JPS61275290A - Deoxyphosphononucleoside and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> and R<2> are H or acyl; R<3> and R<4> are H or lower alkyl). EXAMPLE:1',3'-Dideoxy-1'-methylphosphono-beta-D-fructofuranosylu-racil shown by the formula II. USE:An inhibitor against biosynthesis of nucleic acid, useful as a carcinostatic agent and an antiviral agent. PREPARATION:An aldehyde shown by the formula III or formula IV (A is OH-protecting group; R<5> is lower alkyl) or an aldehyde equivalent compound is reacted with a dialkyl phosphite shown by the formula V (R<6> is lower alkyl) in the presence of a base. Then, the OH group of a saccharide at 1'-position is converted into an active thioester, reduced, and deprotected, or converted into the active thioester, reduced, deprotected, dealkylated or converted into the active thioester, reduced, deprotected and further acylated.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention is based on the general formula (1) (wherein R and R represent a hydrogen atom or an acyl group)
R3 and R4 are the same or different and each represent a hydrogen atom or a lower alkyl group) and a method for producing the same.

More specifically, the present invention relates to the deoxyphosphononucleoside 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.

[Conventional technology]

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

Among phosphononucleosides, a large number of 5'-phosphonate compounds have been synthesized, including 5'-deoxy-5'-phosphonouracil (
A, Holy Tetrahsdro'n La
ttera.

881 pages 1967). However, there is no description of a nucleoside 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, in the pyrimidine biosynthetic pathway, the orotate phosphoryzosyl trans-7erase (0rotate phoap
horibosyl tranaferase) and phosphoribosyl pyrophosphate (Pho
gphoribosyl pyrophosphate
) Studies on competitive inhibitors corresponding to the transition state in the condensation step have not yet been conducted.

The present inventors planned to synthesize a transition state-like compound as a competitive inhibitor in which the oxygen in the carbon-oxygen-phosphorus bond at the 1st position of phosphoribosyl pyrophosphate was changed to carbon and a nucleobase was introduced 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]

The present invention provides a novel compound which is a competitive inhibitor corresponding to the transition state in the condensation step of a nucleobase and phosphoribosyl pyrophosphate by orotate phosphoryzosyl trans-7erase, and a deoxyphosphononucleoside having the following general formula (1). and its manufacturing method.

The deoxyphosphononucleoside of the present invention having the general formula (1) (wherein R1 and R2 represent a hydrogen atom or an acyl group, and R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group) can be prepared by the following method. Can be synthesized.

That is, the known substance 3'-deoxy-β-D-fructofuranosyluracil (2) (A, Holy + N
uclsieAcid R@m, e Vol. 1, p. 289, 1974) was used as the t-starting material.

In this compound (2), the hydroxyl groups at the 4' and 6' positions of the sugar are selectively protected to form a compound (3) (the person in the formula represents a protecting group). 4' and 6'
Any material may be used as long as the hydroxyl group at the position is protected, but dichlorotetraisopropyldisiloxane is the best.

This compound is then oxidized to form an aldehyde or an aldehyde isoside having the general formula (4) % formula % (in the formula, the human beings have the same meanings as above, and R represents a lower alkyl group).

The oxidizing agent used here is preferably dimethyl sulfoxide, such as dimethyl sulfoxide and trifluoroacetic acid/pyridine/dicyclohexylcalgediimide (hereinafter abbreviated as DCC), dimethyl sulfoxide and phosphoric acid/DC
C, dimethyl sulfoxide and acetic anhydride. The temperature of this reaction 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 an alcohol represented by the general formula ROH (where R5 has the same meaning as above) to form an aldehyde equivalent of the general formula (4).

This aldehyde equivalent (4) and the general formula (5)%formula%)(
5) When reacted in the presence of a dialkyl phosphite tribase represented by (wherein R6 represents an alkyl group), a phosphonononucleoside having the general formula (6) (wherein R6 represents an alkyl group) is obtained. can get.

The base used here includes trialkylamines such as triethylamine, diisopropylethylamine, triisopropylamine, etc., and metal alkoxides such as sodium methoxide 9, sodium ethoxide, potassium ethoxide, potassium t-butoxide, etc. Also suitable is sodium hydride.

For example, when benzyl phosphite or diphenyl phosphite is used instead of dialkyl phosphite, the general formula (6
), wherein R6 is a benzyl group or a phenyl group, respectively.

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

In order to remove the 1'-position hydroxyl group of this compound (6), it is first converted into a thioester. As a thioesterifying agent, for example, 1
, 1'-thiocal is an active thioesterifying agent such as nyldiimidazole and phenylchlorotheonocargenate.

By reacting these reagents in a chlorine, hydrocarbon, or ether solvent in the presence of a base or without a base, the general formula (7) is obtained. (representing a heterocyclic group or an aryloxy group). The base used at this time is preferably an aromatic amine or a trialkylamine, such as triethylamine, pyridine, and dimethylaminopyridine.

The thioester group of this compound (7) is then subjected to radical reduction to form a phosphononucleoside (3) with a protected hydroxyl group having the general formula (3) (in the formula, human and R have the same meanings as above). can get.

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.

To deprotect this compound (3) and synthesize the deoxyphosphononucleoside which is the compound of the present invention, a general surface deprotection reaction may be used. For example, the silyl-based protecting group may be one that does not participate in this reaction.

