JPS61205294A - Arabinophosphononucleoside and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or acyl; R<2> and R<3> are H or lower alkyl). EXAMPLE:2,3'-O-anhydro-1'-diethylphosphono-4',6-O-(tetraisopropy-l-dis iloxane-1, 3-diyl)-beta-D-fructofuranosyluracil of formula II. USE:An agent to suppress the biosynthesis of uncleic acid, ad expected to be useful as a carcinostatic agent and antiviral agent. PREPARATION:The aldehyde-equivalent compound of formula III (R<4> is OH- protecting group; R<5> is lower alkyl) is made to react with the dialkylphosphite of formula IV (R<6> is lower lakyl) in the presence of a base. The 1'-OH group of the sugar is converted to active thioester, and then subjected to reduction and deprotection, and optionally, dealkylation. As an alternative method, the OH group is converted to active thioester, and subjected to reduction, deprotection and acylation.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to compounds of the general formula (1) (wherein R represents a hydrogen atom or an acyl group, and R2 and R are the same or different and represent a hydrogen atom or a lower alkyl group). The present invention relates to a novel compound an-drophosphononucleoside having the following formula and a method for producing the same.

More specifically, it relates to the anhydrophosphononucleoside represented by the general formula (1), which is a nucleic acid biosynthesis inhibitor and is therefore expected to develop in the future as an anticancer agent and an antiviral agent. be.

[Conventional technology]

Many nucleic acid biosynthesis inhibitors have been synthesized, and 6-mercaptopurine is well known as a sibulin-based biosynthesis inhibitor, and 5-fluorouracil is well-known as a pyrimidine-based biosynthesis inhibitor.

Among phosphononucleosides, a large number of 5'-phosphonate compounds have been synthesized, including 5'-deoxy-5'-phosphonouracil (
A.HolyTetrahsdrone Lett
ers.

881 pages 1967). However, it is dangerous to describe anything about nucleosides having a phosphono group or a phosphonomethyl group at the 1' position.

[Problem that the invention seeks to solve]

Many efforts have been made to discover nucleic acid biosynthesis inhibitors and apply them to anticancer and antiviral drugs. However, among the pyrimidine biosynthetic pathways, orotate phosphorylation?
Syltransferase (0rotat@Phosph
Nucleic acid base and phosphoryl by oribosyl Transf@rase)? Silpyrophosphate (Phos
phoribosyl pyrophosphat*
) Studies on competitive inhibitors corresponding to the transition state in the condensation step have not yet been conducted.

The present inventor planned to synthesize a transition state analogous compound as this competitive inhibitor, in which phosphoryl replaces the oxygen in the carbon-oxygen-phosphorus bond at the 1st position of silpyrophosphate with carbon and introduces a nucleobase at the 1st position.

These biosynthesis inhibitors are expected to be used not only as anticancer agents and antivirals, but also as central nervous system agents and agricultural chemicals, such as insecticides.

[Means for solving problems]

Is this invention an orotate phosphoryl? Nucleobase and phosphorylation by syltransferase? The present invention is a novel compound that is a competitive inhibitor corresponding to the transition state in the condensation step of silpyrophosphate, an anhydrophosphononucleoside having the following general formula (1), and a method for producing the same.

The anhydrophosphononucleoside of the present invention having the general formula (1) (in the formula, 81 represents a hydrogen atom or an acyl group, and R2 and R are the same or different and represent a hydrogen atom or a lower alkyl group) can be obtained by the following method. It can be synthesized well.

That is, 2,3'-anhydro-β-D-fructofuranosyluracil (A, Ho1- et al. Nuel@le
Ac1d R@I m, vol. 1, p. 289, 197
4 years) was used as the starting material.

In this compound (3), the hydroxyl groups at the 4' and 6' positions of the sugar are selectively protected to form a compound (4) (R4 in the 2' represents a protecting group). Any protecting group may be used here as long as the 4' and 6' positions of the sugar are selectively protected at the same time, but dichlortetraisoprobyl disiloxane is preferably used as a preservative.

By then oxidizing this compound (4), the general formula (
5) An aldehyde isoside having the formula (wherein R4 represents the same meaning as above and R5 represents a lower alkyl group) is obtained.

The oxidizing agent used is preferably dimethyl sulfoxide, such as dimethyl sulfoxide and trifluoroacetic acid/pyridine/dicyclohexylcarbodiimide, dimethyl sulfoxide and phosphoric acid/dicyclohexylcarbodiimide, and dimethyl sulfoxide and acetic anhydride.

Further, the reaction temperature is preferably room temperature to 50°C.

In this oxidation reaction, the aldehyde product tends to form a hydrate, and the solvent used in the purification process,
In particular, it reacts with alcohol to obtain an aldehyde equivalent represented by the general formula (5).

For example, when silica gel column chromatography is used for purification and elution is performed with methylene chloride/methanol, the group R becomes a methyl group.

