-protecting groups are suitable as the hydroxyl-protecting group of the residue of the nucleic acid base or when R2 is a hydroxyl-protecting group.

For example, triorganosilyl group (iqJM group such as alkyl, aryl, or alkylalkyl)
The aromatic nucleus of the acyl group or alkyl group may have a substituent such as an alkyl group, alkoxyno, or ξ. Further, the three organic groups bonded to the silicon atom of the triorganosilyl group may be the same or different from each other. in particular,
For example, trimethylsilyl group, triethylsilyl group,
There are protecting groups such as butyldimethylsilyl group, phenyldimethylsilyl group, acetyl group, benzoyl group, benzyl group, trityl group, dimethoxytrityl group, monomethoxytrityl group, and in some cases, alkyl group. A lower alkyl group, especially a methyl group, is suitable as the alkyl group used as a protecting group.

1); The cyclopentane derivative represented by item 1 [1] is
The -OX group is preferably produced by converting the 10x group into a hydrogen atom from a derivative having an 10x group at the 2-position represented by the following formula [1)]. It is an activated hydroxyl group obtained by reacting a chemical agent. By reducing this (activated) hydroxyl group, the 10x group is converted into a hydrogen atom.

1! 'I +': In formula 2 [1)], A may be present on the −OXX base surface side or A may be present on the β surface side.

1 (3 is the same group as +iiJ P, but hydroxyl), (
When containing reactive groups such as 1 and 1, they need to be protected as they may interfere with the reduction reaction. For example, hydroxyl, %, amino groups, etc. In the residue of the nucleobase Xfl that is a reactive group, the reactive group must be protected with the above-mentioned protecting group. When R'' is an amino group, The amino group needs to be protected with a protecting group as described above.For the same reason, R4 needs to be a hydroxyl protecting group.The -○x group may be a hydroxyl group, but in this case A relatively strong reducing agent is required, and groups such as -〇R4 may also be affected by it. Therefore, it is preferable that the -〇x group is a group that is more easily reduced. It is preferable to convert X into an active group derived from the reactant and then reduce the reactant.

N,N'-diocarponyldiimidazole, phenylchlorothionocarbonate, N,N'-dimethylbenzamide-phosgene-hydrogen sulfide (details: 0.1). R,
13arLon et al., J.C.S., I'crkin l.
(1975) 15741 etc. can be used,
As the reducing agent, triplicyltin hydride, triphenyltin hydride, etc. can be used. Furthermore, after the hydroxyl group is m-trifluoromethylbenzoylated, the hydroxyl group can be selectively removed using a light source q.I. ('l', MaLumura et al., J, Δm, C
ham, Sac, .

(19861) 08, 31) 51. This reduction reaction is usually carried out in an inert solvent such as benzene or toluene, and is carried out at 0°C.
Reaction temperatures within the range of melt reflux temperatures are employed, and in particular temperatures of the order of 120° C. are employed in chambers 8 and 7. Further, it is preferable to use N,N-azobisisobutyronitrile, benzoyl peroxide, or the like as a reaction initiator.

1); 1°C The cyclopentane derivative represented by the formula [1)] (where X is a hydrogen atom) is a new compound. This derivative and its production method are described in patents pending by the applicant (see Japanese Patent Application No. 18573/1982 and Japanese Patent Application No. 27290/1982). This derivative has a hydroxyl group at the 0-position or β-position of the 2nd position, and a fluorine atom at the 0-position of the 3rd position. Also, 2nd place 0
The derivative having a hydroxyl group at the 3-position and a fluorine atom at the 3-position is described in another patent application filed by the present applicant (see Japanese Patent Application No. 1982-1'10454, MeitIn:'F).
. As an example, a derivative having a hydroxyl group at the α-position at the 2-position and a fluorine atom at the β-position at the 3-position can be produced by fluorination of the corresponding 2a,3β-epoxy derivative (known compound); The compound having a hydroxyl group at the 3-position and a fluorine atom at the 3-position is a fluorinated compound of the corresponding 2C1,3 (I epoxy derivative (produced by epoxidation of the corresponding known 2a, 3a-dihydroxy compound). Of course, the cyclobencune derivative represented by formula [II] is not limited to those obtained by these methods.

