JPH0228161A - Novel cyclobutane derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [A is H, OH, azido or amino; B is group of formula II (X is H, halogen or lower alkyl) or formula III]. EXAMPLE:(+ or -)-1-[(1beta,2alpha,3beta)-2-hydroxy-3-hydroxymethyl-cyclobutan-1-yl]- 2,4(1H,3H)- pyrimidinedione and its optically active isomer. USE:An antiviral agent. It has broad antiviral activity and is useful for the remedy of lip herpes, herpes genitalis, herpes zoster, viral hepatitis, AIDS, etc. PREPARATION:The compound of formula I can be produced by reacting a compound of formula IV (R is H or protecting group) with a compound of formula V, VI or VII (Y is O-silyl or NR-silyl; Z is silyl) in the presence of an acid catalyst (e.g., boron trifluoride etherate) or a basic catalyst (e.g., potassium carbonate) and removing the protecting group from the product.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to cyclobutane derivatives that are expected to be used as pharmaceuticals such as antiviral drugs.

[Prior Art] Many nucleic acid-related substances are known to have antiviral effects, and some of them are in clinical use as useful medicines. For example, vidarabine (M, Pr1vat de Garilhe) is an antiviral agent.
and J, de Rubber, C, R, Aca.
d, Soc, D (Paris) 259.2725 (19
64)), acyclovir (G, B, Elion eta
+,, Proc, Natl, Acad, Sci, U
SA, 74.5716 (2977)), azidothymidine (H, Mitsuya et al., Proc.
Natl, Acad, Sci, tJSA, 82.7
096 (1985)) etc. are known.

[Problems to be Solved by the Invention] However, the above antiviral drugs have a narrow scope of application, and the administration methods are limited due to the effects of solubility, oral absorption, metabolism, etc., and long-term administration is limited due to side effects such as pre-marrow Many problems remain, such as the difficulty of Furthermore, for many viral diseases, such as viral hepatitis and viral gastrointestinal and respiratory diseases that frequently occur in children, there are no suitable antiviral drugs, and patients rely on symptomatic treatment. Also,
BACKGROUND OF THE INVENTION Since malignant viral diseases such as acquired immunodeficiency syndrome (AIDS) and adult T-cell leukemia (ATL) are on the rise, the development of excellent antiviral drugs is desired.

[Means for Solving the Problems] Therefore, as a result of various studies, the present inventors found that the general formula (I) [wherein A is hydrogen, a hydroxyl group, an azide group, or (where X is a hydrogen atom, a halogen It has been discovered that a nucleoside derivative having a cyclobutane skeleton, which was completely unknown until now, as shown in the formula (n) [where R is It has also been found that it can be easily derived from a cyclobutane derivative represented by a hydrogen atom or a protecting group.

The compound represented by general formula (I) is expected to be effective against viral diseases caused by various viruses.

The present invention was completed based on the above findings.

Examples of the compound represented by the general formula (I) of the present invention include the following compounds. Regarding the relative steric configuration, when cyclobutane is considered to be a plane, a substituent located below the plane is indicated by α, and a substituent located above the plane is indicated by β.

1, (±)-1-[(1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4(IH,3H)-pyrimidinedione and its optically active form.

2, (±)-5-fluoro-1-4 (1β, 2α.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2,4(IH,3H)-pyrimidinedione and its optically active substance.

3, (±)-1-[: (1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl-5-methyl-2,4(1H,3H)-pyrimidinedione and its optical activity body.

4, (±)-4-amino-1-[(1β, 2α.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2(IH)-pyrimidinone and its optically active substance.

5, (±)-1-[(1α, 2β, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4(IH,3H)-pyrimidinedione and its optically active form.

6, (±)-5-fluoro-1-[(1α, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco-2,4(IH,3H)-pyrimidinedione and its optically active substance.

7, (±)-1-[(1β,2β,3B)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]
-2,4(IH,3H)-pyrimidinedione and its optically active form.

8, (±)-5-fluoro-1-[(1β, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2,4(IH,3H)-pyrimidinedione and its optically active substance.

9, (±)-1-[(1β, 2β, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]
-5-methyl-2,4(IH,3H)-pyrimidinedione and its optically active form.

10, (±)-4-amino-1-4(1β, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2(IH)-pyrimidinone and its optically active substance.

11, (±)-1-4(1β, 2α, 3β)-2-azido-3-hydroxymethylcyclobutan-1-yl]
-2,4(IH,3H)-pyrimidinedione and its optically active substance 12, (±)-1-[(1β, 2α, 3β)-2-azido-3-hydroxymethylcyclobutan-1-yl]-
5-Fluoro-2,4(1H,3H)-pyrimidinedione and its optically active substance 13, (±)-1-[(1β, 2α, 3β)-2-azido-3-hydroxymethylcyclobutan-1-ylco 5-methyl-2,4 (IH.

3H)-pyrimidinedione and its optically active form 14, (±)-4-amino-1-[(1β, 2α.

3β)-2-azido-3-hydroxymethylcyclobutan-1-yl]-2(IH)-pyrimidinone and its optically active substance 15, (±)-1-[(1β, 2α, 3β)-2-amino- 3-hydroxymethylcyclobutan-1-yl]
-2,4(IH,3H)-pyrimidinedione and its optically active substance 16, (±)-1-[(1β, 2α, 3β)-2-amino-3-hydroxymethylcyclobutan-1-yl]-
5-Fluoro-2,4(IH,3H)-pyrimidinedione and its optically active form 17, (±)-1-[(1β, 2α, 3β)-2
-amino-3-hydroxymethylcyclobutan-1-yl]-5-methyl-2,4(IH.

3H)-pyrimidinedione and its optically active form 18, (±)-4-amino-1-[(1β, 2α.

3β)-2-amino-3-hydroxymethylcyclobutan-1-yl] -2(IH)-pyrimidinone and its optically active substance 19.1-[(1β,3β)-3-hydroxymethylcyclobutan-1-yl] -2,4(IH,3H)-pyrimidinedione 20.5-fluoro-1-[(1β,3β)-3-hydroxymethylcyclobutan-1-yl]-2,4(IH
,3H)-pyrimidinedione 21.1-[(1β,3β
)-3-hydroxymethylcyclobutan-1-yl]-
5-Methyl-2,4(IH,3H)-pyrimidinedione 22.4-Amino-1-[(1β,3β)-3-hydroxymethylcyclobutan-1-yl]-2(IH)-pyrimidinone General formula ( Examples of the compound represented by n) include the following.

a, (±)-(1α, 2β, 4α)-2-hydroxymethyl-5-oxabicyclo[2,1°0]pentane and its optically active substance.

b.(±)-(1α, 2β, 4α)-2-acetoxymethyl-5-oxabicyclo[2,1°0]pentane and its optically active substance.

c, (±)-(1α, 2β, 4α)-2-benzoyloxymethyl-5-oxabicyclo[2°1.0 Copentane and its optically active form.

d, (±)-(1α, 2β, 4α)-2-t-butyldimethylsilyloxymethyl-5-oxabicyclo[
2,1,OF pentane and its optically active form.

e, (±)-(1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1,O]pentane and its optically active form.

f.

g. h.

l.

j・ k.

1°(±)-(lα, 2β, 4α)-2-benzyloxymethyl-5-oxabicyclo[2°1, O]pentane and its optically active substance.

(±)-(1α, 2β, 4α)-2-methoxymethoxymethyl-5-oxabicyclo[2°1.01 Pentane and its optically active form.

(±)-(1β, 2β, 4β)-2-hydroxymethyl-5-oxabicyclo[2,1°0 copentane and its optically active form.

(±)-(lβ, 2β, 4β)-2-acetoxymethyl-5-oxabicyclo[2,1°0 copentane and its optically active form.

(±)-(1β, 2β, 4β)-2-benzoyloxymethyl-5-oxabicyclo[2°1.0 Copentane and its optically active substance.

(±)-(1β, 2β, 4β)-2-t-butyldimethylsilyloxymethyl-5-oxabicyclo[2,1,
0] Pentane and its optically active substance.

(±)-(lβ, 2β, 4β)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0] Pentane and its optically active substance.

m, (±)-(1β, 2β, 4β)-2-benzyloxymethyl-5-oxabicyclo[2°1.0]pentane and its optically active substance.

n, (±)-(1β, 2β, 4β)-2-methoxymethoxymethyl-5-oxabicyclo[2°1.0]pentane and its optically active substance.

Among the compounds of the present invention represented by the general formula (1), the compound represented by the general formula (■A) [where B is the same as B in the general formula (I)] can be produced as follows.

That is, the compound represented by the general formula (n) has a compound represented by the general formula [where X is the same as in the general formula (I), Y is an 0-silyl group or an NR-silyl group, and Z is a silyl group] be. In addition, R represents a hydrogen atom or a protecting group, ] (I [I) - (V) is reacted with a compound represented by - general formula (VIA) (where X is a hydrogen atom, a halogen atom, or, R represents a hydrogen atom or a protecting group, and then the remaining protecting group is removed, or further,
The compound represented by the general formula (VIA) was prepared using the Mitsunobu method (0
, Mitsunobu, 5ynthesis, 1, (1
981)) Alternatively, by methods such as oxidation-reduction, 2'
The protecting group of the compound represented by the general formula (■A) obtained by inverting the hydroxyl group at the position may be deprotected using an appropriate reagent.