By this deprotection reaction, the compound of the present invention having the general formula (1a) (wherein R represents the same meaning as above) is obtained. When this compound (la) is t-acylated, another compound of the present invention having the general formula (lb) (wherein R represents the same meaning as above and B represents an acyl group) is obtained. This compound (1b) can be prepared using a common method, namely with an acylating agent such as acetic anhydride, acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, benzoyl cyanide, toluyl chloride or cinnamoyl chloride in the presence of a base or in the presence of a base. It is obtained by reacting the compound of general formula (1a) in the absence of the compound.

Further, by treating the aforementioned compound (3) and (la)t alkylsilyl iodine or trialkylsilyl halide with sodium iodide or potassium iodide, a deoxyphosphononucleoside having the formula (1c) can be obtained. 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 compound (1a) is a methyl group, a dealkylation reaction occurs, for example, by heating with t-butylamine, resulting in formula (Id) (wherein R represents the same meaning as above). A deoxyphosphononucleoside having the following properties is obtained.

The novel deoxyphosphononucleosides of the present invention can also be obtained using the following method.

Namely, the known compound 2,3'-anhydro-β-D
-Fructofuranosyluracil (A,Holy LaNu
Cleic Ac1d Rag, Volume 1, Page 289, 19
The aqueous groups at the 4' and 6' positions of the sugar moiety of 1974) were selectively protected to give compound (8) (in the formula, the human beings have the same meanings as above). The protecting group used here may be any as long as it selectively protects the 4' and 6' positions of the sugar, but dichlortetraisoprobyl disiloxane is preferably used as the protecting agent.

This compound (8) is then oxidized to give the general formula (
9) An aldehyde isoside having the formula (in which the humans have the same meanings as above and R5 represents a lower alkyl group) is obtained.

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

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

In this oxidation reaction, the aldehyde product is easily converted into a hydrate form, and reacts with the solvent used in the purification process, especially alcohol (ROM), resulting in the above general formula (9).
The aldehyde equivalent is obtained.

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

This aldehyde equivalent (9) and the general formula (5)%formula%)(
) (In the formula, R is an alkyl group t-i) When a dialkyl phosphite represented by t-i is reacted in the presence of a base, a phosphononucleoside having the general formula CL0 A (in the formula, human and R6 have the same meanings as above) is obtained. I can get it.

Here, the base includes trialkylamines, such as triethylamine, diisoglobylethylamine, and triisopropylamine, and metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like. Also suitable is sodium hydride. If, for example, dibenzyl phosphite or diphenyl phosphite is used in place of the dialkyl phosphite, compounds in which the group R is a benzyl group or a phenyl group, respectively, can be obtained.

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

In order to remove the 1'-position hydroxyl group of the sugar moiety of this compound αQ, it is first converted into a thioester. Examples of the thioesterifying agent include active thioesterifying agents such as 1,1'-thiocarbunyldiimidazole and phenylchlorothionocarbonate. By reacting these reagents in a base, hydrocarbon, or ether solvent in the presence or absence of a base, the general formula The base used is preferably an aromatic amine or a trialkylamine, such as triethylamine, pyridine, dimethylpyridine or dimethylaminopyridine.

The thioester group of the obtained thioester compound α group is
Then, by subjecting it to radical reduction, the phosphononucleoside (a) having the general formula (2) (wherein and R 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.

This compound (6) may be deprotected by a commonly used method. For example, in the case of a silyl-based protecting group, deprotection can be performed using the most common tetraalkylammonium 70lide. Further, the reaction solvent may be any solvent that does not participate in this reaction.

When the general formula αj (in the formula, R represents the same meaning as above) obtained in this way is acylated, the general formula α→ B (in the formula, B represents an acyl group, and R6 represents the same meaning as above). The anhydrophosphononucleoside shown is obtained.

Acylation of 4 is carried out using a common method, i.e. in the presence of an acylating agent such as acetic anhydride, acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, benzoyl bromide, tolyl chloride, benzoyl cyanide or cinnamoyl chloride and a base. Alternatively, it can be easily obtained by reacting without the presence of a base.

The above-mentioned compound (6) and C14 are treated with a mineral acid in an alcoholic solvent to form the corresponding general formula (g) OR' (wherein R1 represents a hydrogen atom or an acyl group, and R6 represents the same meaning as above) ) is obtained. Examples of mineral acids include hydrochloric acid, sulfuric acid,
Examples include nitric acid and phosphoric acid.

The compounds of the present invention represented by general formulas (1a) and (1b) are obtained by treating the hydroxyl group at the 3' position of the sugar of this compound (g) with the above-mentioned active thioesterifying agent and then reducing it.

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.

Production example 1 3'-deoxy-4',6'-0-(1,1,3,3-
Tetraisopropyldisiloxane-1,3-diyl)-
β-D-Fructofuranosyluracil 3'-deoxy-β-D-7 Lactofuranosyluracil 4]6fn9 (1,61 mmol) t50m1 (1')
The mixture was dissolved in fk formamide and then 482 μl of imidazole (709 mmol) was added.

This solution was cooled to -40°C and 1,3-dichloro-1.1
．． 3.3-Tetraisopropyldisiloxane 0.59m
/(1,69 mmol) was added. -40℃ for 30 minutes,
After stirring at room temperature for 3 hours, the solvent was distilled off.

Dilute the residue with chloroform, wash the chloroform layer with water,
After drying over anhydrous magnesium sulfate, 850 μm of a crude product was obtained.

