JPH01100190A - Nucleosides - Google Patents

Abstract

NEW MATERIAL:2',3'-Dideoxy-2',3'-didehydro-2'-fluoronucleosides expressed by the formula (B represents residue of nucleic acid bases). EXAMPLE:2',3'-Dideoxy-2',3'-didehydro-2'-fluorocytidine. USE:An antitumor agent and antiviral agent. PREPARATION:A 2'-deoxy-2'-fluororibofuranoside derivative as a raw material is initially protected at hydroxyl group at the 5-position thereof. After treating free hydroxy group thereof with a base such as NaOH, for example, the resultant compound is reacted with carbon bisulfide and treated with methyl iodide to afford a methyl xanthate, which is dehydrogenated by a method such as heating at 100-250 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel fluorine-containing nucleosides.

Nureoside and its various derivatives compete with essential metabolites and suppress the growth and proliferation of Liao 111 cells.They are used as so-called antimetabolites, as ItNA synthesis inhibitors, and as anti-tumor agents and anti-AIDS agents. It is widely used in medicines such as antiviral agents.

In particular, nucleosides containing fluorine, especially nucleosides containing a fluorine atom in the sugar moiety, have attracted attention in recent years as antitumor and antiviral agents. This is because the fluorine atom has electronic equivalence compared to the hydroxyl group, has an extremely greater bonding force to carbon atoms than the hydroxyl group, is inert, and has an atomic size similar to that of the hydroxyl group.

Therefore, it can be expected to have excellent effects in terms of antimetabolism and other effects due to the substitution of fluorine atoms for hydroxyl groups.

However, there are few known examples of nucleosides that bind deoxybenfuranoside, and 2',3-dideoxy-3'-fluorothymidine (1', Langen et al.

TcLrahedron, 272462 (1971)
l 2',3'-dideoxy-3-fluoroguanosine CDI' 209197+, 2'-3°-dideoxy-3°-adenosine (DP l589033°2',3
', 5-trideoxy-3°,5'-difluorothymidine (P, Langan et al., AeLa l1io1.
Med, Germ.

There are only 19 (1989)) in Chengong. Although fluorine-containing nucleosides have attracted much attention, there have been few examples of their synthesis to date. As a result of intensive research and study on fluorine-containing nucleosides, the present inventors have discovered novel fluoronucleosides.

The present invention is Zo, 3°-dideoxy-2',3'-didehydro-2°-fluoronucleosides represented by the following formula (1).

B: Residues of nucleic acid bases In the basic invention, nucleobases refer to purines and pyrimidines that may have a substituent, and the residue (b) refers to a residue (b) that may have a substituent. Good 9-purinyl group and! - Refers to a pyrimidyl group. As a substituent, an amino group,
In addition to oxo groups and methyl groups, other substituents such as halogen atoms, alkyl groups, haloalkyl groups, halobinyl groups, alkoxy groups, hydroxyalkyl groups, alkylamino groups, dialkylamino groups, acylamino groups, mercapto groups, alkylthio groups, cycloalkyl group, aryl group,
It may also be an aryloxy group, an aralkyl group, etc. The bonding position of these substitutions is 2-position in purines,
At least one of the 6th and 8th positions, and at least one of the 2nd, 4th and 5th positions for pyrimidines. Specific examples of purines as substituents include adenine, guanine, hypoxanthine, xanthine, 6-herobulin, 2-halopurine, 2,6-cyhalopurine, 6-
Examples include alkylaminopurine, 6-acylaminopurine, and pyrimidines having substituents include uracil, cytotin, thymine, 5-herouracil, 5-
Examples include halomethyluracil, 5-halothymine, 5-halomethylthymine, and 5-β-bromovinylthymine. Preferred nucleobases are 2- and/or 6-substituted purines, especially adenine, guanine, hyboxanthin,
xanthine, 2.6-diamitzadenine, Z-haloadenine, N''-riI! converted adenine, 6-herobulin, 2
．． 6-cyhalopurine, uracil, cytosine, thymine, 5
- Herouracil and the like are preferred.

2',3'-dideoxy-2' represented by the above formula (1)
, 3'-didehydro-2-fluoronucleoside is 2-
Manufactured from deoxy-2-fluororibofuranoside derivatives through a dehydration process, or from 2',3'-dideoxy-2-fluoro-3-haloribonucleoside derivatives through a dehydrohalogenation process. . The 2°-deoxy-2-fluororibofuranoside derivative can be produced by a known method. [For example, 2°-deoxy-
2-Fluorouridine (J, J, Fox et al., Ca
nudian J, Chem.

Raw+131 (see, 196(1)), etc.].

When the 5-position hydroxyl group and the residue of the nucleobase have an amino group before the dehydrogenation step (for example, the amino group at the 6-position of a purine or the 4-position of a pyrimidine needs to be protected).