The derivative obtained by converting the -OX group into a hydrogen atom, or the derivative obtained by deprotecting the protecting group if necessary, has the formula [1
] It is a cyclopentane derivative represented by. Also, 1(
Derivatives in which 1 is an amino group can of course be obtained by deprotecting the protected amino group, and can also be obtained by converting the azido group of a product in which 1(+ is an azido group) into an amino group. Conversion of acid group to amino group is
For example, it can be carried out by a reaction similar to Synthesis Example (2) described below. When II' is not an optionally protected nucleobase residue, the 1st position can be converted to a nucleobase residue, for example, by a reaction similar to the synthesis example [phase] described below.

The present invention further provides a cyclopentane derivative represented by the +i:1 formula [Ill] or a pharmaceutical thereof! It is an antitumor agent containing two acceptable salts as active ingredients.

In the formula [Ill], 13 is a residue of a nucleobase as described in +iii. The derivative represented by the formula [III] is a compound in which 1 (1 is a residue of a nucleobase) and does not have a Q group among the derivatives represented by It is a compound considered to be a fluorine carbocyclic nucleoside.Formula [Il
The derivatives represented by [1] can be used as they are, but the salts that can be used as salts are salts with acidic substances, such as hydrochloric acid, sulfuric acid, etc. , 1) 1-organic acids and acidic acids such as phosphoric acid
There are 7 acids such as hydrochloric acid and acetic acid.

EXAMPLES The present invention will be specifically explained below using Examples and Synthesis Examples, but the present invention is not limited to these Examples. Furthermore, the following synthesis example shows the synthesis of a compound represented by formula [II]. Note that the positions of the substituents are determined for each individual compound, and therefore do not necessarily match the positions in the above explanation.

Synthesis Example 1 ■ Synthesis of 2β,3β-epoxycyclopentene-10-methanol.

Molybdenum hexacarbonyl 0.16g (0.6mm
o l ) and thi-butyl hydroperoxide 3.0
g (To 30 mmall of benzene (+10 ml) suspension, add 2.0 g of 2-cyclobenzone methanol (20 m
mol) of benzene solution (20ml) was added, and 1
．． The mixture was heated under reflux for 5 hours. The reaction mixture was treated with cold saturated aqueous sodium sulfite solution and extracted with ethyl acetate.

After drying the organic layer with magnesium sulfate, it was concentrated, purified by column chromatography, and purified with epoxy alcohol 1.61 ((
A yield of 70% was obtained.

'II-NMR (CDC1,l: δ 0.
(1-1,4(m, ll1l, 1.4-2.5
(m, 51) 1, 3.56 (brs,
21)), 3.7(1(d,Ji6.51)z
, 21) 1゜■ 2β, 31]-epoxy-1β-
Synthesis of cyclopentanemethyl benzyl needle.

Sodium hydride (55%) 5.7g (0.13m
ol) was suspended in tetrahydrofuran (9 Gml) and cooled to 0°C, and then 12.32 g (0,1 Imol) of the epoxy alcohol obtained in Synthesis Example 2 was dissolved in tetrahydrofuran (40 ml) and added thereto. After stirring at room temperature for 30 minutes, 25.9 g of benzyl bromide (0
, 15mt+ll was added thereto, and the reaction was carried out under reflux conditions for 30 minutes. 21.0 g of benzyl ether was post-treated in the usual manner.
(yield 99%).

'II-NIJR (CDCItl: δ 0.8-1
．． '5 (m, 51)).

2.4-2.7 fm, 41)), 3.62 (s
, 21) 1 , 7.44 [s, 51)) Synthesis of 026-hydroxy-3-cyclobenzone-10-methyl benzyl needle.