This crude product was subjected to silica dull column chromatography and eluted with methanol/methylene chloride (5:95) to obtain the title compound 403# (yield 50%). KBr, cy+s)22940.
2860, 1710° 1700, 1680, 1470,
1300, 1260, 1120.1040 UV hard vector (λmlX + nmr ethanol): 262.7
(ε=9870) Mass quictor (TV/z)=457 (M+-〇5H7
), 389 (base) NMR spectrum (CDC1,, δppm): 9.
43 (br, s, IH) 7.97 (d, I H, J
==8.0Hz), 5.64 (d-I H*
J = = 8.0Hz) 4.33 (m, IH), 4.2-3
．． 8 (m, 5H), 3.12 (br, s, IH) 1.1
5-0.8 (m, 28H) Production example 2 3'-deoxy-1'-methoxy-4',6'-0-
(Tetraisopropyldisiloxan-1,3-X)yl)-β-D-fructofuranosyluracil Compound 134 of Production Example 1 was dissolved in 3.44 m/m of dimethyl sulfoxide and 3.44 m of benzene.
6# (3 parts) dicyclohexylcal? Diimide, 0
．． 02161117 (1 equivalent) of pyridine and 0.0
After sequentially adding 103 mA (1/0.5) of trifluoroacetic acid, the mixture was stirred at room temperature all day and night under a nitrogen stream. After filtration, the residue obtained by concentrating solution F was diluted with water and then extracted with ethyl acetate. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The obtained crude product was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (97:3) to obtain the title compound 12611M1 (yield: 94%).

The obtained title compound was a mixture of two types of aldehyde and hemiacetal, and the production ratio was 1:2:1.

Physical properties of aldehyde: Colorless powder NMR sigct/l/(CDCt3.δppm):
9.23 (s, IH) 7.92 (d, IH, J
=8.0Hz), 5.77(d, IH, J=8
．． 0Hz) 4.40 (m, IH), 4.3-3.7 (m
, 3H) = 3.11(dd, IH.

J=13.7, 11.5Hz) -2,34(dd
, IH,J=13.7 e7. IHz) 1.15-
0.85 (m, 28H) Physical properties of hemiacetal (main product) Properties: Colorless powder NMR spectrum (CDCt, , δppm): 2.6
1 (dd, IH.

J=11.9Hz), 2.87 (m, IH), 3.49
(a, 3H), 3.80-4.38 (m, 4H), 5.
24 (brs, IH), 5.65 (d, IH, J=8.
4Hz), 7.90 (d, IH, J=8.0Hz), 8
．． 70 (bra, IH) Physical properties of the other hemiacetal: Colorless powder NMR spectrum pv (CDCt3. Jppm):
2.68 (dd, IH.

J=11.9Hz), 2.92(m, IH)
, 3.39(s, 3H), 3.80-4.3
8 (m, 4H)y4.82 (brs, IH), 5.70
(d,'IH,J=8.8Hz) -7,95(d
, IH, J=8.0Hz), 8.70(brs
, IH) Example 1 3'-deoxy-1'-dimethylphosphono-4/, 6/
-0-(tetraisopropyldisiloxane-1,3-
tetrahydrofuran (2
0d) 0.3311/(lo equivalent) of triethylamine and 21,011 kg (8 equivalents) of dimethyl phosphite were added to the solution under a nitrogen stream, and the mixture was heated under reflux for 11 hours. After concentrating the reaction solution, the residue was subjected to silica dull column chromatography using methylene chloride/methanol (97:3-95
:5) to obtain 121,111 g of the title compound. (
Yield "476q6) The obtained title compound has two types of isomers with respect to the aqueous group (1' position), and the ratio is 1:3.2
Met.

Properties: Amorphous crystal IR spectrum (KBr, m): 2960,286
0.170011470.1350,1120.104
0UV spectrum (λfna X * n ffl +
Ethanol): 261.9 (ε=10.500) Mass spectrum width/z): 565 (M+-CaH2
), 547 NMR of main product (CDCt, , δpp
m) :8. OO(d, IH.

J = 7.97 (z), 5.68 (d, IH
, J=7.9Hz) -4,96(m-IH).

4.28 (dd, IH, J=8.4Hz), 4.17 (
d, IH, J=12.3Hz).

4.05-3.9 (m, 2H), 3.76 (d, 3H,
J=10.6Hz).

3.72cd, 3H, J=IO, IHz), 2.91c
d, 2H, J=8.4Hz)'.

1.15-0.9 (m, 28H) NMR of the other isomer (CDCz 3.δppm
): 7.99 (d, IH, J=8.4Hz), 5.
68 (d, IH, J = 8.4Hz), 4.47 (m, I
H), 4.29 (m, IH), 4.16 (d, IH, J
= 12.4Hz).

4.04-3.95 (m, 2H), 3.83 (d, 3H
, J=9.7Hz), 3.78(d, 3H, J=9.7
Hz), 2.98 (dd, IH, J=12.8, 6.2
Hz).

2.87 (dd, IH, J=12.8, 10.6Hz)
, 1.15-0.9 (m.

