JPS61289095A - Phosphono-orotate derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is H or acyl; R<1> and R<2> are H or lower alkyl; X is H, OH or acyloxy; Y is H or lower alkyl). EXAMPLE:Methyl 2, 3'-o-anhydro-1'-deoxy-1'-diethylphosphono-1-beta-D-fructofu-ranosyl orotate. USE:A carcinostatic agent and an antiviral agent. It has strong effect to inhibit the biosynthesis of nucleic acid and is expected to be useful as an insecticide, etc. PREPARATION:The aldehyde compound of formula II or III (A is OH-protecting group; R<3> and R<4> are lower alkyl) or its aldehyde equivalent material is made to react with the dialkyl phosphite of formula IV (R<5> is lower alkyl) in the presence of a base (e.g. triethylamine) usually in an ether or alcohol solvent preferably at 0-55 deg.C to obtain the compound of formula V. The product is optionally deprotected and, if necessary, subjected to various treatments such as hydrolysis, acylation, reduction, deprotection, etc.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to the general formula (1) (wherein R represents a hydrogen atom or an acyl group, and 8 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group). and XF'i represents a hydrogen atom, a hydroxyl group, or an acyloxy group, and Y represents a hydrogen atom or a lower alkyl group), a pharmacologically acceptable salt thereof, and a method for producing the same.

The phosphonoorotate derivative represented by the general formula (1) is useful as a nucleic acid biosynthesis inhibitor.

[Conventional technology]

Many 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 phosphononucleons, a large number of compounds have been synthesized to date, including 5'-deoxy-5'-phosphonouracil using 5'-phosphonates (Ei, Holly, Tetrahedron Letters CA). , Ho
15. Ttrtrahedron Letters)
, p. 881, 1967). However, there is no description of a nucleoside having a phosphono group or a phosphonomethyl group at the 1' position.

Many efforts have been made to discover nucleic acid biosynthesis inhibitors and apply them to anticancer and antiviral drugs. However, among the pyrimidine biosynthetic pathway, orotate phosphoribosyltransferase (Orotate Phosyltransferase)
phoribosyl Transferase) nucleobases and phosphoribosyl pyrophosphate (Ph
Osphoribosyl Pyrophosphat
Research on competitive inhibitors corresponding to the transition state in the condensation step e) has not yet been conducted.

[Problem that the invention seeks to solve]

The present inventor planned to synthesize a transition-state analogous compound as this competitive inhibitor by changing the oxygen of the carbon-oxygen-phosphorus bond at the 1st position of phosphoribosyl pyrophosphate to carbon and introducing 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]

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 phosphoribosyl transferase, a phosphonoorotate having the following general formula (1). Derivatives, salts thereof and methods for producing the same.

The phosphonoorotate derivative represented by the general formula (1) of the present invention can be synthesized by the following method.

2-amino-β-D-fructofuro C2', a known substance having the formula (2) obtained from D-fructose;
3': 3,4)-oxazoline (A. Holly,
Newkreitsk, acid.

Research (A, Ho1y, Nuclaic Ac1d
Re5), Vol. 1, p. 289, 1974) was used as the starting material.

This compound (2) and di-lower alkyl acetylene dicarboxylate are condensed to give the general formula (3) (wherein Rs represents a lower alkyl group).

The di-lower alkyl acetylene dicarboxylate used here may be any existing dicarboxylate, but dimethyl acetylene dicarboxylate or diethylacetylene dicarboxylate is preferably used.

In this compound (3), the hydroxyl groups at the 4' and 6' positions of Tong are selectively protected, and the compound has the general formula (4) (wherein BS represents the same meaning as above and A represents a protecting group). do. The protecting group used here may be any one that selectively protects the 4' and 6' positions of the sugar, but dichlorotetraisopropyldisiloxane is preferably used as the protecting agent.

By then oxidizing this compound (4), the general formula (
5) An individual such as an aldehyde having the formula (where A and BS have the same meanings as above and R4 represents a lower alkyl group) is obtained.

The oxidizing agent used is preferably dimethyl sulfoxide, such as dimethyl sulfoxide and trifluoroic 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 product aldehyde reacts with a friendly solvent, particularly an alcohol, used in the purification step to obtain aldehydes such as the aldehyde represented by the general formula (5).

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

This aldehyde equivalent (5) and general formula (6)% formula% (6
) (wherein R'' represents an alkyl group) is reacted in the presence of a base to form the general formula (7
) (wherein A, R'' and R5 have the same meanings as above) can be obtained.

Here, the base includes trialkylamines such as triethylamine, diimpropylethylamine, and triimpropylamine, and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like. Also suitable is sodium hydride.

For example, if dibenzyl phosphite or diphenyl phosphite is used instead of dialkyl phosphite, each group R
A compound in which 1 is a benzyl group or a phenyl group is obtained.

In this reaction, the reaction temperature is preferably 0 to 55°C, and the best solvent is an ether or alcohol.