Diphenyl diselenide 33.3g (0,I 1mo
1) Suspended in ethanol (131 ml) and heated at 0°C.
It was cooled to Here is 8.07g of sodium borate hydride.
fO, 21 mol) was added little by little. After stirring at room temperature for 30 minutes, 21.7 g (0,
1 mol) was dissolved in ethanol (I!i, 1 ml) and added dropwise over 45 minutes. After heating under reflux for 1 hour and cooling, 4.5 ml of 30% hydrogen peroxide 1) was added dropwise, and the reaction temperature was 15°C. I tried not to let this happen.

After the reaction was completed, 6.6 g of the title product was obtained by post-treatment as usual.
I got it.

'It-NMR (C1lCIff): δ 2.0-
2.7 (m, 41) 1.3.6-3.0 (m,
21)), 4. [lO(L2+1), 4.8-
5.0 (m, III), 5゜[1-6,2(m
, 21)), 7.44(s, 51)).

■ Synthesis of 2β-butyldimethylsiloxy-3-cyclobenzone-174-methyl benzyl ether.

6.58 g (32.3 m
moll, chloro L-butyldimethylsilane 5.8g
(38.8 mmol) was added to perform silylation.

After reacting at 40°C for 1.5 hours, ice water was added and extracted with hexane. After drying and concentrating the 41 organic layer, it was purified by column chromatography to obtain 9.82 g (95% yield) of silyl needle.

'I to NMR (CDCIs) 2 δ b,
III (s, 61) 1, 1.41 (s,
91)), 2.3-2.7 (m, 31)1
, 3.5-4.0 (m.

21)), 5.14 (d, Jl, 81)z,
21)), 4.9-5.01m.

1) 1) , 5.8-6.2 (m, '21
)1, 7.50 (s, 51)1゜■ 2β
-L-Butyldimethylsiloxy: 3a.

Synthesis of 4a-Eboxycyclobendene-1β-methylbenzyl needle.

Product obtained in Synthesis Example ①'1. lOg (21),5
mmol) in dichloromethane (20 ml) IW
L/, m-chloroperbenzoic acid 6.22 g (34.2 m
mol) of dichloromethane suspension was added. After 2 hours of reaction.

The mixture was treated with saturated sodium bisulfite solution and the mixture was purified by column chromatography to give the title product 7.6.
g (yield 80%) was obtained.

'II-NMR (CDCI=1): δ 0.19
(s, 31)), 0.22 (s, 31)), 1.
00 (s, 91)), 1.3-1.8 (m,
21)).

2.0-2.3 (m, 21)), 3.
4-3.13 (m, 31)), 4.4
6 (dis-LorLod d, J□ 4.01)
z, 1)1), 4.62 (d.

J1)4.31)z, 21)) , ? ,! +
5 (s, 51)).

■ Synthesis of 4β-azido-30-hydroxy-2β-butyldimethylsiloxycyclopentane-10-methyl benzyl needle.

Epoxide obtained in Synthesis Example ① 5.89g (17,6
mmol) was dissolved in water (20 ml) and 2-methoxyethanol (60 ml), and 1.26 g of ammonium chloride and 6.0 g of sodium azide were added and reacted at 75°C for 18 hours. The solvent was distilled off, brine and needles were added, and the mixture was extracted with ether. Purification was performed by column chromatography to obtain 52 g of the title purified product 3 and 2.32 g of raw material.

'II-NMR (CDCI, +l: 6 01 mouth 4 (s, 31) 1, O, 0a (s, 31) 1,
0.98 (s, 91)), 1.6-2.4 (
m, 41)1゜3.3-3.8 (m, 31)1
, 3.9-4.1 (m, 21) 1 , 4.5-4.
6 (m, 21)), 7.3-7.4I (m,
51)).

■ 40-azido-3α-benzyloxy-20-L-butyldimethylsiloxycyclopencune-1β-methyl
Synthesis of benzyl nibbles.

