JPH0477485A - 2',3'-didehydro-2'.3'-dideoxyuridine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [one of R<1>, R<2> is alkyl, alkenyl, alkinyl or halogen (excluding fluorine) and the other is H; R<3> is H, silyl; R<4> is H, lower alkyl]. EXAMPLE:A synthetic intermediate for antiviral agents. USE:A 2',3'-dehydro-2',3'-didehydrouridine derivative of formula II [one of R<11>, R<21> is halogen (excluding F) and the other is H; R<31> is silyl) is subjected to an alkylation, alkenylation or alkinylation reaction and, if necessary, subjected to a desilylation reaction to prepare a compound of formula III (one of R<12>, R<22> is alkyl, alkenyl or alkinyl and the other is H).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides an alkyl group, an alkenyl group, an alkynyl group, or a halogen atom (
However, 2',3'-didehydro-2',3'-dideoxyuridine derivatives (excluding fluorine)
(hereinafter also referred to as the compound of the present invention) and its production method.

When the above substituent is a halogen atom, the compound of the present invention is useful as a synthetic intermediate for 2',3''-dideoxyuridine derivatives, which are known to be used as antiviral agents (antiretroviral drugs, etc.) .

Further, the compounds of the present invention in which the above-mentioned substituent is an alkyl group, an alkenyl group, or an alkynyl group are useful as antiviral agents.

[Prior art and problems to be solved by the invention] Conventionally, 2'-bromo-2', 3'-didehydro-2'
, 3'-dideoxycytidine has been synthesized, and this compound is known to be useful as a synthetic intermediate for 2', 3'-dideoxycytidine (Japanese Patent Application Laid-open No. 1983-1991).
-3194 publication).

In addition, 2',3'-didehydro-2'', 3'dideoxy-2''-fluoronucleoside (JP-A-1-100
190), 2',3'-didehydro-2',3''
-dideoxy-2'-〇-mesyl-3-benzyluridine (J, Org, Chem.

38.598 (1973)) + 2'-Azide-5'
-〇-benzoyl-2'3'-didehydro-2'3'-
Dideoxyuridine (J, Org, Chem, 41
+3148 (1976)) are also synthesized.

In recent years, it has been discovered that 2',3'-didehydro-2',3'dideoxypyrimidine nucleosites are useful as antiretroviral agents (Japanese Unexamined Patent Publication No. 63-10
No. 7924, JP-A-63-146822, JP-A-63
-215632), and the emergence of various derivatives thereof is eagerly awaited.

However, other than the above-mentioned specific derivatives, no compound having a substituent at the 2' or 3' position is known.

The object of the present invention is to use 2',3'-didehydro-2', which has antiviral activity and is expected to have various activities.
The object of the present invention is to provide a useful new H conductor having a substituent at the 2' or 3' position of a 3'-dideoxypyrimidine nucleoside.

[Means for Solving the Problems] The present invention is based on the following general formula [1] [wherein either R1 and R2 is an alkyl group, an alkenyl group, an alkynyl group, or a halogen atom (excluding fluorine)] , the other represents a hydrogen atom, and R3
represents a hydrogen atom or a silyl group, and R4 represents a hydrogen atom or a lower alkyl group.

2'3'-didehydro-2'3'- represented by
The present invention provides dideoxyuridine derivatives.

Further, the present invention provides that in the general formula [+], R1 and R
The following general formula Cm3 in which either one of 2 is a halogen atom and R3 is a silyl group [In the formula, one of R'' and R'' is a halogen atom (excluding fluorine) and the other is a hydrogen atom show,
The present invention provides a 2', 3'-didehydro-2', 3'-dideoxyuridine derivative represented by the following formula, in which Ro represents a silyl group and R4 represents a hydrogen atom or a lower alkyl group.

Further, the present invention provides a method for formula [11], in which R1 and R
2, one of which is an alkyl group, an alkenyl group, or an alkynyl group according to the following general formula [IV] [wherein R" and R" are one of which is an alkyl group, an alkenyl group, or an alkynyl group, and the other is a hydrogen atom , R3 represents a hydrogen atom or a silyl group, and R4 represents a hydrogen atom or a lower alkyl group. ] 2',3'-didehydro-2',3'-dideoxyuridine derivatives are provided.

Furthermore, the present invention provides a compound represented by the general formula [rV ] 2',
A method for producing a 3'-didehydro-2'3'-dideoxyuridine derivative is provided.

Furthermore, in the following general formula [II] above General 2N], one of R1 and R2 is an alkyl group, an alkenyl group, an alkynyl group, or a halogen atom (excluding fluorine), and the other is Specifically, a hydrogen atom has the following general formula [1':I or [1'':]
This means that two types of general formulas are included.

[In the formula, one of R'' and R21 represents a halogen atom (excluding fluorine) and the other represents a hydrogen atom, and when R11 is a halogen atom, R5 represents a hydrogen atom, and R6 represents 5eR7 (Se represents a selenium atom, R7 represents an aryl group, respectively.), when R21 is a halogen atom, RS represents 5eR7, RC represents a hydrogen atom,
R31 represents a silyl group, and R4 represents a hydrogen atom or a lower alkyl group. ] Provides a method for producing a 2″3′-didehydro-2′,3′-dideoxyuridine derivative represented by the above general formula [m], which comprises reacting a compound represented by the formula [m] with a peroxide. be.