This aldehyde equivalent (5) and general formula (6)% formula% (6
) (wherein R6 represents an alkyl group) is reacted in the presence of a base to yield a phosphononucleoside having the general formula (7) (wherein 84 and R6 represent the same meanings as above). It will be done.

Here, the base is a trialkylamine, such as triethylamine or diisopropylethylamine.

Examples include triisofurobylamine and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, and potassium t-butoxide. Also suitable is sodium hydride.

When using dibenzyl phosphite or diphenyl phosphite as a substitute for dialkyl phosphite, each group R
A compound in which is a benzyl group or a phenyl group is obtained.

In this reaction, the reaction temperature is preferably 00 to 55°C, and the best solvent is ether or alcohol.

To remove the 1'-position hydroxyl group of this compound (7), it is first converted into a thioester. As a thioesterifying agent, for example, 1
．． Examples include active thioesterifying agents such as 1'-thiocal-nyldiimidazole and phenylchlorothionocarnate. These reagents can be reacted with the general formula (8) in a chlorine, hydrocarbon or ether solvent in the presence or absence of a base (wherein R and R have the same meanings as above). , Y represents a heterocyclic group or an aryloxy group). The base used is preferably an aromatic amine or a trialkylamine, for example triethylamine, pyridine, dimethylpyridine or dimethylaminopyridine.

The thioester group of the obtained thioester compound (8) is then subjected to radical reduction to form a phosphononucleoside (2) having the general formula (2) (wherein R4 and R6 have the same meanings as above). ) is obtained. The radical reduction referred to here is preferably a method using trialkyltin hydride, and most preferably a method using tributyltin hydride and azobisisobutyronitrile.

Further, the solvent used is preferably an aromatic hydrocarbon type.

A general deprotection reaction is used to deprotect this compound (2) and synthesize an anhydrophosphononucleoside having the present compound (1a) (in the formula, R6 represents the same meaning as above).

For example, in the case of a silyl-based protecting group, deprotection can be performed using the most common tetraalkylammonium fluoride.

Further, the reaction solvent may be any solvent as long as it does not take part in this reaction.

Acylation of the compound of the present invention (1a) yields an anhydrophosphononucleoside of the compound of the present invention having the general formula (wherein 86 represents the same meaning as above and A represents an acyl group). Acylated products are prepared using common methods: acetic anhydride, acetyl chloride.

Obtained by reaction with an acylating agent such as flopionyl chloride, butyryl chloride, inzoyl chloride, benzoyl bromide, tolyl chloride, benzoyl cyanide or cinnamoyl chloride in the presence or absence of a base. .

Alternatively, by treating the above-mentioned compounds (1m) and (1b) with trialkylsilyl iodine or trialkylsilyl iodine and sodium iodide or potassium iodide, an anhydrophosphonoyl compound having the formula (1c) H can be prepared. It becomes a nucleoside (lc).

In this reaction, the reaction temperature is preferably room temperature or lower, and the best solvent is chlorine.

When the group R6 in the above-mentioned compound (1a) is a methyl group, for example, by heating t-butylamine ζ, a dealkylation reaction occurs, and the anhydrophosphononucleoside represented by the formula (1d) is can get.

The anhydrophosphononucleoside represented by the general formula (1) of the present invention can be purified using general column chromatography or preparative thin layer chromatography.

Furthermore, the compound of the present invention represented by general formula (1) is represented by general formula (4).
) The 1'-position hydroxyl group of the compound protected at the 4'- and 6'-positions of the sugar represented by formula (9) (in the formula R
represents the same meaning as above, X represents a mesyl group or a tosyl group), and then treated with potassium iodide or sodium iodide under heating conditions in an amide solvent to obtain the general formula αQ (In the formula, R represents the same meaning as above) After forming a 1'-position deoxyiodine compound, this compound αQ can be reacted with the above-mentioned dialkyl phosphite (6) under heating to form the general formula (2) ( A compound having the formula (in which R4 and R6 have the same meanings as above) is obtained.

Next, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to the scope of these Examples.

Example 1 2.3'-0-anhydro-1'-diethylphosphono-
4',6'-0-(tetraisoprogyldisiloxane-1,3-diyl)-β-D-fructofuranosyluracil Compound 264IR9 of Reference Example 2 was dissolved in 20 M tetrahydrofuran, and 276 da of diethyl phosphite (4
(equivalent) and 0.2811 L/triethylamine (4 equivalent) were added and stirred for one day and night. The reaction solution was concentrated and the residue was subjected to column chromatography on silica gel (50P) and eluted with methylene chloride/methanol (95:5).
The title compound was obtained in a yield of 94 cm.

This compound had 211 isomers regarding hydroxyl group and phosphorus, and the ratio was 65:35.

Physical properties of main product UV spectrum (ethanol, λ.axsnm): 24
7 (8950), 226 (10300) IR Suiktor (KBr, 3): 1660, 1550
, 148ONMR script # (CDC1,, appm
) : o, s~t, x (m *28H), 1.3
7 (t, 6H, J*6.9Hz), 3.9-4.0 (m
.