3.52 g (9.3 mm) of alcohol obtained in Synthesis Example ①
o I l with 0.4'1 g of sodium hydride (Il, 2
mmol) in tetrahydrofuran (20 ml). After stirring at room temperature for 30 minutes, 2.2 g (13.0 mmol) of benzyl bromide was added and heated under reflux for 1 hour. By column chromatography purification with post-treatment in the usual manner. , 4.0 g (yield 93%) of the title purified product was obtained.

'II-NMII (CDCI,): δ 0.
Go (s, 61)), 0.84(s, 91)
), 1. ! J-2, [l (m, 31) 1 , 3
．． 3-3.8 (m.

41) 1, 4.0-4.2 (m, III
), 4.4-4.6 (m, 41) 1°7, 40 (s, I 01l).

■ 4β-azido: Synthesis of 3α-benzyloxy-2β-hydroxycyclobencune-10-methylbenzyl needle.

Silyl needle 4.05g (0,6
5 mmol) was dissolved in tetrahydrofuran (15 ml), and a solution of detrabutylammonium fluoride in tetrahydrofuran (factor = 1) (26 ml, 2
6 mmol) was added over 40 minutes, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, add 1 part of saturated anammonyl chloride to the reaction mixture.
) and extracted with chloroborm. The product was purified by column chromatography to obtain 2.5 [1 g (yield: 85%) of the title compound.

'II-NMR(CDC1,l :δIJ-2,6(m
, 31)), 2.9-3.1 (m, lll1.3.6
-3.9 (m, 41) 1.4.1-4.4 (m,
ll1l.

4,56 (s, zllll, 4.72 (s, 2
1) 1.7.44 (s, 1lIl.

Synthesis of 04β-amino-3a-benzyloxy-20-fluorocyclopentane-1O-methylbenzyl needle.

1.84 g of alcohol obtained in Synthesis Example ■ (5,22
Dissolve mmo I) in dichloromethane (15 ml), dissolve 4.2 ml of pyridine (52 mmall), 2.0 ml of chlorotrimethylsilane [16.0 mmall
was added and stirred at 0°C for 30 minutes. After working up as usual, the crude product was dissolved in dichloromethane (25 ml) and diluted with biperidinoaminosulfur trifluoride 1. Oml (
7.8 mmall was added and reacted at 0°C for 1 hour. Triethylamine (1.2 ml) was added, and the mixture was worked up with a saturated aqueous potassium carbonate solution. Purification was performed by column chromatography to obtain 0.30 ml of triethylamine.

"F-NMR (CDCIOllCCl, F group γS'
j) -1'1). 0(ddd, J・22.5.
30.7.54.31)z).

'If-NMII (CDCI+l: δ1.9-2.
4 (m, 31)), 3.0-4.1 (m, 41)1.
4.2-5.1 (m, 51)), 7.39 (s,
101)).

IR (ncaLl 2160, 1500, 1460
300 mg of the product obtained on cm-' was dissolved in ethanol (5
0 ml), chloroform (2 ml) was added, 5% palladium on carbon (0.5 g) was added, and hydrogenated to obtain the standard aminodiol.

"F-NMII (CDCI, ll: (CCI, F Standard 1-188.10 (ddd, J.24.2.33.
4.513.41)y,).

[Phase] 9-[3α-fluoro-20-hydroxy-4
β-hydroxymethyl-1β-cyclopentyl]-6-
Synthesis of aminopurines.

Aminodiol obtained in Synthesis Example ① 1) Dissolve the product in 1-butanol (Gmll) and dissolve
Dichloropyrimidine 300mg (1.8mmol),
Triethylamine (0.5 ml) was added and heated under reflux for 18 hours. The solvent was distilled off and chloroform-water (1:
The aqueous layer was passed through a column of Dowex CG-100 (Type II) (3 ml) and extracted with 4% aqueous ammonia (2 ml).
00 ml) was used to elute the desired product. The solvent was concentrated to obtain 176 mg of a pyrimidine derivative (yield: %, 2 steps). Pyrimidine derivative 176, mg (0,60 mm
ol) was dissolved in ethyl orthoformate (6 ml), concentrated hydrochloric acid (0.5 ml) was added, and the mixture was heated in an autoclave at 100°C for the same period of time.