In general formula [11], specific examples of substituents other than hydrogen atoms represented by R1 or R2 are as follows.

[1] When the substituent represented by R1 or R2 in general formula [1] is a halogen atom (corresponds to R" or R" in -general formula [m]) Specific examples: bromine, iodine, chlorine [2 When the substituent represented by R1 or R2 in general formula [1] is an alkyl group, alkenyl group, or alkynyl group (R" or R" in general formula [Ih']
(corresponds to) (1) Alkyl group return prime number An alkyl group having about 1 to 10 is preferable. Here, the alkyl group includes an aralkyl group.

Specific examples: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, impentyl, Maro-5ss#JFI1. Octyl, nonyl, decyl, benzyl, phenethyl, nitrobenzyl, etc. (2) Alkenyl group return prime number: 1-alkenyl group, 2-alkenyl group, 3-alkenyl group, etc. of about 2 to 10.

A 1-alkenyl group is particularly preferred, and the alkenyl group includes those having an aromatic hydrocarbon at the end.

Specific examples: ethynyl (vinyl), 1-propenyl, 2-propenyl (allyl), 1-butenyl, 1-pentenyl, 1-hexenyl, cinnamyl, etc. (3) Alkynyl group 1-alkynyl having a carbon number of about 2 to 10 group, 2-alkynyl group, 3-alkynyl group, etc.

Particularly preferred is a 1-alkynyl group. Here, the alkynyl group includes those having a silyl group or aromatic hydrocarbon at the end.

Note that the silyl group is preferably a trialkylsilyl group.

Specific examples: ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butenyl, 1-pentynyl, 1-hexynyl, 1-hebutynyl, 1-octenyl, l-phenyl, 1-decynyl.

Phenylethynyl, tolylethynyl, trimethylsilylethynyl, tert-butyldimethylsilylethynyl, methyl di-tert-butylsilylethyl, and the like.

In addition, the general formula [1, [II], [■, [Ih'
] Examples of the silyl group represented by R3 or R'' include those commonly used as protecting groups for hydroxyl groups.Specific examples of such silyl groups include trimethylsilyl and triethylsilyl.

Examples include isopropyldimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldi-tert-butylsilyl, and triisopropylsilyl.

In addition, in the general formula [■co, [nl, [■co, [■co], the lower alkyl group represented by R4 has 1 to 1 carbon atoms.
An alkyl group having about 5 straight or branched chains is exemplified. Such alkyl groups include methyl, ethyl,
Examples include propyl, isopropyl, butyl, tert-butyl, and pentyl.

Furthermore, in general formula [11], R& or R' is SeR
In the case of an arylselenyl group represented by ', examples of the aryl group represented by R7 include phenyl, p-nitrophenyl, 0-nitrophenyl, and tolyl.

I! Synthetic route of the compound of the present invention! The outline is as follows.

[1st step] [21st step] [4th step] [3rd step] (1) Lithiation agent [5th step] represents a group, and R7
has the same meaning as above. C [Step B] C) Also, general formula [11] which is the raw material compound in the first step
The compound represented by can be synthesized by a known method. For example, methods shown in steps A to C below are exemplified.

[In the formula, R'', R' and R7 have the same meanings as above [C step (C) formula [■C6] [n] Each step will be explained below.

Behold, the starting material compound [■] is a β-halogenoarylseleno compound having a halogen atom at either the 2'- or 3'-position of the sugar moiety and an arylseleno group represented by 5eR7 at the other. This compound is treated in a solvent such as dichloromethane or chloroform using about 1 to 1.5 equivalents of peroxide relative to compound [1], and subjected to a syn elimination reaction of the corresponding selenoxide. In particular, the compound [■] can be obtained. Examples of peroxides used include perorganic acids such as m-chloroperbenzoic acid, perbenzoic acid, monoperphthalic acid, performic acid, peracetic acid, and trifluoroperacetic acid. The reaction is preferably
0 to 50℃ without passing inert gas such as argon
, preferably at a temperature around room temperature for 1 to 24 hours. After the reaction, operations such as neutralization and concentration are performed as necessary, and the nucleoside is isolated and purified using conventional means of isolation and purification (e.g., various chromatography methods such as adsorption or ion exchange, solvent extraction, recrystallization, etc.) The compound [1[+1] can be isolated and purified using methods such as

In addition, compound [ml] is the general formula [11, where either R'' or R2 is a halogen atom (R11, R2
1), and R3 is a silyl group (R'').

Second Step: The compound [ml] obtained in the first step is treated in the presence of a palladium catalyst with an alkylating agent, an alkenylating agent, or an alkynylating agent (hereinafter, in the second step, these are sometimes referred to as cross-coupling agents).