2H), 4.15-4.45 (m, 6H), 5.08 (
dd, IH, J-12, 5, 7, 9Hz), 5.75 (
d, IH, J-5,6Hz) s5.88 (d, IH, J
"7.1Hz), 6.86 (brdd, IH, J=14
．． 4,7.9Hz), 7.70 (d, IH, J=7.1
Hz) Physical property NMR spectrum of the other isomer (CDC1,, δppm): 0
．． 8-1.1 (m *28H), 1.38 (t, 6H
, J-6, 9H1), 1.75 (br.

IH), 3.90-4.05 (m, 2H), 4.15-
4.45 (m.

6H), 5.18 (d, IH, J-12, 7Hz), 5
．． 81 (d.

IH, J-5, 6H $), 5.91 (d, IH, J = 7
．． 1Hz).

7.38 (d, IH, J = 7.1 Hz) Example 2 2.3'-0-anhydro-1'-dimethylphosphono-
4',6'-〇-(tetrinepropyldisiloxane-1,3-diyl)-β-D-fructofuranosyluracil Compound 400JQ of Reference Example 2 was dissolved in 401E/tetrahydrofuran to form diethyl phosphite (342~). 4
equivalent) and 0.43-triethylamine (4 equivalent) were added and reacted in the same manner as in Example 1. Purification was performed using silica gel column chromatography using methylene chloride/methanol (
9:1) to obtain 418 JW (yield: 89%) of the title compound.

This compound had two types of isomers regarding hydroxyl group and phosphorus, and the ratio was 3:2.

The physical properties of the main product are shown below.

Properties: Amorphous crystalline UV (ethanol, λmax s ”m)
*247 (8670), 226 (10100) IR,
1, Vector (KBr s cm): 1660
* 1540 t 147ONMR spectrum k (C
DC23, δppm): 0.8 to 1.1 (m
.

28H), 3.7-4.0 (m, 8H), 4.3-4.
4 (m, 2H).

5.17 (dd, IH, Ja=8.2, 13.2Hz)
, 5.67 (d, IH.

J=4.0Hz), 5.84(d, IH, J-7, 8H
z), 6.97 (dd, IH, J-8, 2, 15, 2H
z), 7.68 (d, IH, J = 7.8Hz) Mass spectrum (m/z): 563 (M+-43) Physical properties of the other isomer: Amorphous crystal NMR spectrum (CDCl2.δppm) :5.71
(d, IH.

J=x4.0Hz), 5.85(d, IH, Jm7.8
Hz), 6.97 (dd, II (, J-8, 2, 15,
2H, 7.43 (d, IH, J = 7.8Hz) Example 3 2.3'-0-anhydro-1'-0-(phenyloxythiocalyl)-1'-diethylphosphono' -4
', 6'-0-(tetraisofuropyrdisiloxa/-
1,3-diyl)-β-D-7 lactofuranosyluracil Compounds 500 to 1 of Example 1 were dissolved in 59a/l of 1,2-dichloroethane to form 140μ of 4-dimethylaminopyridine (1,5 equivalents) and 147 Then, phenylchlorothionocarbinate was added thereto, and the mixture was stirred at room temperature for 1 hour. Next 49m9
of phenylchlorothionocalate was added and the mixture was further stirred for 2 hours at room temperature. Dilute the organic layer with methylene chloride and
After washing twice with water, it was dried and concentrated. Coat the residue with silica gel cz
oy) and eluted with methylene chloride/methanol (99:1 and 97:3).
7rv (98% yield) of the title compound was obtained.

'This product contained 21m isomers regarding thioester and phosphorus, and the ratio was 65:35.

Physical properties of the main product: Properties: Amorphous crystalline UV molecule (ethanol, λ, emergency, nm): 23
9, (#-14100), 229 (g=16200)I
H S-J ctor (KBr, 51): 166
0,1560,147ONMR spectrum (CDcts
, δppm): o, 9o ~ 1.12° (m, 28
H), 1.34 (t, 3H, J=6.5Hz), 1.3
8 (t, 3H, J x6.5Hz), 3.9
5-4.00 (m, 2H) t4.07-4.30
(m, 5H), 4.48-4.55 (m, IH).

5.67 (d, IH, J=5.8Hz), 6.
11 (d, IH, J -7,2Hz), 6.35
(d, IH, J=12.0Hz), 7.02~F1('
lCwI 9TT'+ 71~7Brm QTf)
7g'4 (r4-IH, J-7, 2Hz) Mass spectrum A/ (m/z): 727 (M”
-43) Physical properties of the other isomer: Properties: Amorphous crystal NMRXA ctor (CDCl2.δppm): 5.70
(a, IH.

J x5.8Hz), 6.05(d, IH,
J=7.7H1), 6.38(d, IH, J-12
,7Hz), 7.1-7.5 (m, 4H) Example 4 2.3'-0-anhydro-1'-0-(imidazol-1-ylthiocar♂yl)-X#-diethylphosphono-
4',6'-0-(tetraisoprobyldisiloxane-1,3-diyl)-β-D-fructofuranosyluracil Compound 19°7rn9 of Example 1 was dissolved in 1,2-dichloroethane to form 6.63~ 1,1'-thiocargenyldiimidazole was added and stirred at room temperature for 3 hours. After concentration, the residue was separated with ethyl acetate using a preparative thin layer of silica gel to obtain the title compound I) 15.6I119 (yield 68).