The solvent was distilled off, 5 ml of IN-IIcI was added, and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off, the title fluoroadenosine was purified by reverse phase C-18 silica gel chromatography to give 103 mg of the title fluoroadenosine (yield 61%). I got it.

Melting point 196.2-199.2 (dispersion)” F-N
MII (DMSO-d, 1): (CCI *l・
)-I 05.9 Tdcld, J・2(1, (1,
3G, 0.54.21)7.1.

'II-NMR (DMSO-d,l: δ2.0-3
．． 0 (m, 31) 1, 3.0-3.7 (m, 5
1)), 3.8-4.5 (m, 21)), 5.45 (
d, J□5.51)z, l1l), 7. I'1(br
s, 21)), 8. ll(s, l1l), 0.19(s
.

1+1)° Synthesis Example 2 9-[3C! -Fluoro-2a-hydroxy-4β-butyldimethylsiloxymethyl-! β-cyclopendedel-6-dimethylaminomethyleriminoprine [formula [
I1], where X is a hydrogen atom,! <4 butyldimethylsilyl group, I<' is an adenine residue obtained by protecting the 6-position amino group of adenine with a dimethylaminomethylene group, a fluorine atom, and a compound in which -OX group is on the 0 face] Synthesis.

Using fluoroadenosine produced using the method of Synthesis Example I, a compound represented by the formula [It 2 ] was synthesized. Fluoroadenosine G? Omg (2.7 mmall) was dissolved in dimethylformamide (12 ml), dimethylborumamide dimethyl acetal 2.03 ml (15
, 3 mmol) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. Yield 1) + 00 mg (2,24 mm
ol, 82.9%).

Of this, 520 mg (1,71 mmol) was taken and dissolved in dimethylpolamide (3 ml), and 233 mg (3,42 mmol) of 5-imidazoyl was added and cooled with water. Drop 258mg/2ml,
The mixture was stirred at room temperature for 10 hours.

The reaction solution was dissolved in 50 ml of benzene, washed with water, and the benzene layer was dried and concentrated under reduced pressure.

This residue was purified using a silica gel column to obtain the title protected fluoroadenosine. Yield 264 mg (0,6
3 mmol, 37%), h: 250 mg
(0.82 mmol.

47.9%).

'IT NMR (CDC1) 1: δ 9. [17is
, I Ill , 8.67 (s, till
.

7, 96 (s, 31) 1, 5.31-3.
40 (m, 71)), 3.24 (s, 31)
)13,19 (s, 31)1 ,0.81) (s
, wa 1)) 1 mouth (s, 61)) -”F-NMII+CD
C1,, CC1,+-1= ノ, (γl'i):
-191.3ppm (ddd, JII25.7.
32. G, 5[1,51)7,1.

Example 1 Fluorine with 9-3a-fluoro-4-hydroxymethyl-1-cyclopentyl-6-aminobutene 1:
L! ! Dissolve 1 (230 mg fO, 52 mmol of the alcohol produced in Synthesis Example 2) in dichloromethane (5 ml), add 190 mg (1,56 mmol) of 4-dimethylaminopyridine, and cool to 0°C. Phenylchlorothionocarbonate 170mg
(1.0 mmol) was added to chamber 8. ! The mixture was stirred for 15 minutes.

After water treatment using a conventional method and crude purification using silica gel column chromatography, benzene (10 ml of tributyltin hydride 1) was added. 0 ml), N,N'-azobisisobutyronitrile (5 mgl) was added and the mixture was reacted under reflux conditions for 15 minutes. The reaction mixture was concentrated and crudely purified by silica gel column chromatography.

The silyl needle obtained above was dissolved in tetrahydrofuran (lom
Dissolve butylammonium fluoride (1
1.0 ml of M solution was added, and the mixture was stirred at room temperature for 1 hour.

The desilyl compound was purified by column chromatography. The product was mixed with pyridine-28% aqueous ammonia-water (1: l:
The solution was dissolved in 4.5ml and stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by column chromatography (chloroborum-methanol = 4/l) to obtain 90 mg of the listed compound.