The protecting group is preferably a trimethylsilyl group, a butyldimethylsilyl group, a phenyldimethylsilyl group, an acetyl group, a benzoyl group, a benzyl group, etc., and a protecting group for the hydroxyl group at the 5-position and a protecting group for the amino group of purine or pyrimidine are preferred. may be the same or different. A known method can be used for the dehydrogenation reaction. For example, free hydroxyl groups are treated with a base such as sodium hydroxide or sodium hydride, then reacted with carbon disulfide, further treated with methyl iodide to form methyl xanthate, and heated (100 to 2
50°C) to obtain a carbon-carbon double bond (Chugaev reaction), hydroxyl p-toluenesulfonyl group, methanesulfonyl group, I-lifluoromethanesulfonyl group,
It is converted into a leaving group such as imidasilylsulfonyl group, triethylamine, sodium hydroxide, bis(tetra r1-
butylammonium) oxalate, a method in which the hydroxyl group is reacted with a base such as potassium monobutoxide, a method in which the hydroxyl group is converted to triethylammonium N-carbalkoxysulfamate and then heated to 30°C to 70°C, a method in which the hydroxyl group is reacted with a base such as sodium hydride, etc. After treatment with a base and reaction with dimethylthiolbamoyl chloride, heating (150
~200°C), and in order to carry out the reaction more smoothly, a solvent such as dimethyl sulfoxide or hexamethylphosphoric triamide may be added.

Finally, by removing the protecting group, a nucleoside containing a fluorine atom can be produced, and in some cases, the protecting group can be simultaneously removed in step 1 of dehydration.

[Dehydrohalogenation] When produced through two steps, 2', 3
-Dideoxy-2-fluoro-3'-haloribonucleoside derivatives can be produced from 2-deoxy-2-fluoroxylofuranoside derivatives using a halogen substitution reaction that involves stereoinversion of the hydroxyl group at the 3° position. can. Examples of halogenation methods include converting a hydroxyl group into a leaving group such as mezilad or triflate and reacting it with detrabutylammonium iodide, triphenylphosphine-
A known substitution reaction of halogen from a hydroxyl group can be used, such as the iodine method, the P214 method, and the azodicarboxylic acid diestertriphenylphosphine-lithium iodide (zinc iodide) method.

In the dehydrohalogenation step, potassium monobutoxide, sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo[5,4,0l-7-undecene, 1,6-diazabicyclo[4,3,03- A base such as 5-nonene can be used, and the solvent can be acetonitrile, N,
N-dimethylbormamide, dimethyl sulfoxide, etc. can be used. The reaction temperature ranges from 0°C to solvent reflux, preferably from 0°C to room temperature.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

Example 1 2-deoxy-2°-fluorouridine 240 mg (1
,0 mmol) in 10 m of N,N-dimethylformamide
1, imidazole 200 mg (3,0 mmo
1) was added and stirred. The mixture was cooled to 0°C, and a solution of 150 mg of L-butyldimethylsilyl chloride (3 ml of N,N-dimethylformamide) was added dropwise.
Stirred for 2 hours. The reaction mixture was poured into 10 ml of water, extracted with benzene (10 ml x 3), dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to obtain 190 mg (yield: 53 x 1) of the compound.

1'F-NMR (CDC1, F standard): -203
,8ppm(ddd.

J-51, 19, 1 old IZ).

'II-NMR (CDC1,): δ0, I [s,
611), 0.9 (s, 911).

3.8-4.3 (m, 311), 4.4-4.8 (m
, l1l).

5, 2-5.4 (m, III), 5.2-6.
4 (bs, it).

5, 69 (d, J□0IIy,, III),
6.06 (d, J-+511z).

8,00 (d, JJllz, III).

Yuta ≦ Otsu Ω completed.

107 mg (0.30 mmo) of the silylated product synthesized in
+) was dissolved in 2 ml of pyridine, and 0.046 mg (0.60 mmol) of methanesulfonyl chloride was added.

After stirring at room temperature for 2 hours, add 5ml of a saturated aqueous solution of sodium hydrogen carbonate.
1 and extracted with dichloromethane (5 ml x 3).

After drying with anhydrous magnesium sulfate, it was concentrated and purified by silica gel column chromatography to obtain 120 mg of the compound (
Yield: 91%).

"F-NMR (CDC1, CC1, F group Q'riney 2
01.9ppm (ddd, J!52.15.15+
1z).

'If-NMR (CDC13): δ0. l (s
, [1111, 0,9 (3,911).

3,2 (s, 311), 3.8-4.2 (m
, 211).

4.3-4.5 (m, III), 4.9-5.7 (m
, 211).

5.71 (d, J!811z, III), 6. Eye [d
d, J-3, +311Z, eye 1), 7.82(d
, J snow allz, IIIJ.

60 mg (0.14 mmol) of the mesylated product synthesized in
) with potassium and one butilade 32mg (0.29mm
Add to 1 ml of N,N-dimethyl sulfoxide solution of o l) and add to the room ^? 11 for 2 hours. The solvent was distilled off at 50° C. in a hot water bath, the solvent was completely distilled off using toluene (2 ml×2), and then purified by silica gel column chromatography to obtain 14 mg (yield 29%) of a large-sized compound.

"F-NMR (CD, OD, CC1, F standard) Knee 1
36. i ppm (dd, J=4.9.4.41
1zl.

'II-NMR (CD, ODl: δ3.9-4.0
(m, 211), 6.0 (d, JJllz
, l1l), S',l (L, JI=5+1z, M
l).

7.0-7.2 (m, III), 8.4 (d, J.
811z, 1II).

Example 2 Z゛,3°-dideoxy 2',3' synthesized in Example 1
°-dihydro-2°-fluorouridine (563 mg,
2.50 mmol) was dissolved in 510+ nl of pyridine,
Add acetic anhydride (0.28ml 1.3.00mmol),
Stir at room temperature.

After 2 hours, the reaction solution was diluted with chloroform (10ml), and saturated aqueous sodium bicarbonate (15ml) was added under water cooling, followed by vigorous stirring.

After separating the organic layer, the aqueous layer was diluted with loloform (10 ml x 2
) and combine with the previous organic layer in saturated saline solution (20 m
Washed with l). After drying the organic layer over anhydrous magnesium sulfate, the solvent was thoroughly distilled off under reduced pressure.

The obtained residue was dissolved in acetonitrile (7,5n+ll G:
ffi was dissolved, and triethylamine (1.39 ml.
IO, Ommall was added, followed by diluchloride (1.64 g, 7.50 mmol) in 2-methylene sulfur 4.
was added and stirred at room temperature for 2 hours. Remove the solvent using a vacuum pump 1
．． ) and evaporated under reduced pressure, ammonia-saturated methanol (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 14 hours.

After distilling off the solvent under reduced pressure, the residue was subjected to anion exchange (GC)
The compound (42
0mg, 1. [17 mmol, yield 74.9%] was obtained.

"F-NMR (CD, Rolo, CCl2F standard) Knee 135.7 ppm (L, J-4', 411zl.

't NMR (CD, ODl: δ3.8? (d,
J=2.411z, 211).

4, 9-5.2 (m, III), 5.95 (
s, III).

6, 08 (d, JI17.511z, III),
7.09 (BS, III).

8, 20 (7,511z, l1l).

Example 3 15-lower 1 L/-2'
- Monooxy-2-fluoromidine pano 2°-deoxy-2°-fluorothymidine 500 mg (
1,92 mmol) to N,N-dimethylborumamide 2
After dissolving in 0ml, di-butyldimethylsilyl chloride 318
A solution of mg (2, 11 mmol) in 5 ml of N,N-dimethylformamide was added. After stirring at 0°C for 1 hour, 30ml of saturated sodium bicarbonate solution was added to the reaction solution, and chloroform (30ml) was added to the reaction mixture.
Extracted with lX 3 ). Saturated salt solution (30ml x 2
), dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product 'lQQmg. After silica gel column chromatography purification, 3 oomg of L1-like compound was obtained (yield: 4
2%) was obtained.

"F-NMR (CDCI+, CGIF, standard) Knee 21
9.8 (dd, J 43.8117.1.

'II-NMR(C[lCI+l]: δQ, +4
(s, (ill, Q, 9 (s, 911
).

1. 9 (s, 311), 3.4-5.6
(m, 511).

6, l (bb, , h911y,, III),
7.3 (bs, l1l).

Thymidine A1.

113 mg (0,302 m
Dissolve mol) in 2 ml of pyridine and add 0.047 mg (0.64 mmol) of methanesulfonyl chloride under water cooling.
added. After stirring for 1 hour at 0°C, add 10ml of saturated sodium bicarbonate solution.
was added and extracted with chloroform (IQmlX 3 ). After washing with saturated brine (lOml) and drying over magnesium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product. After silica gel column purification, 67, (1 mg (
Yield: 50%).

'''F-NMR (CDC1, CC1, F standard) Knee 224.3ppm (dd, J=40. Qllz
).

“If-NMR (CDCIs): 60.12 (s
, 311), 0.16 (s, 311).

0.9 (s, 911), 2.0 (s, 311), 3.
2 (s, 311).

3.7-4.6 (m, 411), 4.9-5.6 (m
, III).

6,0 (bd, JII911z, III),
6.0 (bd, JII911z.

l11), 7. ．． 2 (bd, III).

67.1mg (0,1411mm) of the compound produced in ■
ol) in 2 ml of dimethyl sulfoxide, and under water cooling, potassium and monobutoxide 33.2 mg (0,296
mmol) was added. After stirring at room temperature for 20 hours, potassium monobutoxide 33.2 mg (0,296 mmol)
was added and stirred at 50°C for 3 hours. After concentrating the reaction solution under reduced pressure, it was purified with a silica gel column, and the desired compound was purified by 10
mg (yield 27.8%) obtained, “F-NMR (CDCIa, CCl3F standard) Ni 11
7. ippm (dd, 15.6.4.911z)
.

'II-NMR (CDCIa): δ1.8 (d,
l1lz, 311).

3.5-4.5 (m, 311), 5.8-6.1 (m
, III).

6, 4 (bs, l1l), 7.4 (m, I
'll).

Claims (1)

[Claims] (1) 2',3'-deoxy-2',3'-didehydro-2'-fluoronucleosides represented by the following formula (I)▲There are mathematical formulas, chemical formulas, tables, etc.▼---(I) B :Residues of nucleobases