This product had two types of isomers regarding thioester and phosphorus, and the ratio was 6:4.

Physical properties of main product: Properties: Amorphous crystal NMR spectrum # (CDCj3 zδppm):
0.85-1.13 (m+28H), 1.28 (t,
3H, J=7゜6Hz) -1,30(t e3H,
J=7.6Hz), 3.74-3.98 (m, 3H),
4.05-4.26 (m, 4H), 4.58
(dd, IH, J-5, 1, 8, 1H Ri.

5.68 (d, IH, J”5.1Hz), 6.11 (d
, IH,J-7,6Hz), 6.57(d,IH,J-
11,1Hz), 7°12(m.

IH), 7.45 (d, IH, J=7.6Hz'), 7
．． 63 (at, IH).

8.39 (m, IH) Physical properties of the other isomer: Properties: Amorphous crystal NMR spectrum (CDct, , δpPfn): 1
．． 27 (t e 3H.

Jm7.3Hz), 1.36(t, 3H, Jx7.3H
z), 3.86 to 4-00 (m s 3 K) −
4,05~4.36 (m -4H) -4,52 (d
d, IH, J"5.9, 9.2Hz), 5.76 (d,
IH, J = 5.9Hz), 6.08 (d, IH, J-7
, 8Hz), 6.54 (d.

IH, J-12, 1H, 7.11 (m, IH), 7.
34 (d, IH.

J-7,8Hz), 7.43(m, IH), 8.28(
m, IH) Example 5 2.3'-Oj Anhuto0-1'-0-(7!nil, t
(oxythionocar-nyl)-1'-dimethylphosphono-4
',6'-0-(tetraisopropyldisiloxane-
1,3-diyl)-β-D-fructofuranosyluracil Compounds 250 to 9 of Example 2 were reacted and purified in the same manner as in Example 3 to obtain the title compound 28619 (yield 93%). .

Two types of isomers existed in the obtained compound, and the ratio was 3:2.

Physical properties of main product: Properties: Amorphous crystal VV spectrum (ethanol, λmax s nm)
:237(#-15300), 229(t-1610
0) IR spectrum (KBr, cn*):
1660, 1560, 1460 [α) D knee 35.5°
(chloroform) mass spectrum (m/z): 699 (
M+-43).

637 (M"-105) Example 6 2.3'-0-anhydro-1'-deoxy-1'-diethylphosphono-4',6'-0-(tetraisopropyldisiloxane-1,3-diyl )-β-D-fructofuranosyluracil 0.671n9 of azobisisobutyronitrile and 2,8
5 Immediate tri-n-butyltin hydride was dissolved in 20 ml of benzene, heated under reflux for 5 minutes, and then a benzene solution of the compound of Example 4 of 7.3 IH9 was added and refluxed for 1 hour. The reaction solution was concentrated, and the residue was applied to a preparative thin layer of silica gel and separated with methylene chloride/methanol (95:) to obtain the title compound (5.1 rq) (yield: 84%).

Properties: Amorphous crystal [α) D knee 66.7° (chloroform) UV spectrum (ethanol, λmax y nm) @225 ($
= 9040), 247 (ε: 7640) IR Susktor (KBr, cm): 1630, 1540
, 146ONMR spectrum k (CDC1,, δpp
m): 0.93-1.13 (m.

28H), 1.25 (t, 3H, J=7.2Hz), 1
．． 27(t, 3TI.

J==7.2Hz), 2.56(dd, IH, J=18
．． 7, 16.7Hz).

2.63 (dd, IH, J=18.7, 16.7Hz)
, 3.85-4.03 (m, 3H), 4.04-4.2
3 (m, 4H), 4.49 (da.

IH, J=5.2, 8.4H1), 5.48 (
d, IH, J-5, 2H.

6.09 (d, IJJ+=7.8Hz), 7.34Cd
, IH, J=7.8Hz) High resolution mass spectrum (M+) Calculated value: 618.2555, Actual value: 61 & 2542 Example 7 2.3'-0-Anhydro-1'-deoxy-1'-diethylphosphono -4',6'-0-(tetrainfurobyldisiloxane'-1,3-diyl)-/-D-7lacto7lanosyluracil The compound 3161119 of Example 3 was reacted in the same manner as in Example 6, and 17611v The title compound (yield: 70 cm) was obtained.

Example 8 2.3'-0-anhydro-1'-deoxy-1'-dimethylphosphono-4',6'-0-(tetraisofurovirdisiloxane-1,3-diyl)-β-D- 7 Lactofuranosyluracil Compound 286 of Example 5 was reacted in the same manner as in Example 6 to obtain 170# (yield: 75) of the title compound.