'II-NMR (0,0): δ1.6-2.0 (m
, 51) 1.2.75(d, J-5,41)z, 2
1) 1.3.8-4. Nm, 21)), 7. IQ(s,
1II).

7, 24 (s, l1l) ”F-NMR (DJ, CDCl3.C:Cl5) standard)
Knee lG5.9 (dddd, J1) 52.1. 34
．． 5. 30.5. +8.71) z) Example 2 219 mg of N-bromosuccinimide and anhydrous needle 1
After cooling to 0° C., 1 ml of IIF-pyridine solution (70%) was added. Next, cis-4
A solution of 243 mg of 0-acetamidocyclobent-2-ene methyl acetate in JJI% water ether (Irnl) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes and at room temperature for 2 hours.

The reaction solution was diluted with chloroborum, poured into 1 ton of saturated water, and extracted with chloroform. After drying and concentration, silica gel chromatography (chloroform-methanol 50/
1) to obtain 280 mg of the listed compound.

fill・-NMR (CDC1i1 knee 154.0 (d
dd, J-4'1.6.33. 'l.

14.71b,).

'II-NMR [CDCl, l: 1.3-2.8
(m, 31)1, 2.03 (s, 31)1.

2.09 (s, 31)), 4.2-5.5 (m, 51)
), 5.9 (br, s, 1llll.

IR (CDCI, l): 3040, 1750, 1fi9
0.1520cm-'-1-Promid 270B obtained in
5 mg of a,a-azobisisobutyronitrile and 1 part of tributyltin hydride in anhydrous benzene (20 ml) solution of
．． 25 ml was added thereto, and the mixture was heated under reflux at 80°C for 30 minutes.

After distilling off the solvent, purification with silica gel column chromatography (chloroborum-methanol 50/+1,
180 mg of the listed compound was obtained.

” F-NMR (CD (:+1) knee 171.1 (
dddd, J・52', 7.33.2.21), fi
, 21.71)z).

'II-NMtl(CDC1,+l:1.00-2.6
0 (m, 51) 1.1. 'llll+(s, 31) 1, 2
．． 0 (Ns, 31)), 4.00-! i, 40fm, 4
1) 1.5.90 (br, s.

+1) 1゜IH (C:DCIs): l743.16 old], 1520
cm-' Example 3 4β-acetamido-3β-hydroxy-20-fluoro-1 (1-cyclopentane methyl acetate 430 m
g and toluene 3? ml, triphenylbosphine 1.45g, iodine 93fimg, imidazole 3H
mg was added thereto, and the mixture was heated under reflux for 4 hours. After the reaction solution was allowed to cool, it was poured into saturated 1R carbon dioxide solution and extracted with chloroborum. The extract was concentrated, dried, and purified by column chromatography to obtain 55 mg of the listed compound. 1) It was.

+91・-NMllTCDC13) Knee 166.0(
dddl・51.8.2? , 3゜2G, 61)z)
.

'II-NMII(CDCIJl:1.zo-z,6
0 (m, 31) 1, 1.93 (s, 31)
1.

2,03 (s, 31)1,4. Do-5,50
(m, 51)).

- 55 mg of yoshito obtained as described above and anhydrous benzene (3 ml)
) Add 1 mg of α,a°-azodiisobutyronitrile and 0.23 ml of tributyltin hydride to the solution, and heat at 80°C.
The mixture was heated under reflux for 20 minutes. After distilling off the solvent, the residue was subjected to silica gel column chromatography to obtain 37 mg of the listed compound.

Example 4 To 169 mg of the fluoride obtained in Example 2 was added 44 mg of 2N hydrochloric acid.
ml and stirred at 100°C for 8 hours. It was purified with Diaion 5A-1)A to obtain the listed compound '12B. Example: When the fluoride obtained in S was subjected to the same treatment, the same listed compound was obtained.

”F-NMR (0,01 knee 165.l (fibl
tltl, J.54.0. 3G, fi.