28H) Example 2 3'-deoxy-1'-0-(imidazol-1-ylthiocargenyl)-1'-dimethylphosphono-4/,6
/-0-(tetraisopropyldisiloxane-1,3-
diyl)-β-D-fructofuranosyluracil Compound 115 of Example 1 was dissolved in 2011 J of 1,2-dichloroethane, and 132 Da (3,5 amount) of 1,1'-thiocargenyldiimidazole was dissolved. was added and heated under reflux for 4 hours under a nitrogen stream. After distilling off the solvent, the residue was subjected to column chromatography on silica gel and eluted with ethyl acetate to obtain 135 μl of the title compound. (Yield: 100 cm) This compound has two types of isomers regarding the active thioester, and the ratio is 1:2.

Properties: NMR spectrum of colorless powder main product (CDC2, δppm
): 8.43 (brs, IH), 8.37 (a, I
H), 8.0O (d, IH, J=7.9Hz).

7.68 (s, IH), 7.34 (d, IH, J=9.
7Hz'), 7.12(s.

IH), 5.74 (d, IH, J=7.9Hz), 4.
37-4.2 (m, IH) 14.24 (d, 2H, J=
13.2Hz), 4.01 (dd, IH, J=13.2
゜2.6Hz) 13.76 (d, 3H, J=10.1H
z), 3.73(d, 3H.

J=11.9Hz), 3.03(dd, IH, J=13
．． 2.5.7Hz), 2.36(dd, IH, J=13
．． 2.11.9Hz), 1.15-0.8(m, 28H
) NMR spectrum of the other isomer (CDCt3°δppm): 8.25 (s, IH), 8.00 (brs
, lH), 7.87 (d.

] H, J-8, 4Hz), 7.56 (s, IH), 7
．． 04 (s, IH), 6.92 (d = I He J
=9.7 Hz), 5.55 (d, I H-J
=8.4 Hz), 4.42-4.30 (m*
I H) 14.18 (d, 2 HIJ=11.
9 Hz), 4.01 (dd, IH, J-11, 9
, 2,6Hz), 3.86(d, 3H, J=11.5H
z), 3.82 (d, 3H, J=10.6Hz), 3.
32 (dd, IH.

J=12.8.5.7Hz), 3.14(dd, IH,
J=12.8.14.1Hz).

1.15-0.8 (m, 28H) Example 3 1/,3/-dideoxy-1'-dimethylphosphono-4
/,6/-0-(tetraisopropyldisiloxane-1
,3-diyl)-β-D-fructofuranosyluracil Compound 85■ of Example 2 was dissolved in 201117 benzene to give 18.1# azobisisobutyronitrile (1,1
After cooling, the reaction solution was washed with water, dried, and concentrated. The title compound was separated by layer chromatography and developed with methylene chloride/methanol (95:5).
n9 (yield 77%) was obtained.

Properties: Amorphous crystal [α 60° 17.4° (chloroform) Takumi spectrum (λm A K + ethanol): 261.1 nm
(ε=8200) Mass spectrum (m/z): 549 (M+-C
sH7) NMR spectrum (CDCl2, δppm)
:8.31 (brs, LH).

7.99 (d, IH, J=8.4Hz), 5.
67 (d, IH, J = 8.4Hz).

4.33-4.2 (m, LH), 4.17-3.
90 (m, 3H), 3.69 (d.

3H,J = 10.1Hz), 3.68(d, 3H,J
=10.6Hz), 3.15-3.0(m+2H)
, 2.72 (dd, IH, J=18.5.15.9
Hz).

2.55 (dd, IH,, T-12,8,9,7H
z), 1.15-0.8 (m, 28H) Example 4 1', 3'-dideoxy-1'-dimethylphosphono-β-D-fructofuranosyluracil Compound 50 of Example 3 was dissolved in tetrahydrofuran. A 1 molar tetrahydro7 run solution (2 equivalents) of 0.17+d tetra-n-butylammonium fluoride was added at -35°C. After stirring at -35°C for 30 minutes, 3 drops of water were added to the reaction mixture and concentrated.

The residue was subjected to preparative thin layer chromatography on silica gel and developed and separated with methylene chloride/methanol (ss:i5) to obtain the title compound 21 (yield: 68 qb).

Properties: Amorphous crystal NMR spectrum # (CD, OD, δppm): 8.
14 (d, xn.

J=7.9Hz), 5.59(d, IH,
, J=7.9Hz), 4.23 (m, 2H)
.

3.71 (d, 3H, J = 10.6Hz),
3.67 (d, 3H, J=10.1Hz).

3.8-3.5 (m, 2H), 3.3-3.15 (m,
IH), 2.82 (dd.

IH, J=15.9.17.6Hz), 2.8-2.7
(m, IH), 2.67-2.56 (m, IH) Example 5 1', 3'-dideoxy-1'-methylphosphono-4
',6'-0-(tetraisopropyldisiloxane-1
,3-diyl)-β-〇-fructofuranosyluracil/t-butylamine salt Compound 91.7~ of Example 3 was converted into t-p, t-butylamine 20
- and heated in a sealed tube at 100°C for 6 hours. After concentration, the residue was subjected to preparative thin layer chromatography on silica gel and developed and separated with methylene chloride/methanol (90:10) to recover raw material of 15.6Tn9 (17%) and 50.2Tn.
The title compound No. 9 (yield 50%) was obtained.

Properties: Amorphous crystal [α emission]: -46,5° (chloroform) IR spectrum (KBr, m): 3400, 2940, 28
60°1700, 1470, 1390, 1300
, 1200, 1060UV spectral (λm&X
rethanol: 264. Onm(ε=mass spectrum (m/z): 535 (M-CsH7)m
Spect/l/ (CDCL5, δppm) Near,
98 (d, IH.