The protecting group (R) in general formula (n) is not particularly limited as long as it is generally used as a protecting group, for example,
Acyl groups such as acetyl group and benzoyl group; carbamoyl groups such as dimethylcarbamoyl group and diphenylcarbamoyl group; silyl ether type protecting groups such as t-butyldimethylsilyl group and t-butyldiphenylsilyl group; methoxymethyl group and benzyl group; Examples include ether-type protecting groups such as groups.

Examples of the silyl group in the general formula (V) include a trimethylsilyl group, the protecting group is the same as the protecting group in the general formula (II), and the alkyl group includes a butyl group, a benzyl group, Examples include 2-methoxyethoxy group.

In addition, the compound represented by general formula (V) can be prepared by a known method (T
, NishN15hi and 1.1wai, Che
m, Pharm, Bull, 12, 352 (1964
), R, Zou and M, J, Robins, Ca.
n, J. Chem, 65.1436 (1987))
is produced from a compound represented by the corresponding general formula (m) (rV').

Compounds of general formula (II) and general formula (III) '-(V
) The ratio of the compound used is approximately 0.0 equivalent of the former to 1 equivalent of the latter.
5 to 10 equivalents, preferably about 1 to 4 equivalents.

Further, both reactions are carried out in the presence of an acid catalyst or a base catalyst. As an acid catalyst, boron trifluoride Nieteller)
(BF3・0Et2), tin tetrachloride, titanium tetrachloride,
Using Lewis acids such as zinc chloride and magnesium bromide, or acids such as trimethylsilyltrifluoromethanesulfonate, ethanesulfonic acid, and trifluoromethanesulfonic acid, and using organic solvents such as methylene chloride, chloroform, dichloroethane, benzene, toluene, chlorobenzene, and acetonitrile. The reaction is carried out at a temperature ranging from -30°C to the reflux temperature of the solvent, preferably from about 0°C to 30°C. The amount of acid catalyst used is 0.1 to 5 times equivalent to the compound of general formula (n),
Preferably, the amount is about 1 to 2 times equivalent. Potassium carbonate, lithium hydride, sodium hydride, etc. are used as the base catalyst, and the reaction is carried out from around room temperature in a solvent such as dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamide, etc. The reflux temperature of the solvent, preferably from 80°C to 200°C
It is carried out at around ℃. The amount of base catalyst used is determined by the general formula (f
The amount is preferably about 0.01 to 5 times equivalent, preferably about 0.1 to 1.2 times equivalent, relative to the compound I).

The compound represented by the general formula (n) can be obtained by epoxidizing a compound represented by the general formula (■) [where R is the same as R in the general formula (n)].

In the epoxidation reaction, a peracid such as performic acid, peracetic acid, m-chloroperbenzoic acid, or monoperphthalic acid is used in a solvent such as water, formic acid, acetic acid, ethers, benzene, toluene, methylene chloride, or chloroform, or The reaction may be carried out in a mixed solvent of these from 0°C to the reflux temperature of the solvent, or the formula (■) to (
XI) After activation by sulfonylation such as methanesulfonylation, p-)luenesulfonylation, or halogenation such as bromination, iodination, etc., react with an azide ion such as sodium azide or potassium azide. This can be achieved by reacting the resulting oxatiridine represented by the general formula (VIB) in an organic solvent such as benzene, chloroform, or acetonitrile at a temperature ranging from 0° C. to the reflux temperature of the solvent.

Among the compounds of the present invention of general formula (I), the protecting group of the compound represented by general formula (IB) [where B2 and R are the same as general formula (VIA)] can be deprotected using an appropriate reagent. Bye.

Among the compounds of the present invention, the compound represented by the general formula (IC) [where B is the same as B in the general formula (1)] can be produced as follows.

That is, the hydroxyl group at the 2' position of the compound represented by the general formula (VIA) is converted to methanesulfonylation, trifluoro [the compound represented by the same formula (1) as follows] It can be manufactured by

That is, the azide group of the compound represented by the general formula (VIB) is reduced with a suitable reducing agent such as catalytic reduction to obtain the general formula (VIC) [wherein 82 and R are the general formula (VIA)] The protecting group of the compound represented by [the same] may be deprotected using an appropriate reagent.

Among the compounds of the present invention, general formula (ID) [In the formula, B is the same code as in general formula (1) The compound represented by can be produced as follows.

That is, a compound represented by the general formula (Xn) [wherein R is the same as in the general formula (VIA) and X represents a leaving group], a compound represented by the general formulas (III) to (V) may be reacted, and the protecting group of the resulting compound represented by general formula (VID) [wherein 82 and R are the same as in general formula (VIA)] may be deprotected using an appropriate reagent.

The leaving group (X) in general formula (X II) includes sulfonyloxy groups such as methanesulfonyloxy group, p-)luenesulfonyloxy group, and trifluoromethanesulfonyloxy group, and halogens such as chlorine, bromine, and iodine. can be mentioned.

Compounds of general formula (X II) and general formulas (III) to (V
) The ratio of the compound used is approximately 0.0 equivalent of the former to 1 equivalent of the latter.
5 to 10 equivalents, preferably about 1 to 4 equivalents.

Moreover, both reactions are carried out in the presence of a base catalyst or without a catalyst. Potassium carbonate, lithium hydride, sodium hydride, etc. are used as the base catalyst, and the reaction is carried out from around room temperature in a solvent such as dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamide, etc. The reflux temperature of the solvent is preferably about 40°C to 170°C.

The amount of the base catalyst to be used is about 0.1 to 5 equivalents, preferably about 1.0 to 1.2 times the equivalent of the compound of general formula (X II).

The compound represented by the general formula (XI) is produced from the compound represented by the general formula (2). That is, - general formula (II)
The compound represented by the general formula (XI[I) obtained by reducing the compound represented by (R=H) with a reducing agent such as lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminum hydride, etc. A compound represented by the general formula (Xn) is produced by introducing a protecting group into the primary hydroxyl group and guiding the secondary hydroxyl group to a leaving group.

The protecting group (R) in the general formulas (VIA) to (VID) is not particularly limited as long as it is generally used as a protecting group, such as an acyl group such as an acetyl group or a benzoyl group, a dimethylcarbamoyl group, or a diphenyl group. Examples include a carbamoyl group such as a carbamoyl group, a silyl ether type protective group such as a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group, and an ether type protective group such as a methoxymethyl group and a benzyl group. In addition, the general formula (VI
A) Removal of the protecting group of the compounds represented by (VID) is as follows:
This can be achieved by using an appropriate deprotection agent or deprotection method depending on the difference in the protecting group. For example, alkalis such as sodium hydroxide, sodium methylate, ammonia, fluorine reagents such as tetrabutylammonium fluoride,
Examples include acids such as hydrochloric acid, hydrogenolysis, and the like.

Among the compounds represented by the general formula (I), the present invention includes racemic forms and optically active forms of those having an asymmetric carbon. The optically active form can be obtained from the racemate by a known method, such as a method using an optically active ram, or a method of separating and purifying diastereomers obtained by reacting with an optically active resolution aid. Furthermore, by using an optically active compound of general formula (II), it is also possible to obtain an optically active compound of general formula (I).

In addition, possible compounds represented by the general formula (I) can be converted into acid addition salts if desired. Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, as well as formate, acetate, citrate, tartrate, maleate, fumarate, Examples include organic acid salts such as lactate and methanesulfonate.

[Action] As is clear from the following experimental examples, the compound of the present invention
It exhibits antiviral effects against both viruses and RNA viruses.

Experimental example 1゜Herpes simplex virus type 2 (HS), a DNA virus
V-4), the antiviral effect against RNA viruses varicella stomatitis virus (VSV) and Sindbis virus (SBV) was tested by the following method.

(Method 1) Cell culture medium (Eagle M containing 5% fetal bovine serum)
EM medium) to approximately 15X 10' cells/ml.
Cell (derived from African green monkey kidney cells) suspension 100μ
1 was placed in a 96-well microplate and heated at 37°C at 5% (V/
V) After culturing for 24 hours in a carbon dioxide incubator, remove the medium, add 100 μl of a medium containing 50-100 infectious units of virus (serum-incompatible Eagle's MEM medium), and culture for 1 hour under the same conditions to infect the virus. let After infection, the virus solution was removed, 100 μl of a medium (serum-incompatible Eagle's MEM medium) containing a certain amount of the sample was added, and cultured for 48 hours. Add 0.01% Neutral Red (NR') to the cells after culture.
100 μm of a medium containing NR was added, and the uptake of NR by the cells was measured by absorption of light at a wavelength of 546 nm to determine the 50% cytopathic inhibition concentration.

Experimental Example 2 Human cytomegalovirus (HC), a DNA virus
MV) was tested by the following method.

(Method 2) Anti-cytomegalovirus activity was determined by adding 100 PFU (Plaque) of cytomegalovirus (A0169 strain) to 35 dishes containing a monolayer of human fetal fibroblasts.
After adsorption for 1 hour, the cells were infected with a medium containing each concentration of this compound [0.5% agarose, 2% live fetal serum (fetal
calfserum)) and heated at 37°C, 5% (v
/v) in a carbon dioxide gas incubator for 10 days, plaque formation was measured, and the 50% inhibition value (I
Csa) was calculated.