31.3.22.71);/,).

'II-NMII (D20): 0.80-2.
40 (m, 51)), 3.40-5.20 (
m.

41) 1゜Example 5 3a-fluoro-40-hydroxymethyl-10-cyclopentylamine 131) ng (0.90 mmol)
was dissolved in N,N-dimethylformamide (5 ml) and 3-ethoxy-2-propenoyl isocyanate (0
, 4M-benzene solution, 2.5ml 1.1. Ommol
) was added dropwise over 5 minutes. 10/I>, the temperature was returned to room temperature, and the solvent was further heated to 30°C and distilled off. Ethanol (5
After completely distilling off the low-boiling substances with 2 mL of 2N hydrochloric acid, 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 the water heated to 40°C was distilled off. Silica gel column chromatograph t+
150mg of the listed compound (yield 67%)
Obtained.

19F-NMR (020, CC1, F J, li semi-1 knee 159.2 (m).

'II-NMR (02 mouths): δ 1. G-3,1)(+
n,! 1) 1), : 1.1) - 4.0 (m, 21)).

4.9-5.0 (m, +1) 1, +1. In+1).
J=7.91)7. , Il+1.8.00 (d, J.
? , 91)z, l II).

Example 6 200 mg (1.5 mmol) of 3a-fluoro-40-hydroxymethyl-1β-cyclopentylamine was added to N
, dissolved in N-dimethylbormamide (7 ml), 3-
Methoxy-2-methyl-2propenoyl isocyanate (0,4M solution in benzene.

3.8 ml, 1.5 mmol) was added dropwise over 5 minutes. After 10 minutes, the temperature was returned to room temperature, and the solvent was distilled off by further heating to 30°C. After completely distilling off low-boiling substances with ethanol (4 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, heated to 40°C, and water was distilled off. Using a silica gel column chromatograph t+'i, the listed compound was
0 mg (yield '16961 was obtained.

"F-NMR (acetone-dI, CCI, I group γ
<'j) Knee lIl+5.2 (ml.

'II-NMR (acetone-d, l: δ1.G-2
,7(m+s(δ1.8 8), LoLally 8
1) 1.3.0-5.6 (m, 41) 1, 7.68
(br s, Ill.

Example 7 240 mg of uracil derivative produced in Synthesis Example 5 (1,O
mmall was dissolved in anhydrous pyridine (10 ml,
Add 4-dimethylaminopyridine (10 mgl) and glacial acetic acid (l ml) and stir in chamber Δ,! for 30 minutes. The reaction mixture was mixed with 0.5 M potassium dihydrogen phosphate (50 ml).
After extraction with ethyl acetate (50 ml), the ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. This residue was dissolved in anhydrous acetonitrile (10 ml,
-Mesitylenesulfonyl chloride 670mg (3,O
mmall, triethylamine 420 μm (3, Omm
All was added and stirred at room temperature for 50 minutes. The reaction solution was concentrated under reduced pressure, and the residue was mixed with a saturated ammonia-methanol solution (3 m
1) was added and dissolved, and the mixture was stirred at room temperature for 15 hours. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% methanol-water (20%
ml of Amberlite CG-120 (
+M″l-1)), washed with water, and eluted with 5% aqueous ammonia. The eluate was concentrated under reduced pressure to obtain the compound listed in Table 2. Charged 55 mg (24%).

"F-NMII+CD, OD, CCInF group Q'i)
: -IO2,5ppm (+IdL.

J=22.951)z, 30.713I+7. , 53
．． 221) 21.

'II-NMII (CD, ODl: δ1.Il+
4-2.7 [1 (m, 51)), 3.83 (b + I,
21) 1, 5.26 (dm, J・53.221)
7. , l Ill , 5.38 (m, III), 6
．． 13(d, Jl, 51)z, l1) 1.7. '15 (
d, J□7, 51)z, l II).