J=8.4Hz), 5.63(d, IH,J
=8.4Hz), 4.3-3.8(m.

4H), 3.52 (d, 3H, J=10.6Hz), 3
．． 15-3.0 (m, 2H).

2.4-2.1 (m, 2H), 1.30 (s, 9H, t
-butylamine).

1.1-0.9 (m, 28H) Example 6 1',3'-dideoxy-1'-methylphosphono-β
-D-72 Cutofuranosyluracil Compound 53Iv of Example 5 was dissolved in 25-nato-2-hydrofuran and 0.162 m of tetra-n-butylammonium fluoride (1 molar solution in tetrahydrofuran, 2 eq.) at -50°C. was added and stirred for 10 minutes.

After distilling off the solution, ion exchange resin (Dow@x 50wx
The product was subjected to column chromatography as described in 4) and eluted with methanol to obtain the title compound 23 (yield: 83%).

Properties: Amorphous crystal NMR spectrum (CD, OD, δppm): 8.
16 (d, LH.

J=7.9Hz)5.57(d,IH,J=7.
9Hz), 4.28-4.1(m.

2H), 3.7-3.5 (m, 2H), 3.57 (d,
3H, J=10.6Hz).

3.1-2.6 (m, 2H) Example 7 1/, a/-dideoxy-1'-dimethylphosphono-
4/, S/-〇-dibenzoyl-β-D-fructofuranosyluracil 6911 g (1,2 equivalents) of tri-n-butyltin hydride was weighed in toluene, and 33 Da (1k per 1,2) of azo Add bisisobutyronitrile and leave under nitrogen for 10 minutes9
Heated to 0°C. Add the metal compound 137W of Reference Example 9 to this solution.
A toluene solution of No. 9 was added and heated to 90° C. for 1 hour.

The reaction solution was washed with water, dried, and concentrated, and the residue was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (97:3) to obtain 86 da of the title compound (yield: 80%).

Properties: Amorphous crystal [α]2D'. Knee 37.1° (chloroform) IR spectrum (KBr, cm-'): 1720.1710.
1690° 1460.1270, 1030.715 buying spectrum (λmaX l ethanol): 261.5Hm
(ε=10800), 231. Onm(ε=2430
0) Mass spectrum (m/z): 446 (b, p), 3
24NMR spectrum (CDCL, , δPprn)
:8.53 (br-s, IH).

8.10-7.35 (m, 10H), 7.88 (d, I
H, J = 8.4Hz).

5.57 (m, IH), 5.53 (d, LH
, J=8.4Hz), 4.89(m.

IH), 4.74 (dd, IH, J=12.3, 3.
1Hz), 4°56 (dd, IH.

J=12.3, 3.1Hz), 3.68(d
, 3H,J=10.1Hz), 3.66(d,
33. J=10.1Hz), 3.23(dd, IH,
J=15.9.18.5Hz), 3.14(d,
IH, J=14.1Hz) 3.06-2.90(
m, IH).

2.69 (dd, LH, J=15.9, 18.5Hz)
Example 8 1/,3/-dideoxy-1'-methylphosphono-4'
+6'-0-nopenzoyl-β-D-fructofuranosyluracil/t-butylamine salt Compound 129 of Example 7 was dissolved in t-butylamine and heated at 100° C. for 3 hours in a sealed tube. After concentration, the residue was subjected to preparative thin layer chromatography on silica gel and developed and separated with methylene chloride/methanol (85:15) to obtain the title compound 96 (yield 67).

Properties: Amorphous crystal NMR spectrum (DMSO-d 6.δppm):
8.05-7.4 (m.

11H), 5.42(m, IH), 5.24(
d, IH, J=8.2Hz), 4.79(m,
IH), 4.48 (m, 2H), 3.19 (d
, 3H, J=10.3Hz).

2.96 (m, 2H), 2.5-2.32 (m, IH
), 2.14 (dd, IH.

J"15.6Hz) Example 9 1/,3/-nobuoxy-1'-methylphosphono-β-
D-Fructofragil 2 Sil Compound 94M9 of Example 8 was dissolved in 37 m of methanol, and xoa* (5 equivalents) of potassium carbonate was added at 0°C.
Stir for hours. Add ion exchange resin (Dowsx) to this solution.
5QWX4) was added for neutralization, and after filtration, the solvent was distilled off.

The residue was dissolved in water and treated with ion exchange resin (Dowex 1-
X2 ) with 0. Elute with IN hydrochloric acid to obtain 45% of the title compound.
DA (yield 79%) was obtained.

Example 10 1'-deoxy-1'-noethylphosphono-4',6'
-0-nopenzoyl-β-D-fructofuranosyluraciltoluene 20d to tri-n-butyltin hydride 36
(3.3 equivalents) and azo and swissoptilonitrile 6.8 # (3.3 equivalents) were added, and the mixture was heated and stirred at 80° C. for 2 hours under an argon stream. Compound 2 of Reference Example 10 was added to this solution.
A toluene solution of No. 7~ was added thereto and treated in the same manner as in Example 7 to obtain 1 oz (yield: 47 g) of the title compound.

Properties: Amorphous crystal mx pect/I/ (cDct5 +δppm): 8.
06-7.4 (m, 10H).

7.90 (d, IH, J=8.1Hz), 5
．． 58 (m, LH), 5.52 (d, I He
J=8.1 Hz) -4,88(m, IH)
, 4.73 (d d , I H.