To remove the 1'-position hydroxyl group of this compound (7), it is first converted into a thioester. As a deoesterifying agent, for example, 1
, 1'-thiocarbonyldiimidazole and phenylchlorothionocarbonate. By reacting these reagents in a chlorine-based, hydrocarbon-based or ether-based solvent in the presence or absence of a base, the general formula (8) (wherein A, R3 and BS represent the same meanings as above, zVi 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 obtain a phosphononucleoside having the general formula (9) (wherein A, R'' and BS represent the same meanings as above). .

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 (9) was deprotected to produce the compound of the present invention (lcL) (
A general deprotection reaction is used to synthesize the phosphonoorotate derivative having the formula (R represents the same meaning as defined above).

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 the main reaction.

When this invention compound (1α) is acylated, the general formula (1
b) A phosphonoorotate derivative of the compound of the present invention having the formula (wherein Ba and R1 have the same meanings as above and B represents an acyl group) is obtained. The acylated product can be prepared using common methods, i.e. with acylating agents such as acetic anhydride, acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, benzoyl bromide, toluyl chloride, benzoyl cyanide or cinnamoyl chloride. It can be obtained by reacting in the presence or absence of a base.

When the phosphonoorotate derivative dried with the above formula (lcL), which is a compound of the present invention, is treated with a weak base, the general formula (lcL) is treated with a weak base.
1c) A phosphonoorotate derivative having the formula (wherein R5 represents the same meaning as above) is obtained.

As the base, dilute lithium hydroxide aqueous solution, dilute barium hydroxide aqueous solution, etc. are suitable.

Further, when compound (1α) is treated with trimethylsilyl iodine, a phosphonoorotate derivative represented by formula (1d) υn is obtained.

In the compound of general formula (1α), when R5 is a methyl group, the phosphonoorotate derivative represented by the formula can be obtained by heating with t-butylamine.

On the other hand, in order to synthesize the phosphonoorotate derivative of the present invention, in which 81 and R1 have the same meanings as above, the above-mentioned compound (7) is deprotected. A protection reaction is used.

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

Moreover, any reaction solvent may be used as long as it does not participate in this reaction.

When this compound (1f) is treated with a weak base, a phosphonoorotate derivative having the general formula (wherein R$ represents the same meaning as above) is obtained.

The weak base used here is preferably a cold aqueous solution of lithium hydroxide. Furthermore, it is clear that when treated with an amine such as tribudelamine as a weak base, a tributylamine salt of the compound having the general formula (ig') H (wherein B5 represents the same meaning as above) is obtained.

In this compound (1g): 9 and (1y'), when R1 is a methyl group, dealkylation occurs by heating with t-butylamine, yielding a phosphonoorotate derivative represented by formula (1h). .

Further, when the phosphonoorotate derivative represented by the general formula (1g) is treated with trimethylsilyl iodine, the phosphonoorotate derivative represented by the formula (11) is obtained.

When the above-mentioned compound (7) is acylated, the general formula (10) (
In the formula, A, E" and Rs have the same meanings as above, and B
represents an acyl group).

Acyl derivatives can be prepared by common methods, namely acetic anhydride, acetyl chloride, propionyl chloride, butyryl chloride,
It is obtained by reacting with an acylating agent such as benzoyl chloride, benzoyl bromide, toluyl chloride, benzoyl cyanide, or cinnamoyl chloride in the presence or absence of a base.

The obtained compound (10) was deprotected to give the compound of the present invention (lj
) (In the formula, R3, R5 and B have the same meaning as above)
A general deprotection reaction is used to synthesize the phosphonoorotate derivative having .

For example, in the case of a silyl protecting group, deprotection can be performed using the most common tetraalkylammonium chloride. Further, the reaction solvent may be any solvent that does not participate in this reaction.

When this compound (1j) is acylated, the general formula (1k) (
In the formula, E, R'' and BsFi have the same meanings as above,
B' represents an acyl group). Acylation may be carried out by a common method, and may be the same as the method for obtaining the uninvented compound (16).

EXAMPLES The present invention will be more particularly illustrated by the following examples, but it will be clear that the invention is not limited thereto.

Example 1゜Methyl+2.3"o-anhydro-1'-dimethylphosphono-4',6'-o-(tetraisopropyldisiloxane-1,3-diyl)-1-β-D-7lacto To a solution of the compound (1.14 g) of Furanosylrotate Reference Example 3 in tetrahydrofuraf C5smtt) was added 1.03 g of dimethyl phosphite per C4.8 and 943'V (4.8 equivalents) of triethylamine, and the mixture was heated to 20 ml at room temperature. Stir for hours.

After concentration, the residue was subjected to column chromatography on silica gel and eluted with methylene chloride/methanol (95:5) to obtain the title compound 1.129. (Yield 87%) This compound has two stereoisomers at the 11th position of the sugar.
The ratio f'il was 1.9.