Example 8 3G-fluoro-4fl-hydroxymethyl 1β-cyclopentylamine'llOmg (6, Ommall to 1
-butanol (dissolved in 30 ml, 2-amino-4
, 6-cyclobilimicin 2.49g (15,22mm
oll, triethylamine 2.1ml (15,
2 mmol) was added thereto, and the mixture was heated under reflux for 15 hours. After cooling the reaction solution with water and filtering off the precipitate, the mother liquor was concentrated under reduced pressure. Add vinegar to this residue! iI2 (34 ml), water (
34 ml) of sodium acetate trihydrate (13.6 ml)
g, 4-chloropensene diazonium chloride solution 1
6ml (7.5mmall) was added, stirred at room temperature for 15 hours, and the resulting precipitate was collected by filtration and dried.
% ethanol-water (100 ml, acetic acid (1) ml
was added, 1) g of zinc powder was added, and the mixture was stirred at 70°C for 1 hour. After filtering the reaction solution, Amberlite Cf1-120
After adsorption (If+ type) and washing with water, it was eluted with 5% ammonia water and concentrated under reduced pressure to obtain the listed compound (1) 1. Income: 1) 31
)Umg (20%).

IR (film) 330cm-' 1st round 190mg of pyrimidine synthesized in O above (0,6'
1 mmol) was dissolved in N,N-dimethylborumamide (2 ml).
) and dissolve Nisdel triethylol-1-formate (30
ml), i3 hydrochloric acid (Ill) and 48 mL at room temperature.
Stir for hours. The reaction solution was concentrated under reduced pressure, and 2N-hydrochloric acid (20ml) was added to the residue and heated under reflux for 4 hours.The reaction solution was adsorbed onto Amberlite CG-120+ 1)'' type) and eluted with 5% aqueous ammonia. was concentrated under reduced pressure to obtain the title compound. 101 mg (55%) of the yield.

"F-NMII (CD, OD, CCI, F group r'i
't): -IO2,5 (ml.

'll-N1)llll (CD, ODl: δ1.91
-2.89 (m, 51)), 3. [17fbd, 21)
1.5.02-5.68 (m, 21)), 8.09fs
, Ill Example 9 190 mg of the pyrimidine compound (0,6
'1mall of N,N-dimethylborumamide (2m
Dissolved in 1 ml of Nisdel II+'/triethylorthoformate (30 ml) and concentrated hydrochloric acid (1 ml) were added to the chamber.
! The mixture was stirred for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with saturated ammonia-methanol? f'j? ffl (3ml
1 was added and left at 70°C for 15 hours. The reaction solution was concentrated under reduced pressure, then dissolved in 10 ml of water, adsorbed on Amberlite CG-120 (II"l), washed with water, eluted with 5% aqueous ammonia, and the eluate was concentrated under reduced pressure to obtain the listed compound. Yield: 147 mg (40%).

"F-NMR (CDJD, CC1aF group Q'j):
-167.3 ppm (ml.

'II-NMII (CD, OD): δ1.89-2
．． [16 (m, 41) 1 , 3.88 [bd, 21
)), 5.04-5. G6 (m, 21)), 8.14 (
s, 1llll.

Claims (3)

[Claims] (1) A 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] R^1: Residues of nucleic acid bases that may be protected, azide groups, amino groups, or protected amino groups. R^2: Hydrogen atom or hydroxyl group protecting group. (2) OX of a 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula [II]
A method for producing a 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula [I], which comprises converting a group into a hydrogen atom and, if necessary, deprotecting a protecting group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] R^1: Residues of nucleic acid bases that may be protected, azide groups, amino groups, or protected amino groups. R^2: Hydrogen atom or hydroxyl group protecting group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] R^3: Residues of nucleobases (However, if they have a reactive functional group, they are protected with a protective group) Azide group, or protected amino group. R^4: Protecting group for hydroxyl group. X: hydrogen atom or activating group. (3) An antitumor agent containing a 1-substituted-3-fluoro-4-hydroxymethylcyclopentane derivative represented by the following formula [III] or a pharmaceutically acceptable salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [III] B: Residues of nucleobases.