Properties: Amorphous crystal [α) D knee 57.3° (chloroform) UV spectrum (ethanol, λwax * nm): 248 (
g-7830), 226 (g-9000) IR soot vector KBr, am-'): 1650,15
50,147ONMR quictor (CDC1, δPp
m): 0.85-1.13 (m, 28H), 2.
62 (dq, 2H, J=16.7, 18.4Hz).

Qq ′I (a ffM−, T=11 9′
Mv )-1-76c d-3H, J-11, 2Hz
), 3.89 (dd, IH, J-13,0-
4.9Hm) *3.96(dd, 1)f, J=1
3.0.4.9Hz), 4. O3Cm.

IH), 4.50 (dd, IH, J=8.9, 5.5H
z), 5.43 (d z I Hp J l-5,5H
z) s 6.09 (d s I H* J-8,
1Hz) t7.39 (d, IH, J=8゜IHz)
-r Soot vector (m/z): 547 (M -43)
Example 9 2.3'-0-Anhydro-1'-deoxy-1'-diethylphosphono-β-D-fructofuranosylura Compound 809 obtained in Example 6 was dissolved in 5d anhydrous tetrahydro7rane, n-tetrabutylammonium 7 under water cooling.
cr lid in tetrahydrofuran (1 molar solution 0.26
R1) solution was added and stirred for 30 minutes. After adding 3 drops of water to the reaction solution and concentrating it, the residue was subjected to preparative thin layer chromatography and diluted with methylene chloride/methanol (87.5:12.
5) to obtain the title compound 31.1rR9 (yield: 64%).

Properties: Amorphous crystal [α) T, knee 6.82° (methanol) UV quictor (λm, x, nm, methanol): 255Cg
-5590) 1B spectrum (KBr, aII): 3300,16
60°1530.148O NMR Spect/I/ (CDCLs @ J ppm
): 1.30 (t p 3 H*J=6.6H
z), 1.34 (t, 3H, J-6, 9Hz), 2.8
3(d.

2H, J=17.9Hz"), 3.52-3.67 (m
, 2H), 4.05-4.18 (m, 5H), 4.38
(tn, IH), 5.45 (s, IH).

6.01 (d, IH, J-7,8Hz), 7.48 (d
, IH, Jm7.8Hz) High-resolution mass spectrum calculated value: 376.1035 Actual value: 376.1055 Example 10 2.3'-〇-Anhydro 4', 6'-〇-diacetyl-1'-deoxy-1 '-diethylphosphono-β-D
-Fructo7-lanosyluracil 15.6 fkg of the compound obtained in Example 9 was dissolved in 2d of anhydrous pyridine, 1- of acetic anhydride was added, and the mixture was stirred at room temperature under a nitrogen stream for 2 hours. The reaction solution was concentrated, the residue was dissolved in methylene chloride, and the organic layer was washed with water.

After drying, it was concentrated, and the residue was subjected to silica dal preparative thin layer chromatography and developed with methylene chloride-methanol (95:5) to obtain 12.7 #Il (yield: 66%) of the title compound.

Properties: Amorphous crystal NMR spectrum (CDCL3, δPPm): 1
．． 28 (t, 3H.

J-7,2Hz), 1.31(t, 3H, J-7,2H
z), 1.99 (1,3H), 2.17 (1,3H),
2.62 (dd, IH, J 16.6, 18.7Hz)
, 2.83 (dd, IH, J=16.6, 18.7Hz
)t4-00(ddylH9Jm12.5, 3.8Hz
), 4.02-4.17 (m, 4H), 4.26 (dd
, 11. J=12.5, 4.1Hz).

4.49 (m, IH), 5.38 (m, IH), 5.6
2 (brs.

IH), 6.11 (d, IH, J=7.4Hz), 7.
34 (d, IH.

J-7,4Hz) Example 11 2.3'-0-anhydro-4',6'-0-dibenzoyl-1'-deoxy-1'-diethylphosphono-β-
D-7 Lacto7 Lanosyluracil Compound 9.0 of Example 9 was dissolved in 1 g of acetonitrile, 3 drops of triethylamine and 7.3 In9 benzoyl cyanide (2-2 equivalents) were added, and the mixture was heated at room temperature for 1.5 hours. Stirred. Furthermore, 3.65~ of benzoyl cyanide was added and stirred for 1.5 hours. Dilute the reaction solution with methylene chloride,
It was washed twice with water and dried. The residue after concentration was subjected to silica dal preparative thin layer chromatography and developed with methylene chloride-methanol (95:5) to obtain the title compound of 11.9In9 (yield 85%).

Properties: Amorphous crystal NMR spectrum -/L- (CDCL, , δppm)
: 1.27, 1.30 (t.

3H, J-7, 4Hz), 2.70 (dd
, IH, J-16, 3.

18.4 Hz) = 2.85 (dd - I H
-J-16,3*1 B-4Hz) -4,02~
4.18 (m, 4H), 4.35-4.50 (m, 2H
).

4-79 (rn * I H) a 5.78 (m
*IH) *5-84 (br a -IH
), 6.05 (d, IH, J,, 7.7Hz), 7.3
3'(d, IH.