J=2.9, 12.3Hz), 4.55(dd, LH
, J=12.3, 3.6Hz).

4.1-3.98 (m, 4H), 3.22 (dd, I
H, J = 16.2.19.1Hz).

3.14 (m, IH), 2.98 (dt,
II (, J = 14.9, 5.8 Hz).

2.68 (dd, IH, J=15.9, 19.1
Hz) Reference Example 1 2.3'-anhydro-4', 6'-0-(tetrainglobildisiloxane-1,3-diyl)-β-D-
Fructofuranosyluracil 2. 3'-0-Anhydro-β-D-fructofuranosyluracil 909 µ (3,55 mmol) was dissolved in 50 - dimethylformamide and then 990 µ imidazole (14,56 mmol) was added. Ta. Add this solution to 2
Cool to 0° C. and add 1,3-dichloro-1,1,3,3-tetrainglobyldisiloxane (1,29d, 3.75 mmol). 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 a crude product of 1.60.9.

This crude product was subjected to silica gel column chromatography and eluted with methanol/methylene chloride (5:95) to obtain the title compound 928 da (yield 53%).

Properties: Colorless oily substance IR spectrum (film, cm-'): 3250*2
950°2860, 1630, 1530, 147
5, 1405NIIIR spectrum (CDCt,,
δppm): 0.9-1.15 (m, 28H)
.

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, LH, J=5.2Hz)
, 5.92 (d, IH, J = 8.1 Hz), 5.98 (
dd, IH.

J=9.2, 6.0Hz), 7.33(d, IH, J=
8.1Hz) Reference Example 2 2.3'-0-anhydro-1'-methoxy-4/,
6/ -0-(tetraisoglobildisiloxane-1,
3-diyl)-β-D-fructofuranosyluracil Compound 2.12.9 of Reference Example 1 was dissolved in 42-hydrous dimethyl sulfoxide to obtain anhydrous benzene 42WLt.

0.34 m (1 equivalent t) of anhydrous pyridine, 0.161117 (0.5 equivalent) trifluoroacetic acid, and 2.63 Il (3 equivalent) dicyclohexyl carmediimide were added in sequence, and the mixture was left at room temperature overnight.

Insoluble materials were separated from each other, ethyl acetate was added to the solution, washed twice with water, dried (anhydrous magnesium sulfate), and concentrated. The residue was subjected to 7-licage column chromatography and eluted with methylene chloride/methanol (97:3 to 90:10) to obtain the title compound in 2.12. F (yield: 97 cm) was obtained.

The main product has the following physical properties.

IR spectrum (KBr, cIR): 1660.154
0,1470 cold speed, x4 kutle (CDCt3.δppm
): 0.8-1.2 (m, 28H).

3.50 (s, 3H), 3.8-4.2 (m,
4H), 4.3-4.6(m, IH).

5.06 (brs, IH), 5.33 (d, IH, J=
6.0Hz), 5.90(d, IH, J=7.8H
z), 7.60 (d, IH, J=7.8Hz
) Physical property NMR spectrum of the other isomer (CDC43+δppm): 0.8-
1.2 (m, 28H).

3.50 (s, 3H), 3.8-4.2 (m, 4H),
4.3-4.6(m, 1I().

4.98 (brs, IH), 5.43 (d, lH, J=
6.0Hz, 5.94 (d.

IH, J = 7.8 Hz), 7.38 (d, IH, J =
=7.5Hz) Reference Example 3 2.3'-0-anhydro-1'-tmethylphosphono-
4',6'-〇-(Nat-2-inpropyldisiloxane'-1,3-diyl)-β-D-fructofuranosyluracil 400η of the compound of Reference Example 2 was dissolved in 49m/ml of tetrahydrofuran, and 342Da of dimethyl phosphorus was dissolved. Fight (4 hits i)
t) and 0.43 Ill of triethylamine (4 equivalents)
was added and reacted. Purification was carried out using silica gel column chromatography eluting with methylene chloride/methanol (9:1) to obtain the title compound of 418~ (yield: 89 qb).

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 crystal UVx vector (ethanol, λmax+nm):
247 (8670), 226 (10100) IH7, vector (KBr, m-'): 1660,
1540, 147ONMR spectrum (CDC23,
δppm): 0.8-1.1 (m, 28H)
.

3.7-4.0 (m, 8H), 4.3-4.4 (m, 2
H), 5.17 (dd, IH.

J = 8.2.13.2Hz), 5.67 (d, IH, J
=4.0Hz), 5.8'4(d, IH, J=7.
8Hz, ), 6.97 (dd, IH, J=8.
2, 15.2Hz).

7.68 (d, IH, J = 7.8Hz) Mass spectrum (m/z): 563 (M''-43) Physical properties of the other isomer: Amorphous crystal NMR spectrum (CDCl3 #δppm): 5 ．．
71 (d, IH, J==4.0Hz), 5.85
(d, IH, J=7.8Hz), 6.97 (dd, IH
.