These two isomers can be easily separated by preparative thin layer chromatography on silica gel.

Physical properties of main product: Colorless crystal Melting point: 95-97°C [α]n: 110-6" (c = 0-21, chloroform) IR squictol (KBr, cm-'): 322o, 17
50% 1640 UV Spectrum (17M Z% Chloroform): 27
5 nm (g = 6100) mass spectrum Cm/z): 664 CM”), 68 high resolution mass spectrum (as CnHuOnNtSitP) Calculated value: 66!!>2327 Actual value: 66!l>2383 Physical properties of the other isomer Properties: Colorless crystal 0 points: 165-166°C [α] D knee 117.5° (cm0.16, riooform) IR spectrum CKBr, cm-'): 321
0.1750.1640 UV spectrum (λm, ar, chloroform): 276
nm (t = x6230) Mass spectrum (yrL/z): 665 (&++
1), NMRx”! act# (CDC11, δpprn)
: 0.82-1.12 (rn, 28H), 3.6
8 (d.

3g,,7=i0.5ttz),3.76Cd,3
H, J = 10.8 Hz), 3.81-4.00 (
m, 2H), 3.91 (s, 3H), 4.15 (rn,
IH), 4.42 (dd, IH.

J = 6.7, 9.4 Hz), 5.43-5.
56 (rrL, 2H), 5.61 (d, Iff, 7=
6.7Hz), 6.67(s, IH) Example 2゜Methyl, 2,3'-o-anhydro-1'-diethylphosphono-4',6'-o-(tetraisoprovir di70xane- 1,3-diyl)-1-β-D-fructofuranosyl orotate Using the compound of Reference Example 3, the title compound was obtained in a yield of 90% by condensing it with diethyl phosphite in the same manner as in Example 1. Ta.

As in Example 1, this compound also had two isomers, and the ratio was 2.8:1. These two isomers can be easily separated by preparative thin layer chromatography on silica gel.

Physical properties of main product: Colorless crystals Melting point: 81-83°C [α:]D: -96,6° (c=0.53, chloroform) IR spectral (KBr, α-'): 3200.
2950.1750.1640.1550UV sictor (λm, chloroform): 276rLm (gz59
20) -r Soot < Kutle (yn/g): 693 (A
f++1) NMR quictor (CDCl5.δppr
n): 0.80-1.10 Cm, 28H), 1
．． 37 (t.

3H, J=7.2Hz), 1.38 (t, 211
゜J=7.2Hz), 3.88(q, IH, J=17.
5Hz), 3.95 (s, 3H), 4.17-4
．． 40 (m, 6H), 5.39 (d d.

I H, J = 7.3, 13.7 Hz), 5.87 (
d, IH, J=6.2Hz), 5.96(#.

I H, J = 7.3, 16.8 Hz), 6.48 (
s, LH) Physical properties of the other isomer: Colorless crystal Melting point: 156-158°C [α) D knee 97.2° (c = 0.25, chloroform) IR Suscuttle (KBr, cIn-'): 3180 ．．
2950.175011635.1550UV chromatography (λ1.z1 chloroform): 278nrnct =
5560) Mass quictor (rIL/z): 693 (M
++1) NMR spectrum/l/(CDCIssδpp
m): 0.85-1.13 (m, 28H), 1.
19 (t.

3H, J-7, 2Hz), 1.30 (t, 3H
.

J=7.2Hz), 2.81 (m, LH), 3.85
3.96℃m, 2H), 3.92(g, 3H), :3
．． 97-4.20 (m, 5H), 4.42 Cd
d, IH, J=6.2.

9.4 Hz), 5.46 (d, IH, J-
7,7ffz), 5.63 (d, IH, J=6.
2Hz), 6.70 (s, IH) Example 3゜Methyl, 2,3'-o-anchitro-1'-dimedelphosphono-1'-〇-(imidazol-1-yl)thiocarbonyl-4'#e' -o-(tetraisopropyldisiloxane-1,3-diyl)4-β-D-fructofuranosyl orotate A solution of the compound of Example 1 (14zm9) in 1,2-dichloroethane (22m) ζ63.5 1,1'-thiocarbonylimidazole per m9 (1,5) was added, heated under reflux for 4 hours, concentrated, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate to determine the stereoisomerism regarding the 1' position of the sugar. body mixture 91.1 mg (production ratio 1:
The title compound of 2.6) was obtained. (Yield 55%) These two isomers can be easily separated by preparative thin layer chromatography.

Physical properties of main product: Colorless crystal Melting point: 93-96°C [α]D: 40.46 (cm0.17, chloroform)
IR susceptor (chloroform, cm-”): UV
Spectrum (λ, 2, chloroform): 274℃m (ε
=12450) NMR spectrum (CDCl3, δpprn):
0.8-1.2 (yrL, 28H), 3.72 (d
, 3H.

J-11, 1Hz), 3.74 (d, 3H.

J=11.1Hz), 3.85-3.95 (m.

3H), 4.00CB, 3H), 4.55-4.65(
m, LH), 5.64 Cd, 14°J=4.9H2
), 6.82 (s, LH), 7.09 (brs,
IH), 7.68 (brs, LH), 7.86 (
d, 14. ．． 7=10.0Hz), 8-42 (brs
, lH) Physical properties of the other isomer: colorless crystal melting point near 8-80°C [α] D knee 70.0 @ (cm0.06, chloroform) IHz (chloroform, 礪-'): UV spectrum ( λrn, engineering, chloroform): 272rLrn
(cm3150) NMR spectrum (CDCl, δppm): 0
．． 75-1.20 (rx, 28H), 3.78 (d
.

3H, J-11, 3Hz), 3.97 (d, 3H.

J=11.3Hz), 4.01 (s, 3H), 4
．． 22 (dd, IH, J=5.9.3.5H2),
4.30-4.60 (FPL, 3H), 5°88 (d
, I H, J-5,9Hz>, 6.71 (s.

IH), 7.07 (brs, IH), 7.51 (br
8. IH), 7.54 (d, IH, J=12-4Hz
), 8.27 (brs, IH) Example 4゜Methyl, 2,3'-o-anhydro-1'-diethylphosphono-1'-o-(imidazol-1-ylcothiocarbonyl-4', 6'-o-(tetrinepropyldisiloxane-1,3-diyl)-1-β-D-fructofuranosylrotate Using the compound (94■) of Example 2, react in the same manner as in Example 3. This gave a mixture of stereoisomers at the 1' position of the sugar of the title compound, 96IIT9.

(Production ratio, 1 nia) (yield 88%) These two isomers can be separated using preparative thin layer chromatography on silica gel.

Physical properties of the main product: Colorless crystals Melting point: 139-140°C [α] D knee 43.5° (cm 0.24, chloroform) IHz to Ktor (KEr, cm-'): 29
60゜1750.1640.1565 UV spectrum (λ2, chloroform): 2754m
(cm5920) NMR spectrum (CDCl5, δpprn):
0.85-1.15 Cm, 28H) 1.25 Ct,
3H.

J = 6.7 Hz), 1.27(t, 3H, /=
6.7Hz), 3.63 (dd, IH,,7=132
゜8.2Hz), 3.90 (dd, IH, J=13.
2゜3-6Hz)-3-q q (* 'JR)
QQ7-4.20 (m, 5H), 4.61
(dd.

IH, J-4, 1, 6, 7Hz), 5.66 (d.

IH,J=4. IHz), 6.82 (s, LH
), 7.08 (m,, IH), 7.69 Cm, LH)
, 7.81 (d, IH, J=9.6Hz), 8.
42 (brsAH) Physical properties of the other isomer: Colorless crystal Melting point: 138-139°C [α]D: 83.5 @ (cm0.17, chloroform)
IHz to CKBr%cm-'): 2930.1
750.1680.1635.1560 UV spectrum (λmaxs chloroform): 275°C m (ε=603
0) Example 5゜Methyl, 2.3"0-anhydro-1'-deoxy-
1′-dimethylphosphono-4′, 6” O-(tetraisopropyldisiloxane-1,3-diyl)-1-β
-D-fructofuranosyl orotate toluene (20 m
Add tri-n-butyltin hydride (8(In) and azobisisobutyronitrile (38) to
After heating for 0 minutes, a toluene solution of the compound of Example 3 (195■) was added, and the mixture was heated for 40 minutes with stirring at the same temperature. The reaction solution was diluted with benzene, washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography using methylene chloride/methanol (95:5).
The title compound 1041n9 was obtained by elution.

(Yield 64%) Properties: Colorless crystals [α) D: -82,5@(c = 0.03, chloroform) IR susceptor (KBr, cm-''):
1750, UV spectrum (λmaw, chloroform)
: 280nm (e=4840) Mass spectrum/' (m/z) : 604 (M
105H1-1), 44 NMR Stainless Steel (CD (Jls, δppm): 0.7
-1.45 (rrL, 28H), 2.94 (dd.

lH, J=20.4, 16.6 Hz), 2.32
Cdd, IH, J-20, 4, 16, 6Hz), 3.7
2 (d, 3H, J=11-1-0H, 3,74(
d, 3H, J=11.0Hz), 3.71 (d
, 3H,J-11,0Hg), 3.74 (d,
3H, J-11, 6Hz), 3.88 (dd, IH,
J=12.5.4.3Hz), 4-94 (s, 3
H), 4.95 (dd, IH.

J = 12-5, 4-3 Hz), 4.0-4.1
(rrL.

14), 4.45 (dd, IH, J = 8.9.

5.8Hg), 5.38 (d, 14, /=5.8
Hg), 6.71 (rx, IB) Example 6゜Methyl, 2.3"o-anhydro-1'-deoxy-
1'-diethylphosphono-4',6'-o -(tetraisopropyldisiloxane-1,3-diyl)-1-
β-D-Fructofuranosyl orotate The compound of Example 4 was reacted in the same manner as in Example 5 to obtain the title compound in a yield of 84%.

Properties: Colorless crystal Melting point: 153-155°C [α) D knee 103.9° (C = 0.46, chloroform) IR density (KEr, cm-'): 2
950°1750.1670.1630 UV radiation (λ4, chloroform): 276nm
ct=6260) Mass (cuttle (nL/g): 676 CM+)
, 386 NMR squictol (CDCIB, δppm)
: 0.85-1.12 (rn, 28H), 1.
28 (n.

6H), 2.83 (dd, IH, J=15.8°20
．． 4Hz), 3.39 (dd, IH,!=15.8
, 18.5 Hz), 3.88 (dd, IH.

J = 12.2.4.1Hz), 3.94 (g, 3H
), 3.96-4.14 (m, 6H), 445 (dd
, IH,J=5.5.8.4Hz), 5.38(d,
IH, J=5.5Hz), 6.72(S.

Example 7゜Methyl, 2,3'-o-anhydro-1'-deoxy-1'-diethylphosphono-1-β-D-fructofuranosylrotate A solution of compound 163 of Example 6 in tetrahydrofuran (
A tetrahydrofuran solution of tetrabutylammonium fluoride (Q, 49d) was cooled to -78°C.
After stirring at the same temperature for 1 hour, adding 10 drops of water and concentrating with OC, the residue was subjected to silica gel column chromatography and togelaf fluoride.
90:10) to give 50.2 m9 of the title compound.

(Yield 48%) Properties: Colorless crystal Melting point: 35-37°C [α)D: 456@(c-0-10s chloroform) IR spectrum (KEr%cyt-Otori): 34
00.1750.1635.1545 Mass Spect/'CWL/Z): 434 CM+
), 345NMB spectrum (CD, OD, δpprn
:1.25-1.60 (rn, 12H), 3.01 (
dd, IH,, yz19. o, 1s, 8gg), 3.
4-3-7 (rn, 2H), 3.79 (dd, IH.

! = 18.0, 15.8 Hz), 3.95-4
．． 25 (door, 4H), 4.06 (8, 3H), 4.3
-4-45 (m, IH), 4.55-4.65 (
m, LH), 5.39 (brs, IH), 6.73 (
a, IH) High-resolution mass spectrum (as C1, H,, 01°N, P) 211' calculation Iro)::434.1071 Actual value:
434.1069 Example 8゜Methyl,2,3'-o-anthro-4',6
'-o-Diacetyl-1'-deoxy-1'-diethylphosphono-1-β-D-fructofuranochlorotate Compound of Example 7 217In9-? After adding 20 ml of E-i water and pyridipyridine and adding 2 d of anhydrous vinegar and stirring with a trowel at room temperature for 5 hours, the residue was subjected to silica gel column chromatography and diluted with methylene chloride/methanol (95:5).
) to obtain 2201 ng of the title compound. (Yield 85
%) Properties: Amorphous crystal NMR spectrum (CDCIl, δFpFW): 1
．． 24.1.30 (each t, 3H, J=7.2ff
g), 1.94, 2.18 (8.3H each), 2.60 (
dd, LH,! -15,8,18,7Hz), 3.73
(dd, LH, J-15, 8, 18, 1Hz), 3.
94 (s, 3ff), 3.96 (dd.

IH, J-12,7, 3,7Hz), 3.97-4.2
7 (rrL, 4H), 4.50 (dd, IH.

J-5,2Hz), 4.54 (m, IH), 5.3
4 (bt-s, 1g), 5.62 (brg, IH)
, 6.88 (s, IH) Example 9゜Methyl, 2.3"o-anhydro-4',6'-o
-dibenzoyl-1'-deoxy-1'-diethylphosphono-1-β-D-fructofuranosyl orotate Compound 156 of Example 7 was dissolved in 20 m acetonitrile, 0.5 d triethylamine and 116 rn
c! Add ('2..1 equivalents) of benzoyl cyanide,
The mixture was stirred at room temperature for 1 hour and concentrated. The residue was subjected to 7 silica gel column chromatography and eluted with methylene chloride 7/methanol (97:3) to give the title compound 181. (
Yield: 78%) Properties: Amorphous crystalline NME sic # (CDCIssδppm): 1.
26.1.28 (each t, 3H, J-7, 2Hz)
, 2.83 (dd, LH9J=16.0.19.
7Hz), 3.63 (dd, LH,,7=16.
0.18.710), 3.80 (S, 3H), 4.0
0-4.12 (m, 4H), 4.42Cdd.

IH, J = 12.5.6.2Hz), 4.50 (dd,
IH, J-12,5, 4,2Hz), 4.79 (m,
17/), 5.69 (d, IH.

J=1.9Hz), 5.76 (dd, LH, J=
1.9, 3.0 Hz), 6.59 (s, 14),
7,43 (m, 2H), 7.50 (rn,
2H27,58 (m, IH), 7.65 (rn,
IH) 7.90 (yyc, 2H), 8.05 (rrL
, 2H) Example 10゜methyl,2,3'-anhydro-4'16'-〇-
(Tetraisopropyldisiloxane-1,3-diyl)
-1/++ o-acetyl-1'-diethylphosphono-1-β-D-fructofuranosyl orotate Example 2
Compound 1001119 was dissolved in pyridine 201111, and 3r! After adding Lt of acetic anhydride and stirring at room temperature for 1 day, it was concentrated, and the residue was purified with methylene chloride/methanol (95:5) using preparative thin layer chromatography on silica gel.
The title compound 90 was obtained by separation and development. (yield 85%
) This compound has two stereoisomers at the 1' position, with a production ratio of 2.8:1. The two isomers can be easily separated by preparative thin layer chromatography on silica gel.

Properties: NMR characteristics of amorphous crystalline main product (CDCIs, δpprr
L): 0.90-1.13 (3,2877), 2.
23 (s, 3H), 3.90-4.15 (?7L, 7
H), 3.96 (s, 3H), 4.52Cdd.

IH, J-4,8,7,4Hz>, 5.62 (dd.

IH, J=4.8Hz), 6.77 (s, lH
), 6.91 (d, IH, J-11,0Hz)
, ゛NMR spectrum of the other isomer (CDC
l s, δppryb> : 0.83-1.12 (r
n, 28 H), 1.35 (t, 3H, J-
7,0Hz), 1.41(t, 3 II, J
=7.0 Hz), 2.03(S.

3H), 3-86-3.98 (771,2H), 3.
96 (s, 3H), 4.16-4.44 (m.

6H), 5.80 5.88 (m, IH), 6.71
(d, lH, J-13,7Hz), 6.72 (g,
LH) Example 11゜Methyl#2t3'-Q-anhydro-1'-〇-acetyl-1'-diethylphosphono-1-β-D-fructofuranosyl orotate 50 Inq of the main product of Example 10 was added to 10 d of Dissolve in tetrahydrofuran and add 0.0% tetrabutylammonium fluoride solution (1 molar solution) in tetrahydrofuran while cooling with water.
After stirring for 1 hour, 3 drops of water were added and the residue was separated using preparative thin layer chromatography on silica gel with methylene chloride/methanol (90:10) to obtain the title compound 18m9. (Yield 56%) Properties: Colorless powder NMR solution (d, -DMSO, δppm): 1.
11 (t, 3H, J=7-O1ft), 1.1
8(t, 3H,!=7.0Hz), 2.20(a.

3H), 3.36-3.54 (yrL, 2ff),
3.82-4.12 (rrL, 5H), 3.90 (a,
3H), 4.43 (brs, IH), 5.23 (
rrL, LH), 5.35 (bra, LH), 5.51
(brs, IH), 6.51 (s.

lH), 6.77Cd, LH, J=10.8Hz) Example IZ 2.3'-Anhydro-1'-dimethylphosphono-1-
β-D-fructofuranosyl orotate Compound 129 of Example 1 was dissolved in 20 d of tetrahydrofuran,
Add 0.39 ml of a tetrahydrofuran solution (1 molar solution) of tetrabutylammonium fluoride, stir at -30C for 30 minutes, add 4#1 water and concentrate, and the residue was subjected to preparative thin layer chromatography on silica gel. After separation using methylene chloride/methanol (85:15), the obtained tetrabutylammonium salt of the title compound was applied to a column of ion exchange resin such as DOWEX 50W x 4 (Dowez x 50 x 4, manufactured by Dow Chemical Company). Elution with methanol gave the title compound 59■. (
(Yield: 80%) Properties: Amorphous crystalline IR suspension (KEr, am-'): 340
0.1745.1640,154O NMR spectrum A-(CD30D, δppm): 3.
5-3.7 (F7L, 2H), 3.64Cd, 3H.

J-10-5Hz), 3.79Cd, 3H.

, 7=10.5Hz), 4.2-4.1 (m, IH
), 4.50 (dd, IH,!=4.4.2.5Hz
), 5.46 (d, IH, J=2.5Hz), 5
．． 59 (d, IH, J=10.9Hg), 6.63
(,!l.

Example 13゜2.3'-a/hydro-1'-methylphosphono-1-β
-D-Fructofuranosyl orotate Compound 294~ of Example 1 was dissolved in 20 g of tetrahydrofuran, and 0.89 iu of tetrabutylammonium fluoride in tetrahydrofuran solution (1 molar solution) was added under ice cooling, and stirred for 30 minutes. After that, 41 g of water was added and condensed, and the residue was subjected to column chromatography on silica gel and eluted with methylene chloride/methanol (85:15). The obtained product was t-
Add butylamine 5d to ρ, heat under reflux for 3 hours, concentrate, and transfer the residue to an ion exchange resin (Dowex 50WX 4
) to give the title compound 113η. (
Yield 70%) Properties: Colorless powder 1B Spect A/ (KBr, cm-”): 3
350°171 O NMR strut (CD, OD1δpprrL):
3.6-3.9 (yn, 2H), 3.76 (d, 3H.

J=9.8Hz), 4.2-4.7 Cm, 2H),
5.52 (d, IH, J=8.9Hz), 5.
72 (s, IH), 6.75 (J, iH) Example 1 1゜Methyl, 2,3'-o-anhydro-1'-diethylphosphono-1-β-D-fructofuranosyluracil and Tetrabutylammonium, 2,3'-0-
Anhydro-17-dinithylphosphono-β-D-fructofuranosyl orotate u, u Compound 158 of Example 2 was mixed with 20 g of tetrahydrofuran ζ and cooled with water in 0.46 m of tetrabutylammonium fluoride. A tetrahydrofuran solution (1 mol solution) was added, stirred at the same temperature for 15 minutes, and 3 to 14 mol of water was added for densification. The mixture was subjected to preparative thin layer chromatography on silica gel (methylene chloride/methanol (85:15)). By developing and separating with
9 (yield 60%) P and the title tetrabutylammonium salt 40+n9 (yield 435%) were obtained.

Physical properties of methyl ester: Amorphous crystal NMR spectrum (d6-DME O, δppm):
1.25 (t, 6 H, J=7.2Hz), 3.
25-3, 45 (m, 2H), 3.84 (a, 3H),
4.00-'4.20 (rn, 5H), 4.28 (
m, IH7), 4.69 (t, IH.

J=4.9H2), 5.12 (dd, IH, J=7.
4, 12.1 Hz), 5.45Cd, IH.

J = 3.1 Hz), 5.96 (d, IH, J-
7,7Hz), fi39 (j, LH), 6.81(
dd, IH, J=7.4.12.0Hg) Physical properties of ammonium salt: Amorphous crystalline NMR spectroscopy (d6-DMSO, δppyrL)
:1.08, 1.15 (each t, 3H, J=7
．． 0Hz), 3.30-3.47 (rn, 2H)
, 3.80-4.07 (rn, 5H), 4.12
(dd, IH, J=3.4.4.8Hz), 5.20(
d, IH, J-3,4Hz), 5.37 (d.

IH, J=1'1.8Hg), 5.50 (brs
.

IH) Example 15゜2,3'-o-anhydro-1'-diethylphosphono-1-β-D-fructofuranosylrotate Example 1
The title compound 34 was obtained by applying 40 ml of the ammonium salt of No. 4 to an ion exchange resin (Dowex 50WX 4 ) and eluting with water. (Yield 4100%) Properties: Amorphous crystal NMR spectrum (d6-DMSO, δppm):
1.07, 1.16 <? ! rt, 3H, J=7
-2fiz), 3.25-3.45 (rn, 2H
), 3.75 4.05 (rn, 5H), 4.06℃m
, IH), 4.29 (yrL, IH), 5.31 (rr
L, IH), 5.33 (d, IH.

J = 2-9 Hz), 5.82 (rrL, IH)
, 6.25 (brs, 1.”l), 6.90 (ryb
, 1H) Reference Example 1゜Methyl+2*3'-o-anhydro-1-β-D
-Fructofuranosylrotate 2-amino-D-fructofuro (2', 3': 4
.

5] Methanol solution of oxazoline (4.08g) (5)
0mg) to dimethylacetylenedicarboxylate)(4
,91ag) (2 equivalents) and heated under reflux for 2 hours,
After concentration, the residue was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (85:15) to obtain 3.83 g of the title compound. (Yield 61%) Properties: Colorless crystals Melting point: 177-178 @ [α)D: 80.3" (c = 0.36, ethanol)
50.3380.1750.1640 UV spectrum (λmaw, ethanol/'): 273g
m (g=6300) Mass quictor (yrL/g): 313 (M+
-1), NMR spectrum (d, -DMSO, δppr
n): 3.21-3.43 (m, 2H), 3.6
3 (ddAH, J=12.4.6.6Hz), 3.86
(g, 3H), 4.12 Cm, IH.

4.27 (dd, IH, J=12-4.6.6.

Hz), 4.38 (rrL, LH), 4.93 (t.

IH! =5.0Hz), 5.02 (brs, IH
), 5.62 (t, L H,!=6.6Hz)
, 5.93 (d, I H, f = 4.8Hg),
6.36 (s, LH) Reference Example 2゜Methyl, 2,3'-o-anhydro-4', 6''
o -(tetrinepropyldisiloxane-1,3-
diyl)-1-β-D-fructofuranosyl orotate Compound of Reference Example 1 (20 g) and 1.9 g (4.4 equivalents)
imidazole was dissolved in 140 g of dimethylformamide, cooled to -30°C, and 2-92 g (1,1)
After adding dichlorotetranepropyldisiloxane of 100 ml and stirring with a trowel at the same temperature for 40 minutes, the reaction solution was gradually warmed to room temperature and stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography using methylene chloride/methanol (
95:5) to give the title compound 1.22/i (
yield 35%).

Properties: Colorless crystal Melting point: 56-58.5C [α)D: 102-0" (c = O-57, chloroform) IR Suscutor CKEr, cm-')
: 3320, UV spectrum (λrnaZ, chloroform): 275 nmct, =6030)
+), 481 NMR spectrum (CDCIssδff)
ptrL): 0.86-1.12 (m, 28H)
, 3.80-4.00 (rn, 4H), 3.92
(s, 3H), 4.44 (dd, IH, J=5
．． 5, 8.4Hz), 4.66 (dd, IH, J=
13.0, 5.8Hz), 5.27 (t, I
H, J = 5.8 Hz), 5.38 (d, I H, J
= 5.5 Hz), 6.54 (a.

IH) Reference Example 3゜Methyl+2, 3'-o-anhydro-1'-formyl-3', 5'-o-(tetrinepropyldisiloxane-1,3-diyl)-1-β-D- Arabinofuranosyl orotate and methyl p2 #3'-o-anhydro-1'-methoxy-4', 6'-o-(tetraisopropyldisiloxane-1,3-diyl)-1-β-D- Fructofuranosyl orotate Compound (525■) of Reference Example 2 was dissolved in benzene (9,4rI
Lt) and dimethyl sulfoxide (9.4 M), 75 Jnq (1 equivalent + i) of pyridine, 5
4 to (0,5) trifluoroacetic acid and 583m
After adding 3 equivalents of dicyclohexylcarbodiimide and stirring at room temperature for 22 hours, the mixture was filtered and concentrated. The residue was diluted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (95:5) to obtain 5311 ng of the title compound. (Yield 96%) There are two types of stereoisomers regarding the 1' position of the obtained hemiacetal Vi sugar, and the production ratio of the aldehyde and hemiacetal (two i-type K) of the obtained title compound is 1 :1
:1.

Physical properties of three types of mixture: Colorless powder [α) D: -119,3@(cm0.14, riooform) JR Suskutol (KBr, am-'):
17 s.

UV spectrum (λ1αx1 chloroform): 277.
2Cmct = 2340) Mass spectrum (nz/z): 524.51ONM
R spectrum (CDCI, δpprn): 0.8
3-1.17 (rrL, 28H), 3.36.3.56
(each S1%H), 3.94.3.96.3.98 (each s
, 3H), 3,85 4.20 (m.

3H), 4.38.4.43.4.56 (each dd, I
H), 5.12.5.48.5.57 (each d, 14)
, 5.59.5.67 C each d1XH), 4.57.6
．． 13 (each d, LH), 6.53.6.64.6.80
(Each s, IH), 9.77Cs, 〆H) [Effect of the invention] Since the novel compound represented by the uninvented general formula (1) has a strong nucleic acid biosynthesis inhibitory effect, it can be used as a new type of antitumor, It is expected to be used as an antiviral drug and as a pesticide, especially as an insecticide.

Patent applicant: Suntory Ltd. (5 other people)

Claims (6)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a hydrogen atom or an acyl group, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkyl group, represents a hydrogen atom, a hydroxyl group, or an acyloxy group, and Y represents a hydrogen atom or a lower alkyl group), and pharmacologically acceptable salts thereof. (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, an ethyl group, a propyl group, or a butyl group. (4) 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 protecting group for the hydroxyl group, R^3 and R^
4 represents the same or different lower alkyl group) or its aldehyde equivalent, and a dialkyl compound having the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^5 represents a lower alkyl group) Phosphites can be reacted in the presence of a base and then deprotected, reacted and deprotected and further hydrolyzed, reacted and deprotected and then dealkylated, reacted and acylated and deprotected, or reacted and acylated. Either deprotection and further acylation are performed, or dialkyl phosphite is reacted in the presence of a base, and then the 1'-position hydroxyl group of the sugar is converted into an active thioester and reduced and deprotected, or the 1'-position hydroxyl group of the sugar is converted into an active thioester and reduced and deprotected.
General formulas characterized by deprotection and further dealkylation, reduction and deprotection as active thioesters and further hydrolysis, or reduction and deprotection as active thioesters and further acylation ▲Mathematical formulas, chemical formulas, tables etc.▼ (In the formula, R represents a hydrogen atom or an acyl group, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkyl group, X represents a hydrogen atom, a hydroxyl group, or an acyloxy group, Y represents a hydrogen atom or a lower alkyl group) and a method for producing a pharmacologically acceptable salt thereof. (5) The production method according to claim 4, wherein the reducing agent used in the reduction reaction is trialkyltin hydride. (6) The dealkylating agent used in the dealkylation reaction is t
-butylamine.The manufacturing method according to claim 4.