J=7.7Hz), 7.40-7.68 (m, 6H),
7.90-8.12 (m, 4H) Example 12 2.3'-0-anhydro-1'-deoxy-1'-dimethylphosphono-β-D-fructofuranosyluracil Obtained in Example 8 Compound 70619 under nitrogen stream 5017
Dissolve tetra-n-butylammonium fluoride in tetrahydrofuran (1 molar solution 2
．． 631! j) The solution was added at -25°C and stirred for 15 minutes. The reaction solution was decomposed by adding 7 drops of water, concentrated, and the residue was subjected to column chromatography on silica gel (60?). Methylene chloride-methanol (200jE/87.5:12.5).

Elution with 200117) at 85:15 gave the title compound 393II9 (94% yield).

Properties: Amorphous crystal UV suction (ethanol, λmax t”
I"): 249 (ε-7480), 224Ca-9
670) IR spectrum (KBr, tyn): 166
0,1630°1530.148O NMR spectral (CD, OD, δppm): 2.9
6 (dd.

IH, J=19.0, 16.1Hz), 3.42-3.
50 (m, 2H).

3.72 (d13H-J; 11-5 Hz)
*3.78 (d-3H-J ~11.0H1)
, 4.25-4.33 (m, IH) 14.52-4.5
6 (d, IH), 5.41 (s, IH), 6.07 (d
, IH, J=7.4Hz), 7.98 (d,
IH, J=7.4Hz) Mass spectrum (m/z)
: 348 (M) *331 (M -0R) Example 13 2.3'-0-Anhydro-1'-deoxy-1'-methylphosphono-β-D-7 Lactofuranosyluracil Compound 123m9 of Example 12 1711117Ot-
Dissolved in butylamine and heated under reflux for 4 hours, then concentrated.
Dissolve the residue in water and add Dovrex resin (Dovrex50).
It was subjected to chromatography using WX4) and eluted with water. When the eluate was concentrated, the title compound with a yield of 118~ (yield: quantitative) was obtained. This compound had two isomers with respect to phosphoric acid, and the production ratio was 8:3.

Physical properties of the main product: [α] D layer - 23.9° tanol) UV spectrum (ethanol, λmax * nm): 253 (g
-6660), 222 (g=7440) IR spectrum (KBr, z-'): 3500, 1660°1540.
148O NMR spectrum (CD5OD sδPprll): 2
．． 73 (dd.

IH, J-18, 2, 16, 3Hz), 2.88 (dd
, IH, J-17, 3, 16, 3Hz), 3.46 (t
, 2H, J-3, 8Hz) *3, 63 (d = 3
H, J ~11.0 Hz) t 4.25 ~ 4-3
2 (m.

IH), 4.50-4°53 (m, IH), 5.50 (
1, III).

6.09 (d, IH, J=7.2Hz), 7.97 (
d, LH, J-7,21(z) Mass spectrum (m/z): 299 (M”-35
) Physical properties of the other isomer: NMR spectrum (CD30D, δppm): 2.8
3(aa.

IH, J=18.7, 15.4Hz), 3.4
8 (t, 2H, J-4, 1Hz) + 3-63
(d m 3 H * J ; I L 5 Hz)
-4-23~4.2.8(m, IT(), 4.4
6~4.49Cm, IH), 5.38 (1, I
H).

6.03 (d, IH, J”7.0Hz), 7.68 (d
, IH, J-7,0Hz) Example 14 2.3'-0-anhydro-4',6'-0-diacetyl-1'-deoxy-1'-dimethylphosphono-β-D
-Fructofuranosyluracil 16.2q of the compound of Example 12 was dissolved in 2 rats of anhydrous pyridine, 1 d of acetic anhydride was added, and the mixture was stirred at room temperature for 2 hours.

The reaction solution was concentrated, the residue was diluted with methylene chloride, the organic layer was washed with water, dried, and concentrated. The residue was subjected to silica gel preparative thin layer chromatography and methylene chloride-methanol (9
By developing and separating at a ratio of 5:5), 16.6 da (yield: 8
The title compound of 3 H) was obtained.

Properties: Amorphous crystal Example 15 2.3'-〇-anhydro-4',6'-0-dibenzoyl-1'-deoxy-1'-dimethylphosphono-β-
D-Fructofuranosyluracil The compound 292In9 of Example 12 was dissolved in 30 g of acetonitrile to give 0.5911 I/l of triethylamine (5
i) and 255 Da of benzoyl cyanide (2,2 equivalents)
was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated and extracted with methylene chloride. The organic layer was washed with water, dried, and concentrated, and the resulting residue was subjected to nine column chromatography using silica gel (50iIF), and methylene chloride/methanol (97:3°100i1) and methylene chloride/methanol (95:5, By elution with 10011j), the title compound of 349 (yield 75%) was obtained.