Experimental Example 3 The effect on hepatitis B virus (HBV), a DNA virus, was tested by the following method.

(Method 3) Cultured liver cell line HB that produces and releases active hepatitis B virus
611 (Proc, Natl, Acad, S
ci, USA84 (1987), P444)
I modifiedEag I according to becco
10% calf serum in e-medium (GIBCO), 20
0 μg/-G41B, 100 u each of penicillin and streptomycin C at 37°C, 5% CO
2. 5 x 10'ce in 6-hole plate
Inoculate 1 liter/hole (35 mm), 1 to 2 days later 5
When it reached 0% confluence, a certain amount of this compound was added and cultured, and the culture was continued for 15 days, replacing the medium with a medium containing the drug at the same concentration every 3 days, after which the medium was removed. Lysis buff
er) (10mM TristlCl pH7,8
15mM Na2EDTA, 1%50510.1mg
The ONA was treated with Pronase K) at 37°C for 1 hour and dissolved, and the obtained ONA was purified by RNase treatment, phenol◆chloroform treatment, and ethanol precipitation.

Next, 5 μg of DNA was treated with Hindm, and the DNA pattern was analyzed by Southern method using 32p-labeled hepatitis B virus DNA as a probe.

Experimental Example 4 The effect on AI DS virus (HI■), which is an RNA virus, was tested by the following method.

(Method-4) Anti-HIV (Human 1 mmunodefici
Approximately 50,000 MT-4 cells/+nlJ were placed in a 24-well tray, 100 μΩ of a solution containing a certain amount of the compound of the present invention was added, and the cells were incubated at 37°C with 5% (V/V
) After culturing for 2 hours in a carbon dioxide gas-filled incubator, HIV
After adding 103 to 104 infectious units and culturing for 4 days, a portion of the culture solution was smeared onto a slide glass, fixed with acetone, and then the expression of virus antigen was observed using a fluorescent antibody method.

Incidentally, AIDS patient serum was used as the primary antibody for the fluorescent antibody method, and anti-human ■gG labeled with FITC was used as the secondary antibody.

(Result) II 35+
; 30% at 35ug/ml [Effects] The compound represented by the general formula (1) of the present invention has a broad antiviral effect, so it can be used against oral herpes, genital herpes, herpes zoster, and herpes simplex virus during immunosuppression. Type 1, type 2 (H
SV-I, II), Valicella sister virus (V
ZV), cytomegalovirus (CMV), Epstein-Perr virus (EBV) 9 infection, viral hepatitis, viral respiratory disease, viral gastrointestinal disease, AI
It is expected to be effective against many viral diseases such as DS and ATL. It is also expected to have anticancer effects.

When the compound of the present invention obtained as described above is used as an antiviral agent, it can be administered orally, intravenously, or transdermally. The dosage varies depending on the patient's symptoms, age, and administration method, but is usually 0.1-500 m
g/kg/day.

The compound of the present invention is administered in the form of a preparation prepared by mixing it with a suitable pharmaceutical carrier. The formulations used include tablets, granules, fine granules, powders, capsules, injections, creams, and suppositories.

[Example] Next, the production of the compound of the present invention will be specifically explained with reference to Examples.

Example 1゜(±)-1-[(1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2
．． 4 (IH,3H)-pyrimidinedione (compound 1
) Production process 1゜(±)-1-[(1β, 2α, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylco2.4(1H,3H)-pyrimidinedione Production of (±)-(lα, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicycloC2,1
,O]pentane (compound e) (339 mg, 1.
0 mmol I) and 2,4-bistrimethylsilyloxypyrimidine (1,03 g.

4.0 mmol I) was dissolved in anhydrous methylene chloride (10 ml), a solution of boron trifluoride etherate (170 mg, 1.2 mmol) in anhydrous methylene chloride (1 ml) was added at room temperature in an argon atmosphere, and the solution was left as is for 1 day. Stir. Add 0.2M phosphate buffer (pH 7.0) to the reaction solution.
After stirring for a while, extract with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 5 (): 1 (v
/v)) and (±')-1-[(1β, 2α,
3β)-3-t-butyldiphenylsilyloxymethyl=2-hydroxycyclobutan-1-yl]-2゜4(
IH,3H)-pyrimidinedione (222 mg, 49%
).

NMR (400MHz・FT, DMSO-d6) δ
:1.01 (9H, s).

1.49 (ILapparent q, J=9.9Hz
).

2.05 (IH, m).

2.12(1,)1. apparent Q, J:8.
8H2).

3.77 (2H, d, J=4.782).

4.08(l)I, apparent q, J=7.3
Hz, changed to apparent
(J=7.3Hz) after addition
of 020).

4.41 (IH, parent Q, J: 8.68
2).

5.595(1)1. d, J=7.0Hz, excha
ngable with 020).

5.601 (IH, d, J=8.IH2).

7.38-7.52 (6H, m).

7.60-7.66 (4H, m).

7.66 (IH, d, J=8.1Hz).

11.27 (IH, s, exchangeable w
ith D20).

Step 2゜(±) -1-[(1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]
-2,4(IH,3H)-pyrimidinedione (compound 1
) Production of (±)-1-[(1β,2α,3β)-3-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-2,4(IH,38)-pyrimidinedione ( 90 mg, O-20m0-2O was dissolved in methanol (1 ml) and 4N-hydrochloric acid/dioxane (0
, 1ml, 0. 4 mmol) and stirred at room temperature overnight. After concentrating the reaction solution, the ether-soluble portion is removed and purified by Sephadex LH-20 column chromatography (methanol). The purified product was dissolved in water and then lyophilized to give (±)-1-[(1β, 2α.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2,4(IH,3H)-pyrimidinedione (compound 1) (42 mg, 99%) is obtained.

NMR (400MH2・FT, CD30D+020) δ
:1.60(ltl,apparent q,J=9.
8) 1z).

2.14(1)1. IrI).

2.30 (IH, apparent q, J=9.3H
z).

3.71 (2N, m).

4.16 (IH, apparent t, J=7.0H
z).

4.47 (IH, apparent q+J=8.4H
z).

5.80(1)1. d, J: 8.1Hz).

7.67 (IH, d, J = 8.IH2).

Example 2゜ (±)-5-fluoro-1-[(1β, 2α.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl] -2,4(IH,3H)-pyrimidinedione (compound 2) manufacturing process 1°(±)-1-[:(1β,2α , 3β)-3-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl-5-fluoro-2,4(IH,
Preparation of 3H)-pyrimidinedione (±)-(1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0] Pentane (Compound e) (135 mg, 0.40 m
mol) and 2,4-bistrimethylsilyloxy-5
-Fluoropyrimidine (329 mg, 1.20 mmol
) was dissolved in anhydrous methylene chloride (4 ml), and boron trifluoride Nieteller (68 mg) was dissolved at room temperature in an argon atmosphere.
.

0.48 mmol) of anhydrous methylene chloride solution (1 m
1) and stir for 1 day. 0.2 to the reaction solution
Add M-phosphate buffer (pH 7.0), stir for a while, and then extract with methylene chloride.

After drying the extract over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 (v
/v)) and purified with (±)-1-[(1β, 2α, 3
β')-3-t-Butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl-5-fluoro-2,4 (IH.

3H)-pyrimidinedione (140 mg, 75%) is obtained.

NMR (400MHz-FT, CDCl5) δ: 1.0
7 (9H, s).

1.71 (IH, m).

2.13-2.27 (2H, m).

3.51 (H, brs).

3.74 (11, dd, J=3.0Hz, J=11.0
tlz).

3.84()I, dd, J: 3.3) 1z, J=11.
0flz).

4.20 (H, m).

7.20 (H, d, J = 5.8 tlz).

7.33-7.50 (6H, m).

7.60-7.70 (4H, m).

9.25 (IH, brs).

Process 2゜ (±)-5-fluoro-1-[(1β, 2α.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4 Production of (18,38)-pyrimidinedione (compound 2) (±)-1-[(1β
, 2α, 3β)-3-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl-5-fluoro-2,4(IH,3H)-pyrimidinedione (140 mg, 0.30 mmol) in methanol (
2 ml) and 4N-hydrochloric acid/dioxane (0°15
ml, 0. Add 6 mmol I) and stir overnight at room temperature. After concentrating the reaction solution, the ether-soluble portion is removed and purified by Sephadex LH-20 column chromatography (methanol). The purified product was dissolved in water and then lyophilized to give (±)-5-fluoro-1-[(
1βl 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4 (IH
,38)-pyrimidinedione (compound vA2) (67 mg
, 97%).

NMR (400M) lz-FT, cD30D) δ:
1.57 (lH, apparent Q, J: 10.3
H2) 12.05 (II(, m).

2.24 (ift, parent Q, J: 9.0
H2).

3.60-3.75 (2H, m).

4.10 (IH, apparent t, J=7.7H
z).

4.46(It(, relative q+J=8.7
Hz).

7.86<IH, d, J=6.6H2).

Example 3゜(±)-1-[(1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-5
-Methyl-2,4(IH,3H)-pyrimidinedione (
Production process of compound 3) 1゜(±)-1-[(1β, 2α, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-5-methyl-2,4 (lH, 3H
)-Preparation of pyrimidinedione (±)-(1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,01 pentane (compound e) (169 m'g, 0.50
mmol) and 2,4-bistrimethylsilyloxy-5-methylpyrimidine (541 mg, 2.OOmmo
1) was dissolved in anhydrous methylene chloride (51 TI l ) to obtain boron trifluoride (Niteller) (85 mg) at room temperature in an argon atmosphere.

0.60 mmol) of anhydrous methylene chloride solution (1 ml
) and stir for one day. 0.2M to the reaction solution
- Add phosphate buffer (pH 7,0) and stir for a while, then extract with methylene chloride.

After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 (
(±')-1-[(1β
, 2α, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-
5-methyl-2,4 (IH.

3H)-pyrimidinedione (153 mg, 66%) is obtained.

NMR (400MHz-FT, CDC13) δ: 1.0
7 (9N, s).

1.75 (IH, m).

1.93 (3H, s).

2.15-2.30 (2H, m).

3.66 (1N, brS).

3.76 (ltl, apparent d, J=10.
6Hz).

3.84 (lH, apparent d, J=10.6
Hz).

4.15 (2H, m).

6.95 (ltl, s).

7.33-7.50 (6t(,m).

7.60-7.70 (4H, m).

8.94(1)1. br).

Step 2゜(±)-1-[(1β, 2α, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-5
-Methyl-2,4(IH,3H)-pyrimidinedione (
Production of compound 3) (±)-1-[(1β, 2α, 3β>
-at-butyldiphenylsilyloxymethyl-2-
Hydroxycyclobutan-1-yl-5-methyl-2
,4(IH,38)-pyrimidinedione (142mg,
0.31 mmof) was dissolved in methanol (1 ml), and 4N-hydrochloric acid/dioxane (0.15 ml 1.0.
6 mmol) and stirred at room temperature overnight. After concentrating the reaction solution, the ether-soluble portion was removed and purified by Sephadex LH-20 column chromatography (methanol). After the purified product is dissolved in water, it is freeze-dried (
±)-1-[(1β, 2α, 3β)-2-hydroxy-
3-Hydroxymethylcyclobutan-1-yl]-5-
Methyl-2,4(IH,3H)-pyrimidinedione (compound 3) (67 mg, 97%) is obtained.

NMR (400MH2・FT, DMSO-d6) δ:1
．． 40 (lH, apparent q, J=9.9Hz
).

1.80 (3H, s).

1.90 (ILm).

2.03(it(,parent Ql=8.88
2).

3.43-3.60 (2tl, m).

3.97 (IH, apparent q, J=7.5H
z, changed to apparent t(J
=7.7Hz) after addition of
D20).

4.41 (IH, apparent QJ: 8.6) 1
2) 14.57 (IH, t, J=5.3Hz, exch
angelabte with 020).

5.47(1)1. d, J=6.6Hz, exchan
easy with 020).

7.55 (IH, s).

11.24 (IN, brs, exchangeable
with D20).

Example 4゜(±)-4-amino-1-[(1β, 2α, 3β)-2
-Hydroxy-3-hydroxymethylcyclobutane-1
-Production process of 2(IH)-pyrimidinone (compound 4) 1°(±)-4-amino-! −[(]β, 2α, 3β)−3
Production of -t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-2(IH)-pyrimidinone (±)-(1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5 -oxabicyclo[2,1
,0 Copentane (Compound e) (17smg, o, 53m
mol) and bistrimethylsilyl-N-acetylcytosine (476 mg.

1.60 mmol) was dissolved in anhydrous methylene chloride (5 ml), a solution of boron trifluoride etherate (90 mg, 0.63 mmol) in anhydrous methylene chloride (1 ml) was added at room temperature in an argon atmosphere, and the mixture was stirred for one day. . Add 0.2M phosphate buffer (pH 7.0) to the reaction solution, stir for a while, and then extract with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol = 50:1 followed by 30:1 (v/v)) to produce (±)-4-acetylamino-1-[(1β, 2α, 3β)-3-t-Butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-2(IH)-pyrimidinone (83 mg, 32%) is obtained.

NMR (400MHz-FT, CDC13) δ: 1.0
3 (9H, s).

1.83(1)1. m).

2.20-2.40 (28, m).

2.25 (3H, s).

3.75 (IN, dd, J=2.7) 1z, , I=1
0.8tlz).

3.83(1)1. dd, J=3.5112. J=10
．． 882).

4.11(1)1. apparent t, J=6.8
11z).

4.20 (1B, separate q, J=7.5t
tz).

4.54 (IH, s).

7.32-7.54(8)1, m).

7.57-7.70 (4N, m).

8.86 (IH, brs).

Step 2゜(±)-4-amino-1-[(1β, 2α, 3β)-2
-hydroxy-3-hydroxymethyldimethylcyclobutan-1-yl] -2('I H) - Preparation of pyrimidinone (compound 4) (±)-4-acetylamino-1-[(1β.

2α, 3β)-3-1-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylco2
(IH)-pyrimidinone (76 mg.

0.16 mmol) was dissolved in methanol (2 ml),
IM-sodium methylate/methanol (0.2 m
l, 0. Add 2 mmol 1) and stir at room temperature for 30 minutes. Amberlistl 5 (42
mg, 0.21 mmol) and stirred for 10 minutes.
After removing the resin by filtration, it is concentrated. The residue was dissolved in tetrahydrofuran (2 ml), and IM-tetrabutylammonium fluoride/tetrahydrofuran (0,25
1.0.25 mmol) and stirred at room temperature for 7 hours. The reaction solution was diluted with methanol and added to Amberlyst1.
5 (52 mg, 0.25 mmol) was added and stirred, then the resin was filtered off and the solvent was distilled off. The residue was purified by Sephadex LH-20 column chromatography (methanol) after removing the ether-soluble portion. (±)-4-amino-1-[(1β, 2α, 3β)-2-hydroxy-3
-Hydroxymethylcyclobutan-1-ylco-2(I
H)-pyrimidinone (compound 4) (36 mg, quantitative) is obtained.

NMR (400MH2-FT, DMSO-d6) δ:1
．． 57(1)1. m).

1.89(1)1. m).

2.04 (IH, apparent Q, J=9.0H
2) 13.40-3.56 (2B, +o).

3.90(1)1. m).

4.39 (IH, apparent Q, J=8.8)
12).

4.56(lH,brs,exchan3able
with 020).

5.39 (IH, brs, exchangeable
with D2CI).

5.70 (ill, d, J=7.3)12).

7.01(2)1,brd) Example 5゜(±)-1-[(1α, 2β, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2
．． 4 (IH,3H)-pyrimidinedione (compound 5
) Production process 1゜(±)-1-[(1α, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-2,4(IH,3H)- Production of pyrimidinedione (±)-(1β, 2β, 4β)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0] Pentane (Compound 1) (102 mg, 0.30 m
mol) and 2,4-bistrimethylsilyloxypyrimidine (308 mg.

1.2 mmol) was dissolved in anhydrous methylene chloride (3 ml), and a solution of boron trifluoride Nieteller (51 mg, 0.36 mmol) in anhydrous methylene chloride (1 ml) was added at room temperature in an argon atmosphere. Stir for a day. Add 0.2rVf-phosphate buffer (pH 7) to the reaction solution.
, 0) and stirred for a while, then extracted with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue) was subjected to silica gel column chromatography (methylene chloride:methanol=50:1).
(v/v)), (±) −1−[(1α,
2β,3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylco2
゜4(IH,3H)-pyrimidinedione (88 mg.

65%).

NMR (400Mflz-FT, CDCl5) δ:
1.10 (9H, S).

1.92 (IH, apparent Ql: 10.3H
2).

2.26 (IH, apparent t, J=10.8
Hz).

2.64 (IH, m).

3.70 (ill, d).

3.95 (IH, dd, J=4.8Hz, J=11.0
Hz).

4.02 (Itl, ddj=5.3Hz, J:11.0
Hz).

4.46 (IH, apparent q, J=7.3H
z').

4.68 (IH, apparent Q, J: 8.71
12).

5.74 (IH, dd, J=1.8tlz, J:
8.1tlz).

7.24 (IH, d, J=8.1112).

7.43(6)1. m).

7.69 (4ft, apparent t, J=7.0
flz).

9.13 (IH, brs).

Step 2゜(±)-1-[1α, 2β, 3β)-2-hydroxy-
3-hydroxymethylcyclobutan-1-yl] -2
, 4(IH,3H)-Preparation of pyrimidinedione (compound 5) (±)-1-[(1α, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl] -2,4(IH,3H)-pyrimidinedione (24 mg, 0.053 mmol) was dissolved in tetrahydrofuran (1 ml), and 1M-tetrabutylammonium fluoride/tetrahydrofuran (0.1M
1. After stirring at room temperature for 3 hours, it was diluted with methanol and mixed with Amberl 1st-15 (6
After stirring for a while and removing the resin, the solvent was distilled off under reduced pressure. The residue was purified by Sephadex LH-20 column chromatography (methanol), then dissolved in water and lyophilized to give (±'
)-1-[1α, 2β, 3β)-2-hydroxy-3-
Hydroxymethylcyclobutan-1-ylco2. 4
(IH,3H)-pyrimidinedione (compound 5) (1
2 mg, quantitative).

NMR (400MHz・FT, CD30D) δ: 1.9
4 (IH, apparent Q, J:lo, 3H2)
.

2.13 (IH, apparent t, J=10.5
Hz).

2.57 (IH, m).

3.76 (IH, dd, J=8.4Hz, J=1.1.
2Hz).

3.89(it(, dd, J=5.6Hz, J=11.
2Hz).

4.57(1)1. apparent t, J=8.4
Hz).

4.79 (IH, apparent Q, J: 8.9H
2) T5.69 (lH, d, J=8.1)iz).

7.71 (IH, d, J=8.1H2).

Example 6゜ (±)-5-fluoro-1-[(1α, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl] -2,4(IH,3H)-pyrimidinedione Production process of compound 6) 1°(±')-1-[(1α,2β , 3β)-3-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-5-fluoro-2,4(IH,
Preparation of 3H)-pyrimidinedione (±)-(1β, 2β, 4β)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0] Pentane (Compound I) (169 mg, 0.50 m
mol) and 2,4-bistrimethylsilyloxy-
5-fluoropyrimidine (549 mg, 2.0 mmo
1) was dissolved in anhydrous methylene chloride (5 ml) and dissolved with boron trifluoride Nieteller) (8 ml) at room temperature in an argon atmosphere.
5mg.

0.6 mmol) in anhydrous methylene chloride solution (1 m
Add 1) and stir for 1 day. 0゜2M to the reaction solution
- Add phosphate buffer (pH 7,0), stir for a while, and then extract with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol = 50:1 (v/v)), and (±'
)-1-[(1α.

2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-5
-Fluoro-2,4(IH,3H)-pyrimidinedione (136 mg, 58%) is obtained.

NMR (400M) Iz・FT, CDCl5) δ:
1.11(9)1. S).

1.89 (IH, apparent Q, J: 9.5H
2).

2.25(1)1. apparent t, J=10.
5Hz).

2.63 (lft, m).

3.62 (IH, d, J = 7.011z), 3.94 (
IH, dd, j=5. OH'z, J-10,8)Lz)
.

4.02 (IH, dd, J: 4.8Hz, J=10.8
Hz).

4.45 (lLapparent qlJ=7.5)1
2).

4.75(1)1. apparent Q, J=9.0
112).

7.300H, dJ=5.9Hz).

7.33-7.50 (6H, m).

7.60-7.75 (4H, m).

8.90 (IH, brs)- Process 2゜ (±)-5-fluoro-1-[(1α, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4 Production of (IH,3H)-pyrimidinedione compound 6) (±)-1-[(1α
, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylchora-fluoro-2,4(IH,3H)-pyrimidinedione (123 mg, 0.26 mmo 1 ) in methanol (2 ml). ), 4N-hydrochloric acid/dioxane (0.15ml, 0.6ml) was added and stirred overnight at room temperature. After distilling off the solvent under reduced pressure, the reaction solution was purified with Sephadex L H-20 (methanol) after removing the ether-soluble portion, and then dissolved in water and freeze-dried (±).
-5-Fluoro-1-[1α.

2β,3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-2,4(IH.

3H>-pyrimidinedione (compound 6) (48mg,
79%).

NMR (400M) 12 FT, CD30D) δ: 1.
93 (H, apparent q, J=10.611z
).

2.12 (H, apparent t, J=10.3)
1z).

2.56 (H, m).

3.76 (H, dd, J=7.5Hz, J=11.:l
z).

3.88 (H, dd, J=5.9Hz, J=11.2)
tz).

4.54()I,apparent t,J=8.21
(z)+4.84(H,l?I).

7.97 (H, d, J = 6.682).

Example 7゜ (±)-5-fluoro-1-[(1β, 2β.

3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2. 4 Production process 1 of (IH,3H)-pyrimidinedione (compound 8), (±)-1-[(1β, 2β, 3β)-3--butyldiphenylsilyloxymethyl-2-hydroxycyclobutane-1- yl]-5-fluoro-2,4(IH,3
H)-Preparation of pyrimidinedione Oxalyl chloride (350 μl) was added in an argon atmosphere.
, 4.1 mmol) of anhydrous tetrahydrofuran (9 m
l) solution at -78°C with dimethyl sulfoxide (58
After gradually adding 3 μl, 8.2 mmof), -35
The mixture was heated to ℃ and stirred for 5 minutes at the same temperature. Add the reaction solution again.
Cool to 8℃, (±)-1-[(1β, 2α, 3β)
-3-t-butyldiphenylsilyloxymethyl-2-
Hydroxycyclobutan-1-ylcololafluoro-
2゜4(IH,3H)-pyrimidinedione (1,60m
g, 3.4 mmol> of anhydrous tetrahydrofuran (4 m
l) After gradually adding the solution, the temperature was raised to -35°C and stirred for 15 minutes. After further cooling this reaction solution to -78°C,
Add 2.4 ml (1.17 mmol) of triethylamine, heat to -35°C, and stir for 15 minutes. The reaction solution was cooled to -78°C, a solution of lithium tri(t-butoxy)aluminum hydride (4.35 g, 17 mmol) in anhydrous tetrahydrofuran (10 ml) was added, and the temperature was gradually raised to room temperature while stirring. . Add 0゜2M- to the reaction solution.
Add phosphate buffer (pH 7,0) and methylene chloride,
After removing insoluble matter, extract with methylene chloride. The extract is dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (
methylene chloride: ethyl acetate = 4: 1 (v/v))
(±)-1-[(1β, 2β, 3β)-3
-t-Butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylcolola-fluoro-2°4(IH,3H)-pyrimidinedione (628 mg, 3
9%).

NMR (400μl2・FT, CDCl5) δ: 1.0
7 (9H, S).

2.25-2.45 (3H, m).

3.21(1)1. d, J=4.0H2).

3.85 (IH, dd, J = 6.2t (z, j = 11.
0Hz).

3.94 (IH, cld, J=3.5)1z, J
= 11.0Hz).

4.71 (IH, m).

4.79 (IH, m).

7.32-7.50(6)1. m).

7.54 (Ill, d, J=6.6)12).

7.65 (48,d, J=6.6Hz).

8.77 (IH, brs), Process 2゜ (±)-5-fluoro-1-[:(1β, 2β.

Preparation of (±)-1-[(1β,
2β, 3β) -3-t-Butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylgo-5-fluoro-2,4(IH,3H)-pyrimidinedione (94 mg, 0.20 mmol) was added to methanol (1
4N-hydrochloric acid/dioxane (0.1 ml, 0.4 mmol!) was added to the solution dissolved in ml), and the mixture was stirred overnight at room temperature. After distilling off the solvent under reduced pressure, the reaction solution was purified by Sephadex LH-20 column chromatography (methanol) after removing the ether-soluble portion.
-5-Fluoro-1-[(1β.

2β,3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco2.4 (IH.

3H)-pyrimidinedione (compound 8) (44 mg, 9
5%).

NMR (400MH2-FT, CD30D) δ:
2.27-2.47 (3H, m).

3.62 (IH, dd, J=5.1) 1z, J=11.
0Hz).

3.80 (IH, dd, J=7.382.J=11.0
H2).

4.58 (IH, m).

4.79 (IN, m).

7.91 (IH, d, J=7.0Hz).

Example 8゜(±)-1-[(1β, 2β, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-5
-Methyl-2,4(IH,3H)-pyrimidinedione (
Manufacturing process of compound 9) 1゜(±)-1-[(1β, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-5-methyl-2,4 (IH, 3H
)-Production of pyrimidinedione Oxalyl chloride (205u
l, 2.4 mmol l) of anhydrous tetrahydrofuran (5
After gradually adding dimethyl sulfoxide (341μ1.4.8mmol) to the solution (ml) at -'78°C, -
The temperature was raised to 35°C, and the mixture was stirred at the same temperature for 5 minutes. The reaction solution was cooled again to -78°C, and (±)-1-[(1β, 2α, 3
β)-3-t-butyldiphenylsilyloxymethyl-
2-Hydroxycyclobutan-1-ylcolola-methyl-2,4(IH,3H)-pyrimidinedione (929m
g.

2.0 mmol) of anhydrous tetrahydrofuran (2 ml
) After gradually adding the solution, the temperature was raised to -35°C and stirred for 15 minutes. The reaction solution was further cooled to -78°C, triethylamine (1.4 ml, 10 mmol) was added, and the mixture was heated to -35°C and stirred for 15 minutes. The reaction solution was cooled to -78°C, a solution of lithium tri(t-butoxy)aluminum hydride (2.54 g, 10 mmol) in anhydrous tetrahydrofuran (10 ml) was added, and the temperature was gradually raised to room temperature while stirring. Add 0.2M phosphate buffer (pH 7.0) and methylene chloride to the reaction solution, remove insoluble matter, and then extract with methylene chloride. The extract is
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 4: 1 (v/v)) to give (±)-1-[(1β, 2β, 3β)-3-
t-Butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-ylcolola-methyl-2,4(
IH, 38)-pyrimidinedione (382 mg.

41%).

NMR (400Mtlz・FT, CDCl2) δ
:1.08 (9M, S).

1.90 (3H, s).

2.32 (IH, m).

2.37-2.50 (2H, m).

3.32 (IH, m).

3.80-3.95 (2H, m).

4.68-4.77 (2H, m).

7.22 (Ill, S).

7.35-7.50 (6H, m).

7.67 (4H, dd, J: 1.8) 1z, J=6.
2tlz).

Step 2゜(±)-1-[(1β, 2β, 3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-yl2 5
-Methyl-2,4(IH,3H)-pyrimidinedione (
Production of compound 9) (±)-1-[(1β, 2β, 3β)
-3-t-butyldiphenylsilyloxymethyl-2-
Hydroxycyclobutan-1-yl-5-methyl-2
,4(IH,3H)-pyrimidinedione (90 mg, 0
．． 19 mmol) was dissolved in methanol (1 ml), 4N-hydrochloric acid/dioxane (0.1 ml 1.0
．． 4 ml) and stirred at room temperature overnight. After distilling off the solvent under reduced pressure, the reaction solution was purified with Sephadex LH-20 (methanol) after removing the ether-soluble portion.±)-1
−[(1β.

2β,3β)-2-hydroxy-3-hydroxymethylcyclobutan-1-ylco-5-methyl-2,4(IH
,3H)-pyrimidinedione (compound 9) (43mg,
98%).

NMR (400MH2・FT, CD30D) δ:1
．． 89 (3H, s).

2.29-2.48(3)1. m).

3.62 (lH, dd, J=4.9Hz, J=10.8
tlz).

3.80 (IH, dd, J=6.8Hz, J=1
0.8Hz).

4.58(l)I,m).

4.71 (IH, m).

7.53 (IH, s).

Example 9゜(±)-1-[(1β, 2α, 3β)-2-azido-3
-Hydroxymethylcyclobutan-1-ylcola-fluoro-2,4(IH,3H) -pyrimidinedione (
Manufacturing step 16 of compound 12) (±)-1-[(1β, 2β, 3β)-3-butyldiphenylsilyloxymethyl-2-methanesulfonyloxycyclobutan-1-ylcola-fluoro-2,
Preparation of 4(IH,3H)-pyrimidinedione (±)-1-[(1β,2β,3β)-3-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl]-5-fluoro- 2,4(IH,3
H)-pyrimidinedione (94 mg, 0.20 mmo
1) and triethylamine (50 μl, 0.36 mmo
To a solution of 1) in anhydrous methylene chloride (1 ml) was added methanesulfonyl chloride (23 μl.0.30 ml) under water cooling.
mol) and stirred at the same temperature for 30 minutes. Furthermore, triethylamine (83 μm, 0.60 mmol) and methanesulfonyl chloride (23 μm, 0.3
0 mmol) and stirred for 1 hour. 0゜2M to the reaction solution
- Add phosphate buffer (pH 7,0) and extract with methylene chloride. The extract is dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 20:
1 (V/V)) ±)-1-[:(1β,
2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-methanesulfonyloxycyclobutane-1
-Ylcola-fluoro-2,4(IH,3H)-pyrimidinedione (36 mg, 33%) is obtained.

Step 2゜(±)-1-[(1β, 2α, 3β)-2-azido-3
-t-butyldiphenylsilyloxymethylcyclobutane, -1-yl]-5-fluoro-2,4(IH,3H
)-pyrimidinedione and (±)-1-[(1β,2
α,3β)-2-azido-3-hydroxymethylcyclobutan-1-yl]-5-fluoro-2,4(18,3
Preparation of H)-pyrimidinedione (compound 12) In an argon atmosphere, (±)-1-[(1β, 2β, 3
β)-3-t-butyldiphenylsilyloxymethyl-
2-methanesulfonyloxycyclobutan-1-yl]
-5-Fluoro-2,4(IH,3H)-pyrimidinedione (75 mg, 0°14 mmol) and dry sodium azide (90 mg, 1.4 mmol)
Anhydrous dimethylformamide (2 ml) solution of 110
Stir at ℃ for 7 hours. Add water to the reaction solution and extract with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 15: 1 (v/v)).
(1β,2α,3β)-2-azido-3-t-butyldimethylsilyloxymethylcyclobutan-1-ylco-5-fluoro-2,4(IH,3H)-pyrimidinedione (15 mg).

22%).

NMR (400MH2・FT, CDCl5) δ: 1.1
1 (9H, s).

1.97 (IH, m).

2.22-2.35 (2H, m).

3.72 (IH, dd, J=3.3) IZ, J-11,
4Hz).

3.87 (1, H, dd, J=2.6Hz, J=11.
4Hz).

3.95 (IH, apparent t, J=7.7)
1z).

4.68 (IH, m).

7.30 (IH, d, J=5.5Hz).

7.32-7.50 (6H, m).

7.57-7.72(4)1. m).

8.72 (ILbr).

The aqueous layer subjected to the previous extraction is further extracted continuously for one day with methylene chloride. The methylene chloride extract was purified by silica gel preparative thin layer chromatography (methylene chloride: methanol = 15: 1 (v/v)), and purified with (±')
-1-[(1β,2α,3β)-2-azido-3-hydroxymethylcyclobutan-1-yl]-5-fluoro-2,4(18,3H)-pyrimidinedione (compound 1
2) (4.8 mg, 14%) is obtained.

NMR (400M) Iz・FT, CDCl5) δ: 2.
03 (IH, apparent Ql:9.6H2)1
2.26-2.45 (2tl, m).

3.74 (IH, dd, J=3.8Hz, J=11.0
)1z).

3.87 (IH, dd, J=3.3112.J=11.
0H2).

4.55 (IH, brs).

4.57-4.70 (2H, m).

7.40 (IILd, J=5.9)12).

8.23 (ltl,brd).

IR (KBr) cm-1: 2110° Example 10° (±)-1-[(1β, 2α, 3β)-2-azido-3
-Production process of hydroxymethylcyclobutan-1-yl-5-methyl-2,4(IH,3H)-pyrimidinedione (compound 13) 1°(±)-1-[(1β, 2β, 3β)-3-t -butyldiphenylsilyloxymethyl-2-methanesulfonyloxycyclobutan-1-ylco-5-methyl-2
, 4(IH,3H)-Preparation of pyrimidinedione (±)-1-[(1β, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-hydroxycyclobutan-1-yl-5-methyl-2 ,4(IH,3H
)-pyrimidinedione (300mg, 0.65m
mo 1 ) and triethylamine (0.5 ml 1.3.
．． To a solution of 6 mmol of anhydrous methylene chloride (5 ml) was added methanesulfonyl chloride (150 mg) under water cooling.
, 1.3 mmol) in methylene chloride (1 ml) and stirred at the same temperature for 30 minutes. Furthermore, equal amounts of triethylamine and methanesulfonyl chloride were added and stirred for 1 hour. Add 0.2M phosphate buffer (pH 7.0) to the reaction solution.
) and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 3:1 (v/v)).
)-1-[(1β.

2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-methanesulfonyloxycyclobutane-1
-yl]-5-methyl-2,,4(IH,3H)-pyrimidinedione (184 mg, 53%) is obtained.

Step 2゜(±) -1-[(1β, 2α, 3β)-2-azido-
3-t-Butyldiphenylsilyloxymethylcyclobutan-1-yl-5-methyl-2゜4(IH,3H)
- Production of pyrimidinedione In an argon atmosphere, (±)
-1-[(1β, 2β, 3β)-3-t-butyldiphenylsilyloxymethyl-2-methanesulfonyloxycyclobutan-1-yl]-5-methyl-2,4(IH
.

3H)-pyrimidinedione (25mg, 46μmof)
and dry sodium azide (15 mg.

230 μmol) of anhydrous dimethylformamide (1 ml
) The solution is stirred at 110°C for 10 hours.

Add water to the reaction solution and extract with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1 (v/v)
)) to purify it with ±) -1-[(1β, 2α, 3β)-
2-azido-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-methyl-2,4(
IH,3H)-pyrimidinedione (16mg, 71%)
get.

NMR (400MHz-FT, CDCl3) δ: 1.1
2(9)1. s).

1.90 (3H, s).

2.04 (iH, m).

2.18-2.34 (2H, m).

3.72 (IH, dd, J=2.911z, J=11.
4Hz).

3.83(1)1, dd, J=2.2Hz, J=1
1.4Hz).

4.03(iH,t,J=7.'7)1z).

4.75(I)1. Q, J=8.8H2).

7.08 (1N, s).

7.33-7.51(6)1. m).

7.65 (4H, m).

8.72 (IH, br).

Step 3゜(±)-1-[(1β, 2α, 3β)-2-azido-3
-hydroxymethylcyclobutan-1-yl]-5-methyl-2,4(IH,3H)-pyrimidinedione (compound 13) production (±)-1-[(1β, 2α, 3β)-2-azido- 3
-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-methyl-2゜4(IH,3H)-
Pyrimidinedione (111 mg, 0.23 mmo
1) in methanol (1 ml),
4N-hydrochloric acid/dioxane (0°15m 1.0.6
mmol) and stirred at room temperature overnight. The reaction solution is
After distilling off the solvent under reduced pressure, remove the ether-soluble portion and purify with Sephadex LH-20 column chromatography (methanol).±)-1-[(1β, 2α, 3β)
-2-azido-3-hydroxymethylcyclobutane-1
-yl2-5-methyl-2,4(IH,3H)-pyrimidinedione (compound 13) (58 mg, quantitative) is obtained.

NMR (400MHz・FT, CDCl5) δ: 1.9
4(3)1. S).

2.08(1)1. m).

2.22-2.40(3)1. m).

3.74 (IH, dd, J=4.0Hz, J=11.4
Hz).

3.86 (IH, dd, J=3.3Hz, J=11.4
Hz).

4.14(1)1. apparent t, J=7.7
Hz).

4.55(l)1. Apparent Q, J: 8.9
H2).

7.11 (IH, s).

9.09(II(,b'').

IR (neat) cm-1:2120゜Example 11゜(Sat)-1-[(1β, 2α, 3β)-2-amino-3
-Hydroxymethylcyclobutan-1-yl2-5-fluoro-2,4(IH,3H) -pyrimidinedione (
Manufacturing process of compound 16) 1゜(±)-1-[(1β, 2α, 3β)-2-amino-3
-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-fluoro-2,4(IH,3H)
-Production of pyrimidinedione (±) -1-[(1β, 2α
, 3β)-2-azido-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl2-5-fluoro-2,4(IH,3H)-pyrimidinedione (14m
g, 28 amol) in methanol (1 ml
), 10% palladium on carbon (3 mg) was added thereto, and the mixture was stirred for 24 hours in a hydrogen stream. The reaction solution was filtered to remove the catalyst, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1).
(v/v)) ±”)-1-[(1β, 2α
, 3β)-2-amino-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl2-5-fluoro-2,4(IH,3H)-pyrimidinedione (7,2
mg.

Ru.

NMR (400MHz・FT, CDCl2) δ:t
, to (9u, s).

1.72 (IH, apparent q, J=lO, I
Hz).

1.90 (IH, m).

2.20 (IH, apparent Q, J=8.9H
2).

2.75-3.50 (2) 1. br).

3.36 (IH, apparent t, J=8.3
)1z).

3.72 (IH, dd, J: 3.8Hz, J: 11.0
Hz).

3.83 (IH, dd, J: 3.3) 1z, J=11.
01(z).

4.42 (III, m).

7.30-7.50 (68, m).

7.35 (IN, d, J=5.982).

7.50-7.75 (4)1. m).

54%) obtained in step 2゜(±)-1-[:(1β, 2α, 3β)-2-amino-
3-Hydroxymethylcyclobutan-1-yl]-5-
Preparation of fluoro-2,4(IH,3H)-pyrimidinedione (compound 16) (±)-1-[(1β,2α,3
β)-2-amino-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl-5-fluoro-
2,4(IH,3H)-pyrimidinedione (7 mg, 1
5 μmol) was dissolved in methanol (1 ml), and 4N-hydrochloric acid/dioxane (0°1 ml, 0.4 mm
ol) and stirred at room temperature overnight. After distilling off the solvent under reduced pressure, the reaction solution was purified by Sephadex LH-20 column chromatography (methanol) after removing the ether-soluble portion.
Amino-3-hydroxymethylcyclobutan-1-yl]-5-fluoro-2,4(IH,3H)-pyrimidinedione hydrochloride (Compound 16) (4 mg.

quantitative).

NMR (400MH2-FT, CD30D) δ: 2.
10 (IH, apparent q, J=9.6Hz)
.

2.3C12,52 (2H, m).

3.56-3.78 (3H, m).

4.56 (IH, apparent q, J=8.5H
z).

7.79 (IH, d, J=6.382).

Example 12゜(±'')-1-[(1β, 2α, 3β)-2-amino-
3-Hydroxymethylcyclobutan-1-yl]-5-
Production process of methyl-2,4(IH,3H)-pyrimidinedione (compound 17) 1°(±)-1-[(1β, 2α, 3β)-2-amino-3
-t-butyldiphenylsilyloxymethylcyclobutan-1-yl-5-methyl-2゜4(IH,3H)-
Production of pyrimidinedione (±)-1-[(1β, 2α,
3β)-2-azido-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-methyl-
2°4(IH,3H)-pyrimidinedione (12 mg.

Dissolve 25 μmol) in methanol (2 ml) to give 10%
Add palladium on carbon (2 mg) and stir in a hydrogen stream for 10 hours. The reaction solution was filtered to remove the catalyst, the solvent was distilled off, and the residue was purified using silica gel column column chromatography (methylene chloride: methanol = 20:1 (v/v)).
-1-[(1β,.

2α, 3β)-2-amino-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-methyl-2,4(IH,3H)-pyrimidinedione (10
mg, 88%).

NMR (400 Ml (z-FT, CDCl5) δ: 1.
08 (9H, S).

1.90 (3H, s).

2.32(1)1. m).

2.38-2.52 (214, m).

3.32 (IH, m).

3.85-3.95 (2 tl, m).

4.66-4.78 (2H, m).

7.22 (IH, S).

7.33-7,49(6)1. m).

7.67(4)1. dd, J=1.8Hz, J=8.2
)1z).

Step 26 (±')-1-[(1β, 2α, 3β)-2-amino-
3-Hydroxymethylcyclobutan-1-yl]-5-
Preparation of methyl-2,4(IH,3H)-pyrimidinedione (compound 17) (±)-1-[(1β, 2α, 3β)-2-amino-3
-t-butyldiphenylsilyloxymethylcyclobutan-1-yl2-5-methyl-2゜4(IH,3H)-
Pyrimidinedione (10 mg.

To a solution of 22 μmol) dissolved in methanol (1 ml) was added 4N-hydrochloric acid/dioxane (0.1 ml).
．． 4 mmol) and stirred at room temperature overnight. After distilling off the solvent under reduced pressure, the reaction solution was purified by Sephadex LH-20 column chromatography (methanol) after removing the ether-soluble portion.
, 3β)-2-amino-3-hydroxymethylcyclobutan-1-yl-5-methyl-2,4(IH,3H)
-Pyrimidinedione hydrochloride (compound 17) (7 mg, quantitative) is obtained.

NMR (400MH2・FT, CD30D) δ:1
．． 94 (311,9).

2.17 (IH, Q, J=9.0F12).

2.40-2.60 (2H, n+).

3.63(1)1. m).

3.65-3.85(2)1, m).

4.57 (IH, Q, J: 8.5H2).

7.43 (IH, s).

Example 13゜1-[(1β,3β)-3-hydroxymethylcyclobutan-1-yl]-5-methyl-2,4(IH,3H)
-Preparation of pyrimidinedione (compound 21) In an argon atmosphere, (1α, 3β)-3-t-butyldiphenylsilyloxymethyl-1-methanesulfonyloxycyclobutane (126 mg).

0.3 mmol) in dimethylformamide (3 ml)
Add bistrimethylsilyl-5-methyluracil (325 mg, 1.2 mmol I) and stir at 120° C. overnight. Add 0.2M phosphate buffer (pH
7-0) and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol = 50:1 (v/v)) to obtain crude 1-[(1β , 3β)-3-t-butyldiphenylsilyloxymethylcyclobutan-1-yl]-5-methyl-2,4(IH,3H)-pyrimidinedione (40
m g ) is obtained.

This was added to a solution of 4N in methanol (1 ml).
- Hydrochloric acid/dioxane (0.2ml 1.0°8mmol)
and stir overnight at room temperature. After distilling off the solvent under reduced pressure, the reaction solution was subjected to preparative reverse-phase high performance liquid chromatography (OD3.5%-acetonitrile aqueous solution) and Sephadex LH-20 column chromatography (methanol). Separate and purify 1-[(1β,
3β)-3-Hydroxymethylcyclobutan-1-yl2-5-methyl-2,4(IH,3H)-pinomidinedione (compound 21) is obtained.

Example 14゜(±)-(1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0]pentane (compound e) and (±)-(1β, 2β
, 4β)-2-t-Butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1,0]pentane (compound l) Production of 1-t-butyldiphenylsilyloxymethyl-2-cyclobutene (6,45 g, 20 mmol)
and 2-benzenesulfonyl-3-(4-nitrophenyl)oxatiridine (X m) (F, A, Davis
etal,, Tetrahedron Lett,,
22.917 (1981)) (7.35g, 24mm
ol) in anhydrous acetonitrile (100 ml) and stirred at 60° C. for 4 days in an argon atmosphere. After cooling, acetonitrile was removed under reduced pressure, and the residue was extracted with hexane. After concentration, the hexane extract was subjected to silica gel column chromatography (methylene chloride:hexane = l:3
Subsequently, the unreacted raw material (2.15 g, 33% recovery), (±)-(1α) was separated and purified using a ratio of 1:2 (v/v).

2β,4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1,0 coventane(
Compound e) (1,93g, 29%) and (±)-(1β
, 2β, 4β)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1,0 coventane (compound 1) (0°71 g, 10%) is obtained.

(Compound e) NMR (400MHz-FT, CDC13) δ: 1.0
7(9)1. S).

1.66 (H, dd, J=3.7Hz, J=12.1H
z).

1.83 (H, ddd, J=2.6Hz, J=5.1H
z, J: 12.1Hz).

2.32 (H, m).

3.70 (H, dd, J=8.4Hz, J=10.6H
z).

3.79()1. m).

3.82-3.88 (2H, m).

7.34-7.47 (6H, m).

7.60-7.72 (4JI, m).

(Compound 1) NMR (400MH2-FT, CDCl5) δ: 1.0
6 (9B, s).

1.36 (IH, dt, J=12.1Hz, J=3.6
Hz).

2.08 (IH, dd, J=9.2Hz, J=I2.1
)1z).

2.63 (IN, m).

3.45 (IH, dd, J=6.4Hz, J=10.4
Hz).

3.72-3.82 (2H, m).

3.84 (IH, m).

7.33-7.45 (6tl, m).

7.67 (4H, apparent t, J=7.5H
z).

Example 15°(±)-(1α, 2β, 4α)-2-benzoyloxymethyl-5-oxabicyclo[2,1,0]pentane (Compound C) and (±)-(1β, 2β.

Method for producing 4β)-2-benzoyloxymethyl-5-oxabicyclo[2,1,0]pentane (compound j) 1゜1- t-Butyldimethylsilyloxymethyl-2-
Cyclobutene (1,0 g, 5.0 mmol) and 2-benzenesulfonyl-3-(4-nitrophenyl)oxatiridine (XIII) 2. '3 g (
7°5 mmol) was added to anhydrous acetonitrile (25 ml) and stirred at 60° C. for 2 days in an argon atmosphere. After cooling, acetonitrile was removed under reduced pressure, and the residue was extracted with pentane. After distilling off the solvent under reduced pressure, the pentane extract was dissolved in anhydrous tetrahydrofuran (25 ml) and IM
-Tetrabutylammonium fluoride/tetrahydrofuran (6°Oml, 6.0mmol) was added and stirred at room temperature for 1 hour. 0.2M phosphate buffer)α(
After adding saturated salt (pH 7.0), dilute the solution with methylene chloride-methanol (4:1 (v/v)) mixed solvent.
Extract 0 times. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the extract was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1 (v/
v, )) to obtain 210 mg (42%) of 2-hydroxymethyl-5-oxabicyclo[2,1,0]bentane (mixture of compound a and compound ri). This compound was dissolved in anhydrous pyridine (2 ml), water-cooled, benzoyl chloride (0.37 ml, 1.3.2 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Add water to the reaction solution and extract with ether. The ether extract was washed successively with an aqueous IM-sulfuric acid solution, water, and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. This product can be used for silica gel column chromatography (methylene chloride:hexane=
1:1 (v/v)), and (±)-(1α
, 2β, 4α)-2-benzoyloxymethyl-5-oxabicyclo[2°1.0]-pentane (compound C) (2
68mg.

total yield 26%) and (±)-(1β, 2β.

4β)-2-benzoyloxymethyl-5-oxabicyclo[2,1,0 copentane (compound j) (76 mg,
total yield of 7%).

(Compound C) NMR (400 Ml (2·FT, CDCl5) δ: 1.
82 (IH, ddd, J: 1.8Hz, J: 4.6Hz
, J=12.0)1z).

2.04 (lit, ddd, J=2.8Hz, j:5.
6t(z, J=12.0)lz).

2.55 (H, m).

3.91 (H, m).

3.97 (H, t, J=2.882).

4.39 (H, dd, J=9.0Hz, J=11.7t
lz).

4.55 (H, dd, J=6.0Hz, J=11.7H
z).

7.46 (2H, t, J=8.1Hz).

7.59 (IH, apparent t, J=8.1H
z).

8.05(IH,apparent d,,I:8.I
Hz).

(Compound j) NMR (400M) 12-FT, CDCl5) δ: 1.
62 (IH, dt, J=12.1flz, J=3.6H
z).

2.29 (IH, dd, J=9.582. J=12
．． 1Hz).

2.86 (IH, m).

3.88 (LH, m).

3.92 (IH, m).

4.21 (IH, dd, J=6.5Hz, J=12.
IH2).

4.39 (ltl, dd, J: 8.9) 1z, J=12
．． 1Hz).

7.44 (2H, t, J=8.2)12).

7.56(l)I,apparent t,J=8.2
Hz).

8.04 (IH, apparent d, J=8.2H
z).

Method 2゜1-Hydroxymethyl-2-cyclobutene (252 mg
, 3. 0 mmol) was dissolved in anhydrous methylene chloride (1
5 ml) of 80% m-chloroperbenzoic acid (777 mg, 3.6 mm) under water cooling.

1) and stirred at 0°C for 3 hours. A 10% aqueous sodium bisulfite solution and a 10% aqueous potassium carbonate solution are added to the reaction solution, and the mixture is extracted 10 times with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent is distilled off to obtain a crude product. This was prepared according to method 1 by benzoyl chloride (
0,52ml 1゜4.5mmol) and anhydride and lysine (3
ml) and then separated and purified, (±)
-(1α, 2β, 4α)-2-benzoyloxymethyl-
5-Oxabicyclo[2,1,0 copentane (compound c) (67 mg, 11%) and (±)-(1β,2
β, 4β)-2-benzoyloxymethyl-5-oxabicyclo[2,1,0]pentane (compound j) (180 m
g, 29%).

[Reference Example 1 Production process of (1α, 3β)-3-t-butyldiphenylsilyloxymethyl-1-methanesulfonyloxycyclobutane Production of (1α, 3β)-3-hydroxymethylcyclobutanol (±)-( 1α, 2β, 4α)-2-t-butyldiphenylsilyloxymethyl-5-oxabicyclo[2,1
,0 Copentane (Compound e) (3゜00g, 7.1
7 mmol) was dissolved in tetrahydrofuran (1.0 ml), and IM-tetrabutylammonium fluoride/
Tetrahydrofuran (8.6 ml, 8.60 mmol
) and stirred at room temperature for 3.5 hours. After concentrating the reaction solution, add water to dissolve and wash with hexane. The aqueous layer is continuously extracted with ether for one day. The ether extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (24 ml) and diluted to 70%
-Sodium bis(2-methoxyethoxy)aluminum hydride (4,1,3 g.

A solution of 14.3 mmol (14.3 mmol) dissolved in 8 ml of tetrahydrofuran was added dropwise onto a water-cooled plate, and the mixture was stirred at room temperature for 7 hours. Isopropyl alcohol is added to the reaction solution, and after stirring for a while, insoluble matter is filtered off.

The solvent of the filtrate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20:
1 (v/v)) and separated and purified, (1α, 3β)
-3-hydroxymethyl-cyclobutanol (0,66
g, 90%).

Step 2゜Production of (1α, 3β)-3-) lytyloxymethylcyclobutanol (1α, 3β)-3-hydroxymethylcyclobutanol (660 mg, 6.5 mmol) was added to pyridine (5 ml).
>, and under water cooling, add trityl chloride (2.16g
, 7.75 mmol) and stirred overnight at room temperature.

The reaction solution is concentrated to remove pyridine, and the residue is separated and purified by silica gel column chromatography (methylene chloride) to obtain crude (1α, 3β)-3-trityloxymethylcyclobutanol (898 mg, 40%).

Step 3 Preparation of (1α, 3β)-3-t-butyldiphenylsilyloxymethyl-1-methanesulfonyloxycyclobutane The crude (1α, 3β)-3-)lythyloxymethylcyclobutanol (890 mg, 2.6 mmol) ) was dissolved in methylene chloride (10ml), and under water cooling, triethylamine (1.08mf, 7°76mmol) and methanesulfonyl chloride (445mg, 3.88mmol) were dissolved in methylene chloride (10ml).
mmol) and stir for 30 minutes. 0.0% to the reaction solution.
Add 2M phosphate buffer (pH 7.0) and extract with ether.

After drying the ether extract with anhydrous sodium sulfate,
The solvent is distilled off under reduced pressure. The residue was dissolved in methanol (10 ml
) and Amberlyst15 (529 mg,
2.6 mmol) and stirred at room temperature overnight. After filtering the reaction solution to remove insoluble matter, the solvent is distilled off under reduced pressure. The residue was dissolved in dimethylformamide (8 ml), and triethylamine (1.08 ml, 7.76 mmol) was added under water cooling.
l), and t-butyldiphenylchlorosilane (1
,07g.

3.88 mmol) and stirred overnight. Add water to the reaction solution and extract with ether. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ether=
3: i (v/v)), separated and purified by (1α, 3
β)-3-t-butyldiphenylsilyloxymethyl-
1-methanesulfonyloxycyclobutane (720 mg
, 66%).

Between R(CDCl2)δ: 1.08 (9H, S).

2.34-2.48 (4H, m).

2.53 (IH, m).

2.96 (311, s).

3.65(2)1. d, J=4.8)12).

5.16 (1N, m).

7.37-7.49 (6H, m).

7.65 (4H, d, J=6.282).

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A represents hydrogen, a hydroxyl group, an azide group, or an amino group, and B represents the ▲mathematical formula , chemical formulas, tables, etc. ▼ (where X represents a hydrogen atom, halogen atom, or lower alkyl group) or ▲ numerical formulas, chemical formulas, tables, etc. ▼ ] Cyclobutane derivatives 2, General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) [In the formula, R represents a hydrogen atom or a protective group] Cyclobutane derivatives represented by.