J=8.2, 15.2Hz), 7.43(d
, IH, J=7.8Hz) Reference Example 4 2.3'-0-anhiteq-1'-0-(phenyloxythionocar?nyl,)-17-dimethylphosphono4'+s'-o - trisonorovir disiloxane-1
,3-diyl)-β-D-fructofuranosyluracil 500 μ of the compound of Reference Example 3 was dissolved in 50 m of 1,2-dichloroethane to obtain 140 # of 4-dimethylaminopyridine (1.5 equivalents) and 147119 of phenylchloro. Thionocarbonate was added and stirred at room temperature for 1 hour. Next 49m
g of phenylchlorothionocarbonate was added, and then 2 g of phenylchlorothionocarbonate was added.
Stirred at room temperature for an hour. It was diluted with methylene chloride, and the organic layer was washed twice with water, dried, and concentrated. Remove the residue with silica glue (
The product was subjected to column chromatography on 20.P) and eluted with methylene chloride/methanol (99:1 and 97:3) to give 572 Da (yield: $93 Chi) of the title compound.

This product had two types of isomers regarding thioester and phosphorus, and the ratio was 3:2.

Physical properties of main product: Properties: Amorphous crystal UV spectrum (ethanol, λmax, nm)
:237(ε=15300), 229(ε=16100
) IR spectrum/I/ (KBr, cm-')21
660.1560.1460 [α: ID Knee 35.5
° (chloroform) mass spectrum (m/z): 69
9(M''-43), 637 Physical properties of the other product: Amorphous crystal Reference example 5 2.3'-0-Anhydro-1'-deoxy-1'-dimethylphosphono-4',6'- 0-(Tetraisopropyldisiloxane-1,3-diyl)-β-D-fructoy 12469 (1,1 equivalents) of tri-n-butyltin hydride was weighed in large toluene and 57.31! (1,1 equivalents) ) was added thereto, and after heating under reflux for 5 minutes, a toluene solution of Compound 286 da of Reference Example 4 was added, and the mixture was heated under reflux for 1 hour under a nitrogen atmosphere.

The reaction solution was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was subjected to silica duplex column chromatography using methylene chloride/methanol (97:3 to 95:5
) to obtain the title compound 170Q. (Yield 75%) Properties: Amorphous crystal [α) D knee 57.3° (chloroform) UV spectrum (ethanol, nm): 248 (ε=7830)
.

226 (ε=9000) IR spectrum (KBr, cIn-'): 1650,1
550.1470-NMR spectrum (CDC23
, δ): 0.85-1.13 (m, 28H).

2.62 (dq, 2H) 3.73 (d, 3H) 3.76
(d, 3H), 3.89 (dd, IH), 3.96 (d
d, LH), 4-03(4-03(,4-50(dat
IH), 5.43(d, IH), 6.09(d
, IH), 7.39 (d, IH) Mass spectrum (m/z): 547 (M"-43) Reference example 6 2.3'-0-anhydro-1'-deoxy-1'-tumethylphosphono-β -D-Fructofuranosyluracil Compound 7061R9 obtained in Reference Example 5 was 50-
Dissolve tetra-n-butylammonium fluoride in tetrahydrofuran (1 molar solution 2
．． 63d) 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!i). Methylene chloride-methanol (87,5:12.5
200m.

85:15 (200 Mt) and eluted with 393 Da (yield 94
The title compound of h) was obtained.

Properties: Amorphous crystalline stone (ethanol, λmax r nm):
249 (ε=7480) 224 (g=9670
) IR Suiktor (KBr+m) 2 1660, 163
0,1530゜48O NMR, x, <couple (CD, OD, δppm):
2.96 (dd, LH.

J=19.0, 16.1Hz), 3.42-3
．． 50 (m, 2H), 3.72 (d.

3H, J=11.5Hz) 3.78 (d, 3
H, J=11.0Hz), 4.25-4.33(
m, IH) 4.52-4.56 (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"-0H) Reference Example 7 2.3'-0-anhydro-4',6'-0-dibenzoyl-1'-deoxy-1'-dimethylphosphono-β-
D-Fructofuranosyluracil Compound 292 of Reference Example 6 was dissolved in 30-ace)=tolyl, and 0.59-triethylamine (5 equivalents) and 25
5rIK9 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 (501), and methylene chloride/methanol (97:3,
100d) and methylene chloride/methanol (95:
5,100-), 349fn9(
The title compound was obtained in a yield of 75 cm.

Properties: Amorphous crystal W spectrum (ethanol, λmaxrnm): 230
(g=32800) IR suction (KBr, cm-'): 1720,16
60.1550°1470, 1'280, 1030
, 72ONMR spectral (CDCj, , δppm
): 2.81 (dd, IH.

J=34.7, 16.2Hz), 2.87 (
dd, IH, J=34.3, 16.2Hz).

3.72 (d, 3H, J=10.7Hz),
3.77 (d, 3H, J=12.0Hz).

4.39 (dd, IH, J-=5.8, 12.3
Hz), 4.47 (dd, IM, J = 5.
2,12.3Hz)4.77-4.83(mslH),
5.77 (dd, IH1J=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=7.1Hz), 7.56(m, IM), 7
．． 63 (m, IH), 7.92 (m.

2H), 8.07 (m, 2H) Mass sic # (mA): 431 (M”-125
), 326 (M+-230) Reference Example 8 1'-deoxy-1'-dimethylphosphono-4', 6'
-0-dibenzoyl-β-D-fructofuranosyluracil Compound 3391n9 of Reference Example 7 was dissolved in 23-ml ethanol, 23 mg of 2N hydrochloric acid was added, and the mixture was stirred overnight at a constant temperature. The reaction solution was concentrated, and the residue was subjected to column chromatography on silica gel (51) and eluted with methylene chloride/methanol (95:5) to obtain the title compound 3481n9 (quantitative).