Properties: Amorphous crystal UV spectrum (ethanol, λ1naX t nm
):230(&=32800) IR spectrum/I/(KBr, a+x):1720
,1660°1550.1470,1280,1030
．． 72ONMR spectrum (CDCL, , δppm)
:2.81 (da.

I Ht J =34.7-16-2 Hz) +
2-87 (d d r I Hp J =34.3,
16.2Hz), 3.72(d, 3H, J=10.7H
z).

3.77 (d, 3H, J = 12.0Hz), 4.39 (
dd, IH, J=5-8.12-3 Hz) + 4
-47 (dd TI He J w5-2.12
．． 3 Hz).

4,77~4.83 (m-IH) *5.77
(dd, IH, J = 1.3-3.6Hz),
5.83 (d, IH, J-1, 3Hz), 5.98 (d
.

IH, J=7.1Hz), 7.38-7.46
(m, 4H), 7.48(d, IH, J-7,
IHz), 7.56 (m, IH), 7.63 (m.

I H) + 7.92 (m * 2 H) * 8
．． 07 (m −2H) mass spectrum (m/z): 4
31 (M-125).

326 (M-230) Example 16 2.3'-0-anhydro-1'-deoxy-1'-phosphono-β-D-fructofuranosyluracil 200m
9 of the compound of Example 6 was dissolved in 20 d of methylene chloride under a nitrogen stream, 647IR9 (10 equivalents) of trimethylsilyl iodine was added at 0° C., and the mixture was stirred for 30 minutes. Water was added to the reaction solution, concentrated, and dissolved in methanol. This solution was passed through an ion exchange resin (Dov@x50WX4) and eluted with water. The eluate was concentrated and then treated with an ion exchange resin (Dovr
exlX2). For elution, 0.05 N hydrochloric acid was used, and the eluate was concentrated to obtain the title compound of 86.2~ (83% yield).

Properties: Amorphous crystal [α) D knee 6.51° (methanol) UV spectrum (ethanol, λIIILX l nm): 25
3 (Sana 6720), 223 (ε=6730) IR Suictor (KBr, c!n): 3500,1660
, 148ONMR spectrum/l/ (CD30D, δ
ppm): 2.76 (dd.

IH, J = 18.3, 15.6Hz), 3.10 (dd
, IH, J=18°3, 15.6Hz), 3.47(d
d, IH, J=12.4, 3.0Hz), 3.56(d
d, IH, J=12.4, 3.0Hz), 4.37-4
．． 41 (m, IH), 4.61 (d, IH, J = 1.1
Hz) I5.64 (a, IH), 6.43 (d, IH,
J-7, 3Hz).

8.33 (d, IH, J-7,3Hz) Reference Example 1 2.3'-0-anhydro-4', 6'-0-(1,
1,3,3-tetraisopropyldisiloxane-1,3
-diyl)-β-D-fructofuranosyluranyl2.
3'-0-7: /1: )'Rho β-lofructofuranosyluracil 909■ (3,55 mmol) in 50-
of dimethylformamide and then 990~ of imidazole (14.56 mmol) was added.

Cool the solution of 1,3-dichloro-1, to 20'C.
1,3,3-tetraisopropyldisiloxane (1,2
9m, 3.75 mmol) was added. After stirring at -20°C for 30 minutes and at room temperature for 3 hours, the solvent was distilled off. The residue was diluted with chloroform, and the chloroform layer was washed with water and dried over anhydrous magnesium sulfate to obtain 1,6 Of crude product.

This crude product was subjected to silica dull column chromatography ':4
The title compound 928In9 was obtained by elution with methanol/methylene chloride (5:95) (yield 53%).

Properties: Colorless oil IR spectrum (film, cm): 3250°2
950.2860,1630,1530,1475,1
405NMR spectrum # (CDCAs, δppm)
: O-9~1.15 (m 528H), 3.82
~4.01 (m, 4H), 4.16 (dd, IH.

J-13,5,6,0Hz), 4.47(dd, IH,
J-5, 2, 8, 4Hz), 5.41 (d, IH, J-
5.2Hz), 5.92(d, IH.

J=8.1Hz), 5.98 (dd, IH
, J = 9.2, 6, QHz).

7, 33 (d t I H-J ” 8- I Hz
) Reference Example 2 2.3'-0-anhydro-11-methoxy-4/,
6F -0-(tetraisopropyldisiloxane-1
,3-diyl)-β-D-fructofuranosyluracil Compound 2.1254 of Reference Example 1 was dissolved in 4211j of anhydrous dimethyl sulfoxide to give 42 ml of anhydrous benzene, 0.341+1 J (1 equivalent) of anhydrous pyridine, and 0.16 trifluoroacetic acid. WLl (0.5fi amount) and dicyclohexylcarbodiimide 2.63F (3 equivalents) were sequentially added and left at room temperature overnight.

Insoluble materials were separated, ethyl acetate was added to the solution, the mixture was washed twice with water, dried (over anhydrous magnesium sulfate) and concentrated. The residue was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (97:3 to 90:10) to yield the title compound at 2.12%. iL (yield 97%) was obtained.

The main product has the following physical properties.

IR spectrum (KBr, crn): 1660,154
0,147ONMR spectroscopy (CDCLs, δpp
m): 0.8-1.2 (m.

28H), 3.50(!1,3H), 3.8~4.2(
m, 4H).

4-3 to 4-6 (m, IH), 5.06 (b
rBsIH) -5,33(d.

I Ht J =6-OHz), 5-90 (d
, I H* J =7-8 Hz) +7.60
(d, IH, J=7.8Hz) Physical property NMR spectrum of the other isomer # (CDCL, , Jppm):
0.8-1.2 (m.

28H), 3.50 (s, 3H), 3.8-4.2 (m
, 4H) 14.3-4.6 (m, IH), 4.98 (b
rs, IH), 5.43 (d.

IH, J-6, QHz), 5.94 (d,
IH, J-7, 8H2).

7.38 (d, IH, J=7.5Hz) Reference example 3 2.3'-0-anhydro-1'-methanesulfonyl-
4',6'-0-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-β-D-7 Lactofuranosyluracil Compounds 347 to (0 , 7 mmol) was dissolved in 201117 methylene chloride, and triethylamine 106 rv (1.05 mmol) and methanesulfonyl chloride 9619 (0.83 mmol) were added sequentially at 0°C. After stirring at 0° C. for 1 hour, the mixture was diluted with methylene chloride, and the organic layer was washed with water, dried, and concentrated to obtain 44,011 g of residue.

The residue was subjected to silica dull column chromatography and eluted with methanol/methylene chloride (5:95) to give 331
11 g of the title compound was obtained (yield 83%) Properties: Colorless oil NMR spectrum (CDC23eδppm): 0°86-1.18 (m, 28H), 3.09 (g, 3H)
, 3.88-4.10 (m.

3)t), 4.47 (d, LH, J=12Hz), 4.
50 (m, IH).

4.60 (d, IH, J=12Hz), 5.20 (d,
IH, J = 5.4Hz), 6.10 (d, IH, J = 8
．． 3Hz), 7.30 (d.

IH, J = 8.3Hz) Reference Example 4 2,37-0-anhydro-1'-deoxy-1'-
Iodo-4',6'-0-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-β-D
- Fructofuranosyluracil Reference Example Compound 235In9 (0.41 mmol) was dissolved in 4 Qil of dimethylformamide and potassium iodide 13
6 Da (0.82 mmol) was added and heated to 150-160°C. After stirring for 5 hours, the mixture was concentrated, chloroform was added to the residual liquid, and the mixture was washed with water.

By drying the organic layer and removing the solvent, 337 mg of crude product was obtained. This crude product was subjected to silica gel column chromatography using methanol/methylene chloride (5:
95) to obtain the title compound of 225jt15i1 (yield: 91ch).

Properties: Colorless oil NMR spectrum (coct, , δppm):
0.90~1.12(m-28H)*3-62
(ABq * 2 Ht J-11-2Hz) +3
．． 87-4.06 (m, 3H), 4.54 (dd, IH
, J=5.5°8.6Hz), 5.17(d, IH, J
=5.5Hz), 6.13(d.

IH, J=8.1Hz), 7.25 (d,
IH, J = 8.1 Hz) [Effects of the Invention] The anhydrophosphononucleoside derivative of the compound of the present invention has activity against murine leukemia P388. for example,
The compound of Example 9 shows significant antitumor activity at a dose of 40rn97kg. In view of this, the compound of the present invention is expected to be developed in the future as a new antitumor and antiviral drug.

Claims (6)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a hydrogen atom or an acyl group, and R^
2 and R^3 are the same or different and each represent a hydrogen atom or a lower alkyl group). (2) The compound according to claim 1, wherein the acyl group is an acetyl group, a propionyl group, a cinnamoyl group, or a benzoyl group. (3) The compound according to claim 1, wherein the lower alkyl group is a methyl group, an ethyl group, a propyl group, or a butyl group. (4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^4 represents a hydroxyl group protecting group, R^5 represents a lower alkyl group) and the aldehyde equivalent represented by the general formula ▲ Mathematical formula , chemical formulas, tables, etc.▼ (In the formula, R^6 represents a lower alkyl group) A dialkyl phosphite is reacted in the presence of a base, and then 1 of the sugar is reacted.
A general formula ▲ characterized in that the hydroxyl group at position ′ is reduced and deprotected as an active thioester, or that the hydroxyl group is reduced and deprotected as an active thioester, and then dealkylated, or that the hydroxyl group at position ′ is reduced and deprotected as an active thioester, and then further acylated. There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a hydrogen atom or an acyl group, and R^
2 and R^3 are the same or different and represent a hydrogen atom or a lower alkyl group). (5) The production method according to claim 4, wherein the reducing agent used in the reduction reaction is trialkyltin hydride. (6) The production method according to claim 4, wherein the dealkylating agent used in the dealkylation reaction is trialkylsilyl iodine.