) to cause a cross-coupling reaction, the compound [■'] can be obtained. As the palladium catalyst, divalent palladium catalysts such as bistriphenylphosphine palladium dichloride, bisacetonitrile palladium dichloride, bisbenzonitrile palladium dichloride, and zero-valent palladium catalysts such as tetrakistriphenylphosphine palladium can be used. As the cross-coupling agent, those having the desired alkyl group, alkenyl group, or alkynyl group and commonly used in cross-coupling reactions may be used. For example, organometallic compounds having a tetraalkyl tin sulkyl group can be used as alkylating agents. As the alkenylating agent, an organometallic compound having a desired alkenyl group such as alkenyltrialkyltin (eg, alkenyltributyltin) can be used. As the alkynylating agent, an alkyne having the desired alkynyl group or HCECR' [R
An alkyne having a silyl group at the end represented by " indicates a silyl group" can be used. Also, to promote the cross-coupling reaction, a copper compound (for example, cupric iodide, bromide, etc.) can be used. Copper halides such as cuprous) and bases (triethylamine, tributylamine, N.

N-diisopropylethylamine, dimethylaniline,
diethylaniline, pyridine, etc.) may be added to the reaction solution. The solvent used is not particularly limited as long as it can dissolve compound [1 [[] and is suitable for the coupling reaction. For example, acetonitrile, N,N
-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide,
Aprotic polar solvents such as tetrahydrofuran (THF), 1,4-dioxane can be used.

The reaction is preferably carried out at a temperature of 0 to 120°C using a cross-coupling agent of 1 to 6 equivalents per compound [m] while aerating an inert gas such as argon. It will be completed in time.

After the reaction, compound [IV'] can be isolated using a conventional means for isolating and purifying nucleosides.

In addition, the compound []V'] is represented by the general formula [1],
Either one of R1 and R2 is an alkyl group, an alkenyl group or an alkynyl group (R12, R22),
This is a compound in which R3 is a silyl group (R 3 1 ).

Third step The compound [Ill] obtained in the first step is treated with an electrophilic alkylating agent, an alkenylating agent, and an electrophilic alkylating agent in the presence of a lithiation agent.
Compound [■'] is reacted with an alkynylating agent (hereinafter sometimes referred to as electrophilic agent), and the electrophilic agent is reacted with the lithio form of compound [+111] through a halogen-lithium exchange reaction. Obtainable.

As the lithiation agent, alkyllithiums such as methyllithium, n-butyllithium, tert-butyllithium, and phenyllithium can be used.

As the electrophilic agent, an alkyl halide (such as methyl iodide), an alkenyl halide, an alkynyl halide, etc. having the desired alkyl group, alkenyl group, or alkynyl group can be used.

As the reaction solvent, the same solvent as in the second step (for example,
THF. DMF, acetonitrile, etc.) can be used.

The reaction is preferably carried out under low temperature conditions in the presence of about 1 to 5 equivalents of a lithiation agent and about 1 to 6 equivalents of an electrophilic agent to the compound [m] while bubbling an inert gas such as argon. It is completed in about 15 to 6 minutes at (-78 to -50°C). After the reaction, compound [IV'co] can be isolated and purified using conventional means for isolating and purifying nucleosides.

4th step By subjecting the compound [■'] to a desilylation reaction, 5
By removing the silyl group at the ' position, a compound [■''' can be obtained. For the desilylation reaction, a method commonly used for removing the silyl group of the hydroxyl group of the sugar moiety of a nucleoside is applied. For example, a suitable solvent (e.g., THF,
acetonitrile, 1,4-dioxane, DMSO, etc.)
Among them, tetrabutylammonium fluoride, hydrogen fluoride, pyridine salt, ammonium fluoride, etc. are used.

The reaction may be carried out at room temperature for about 1 to 3 hours. After the reaction, the compound [■'' can be isolated and purified using a conventional means for isolating and purifying nureoside.

Similarly to the fourth step, compound [m is subjected to a desilylation reaction to remove the 5'-position silyl group, and compound [m'
9 Step A Compound [VI] can be obtained by reacting compound [V] with an arylselenium compound. The acyno/group represented by A in the general formula [V] may be any type as long as it can protect the hydroxyl groups at the 3' and 5' positions, such as a pivaloyl group. Examples of the leaving group represented by M include sulfonyloxy groups such as methanesulfonyloxy group (mesyloxy group) and P-toluenesulfonyloxy group (tosyloxy group). As the aryl selenium compound, diaryl diselenide such as diphenyl diselenide can be used. The diaryldiselenide is treated in advance with a reducing agent such as sodium borohydride in a solvent such as anhydrous ethanol, and then reacted with the compound [V 2 ]. The aryl selenium compound thus pretreated and the compound [V] dissolved in a suitable solvent such as THF are heated under reflux conditions for example from 12 to
It is sufficient to react for 48 hours. After the reaction, compound [■] can be isolated and purified by a conventional method.

B process This process is carried out in a two-step reaction. Namely.

The acyl group represented by A of compound [V[] was removed, and then a silyl group was introduced into the 5'-position water vi group to form compound [■]
can be obtained.

Removal of the acyl group can be carried out by conventional methods.

For example, the reaction may be carried out at room temperature in a suitable solvent (such as water-containing ethanol or water-containing methanol) in the presence of an alkali catalyst such as sodium hydroxide or ammonia.

Introduction of a silyl group can be carried out by a conventional method using a silylating agent having a silyl group corresponding to the silyl group represented by R1 in compound [■].

As the silylating agent, the halogenated silyl compounds (for example, chlorinated silyl compounds) having a silyl group as exemplified above can be used. For example, the reaction may be carried out in a suitable solvent (
(e.g., pyridine) at room temperature for 12 to 48 hours. After the reaction, compound [■] can be isolated and purified by a conventional method.

Step C Compound [nl] can be obtained by reacting the compound [■] with a halogenating agent to replace the hydroxyl group at the 2' or 3' position with a halogen atom.

As the halogenating agent, R" or R" of general formula [II]
A thionyl halide having a halogen atom corresponding to can be used.

The reaction produces acid trapping agents (e.g.

For example, using a halogenating agent of about 1 to 5 equivalents to the compound [■] in a suitable solvent (for example, carbon tetrachloride, etc.) to which a compound (such as imidazole) has been appropriately added, under temperature conditions of 0 to room temperature. It can be completed in 1 to 5 hours. After the reaction, compound [U] can be isolated MFt by a conventional method. The obtained compound [11] can be used as a raw material compound in the first step.

[Examples] Hereinafter, the present invention will be specifically explained using reference examples and examples.

Reference example 1 In general formula [VI], A=pivaloyl, R
Synthesis of a compound where 4=hydrogen and R7=phenyl (A-technique 8) Diphenyl diselenide ((PhSe)z) (1, 6
1g, 5. 15 mmol of absolute ethanol (20
Sodium borohydride (8!aB) 1. mQ) solution in a stream of argon. ) (389.8mg, 10
．． After stirring, the color of the reaction solution changed from yellow to colorless, 2',5'-dipivaloyl-3'-methanesulfonyloxyuridine (general formula [V]: A=pivaloyl, M=methane) was added and stirred. Sulfonyloxy.

A solution of R'=H) in THF (20d) was added and refluxed for 48 hours. After neutralizing the reaction solution with 10% acetic acid/methanol, it was applied to a silica gel column (16X2an) and 1%
The target compound (2,
05g, yield SX, 2%) was obtained.

"H-NMR (cDcia) δppm: 1.16°1
．． 27 (18H, respectively s, pivaloyl-t
Bu).

3. 90 (IH, pseudo-t, H-3'
), 4.52 (2H, m, H-5'), 4. 65
(1B, m.

H-4'), 5. 38 (IH, d d, H-
5).

5, 93 (IH, d+ J,', 2'=
4. 9Hz, H-1'), 7.31-7.3
4 (3H, m, arom).

7.51-7.68 (3H, d and m, H-6 and arom), 8, 46 (I H, br-s,
NH)MS (m/z): 11.2 (B+
1), 237 (M-B-Pivalic aci
d The obtained compound (535,・7■, 0.97mm
o1) to Q, 5N sodium hydroxide/nitanol-water (
9, OmQ) was added and stirred at room temperature for 24 hours. After neutralizing with IN hydrochloric acid solution, silica gel column (9,5X1.3C
D), and the 6 eluate eluted with 5% ethanol/chloroform was distilled off under reduced E.

The residue was dissolved in pyridine (3, OmQ) and ter
'L-Butyldiphenylsilyl chloride (T B D
PS C1) (0,63mn, 2,42mmo1)
and stirred at room temperature for 24 hours. After evaporating the reaction solution under reduced pressure, it was dissolved in chloroform and applied to a silica gel column (16X
2cxn) and eluted with 2.5% ethanol/chloroform to obtain the target compound (576.2cm, yield 95.6%).
) was obtained.

"H-NMR (CDCI, +D 20) δ Pp
m two 1. ]](9H,s, TBDPS-tB
u), 3.81 (IH.

pseudo-t, H-3'), 4.04 (
2H, d d d.

H-5'), 4.44 (IH, dd, H-2')
.

4.62 (IH, m, H-4'), 5.40 (
IH, d, H-5), 5.69 (IH, d, J,',
2=3.67Hz, 'H-1'), 7.23-7.2
4 (2H, m, -5ePh), 7.39-7.51 (
9H.

m, TBDPS-arom and -5ePh),
7.66-7.75 (5H, m and d, TB
DPS-arom and H-6) MS (yn/z): 112 (B+1), 565 (M
-tBu)-622(M)' Reference Example 3 In general formula [11], R11=bromine, R2
1 = hydrogen, R31 = tert-butyldiphenylsilyl, R4 = = hydrogen, R5 hydrogen, R' = phenylselenyl compound (A) and R' = = hydrogen 21 = bromine, R31 = tert-butyldiphenylsilyl, R'=hydrogen, RS==phenylselenyl, R'=
Synthesis of compound (B) which is hydrogen (C step) Compound obtained in Reference Example 2 (576.2 mg, 0.84 mm
o1) and imidazole (171,6y,, 2.5
0mmo1) of carbon tetrachloride (ccl,) (2,0mff
) solution with thionyl bromide (SOB) at 0°C in an argon stream.
After stirring for 3 hours, the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was diluted with saturated sodium bicarbonate solution (sat, NaHCO3
)-chloroform (3 times), the chloroform layer was dried over anhydrous sodium sulfate (Na2S04) and evaporated under reduced pressure. The residue was applied to a silica gel column (10×2σ) and eluted with hexane-ethyl acetate (3:1) to obtain a mixture of target compounds (A) and (B) (135.6μ, yield 72.4%). Obtained MS (m/z): 62
6.628 (M -tFlu)” Example 1 General formula [
In ml, R1゛=odor chord, R”=water i, R”=ter
Synthesis of compound (C) in which t-butyldiphenylsilyl, R4 = hydrogen, and compound (D) in which R1' = hydrogen, R21 = bromine, R'' = tert-butyldiphenylsilyl, R4 = hydrogen (first step ) Mixture of compounds (A) and (B) obtained in Reference Example 3 (1
35,6■, 0.20 mmol) of dichloromethane (3
, OmQ) solution in m-chloroperbenzoic acid (mCPBA) (44,9K) under an argon atmosphere.

0.26 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours.

After neutralizing the reaction solution with triethylamine, it was evaporated under reduced pressure, and applied to a Florisil (trade name, manufactured by Florizin) column (18X1.
5σ) and eluted with hexane-ethyl acetate (3:1) to obtain the target compound (C) (15.2μ, yield 14.5%).
and target compound (D) (76.2■, yield 72.9%
) was obtained.

Compound (C) 1H-NMR (CDC1,) δppm: 1.09 (
9H,s, TBDPS-tBu), 3.91 (2H.

t, H-5'), 4.84 (IH, rrl, H-4
' C5, 21 (IH, dd, H-5), 6.35 (
IH, m, H-3'), 6.39 (IH, I
TI, H4F), 7.39-7.44 (6H, m,
TBDP S-arom) + 7-54 7, 8
1 (5H! m +H-6 and TBDPS -ar
om), 8.45 (LH+ br-s r NH
) MS (m/z): 112 (B+1), 357°35
9 (M-B-tBu)”, 469.471 (M
tBu)" Compound (D) "H-NMR (CDCI,) δPPm: 1.11
(9H,s, TBDPS-tBu), 4.07 (2H
.

m, H=5'), 4.78 (IH, m, H-4'
).

4.83 (IH, dd, H-5), 6.05 (LH
, m, H-2'), 6. ” 99 (IH, m, H-
1'), 7.36-7.41 (6H, m, T)
3DPS-arom), 7.54-7.81 (5H
, m.

H-6 and TBDPS-arom), 8.45
(]H, br-s, NH) MS (m/z): 112 (B+1), 357°35
9 (M-B-tBu)÷469,471 (
M-tBu)'' Example 2 In the general formula [I~!'], R12 = phenylethynyl, R22 = hydrogen, R31 = tert-butyldiphenylsilyl.

Synthesis of compounds where R4=hydrogen (No. 2 steps) Compound (C) obtained in Example 1 (50,'7mQ.

Bistriphenylphosphine palladium dichloride ((PPh3), Pc1C12) (7
,○■.

0, O1mmo1), iodide E (Cu1)
(1,9<.

0, O1mrno1) -phenylacetylene (0
, 04 mQ, 0.40 mmol) and triethylamine (0.1 mQ) were added, and the mixture was stirred at 80°C for 1 hour. The reaction solution was partitioned between ethyl acetate and water (3 times), and the ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure.
Elution was carried out with ethanol/chloroform.

After evaporating the solution solution under reduced pressure, it was applied to a preparative layer chromatography (TLC) plate (20X 20 countries) and developed with hexane-ethyl acetate (2:1) to obtain the target compound (38.0IIIg, yield). 72.1%).

1H-NMR ('CDC1,) δppm: 1.
09 (9H,s, TBDPS-tBu)
, 3. 92 (2-H.

ddd, H-5'), 5.00 (IH, m, H-
4' L 5.25 (LH, dd, H-5),
6.48 (IH, m, H-3'), 7.06 (I
H, m.

H=1'), 7.31-7.45 (IIH, m.

arOD and TBDPS-arom), 7.56-
7゜66 (5H, m, H-6 and T B D P
S-arom), 9.32 (I H, br-s,
NH)MS (m/z): 112 (B+1), 37
9(M-tBu-B-1), 380(M
-B-tBu)”.

491 (M-tBu)” Example 3 General formula [1~! ′, R12=hydrogen.

R22=phenylethynyl, R31= tert-butyldiphenylsilyl.

Synthesis of a compound where R'=hydrogen (second step) Compound (D) 27 obtained in Example 1 as a raw material compound,
Using 5 mQ (0,05 mmol), 3.5 mg of bistriphenylphosphine palladium dichloride (0,
OO5mmo1), copper iodide 1.0mg (0, OO5
mmo1) and phenylacetylene 0,02m12
The reaction was conducted and purified in the same manner as in Example 2, except that (0.20 mmol) was used, and the target compound (19.4 mmol, yield 67.8%) was obtained.

1H-NMR (CDC1,) δppm: 1.08
(9H,s, TBDPS-tBu), 4.12 (2
H.

cldd, H-5'), 4.91 (LH, m, H-
4'), 5.00 (LH, dd, H-5), 6.1
1 (IH, m, H-2'), 7.15 (IH, m.

H-1'), 7.2577.45 (11H, m.

arom and TBDPS-arom), 7.5
77, 66 (4H, m, TBDPS-arom)
, 7.87 (LH, dj H-6) + 9.05
(LH! br-8°NH) MS (m/z): 112 (B+1)
, 379(M-tBu-B-1), 3
80 (M-B-tau) ten.

491 (M -tBu)" Example 4 In the general formula [R"], R12=hydrogen, R2
2 = trimethylsilylethynyl, R'' 1 = tert-butyldiphenylsilyl, R4
Synthesis of a compound where = hydrogen (second step) Compound (D) 43 obtained in Example 1 as a raw material compound,
Using 7mQ(0,08m+++o1), 5.8mg of bistriphenylphosphine palladium dichloride (
○, OO8mmo1), copper iodide 1.6■ (○,
OO8mmo1) and trimethylsilylacetylene 0.05 (0.33mm) instead of phenylacetylene
o1) was used, but the reaction was carried out and purified in the same manner as in Example 2, and the target compound (19,3■) was obtained.

A yield of 42.8%) was obtained.

iH-NMR (CDCI,) δppm: o, 2
4 (9H,s, TMS CH), 1.10
(9H, s.

TBDPS-tBu), 4. 09 (2H, ddd
.

H-5'), 4. 77 (LH,
dd, H-5).

4.82 (LH, m, H-4'), 6.05
(IH, m, H-2'), 7.08 (IH,
m, H-1'), 7.34 7.44 (6H
, m, TBDPS-arom), 7. 56-7,
73 (4H, m.

TBDPS-arom), 7.66 (LH, d, H
-6), 8.57 (LH,br-s,NH)MS
(m/z): 112 (B+1), 375° (M-B-
tBu-1), 376 (Mu4 B tBu)
”.

4 8 7 (M -tBu) 10 Example 5 In general formula [IV'], R12=hydrogen, R
Synthesis of a compound in which 22=vinyl, R''=: tert-butyldifninylsilyl, and R'=water cord (second step) Compound (D) obtained in Example 1 (56,3mQ.

0.11mmol1) of acetonitrile (4.0mf1)
Add bistriphenylphosphine palladium dichloride (7,5 rV:, 0.01+nl) to the solution under a stream of argon.
l1o1), vinyltributyltin (0,13+
nQ.

0, 44++++++o1) was added thereto, and the mixture was stirred at 60°C for 24 hours. The reaction solution was partitioned (3 times) between chloroform and 1% potassium fluoride (XF) aqueous solution, and the chloroform layer was dried over anhydrous sodium fluoride and then evaporated under reduced pressure. The residue was applied to a Florisil column (8X1.5an) and 10%
Elution was done with ethanol/chloroform. After distilling off the eluate under reduced pressure, prepare a prepared TLC plate (20
) and developed with hexane-ethyl acetate (1:1) to obtain the target compound (23.2 mm, yield 41.2%).

'H-NMR (CDCI,) δppm: 1.05
(9H,s, BDPS-tBu), 4.06 (2H
.

dcld, H-5'), 5. O○-5,02 (2H.

m and d, H-4' and vinyl-C) I2a)
.

5, 31 (IH, d, vinyl-CH2b),
5.34 (IH, d, H-5), 5.81 (IH
, m, H-2'), 6.50 (IH, dd,
vinyl-CH).

7.00 (IH, m, H-1'), 7.34-
7.44 (6H, m, TBDPS-aro+n),
7.54-7.63 (4H, m, TBDPS-ar
om).

7.82 (LH, d, H-6), 8.80 (I
H.

br-s, NH) MS (m/z): 112 (B+1), 30
5 (M −B −tBu −1), 306 (M
-B-tBu)”.

417 (M - tBu) ÷ Example 6 In the general formula [■''], R12 = hydrogen, R2
Synthesis of a compound in which 2 = methyl, R"" = tert-butyldiphenylsilyl, R' = hydrogen (second step) Compound (D) obtained in Example 1 (54.3 mQ.

Tetrakistriphenylphosphinepalladium ((PPh, ), +Pd) (23,6 mg
, 0.02 mmol), tetramethyltin (0,0
7mQ, 0.50+r1m01) and 1
The 9 reaction mixture stirred at 20°C for 48 hours was diluted with chloroform-1.
% potassium fluoride aqueous solution (three times), and the chloroform layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure.

The residue was applied to a Florisil column (8X1.5an),
Elution was with 10% ethanol/chloroform. After evaporating the eluate under reduced pressure, it was transferred to a preparative TLC plate (20X
Hexane-ethyl acetate (1:1)
Develop the target compound (6.7 mg + yield] 4.1%)
I got it.

"H-NMR (CDCI3) δpprrl: 1.09 (
9H,s, TBDPS-tBu), i, 91 (3H
.

s, CH3), 3.89.4, 06 (2H7 respectively s, H-5'a and H-5' b), 4.65 (
LH, m, H-4'), 4.93 (LH, d d.

H-5), 5.50 (IH, m, H-2'),
6.93 (IH, m, H-1'), 7.30-7.
46 (6H, m, TBDPS-arom), 7.54-
7.65 (5H, m, TBDPS-arom and H
-6), 8.02 (LH,br-s,NH)MS (
m/z): 112 (B+1), 293 (M −B
tBu)'' Example 7 In the general formula [■'], R12=methyl.

Synthesis of a compound where R22=hydrogen atom, R1″1=tert-butyldiphenylsilyl, and R′=hydrogen (third step) Compound (C) obtained in Example 1 (25.8m (1°0,
Methyllithium (CHlL1)/ether solution (f=1.10) (0.2'7 mQ) in THF (4,0d) solution at -78°C in an argon stream.

0.25 mmol) and immediately diluted with methyl iodide (CH
3I) (0.02 mL 0 , 29 mmol) was added.

After 15 minutes, acetic acid was added to stop the reaction, and the temperature was returned to room temperature, followed by partitioning (three times) between chloroform and saturated sodium bicarbonate water, and the chloroform layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was applied to a Florisil column (8x1..5G) and eluted with 10% ethanol/chloroform. After distilling off the eluate, transfer to a preparative TLC plate (20x
20 cm) and 5'-tert-butyldiphenylsilyl-2'3'-didehydro-2'3'-dideoxyuridine (compound (F)) (5.0 cm, yield 22.
8%).

Compound (E) “H-NMR (CDCI,) δpprn: 1.26
(9H,s, TBDPS-tBu), 1.71 (3
H.

s, -C) 1), 3.90 (2H, m, H-5')
.

4.83 (IH, m, H-4'), 5.18 (IH
'.

dd, H-5), 5.84 (1H, m, H-3').

6.84 (LH, m, H-1'), 7.29-7,
50 (6H, m, TBDPS-arom),
7.57-7.79 (5H, m, TBDPS-ar
om and H-6), 8.20 (LH, br-s, N
H) MS (m/z): 112 (B+1), 293 (
M-B-tBu)”, 405 (M-tBu)
"Compound (F)" H-NMR (CDC13) δppm: i, 07
(9H,S, TBDPS-tBu), 3.93 (2H
.

dd, d, H-5' b), 4.90 (IH, m, R
7,02 (IH, m, H-1'), 7.3"77,
45 (6H, m, TBDPS -aro+n
), 7.587.68 (5H, m, TBD]
'S-arom and H-6), 8.63 (IH,b
rs, NH) MS (m/z): ]
] 2 (B+1), 3 9 Yu (M-t
au)" Example 8 Synthesis of a compound of the general formula [1 to 1++1, R12 = phenylethynyl, R22 = hydrogen, R' = hydrogen (4th step) Compound obtained in Example 2 (38.0 mg, 0 .07 mmo
1) in a THF (2,0 mQ) solution in an argon stream,
Tetrabutylammonium fluorite (T
BAF) (26.1mg, 0.0
8 mmol1) was added and stirred for 2 hours. The reaction solution was distilled off under reduced pressure.

The residue was applied to a Florisil column (8 x 1.5 cm),
Elution was with 30% ethanol/chloroform.

After the eluate was distilled off under reduced pressure, it was applied to a preparative TLC plate (20X 20cm) and developed with chloroform-ethanol (15:1) to obtain the target compound (14.9cm, yield 69%). -NMR (CDC+3) δppm: 3.
90 (2H, dd d, H-5'), 5.0
6 (LH, m.

H-41), 5.74 (IH, dd, H-5) 16
．． 53 (IH, m, H-3'), 6.99
(IH, m, H1'), 7.30-7.41 (5H
.

rn r arom) + 7.6 ” (l
H+ d + 8 6 ) +8.04 (
1H, br-s, NH) Example 9 Synthesis of a compound in the general formula [''] where R12 = hydrogen, R22 = ethynyl, R4 = hydrogen (4th step) Compound 22.O ( 0.04 mmo1)
is the raw material compound, TBAF30.3+ng (Q,
09mmol1) was reacted and purified in the same manner as in Example 8 to obtain the target compound (5.5mm, yield 58.1%).

"H-NMR (C'DC13) δppm: 3.3
7 (IH,s, -C:CH), 3.98 (2H,m
.

H-5'), 4.85 (LH, m, H-4').

5.70 (1) (, dd, H-5), 6.11 (I
H+ 171. H2')+7. os (LH, m,
H-1'), 7.78 (IH, d, H-6), 8
．． 53 (I H, br-s, N) () MS (m/z): 1 1 2 CB+
1), U 22 (MB-1) Example 10 Synthesis of a compound with the general formula [IV'' where RI 7-hydrogen, R22=methyl, R4-hydrogen (4th step) Obtained in Example 6 Compound 9.5171[: (0,02m
mo1) as the raw material compound, TBAF8.2■(0,0
3 mmol) was reacted and purified in the same manner as in Example 8 to obtain the target compound (1.8 mmol, yield 39%).

'''H-NMR (CDCI,) δppm: 1.93
(3H, s, C) + 3), 3.89 (28, d d
d, H-5'), 4.68 (LH, m, H-4'
), 5.47 (IH, d, H-2'), 5.65
(1B, d.

H-5), 6.94 (YH, m, H-1')
.

7.74 (IH, d, H-6), 8.37 (I
H.

br-s, NH) Example 11 Synthesis of a compound of general formula [Ih''' where R12-methyl, R22-hydrogen, R4=hydrogen (4th step) Compound (E) obtained in Example 7 7. 0rrc (0,0
The desired compound (1.0 mm, yield 29.4%) was obtained in the same manner as in Example O using 2 mm0] as a starting compound.

"H-NMR (CDCI,) δppm: 1.72
(3H, s, C) + 3), 3.83 (2H, d
d d, H-5'), 4.88 (LH, m, H
-4'), 5.70 (LH, dr3.H-5), 5
．． 92 (LH, d.

H-3'), 6.84 (LH, m, H-1').

7.63 (LH, d, H-6), 8.34 (I
H.

br-s, N H) Example 12 Synthesis of a compound in the general formula [■'] where R″1=1=bromine1=hydrogen and R′=hydrogen (5th step) The compound obtained in Example 1 ( C) 45, 1 mg (0
,09mmol) f! As a chemical compound, TBAF
The product was reacted and purified in the same manner as in Example 8 using 36.9° (0.12 mmol) to obtain the target compound (22.7°, yield 92.4%).

'H-NMR (CDC1,) δppm: 3.
76 (2) (, d, H-5'), 4. 86
(IH, m, 1″.

-4'), 5°70 (IH, d, H-5), 6.5
8 (IH, S, H3'), 6.88 (YH, m
.

H-1'), 7. 95 (LH, d, H-
6) MS (m/z): 112 (B+1),
117°179 (MB)”, 176, 17
8 (M-B-1) Example 13 Synthesis of a compound in the general formula [■'] where R11 = hydrogen, R21 = bromine, and R4 = hydrogen (5th step) Compound (D) obtained in Example 1 18 .8■(0.04m
mo1) as the raw material compound, TBAF16.4mg (0
, 05 mmol) was reacted and purified in the same manner as in Example 8 to obtain the target compound (9.1 mmol, yield 88.3%).

1H-NMR (CDC1,) δppm: 3.98 (
2H, ddd, H-5'), 4.79 (IH, m.

H-4'), 5.69 (Yu H, d df H-
5) 16.03 (LH, m, H-2'), 6.97
(IH, m, H-1'), 7.84 (LH, d,
H-6), 8.88 (IH, br-s, HN) MS
(m/z): 112 (B+1), 11
7゜179 (MB)", 1 76,
178 (M-B-1) [Effects of the Invention] The present invention not only provides novel derivatives of 2'3'didehydro-2',3'-dideoxyuridine that have utility in themselves, but also provides useful compounds. The present invention also provides compounds that can be used as synthetic intermediates.

That is, compounds having an alkyl group, alkenyl group, or alkynyl group as a substituent at the 2' or 3' position are useful as antiviral agents.

In addition, compounds having a halogen atom as a substituent at the 2' or 3' position are useful as 2' or 3' antiviral agents.
It can not only be used as a synthetic intermediate for '-dideoxyuridine derivatives, but also have a carbon chain (
It can also be used as a key intermediate for introducing alkyl groups, alkenyl groups, alkynyl groups, etc.

Claims (1)

[Claims] 1) The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, either R^1 or R^2 is an alkyl group, an alkenyl group, or an alkynyl group. group or halogen atom (
(excluding fluorine), the other represents a hydrogen atom, and R
^3 represents a hydrogen atom or a silyl group, and R^4 represents a hydrogen atom or a lower alkyl group. ] 2',
3'-didehydro-2',3'-dideoxyuridine derivative. 2) In the general formula [I], either R^1 or R^2 is a halogen atom, and R^3 is a silyl group. The following general formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[ III] [In the formula, one of R^1^1 and R^2^1 represents a halogen atom (excluding fluorocarbons), the other represents a hydrogen atom, and R^3^1 represents a silyl group. and R^4 represents a hydrogen atom or a lower alkyl group. ] The 2',3'-didehydro-2',3'-dideoxyuridine derivative according to claim 1. 3) In the general formula [I], one of R^1 and R^2 is an alkyl group, alkenyl group, or alkynyl group [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] [In the formula, one of R^1^2 and R^2^2 represents an alkyl group, an alkenyl group, or an alkynyl group, the other represents a hydrogen atom, R^3 represents a hydrogen atom or a silyl group, and R ^4 represents a hydrogen atom or a lower alkyl group. ] The 2',3'-didehydro-2',3'-dideoxyuridine derivative according to claim 1. 4) 2', characterized in that the compound according to claim 2 is subjected to an alkylation, alkenylation or alkynylation reaction, and optionally subjected to a desilylation reaction to obtain the compound according to claim 3; A method for producing a 3'-didehydro-2',3'-dideoxyuridine derivative. 5) 2',3'-didehydro-2',3 according to claim 4, wherein the alkylation, alkenylation or alkynylation reaction is carried out with an alkylating agent, alkenylating agent or alkynylating agent in the presence of a palladium catalyst. A method for producing a '-dideoxyuridine derivative. 6) 2',3'-didehydro-2' according to claim 4, wherein the alkylation, alkenylation or alkynylation reaction is carried out with an alkylating agent, an alnickelizing agent or an alkynylating agent in the presence of a lithiation agent; Method for producing a 3'-dideoxyuridine derivative. 7) The following general formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, either R^1^1 or R^2^1 is a halogen atom (excluding fluorine) , the other one is a hydrogen atom, and when R^1^1 is a halogen atom, R
^5 represents a hydrogen atom, R^6 represents SeR^7 (Se represents a selenium atom, R^7 represents an aryl group, respectively), and R
When ^2^1 is a halogen atom, R^5 is SeR^
7, R^6 represents a hydrogen atom, R^3^1 represents a silyl group, and R^4 represents a hydrogen atom or a lower alkyl group. A method for producing a 2',3'-didehydro-2',3'-dideoxyuridine derivative, which comprises reacting a compound represented by the following with a peroxide to obtain the compound according to claim 2.