Properties: Amorphous crystal [α: 'D' + 12.9° (chloroform) UV spectrum (ethanol, nm): 261 (t =
11900).

230 (g=27500) IR spectrum (KBr, crn-'): 3300,1
720,1460°1400.1280.11l1 00N spectrum (CDCt, , δppm): 2.6
4 (dd, IH.

J=19.5, 16.2Hz), 3.31 (
dd, IH, J=17.5.16.2Hz).

3.65 (d, 3H, J = 10.9Hz) 3.66 (d
, 3H, J=10.9Hz).

4.63-4.78 (m, 3H), 4.80-4.93
(m, 2H), 5.41 (d.

IH, J = 0.7 Hz) 5.67 (d, IH, J = 7.
6Hz), 7.39-7.51 (m, 4H), 7.52
-7.63 (m, 2H), 7.92 (d, IH, J=7
．． 6Hz)+7.97-8.10(m, 4H)t9.8
3 (bra, IH) mass spectrum (m/z): 462
(M-112), 444°430.326 Reference example 9 1'-deoxy-1'-dimethylphosphono-3'-〇-
Phenyloxytheocardenyl-4',6'-0-dibenzoyl-β-D-fructofuranosyluracil Compound 39 of Reference Example 8 1,2-dichloroethane (10d
) 47.6 μm (6 equivalents) of 4-dimethylaminopyridine and 50 mg (4,4 equivalents) of phenylchlorothionocarbonate were added to the solution under nitrogen flow, and the mixture was heated under reflux for 2 hours.

The reaction solution was washed with water, dried and concentrated, and the resulting residue was subjected to preparative thin layer chromatography on silica gel to extract methylene chloride and
The mixture was developed and separated with methanol (95:5) to obtain 27 ml of the title compound (yield: 57 ml).

Properties: Amorphous crystal [α)'' Knee 29.6° (chloroform) IR spectrum (KBr, cln): 1720.1710,1
700°1460.1280.1100.1030°U
V spectrum (λml!+ethanol): 256.4n
m (g = 12800), 232.3 nm (t =
33600) Mass spectrum (m/z): 599 (b
ass), 567.536 subject spectrum (CDC23,
δppm): 12.0 (a, IH).

8.18-7.12 (m, 13H), 7.85 (d
, LH, J=8.4Hz).

6.95-6.86 (m, 2H), 6.24 (s
, IH), 5.67 (d, IH.

J=8.4Hz), 5.63(d, IH,J
=2.6Hz), 4.88(dd.

IH, J = 11.9.3.1Hz), 4.80 (dd
, LH,J =11.9°4.0Hz), 4.71(m
, IH), 3.69 (d, 3H, J=10.6Hz).

3.67 (d, 3H, J=11.5Hz),
3.52 (t, IH, J=17.2Hz).

2.8Of, dd, LH, J=17.2, 19
．． 0Hz) Reference Example 10 1'-deoxy-1'-diethylphosphono-3'-〇-
Phenyloxythiocargenyl-4', 6'-0-sopenzoyl-β-D-fructofuranosyluracil 1'
-deoxy-11-diethylphosphono-4', 6'-
0-Dibenzoyl-β-〇-fructofuranosyluracil 39rR9 was dissolved in 10-1,2-dichloroethane to give 4.8 parts of dimethylaminopyridine (6 parts), 5 parts
of phenylchlorothionocarbonate (4,4 equivalents) f
: and reacted in the same manner as in Reference Example 9 to obtain the title compound 27 (yield 57%).

Properties: Amorphous crystal spectrum (CDCt5+δppm): 8.14-
7.16 (m.

13H), 7.86(d, IH, J=8.1H
z), 6.96-6.88 (m.

2H), 6.19(s, IH), 5.67
(d, IH, J=8.1Hz), 5.62(d
, IH,J = 2.5Hz), 4.88 (d
d, IH, J=11.3, 3.2Hz).

4.78 (dd, IH, J=11.3, 3.9H
z), 4.73-4.66 (m, IH).

4.15-3.98 (m, 4H), 3.42
(dd, LH, J=16.3.18.1Hz).

2.76 (dd, IH, J=16.3.19.8Hz
), 1.27(t, 6H.

J = 6.9 Hz) [Effects of the Invention] The novel compound represented by the general formula (1) of the present invention is expected to be used not only as a new antitumor and antiviral drug but also as an agrochemical, especially an insecticide.

Claims (4)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 represent a hydrogen atom or an acyl group, and R^3 and R^4 are the same or different and represent a hydrogen atom or a lower deoxyphosphononucleoside having an alkyl group). (2) The compound according to claim 1, wherein the acyl group is an acetyl group, a propionyl group, or a benzoyl group. (3) The compound according to claim 1, wherein the lower alkyl group is a methyl group, ethyl group, propyl group, or butyl group. (4) Represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents a hydroxyl protecting group, and R^5 represents a lower alkyl group) The aldehyde or aldehyde equivalent is reacted with a dialkyl phosphite having the general formula ▲mathematical formula, chemical formula, table, etc.▼ (in the formula, R^6 represents a lower alkyl group) in the presence of a base, and then 1 of the sugar
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 and R^2 represent a hydrogen atom or an acyl group, and R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group.) A method for producing a deoxyphosphononucleoside comprising: