JPH0680670A - Cyclopropane derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antiviral agent. CONSTITUTION:The compound of formula I [B<1> is protected purine derivative residue; R<1> is (substituted) alkoxymethylene or two R<1> together form a (substituted) methylene to form a ring], e.g. 4,4-dimethyl-3,5- dioxabicyclo[5,1,0]octyl-1-methanol. The compound of formula I can be produced by reacting a compound of formula II (X<1> is eliminable group) with a compound of the formula B<1>-H.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cyclopropane derivative which can be used for producing a compound useful as an antiviral agent. Further, the present invention relates to a method for producing such a derivative and an intermediate useful for the production.

[0002]

The present inventors have previously found that the compound represented by the following chemical formula 4 has a strong antiviral activity (Japanese Patent Application No. 4-47178).

[Chemical 4] (In the formula, B ² represents a purine derivative residue.)

[0003]

However, a method for efficiently and simply producing the present compound has not been established, and its development has been desired.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the use of the novel cyclopropane derivative represented by the following Chemical formula 5 makes it easy to obtain the compound of Chemical formula 4 They have found that they can lead to compounds, and have completed the present invention based on this finding.

[0005]

[Chemical 5] (Wherein B ¹ represents a protected purine derivative residue,
R ¹ represents an optionally substituted alkoxymethylene group or an optionally substituted methylene group in which two are taken together to form a ring. )

As the B ^{1 in the} chemical formula 5, for example, the following may be mentioned.

[Chemical 6] (In the formula, Y represents a halogen atom and R ² represents an acyl group.)

[0007]

[Chemical 7] (In the formula, R ³ represents an acyl group, and R ⁴ and R ⁵ each represent an alkyl group or an aryl group.)

[0008]

[Chemical 8] (In the formula, R ⁶ represents an acyl group, and R ⁷ represents an aralkyl group or a substituted alkyl group.)

A particularly preferred example of B ¹ is 2-
Amino-6-chloropurin-9-yl, 2-acetamino-6-chloropurin-9-yl, 2-acetamino-
6- (N, N-diphenylcarbamoyl) oxypurin-9-yl, 2-amino-6-benzyloxypurine-
9-yl or 2-amino-6- (methoxyethoxy)
Purin-9-yl and the like can be mentioned.

Examples of the alkoxymethylene group which may be substituted include a tetrahydropyranyl group, a methoxymethyl group, a methoxyethoxymethyl group and the like, and a methylene group formed by combining two of them is a methylene group, Examples thereof include an isopropylidene group, a cyclohexylidene group, a diphenylmethylene group and the like.

The compound (I) can be produced from the compound (II) by the method shown below.

[0012]

[Chemical 9] (In the formula, X ¹ is a leaving group, and R ¹ and B ¹ are the same as above.)

In the compound (II), X ¹ is a hydroxyl group; halogen such as chlorine atom, bromine atom or iodine atom;
Examples thereof include sulfonyloxy groups such as paratoluenesulfonyloxy group and methanesulfonyloxy group.

In the above reaction, when X ¹ is a leaving group other than a hydroxyl group, it is ¹ to 3 equivalents, preferably ¹ to 1.1, relative to B ¹ .
Using 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents of compound (II) in the presence of an equivalent amount of a base, 0 to 80 ° C. in a polar solvent such as dimethylformamide, acetonitrile and tetrahydrofuran. , 1 to 72 hours. At this time, crown ether may be added to accelerate the reaction.

When X ¹ is a hydroxyl group, it is present in the presence of a condensing agent such as a combination of triphenylphosphine and azodicarboxylate, at -30 to 50 ° C, preferably -20 to 3
The reaction may be performed at 0 ° C for 1 to 72 hours.

The compound (II) which is a reaction raw material can be prepared as follows.

[Chemical 10] (In the formula, R ⁸ represents a lower alkyl group, and B ¹ , B ² ,
R ¹ and X ² are the same as above. )

Compound (III) can be prepared by the method described in the literature in the presence of a base such as sodium alkoxide [Hel
v. Chim. Acta, 72, 1301 (1989)], it can be obtained by reacting a dialkyl malonate with epichlorohydrin. At this time, if optically active epichlorohydrin is used, the optically active compound (III)
Is obtained, and the compound (I
I) can be further led to compound (I).

By selectively reducing the lactone of compound (III) with a reducing agent such as sodium borohydride, the diol of (IV) is obtained. As the reaction conditions at this time, 0.5 to 1.0 equivalent of sodium borohydride with respect to compound (III) is used, and the temperature is 0 ° C. to 50 ° C., preferably 10 to 40 in a solvent such as methanol or ethanol.
The reaction is carried out at a temperature of 1 to 12 hours, preferably 2 to 3 hours.

Next, the hydroxyl group of the diol (IV) is protected to obtain (V). The protective group here needs to be stable under the subsequent reduction and basic conditions, but the stability of (II-1) or (II-2), which is a more unstable three-membered ring compound, and ( Efficient removal of I) is required. The inventors of the present invention have combined two groups such as an optionally substituted alkoxymethylene group such as a tetrahydropyranyl group, a methoxymethyl group and a methoxyethoxymethyl group or a methylene group, an isopropylidene group, a cyclohexylidene group and a diphenylmethylene group. It was found that the ring-forming methylene group was a protecting group satisfying these conditions.

This protecting group can be introduced by a conventional method. For example, in the case of an isopropylidene group, 2 to 10 equivalents, preferably 2 to 3 equivalents of dimethoxypropane are 0.002 to 0.1 equivalents, preferably 0.005-0.
It can be carried out by treating at room temperature in a solvent such as dimethylformamide or benzene in the presence of an acid catalyst such as 02 equivalent of hydrochloric acid or paratoluenesulfonic acid. In the case of a diphenylmethylene group, it can be similarly achieved by using benzophenone or its ketal under the acid catalyst as described above, but in a solvent such as dichloromethane or dichloroethane, 1 to 2 equivalents, preferably 1 to 1.2 equivalents. Equivalent of diphenyldiazomethane and 1-2 equivalents, preferably 1-1.2 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at 0 ° C-50 ° C, preferably 10-30 ° C. It can also be achieved by treating for 1 to 10 hours, preferably 1 to 3 hours.

The resulting ester (V) is reduced with a suitable reducing agent such as sodium borohydride, lithium borohydride and lithium aluminum hydride to give alcohol (I
I-1) is obtained. This reduction reaction is performed with diethyl ether,
It may be carried out using 1 to 3 equivalents, preferably 1 to 1.5 equivalents of a reducing agent in a solvent such as tetrahydrofuran. The reaction time and temperature may vary depending on the reducing agent used, but are 0 ° C to 8
The reaction is carried out at 0 ° C. for 1 to 48 hours. For example, when lithium borohydride is used, the reaction may be carried out at 70 to 80 ° C. for 5 to 20 hours. When sodium borohydride is used, a solvent such as ethanol or methanol can also be used.

If necessary, the compound (II-1) can be converted into the compound (II-2) by converting the hydroxyl group into halogen or sulfonic acid ester. The halogenation method is carried out in the presence of trialkylphosphine or triphenylphosphine, carbon tetrabromide, carbon tetrachloride, bromine, N-
A method of using bromosuccinimide or the like or a method of using a halogenating agent such as phosphorus tribromide is preferable. When using triphenylphosphine-carbon tetrabromide,
Dichloromethane, dichloroethane, dimethylformamide, etc., using 1.1 to 3 equivalents, preferably 1.2 to 2 equivalents of triphenylphosphine and 1.1 to 100 equivalents, preferably 1.5 to 5 equivalents of carbon tetrabromide. In the solvent of
The reaction may be performed at 20 to 40 ° C, preferably 0 to 30 ° C for 5 minutes to 3 hours. In this case, the presence of a base such as triethylamine or pyridine in an amount of 0.1 to 2 equivalents gives better results.

The cyclopropane derivative represented by the chemical formula 5 (I) of the present invention can be deprotected to give the chemical formula 4 (VI) having a strong antiviral activity.

[Chemical 11] (In the formula, B ¹ , B ² and R ¹ are the same as above.)

At this time, the conditions may vary depending on the protective group used and may be one step or multiple steps, but it is desirable to carry out under weak acidic or weak base conditions in order to avoid side reactions.
For example, in (I), B ¹ is 2-acetamino-6-
(N, N-diphenylcarbamoyl) oxypurine-9
When -yl or R ¹ is an acetal-type protecting group, R is at 0 to 50 ° C., preferably room temperature, in a solvent such as methanol or ethanol with a catalytic amount of paratoluenesulfonic acid, hydrochloric acid or the like.
After removing ¹ , add ammonia water so that the final ammonia concentration becomes 8 to 20%, and add 10 to 80 at 0 to 50 ° C.
The compound of (VI) can be obtained by treating for 15 hours to 48 hours at room temperature. Also,
In (I), when B ¹ is 2-amino-6-chloropurin-9-yl and R ¹ is an acetal-type protecting group, 50 to 50
50 ° C to 120 ° C, preferably 70% in 100% formic acid
The compound of (VI) can be obtained in one step by reacting in 90 to 105% formic acid at 90 to 105 ° C.

The cyclopropane derivative shown in Chemical formula 5 and the compound as a precursor thereof include both a racemate and each optically active substance. As described above, if optically active epichlorohydrin is used, each optically active substance can be prepared by a method similar to the above operation. In addition, each intermediate or final product was subjected to optical resolution column chromatography,
It is also possible to divide by fractional crystallization with a diacytereomer salt.

Regarding the relative configuration of each compound, when cyclopropane is considered to be a plane, a substituent located below the plane is represented by α, and a substituent located above the plane is represented by β.

[0027]

INDUSTRIAL APPLICABILITY According to the present invention, a cyclopropane derivative having antiviral activity can be produced efficiently and easily.

[0028]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 Preparation of 4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octyl-1-methanol Step 1 3,3a, 4,4a-Tetrahydro-3-oxo-1H -Preparation of ethyl cyclopropa [c] furan-3a-carboxylate 2.42 g (105 mmol) of sodium metal were dissolved in 200 ml of ethanol at 0 ° C under an argon atmosphere.
To this, 16.7 mg (110 mmol) of diethyl malonate was added, and 7.8 ml (100 mmol) of epichlorohydrin dissolved in 5 ml of ethanol was added dropwise at room temperature. The solution was heated at 75 ° C for 20 hours, then cooled to 0 ° C and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (hexane: ethyl acetate = 5: 1 to 1: 1) to give 12.0 g (70 mmol, 7).
0%) of the title compound was obtained.

Colorless oil; ¹ H-NMR (CDCl ₃ ) δ: 1.31
(t, J = 7.1Hz, 3H), 1.37 (dd, J = 4.8,5.4Hz, 1H), 2.08 (dd, J =
4.8,8.0Hz, 1H), 2.72 (m, 1H), 4.18 (d, J = 9.6Hz, 1H), 4.27
(q, J = 7.1Hz, 2H), 4.36 (dd, J = 4.5,9.6Hz, 1H); FD MA
SS: 170 (M ⁺ ).

Step 2 Preparation of ethyl 1,2-bis (hydroxymethyl) cyclopropanecarboxylate 3,3a, 4,4a-tetrahydro-3-oxo-1H
12.0 g (70 mmol) of ethyl cyclopropa [c] furan-3a-carboxylate was dissolved in 200 ml of ethanol, and 2.0 g (53 mmol) of sodium borohydride was added. The solution was stirred at room temperature for 2 hours and then 27 ml of 2N hydrochloric acid and 100 ml of ethyl acetate were added. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained oily residue was subjected to silica gel chromatography (dichloromethane: methanol = 25: 1) to obtain 8.35 g (48
(69 mmol, 69%) of the title compound was obtained.

Colorless oil; ¹ H-NMR (CDCl ₃ ) δ: 0.76
(dd, J = 4.8,6.6Hz, 1H), 1.27 (t, J = 7.2Hz, 3H), 1.49 (dd, J =
4.8,9.0Hz, 1H), 2.05 (m, 1H), 3.23 (d, J = 12.8Hz, 1H), 3.33
(dd, J = 11.1,12,5Hz, 1H), 4.08 (dd, J = 5.1,12.5Hz, 1H), 4.1
7 (q, J = 7.2Hz, 2H), 4.52 (d, J = 12.8Hz, 1H); FD MAS
S: 175 (MH ⁺ ).

Step 3 Preparation of ethyl 4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octyl-1-carboxylate Ethyl 1,2-bis (hydroxymethyl) cyclopropanecarboxylate 8. 35 g (48 mmol) was dissolved in 100 ml of dimethylformamide, 60 mg of p-toluenesulfonic acid monohydrate and 12 ml of dimethoxypropane (100 mmo).
l) was added. After stirring at room temperature for 12 hours, water was added and the mixture was extracted with hexane-ethyl acetate (1: 1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain 4.99 g (23.3 mmol, 49%) of the title compound.

Colorless oil; ¹ H-NMR (CDCl ₃ ) δ: 1.28
(s, 3H), 1.2-1.3 (m, 2H), 1.37 (s, 3H), 1.41 (dd, J = 3.8,9.5H
z, 1H), 1.80 (m, 1H), 3.75 (d, J = 13.5Hz, 1H), 3.76 (d, J = 13.2
Hz, 1H), 4.05-4.21 (m, 3H), 4.62 (d, J = 13.5Hz, 1H); FD
MASS: 214 (M ⁺ ).

Step 4 Preparation of 4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octyl-1-methanol 4,4-dimethyl-3,5-dioxabicyclo [5,5]
1,0] Ethyl octyl-1-carboxylate 7.92 g
(37 mmol) was dissolved in 20 ml of dry tetrahydrofuran, 20 ml of 2M lithium borohydride tetrahydrofuran solution was added under an argon atmosphere, and the mixture was heated at 72 ° C. for 12 hours. After cooling to 0 ° C., a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, then the solvent was distilled off to obtain 4.07 g (23.6 mmol, 64%) of the title compound.

Colorless oil; ¹ H-NMR (CDCl ₃ ) δ: 0.67
(dd, J = 4.4,8.9Hz, 1H), 0.90 (dd, J = 4.4,5.8Hz, 1H), 1.06
(m, 1H), 1.28 (s, 3H), 1.38 (s, 3H), 3.45 (brs, 2H), 3.69 (dd,
J = 4.2,13.2Hz, 1H), 3.78 (d, J = 12.9Hz, 1H), 4.12 (dd, J = 5.
7,13.2Hz, 1H), 4.17 (dd, J = 12.9Hz, 1H); FD MAS
S: 173 (MH ⁺ ).

EXAMPLE 2 Preparation of 1-Bromomethyl-4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octane 3.08 g (17.8 mmol) of 4 obtained in Example 1 ，
4-dimethyl-3,5-dioxabicyclo [5,1,
0] octyl-1-methanol was dissolved in 100 ml of dimethylformamide and triphenylphosphine 8.4 g (3.2 mmol) and carbon tetrabromide 10.6 g (32 mm) were added at 0 ° C.
ol) was added and stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with hexane-ethyl acetate (1: 1), the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is chromatographed on silica gel (hexane: ethyl acetate = 1).
0: 1) gave 1.31 g (5.6 mmol, 31%) of the title compound.

Colorless oil; ¹ H-NMR (CDCl ₃ ) δ: 0.81
(d, J = 4.2,8.7,1H), 1.11-1.24 (m, 2H), 1.28 (s, 3H), 1.38
(s, 3H), 3.18 (d, J = 10.4Hz, 1H), 3.54 (d, J = 10.4Hz, 1H), 3.6
6 (dd, J = 3.9,13.2Hz, 1H), 3.80 (d, J = 12.9Hz, 1H), 4.11 (dd,
J = 5.3,13.2Hz, 1H), 4.14 (d, J = 12.9Hz, 1H).

Example 3 2-Amino-6-chloro-9-
Preparation of (4 ′, 4′-dimethyl-3 ′, 5′-dioxabicyclo [5,1,0] octyl-1 ′-) methylpurine 2-amino-6-chloropurine 204 mg (1.2 mmo
l), 166 mg (1.2 mmol) of potassium carbonate are dissolved in dimethylformamide, and 235 mg (1.0 mmol) of 1-bromomethyl-4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octane is dissolved. added. After stirring at 0 ° C. for 14 hours, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (dichloromethane: methanol = 19: 1) to give 239 mg.
(0.74 mmol, 74%) of the title compound was obtained.

Colorless solid; ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d
d, J = 4.7,9.2Hz, 1H), 1.06 (t, J = 5.4Hz, 1H), 1.24 (s, 3H), 1.
27 (m, 1H), 1.31 (s, 3H), 3.67 (d, J = 13.2Hz, 1H), 3.73 (dd, J =
13.2,3.9Hz, 1H), 3.95 (d, J = 13.2Hz, 1H), 3.95 (d, J = 14.9H
z, 1H), 4.03 (d, J = 14.9Hz, 1H), 4.17 (dd, J = 5.0,13.2Hz, 1
H), 5.10 (brs, 2H), 7.98 (s, 1H); FD MASS: 323
(M ⁺ ).

Example 4 2-Acetylamino-6-
(N, N-diphenylcarbamoyloxy) -9-
Preparation of (4 ′, 4′-dimethyl-3 ′, 5′-dioxabicyclo [5,1,0] octyl-1 ′-) methylpurine 2-Acetylamino-6- (N, N-diphenylcarbamoyloxy ) Purine 186 mg (0.48 mmol), potassium carbonate 66 mg (0.48 mmol), 18-crown-
6 (127 mg, 0.48 mmol) was dissolved in 8 ml of dimethylformamide, and 94 mg (0.4 mmol) of 1-bromomethyl-4,4-dimethyl-3,5-dioxabicyclo [5,1,0] octane in DMF was dissolved. 0.5 ml was added dropwise. After stirring at room temperature for 14 hours, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 19:
1) yielded 131 mg (60%) of the title compound.

Pale yellow solid; ¹ H-NMR (CDCl ₃ ) δ: 0.99
-1.08 (m, 2H), 1.23 (s, 3H), 1.29 (s, 3H), 1.31 (m, 1H), 2.54
(s, 3H), 3.65 (d, J = 13.5Hz, 1H), 3.71 (dd, J = 5.1,13.5Hz, 1
H), 3.93 (d, J = 13.5Hz, 1H), 4.02 (d, J = 14.4Hz, 1H), 4.12 (d,
J = 14.4Hz, 1H), 4.15 (dd, J = 5.1,13.5Hz, 1H), 7.2-7.5 (m, 10
H), 8.10 (brs, 1H), 8.14 (s, 1H); FD MASS: 542
(M ⁺ ).

Example 5 4,4-diphenyl-3,5-
Production of dioxabicyclo [5,1,0] octyl-1-methanol Step 1 Production of ethyl 4,4-diphenyl-3,5-dioxabicyclo [5,1,0] octyl-1-carboxylate 1, 250 ml of 2-dichloroethane, 6.81 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(30 mmol) was dissolved and 5.23 g (30 mmol) of ethyl 1,2-bis (hydroxymethyl) cyclopropanecarboxylate obtained in Step 2 of Example 1 and 5.83 g (30 mmol) of diphenyldiazomethane were added to 1,2 -A solution dissolved in 130 ml of dichloroethane was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. This solution was concentrated under reduced pressure and dissolved in toluene. The toluene solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (dichloromethane).
72 g (25.77 mmol, 85%) of the title compound were obtained.

Yellow oil; ¹ H-NMR (CDCl ₃ ) δ: 1.22
(t, J = 7.0Hz, 3H), 1.33 (dd, J = 3.6,7.1Hz, 1H), 1.43 (dd, J =
3.6,9.3Hz, 1H), 1.8 (m, 1H), 3.68 (d, J = 13.3Hz, 1H), 3.76 (d
d, J = 3.1,12.9Hz, 1H), 4.1 (m, 3H), 4.65 (d, J = 13.0Hz, 1H),
7.2-7.6 (m, 10H); FD MASS: 338 (M ⁺ ).

Step 2 Preparation of 4,4-diphenyl-3,5-dioxabicyclo [5,1,0] octyl-1-methanol 4,4-diphenyl-3,5-dioxabicyclo [5,5]
1,0] Ethyl octyl-1-carboxylate 7.01 g
(20.7 mmol) was dissolved in 10 ml of dry tetrahydrofuran, 12 ml of 2M lithium borohydride tetrahydrofuran solution was added under an argon atmosphere, and the mixture was heated at 72 ° C. for 16 hours. After cooling to 0 ° C., a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel chromatography (dichloromethane: methanol = 19: 1) to obtain 5.54 g (18.7 mmol, 90%) of the title compound.

White solid; melting point: 93 ° C .; ¹ H-NMR (CD
Cl ₃ ) δ: 0.67 (dd, J = 4.4,8.9Hz, 1H), 0.96 (dd, J = 4.4,5.8H
z, 1H), 1.08 (m, 1H), 3.42 (dd, J = 11.0,27.9Hz, 2H), 3.65 (d
d, J = 3.9,12.9Hz, 1H), 3.76 (d, J = 12.7Hz, 2H), 4.1 (m, 2H),
7.2-7.6 (m, 10H); FD MASS: 296 (M ⁺ ).

Example 6 Preparation of 1-bromomethyl-4,4-diphenyl-3,5-dioxabicyclo [5,1,0] octane 5 g (16.87 mmol) 4,4-diphenyl-3,5
-Dioxabicyclo [5,1,0] octyl-1-methanol was dissolved in 100 ml of 1,2-dichloroethane and 1.2 ml of triethylamine (8.4 mmo at room temperature).
l), triphenylphosphine 7.97g (30.4mmo
l) and 10.1 g (30.4 mmol) of carbon tetrabromide were added, and 2
Stir for 0 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to this, and the mixture was extracted with hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 5.45 g (1
(5.2 mmol, 90%) of the title compound was obtained.

Yellow oil; ¹ H-NMR (CDCl ₃ ) δ: 0.83
(dd, J = 4.2,8.5Hz, 1H), 1.16-1.28 (m, 2H), 3.13 (d, J = 10.2H
z, 1H), 3.60 (dd, J = 3.5,12.9Hz, 2H), 3.80 (d, J = 12.9Hz, 1
H), 4.07 (dd, J = 4.8,13.0Hz, 2H), 7.2-7.6 (m, 10H); FD
MASS: 358 (M ⁺ ).

Example 7 2-Amino-6-chloro-9-
Preparation of (4 ', 4'-diphenyl-3', 5'-dioxabicyclo [5,1,0] octyl-1 '-) methylpurine 2-amino-6-chloropurine 3.09 g (18.24 m
mol) and 2.52 g (18.24 mmol) of potassium carbonate are dissolved in dimethylformamide, and 1-bromomethyl-4,
4-diphenyl-3,5-dioxabicyclo [5,1,
0] Octane 5.45 g (15.2 mmol) was added. After stirring at room temperature for 14 hours, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (ethyl acetate), and 5.78 g (12.9 mmol,
(85%) of the title compound was obtained.

Pale yellow solid; ¹ H-NMR (CDCl ₃ ) δ: 0.98
(dd, J = 4.7,9.1Hz, 1H), 1.17 (t, J = 4.7Hz, 1H), 1.34 (m, 1H),
3.66 (d, J = 13.0Hz, 2H), 3.74 (d, J = 3.3Hz, 1H), 3.91 (d, J = 1
3.2Hz, 1H), 4.02 (d, J = 14.5Hz, 1H), 4.1 (m, 1H), 5.2 (brs, 2
H), 7.2-7.5 (m, 10H), 8.0 (s, 1H); FAB MASS: 448 (MH ⁺ ).

Example 8 2-Acetylamino-6-
(N, N-diphenylcarbamoyloxy) -9-
Preparation of (4 ′, 4′-diphenyl-3 ′, 5′-dioxabicyclo [5,1,0] octyl-1 ′-) methylpurine 2-Acetylamino-6- (N, N-diphenylcarbamoyloxy ) 6.15 g (15.83 mmol) of purine,
2.19 g (15.83 mmol) potassium carbonate and 4.1
8 g (15.83 mmol) of 18-crown-6 was dissolved in dimethylformamide and the 1-bromomethyl-4,4-diphenyl-3,5-dioxabicyclo [5,1,0] octane obtained in Example 6 was dissolved. 4.74 g (13.19 mmol)
20 ml of the dimethylformamide solution of was added dropwise. After stirring at room temperature for 14 hours, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (dichloromethane: methanol = 19: 1) to give 6.3.
Obtained 8 g (9.57 mmol, 73%) of the title compound.

Pale yellow solid; ¹ H-NMR (CDCl ₃ ) δ: 1.05
(m, 1H), 1.15 (m, 1H), 1.4 (m, 1H), 2.47 (s, 3H), 3.64 (d, J = 1
3.1Hz, 1H), 3.69 (dd, J = 3.5,15Hz, 1H), 3.90 (d, J = 13.1Hz, 1
H), 4.1 (m, 3H), 7.2-7.5 (m, 20H), 7.9 (brs, 1H), 8.14 (s, 1
H); FAB MASS: 667 (MH ⁺ ).

Example 9 9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl]
Preparation of methylguanine 2-Amino-6-chloro-9-obtained in Example 3
(4 ′, 4′-Dimethyl-3 ′, 5′-dioxabicyclo [5,1,0] octyl-1 ′-) methylpurine 21
4.5 mg (0.66 mmol) was suspended in 2.5 ml 80% formic acid and heated at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, 2.5 ml of 29% aqueous ammonia was added to the residue, and 2
After stirring at 0 ° C. for 1 hour, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase C18 silica gel chromatography (water: methanol = 4: 1), and 162.3 was obtained.
Obtained mg (0.66 mmol, 92%) of the title compound.

White powder; ¹ H-NMR (DMSO-d6) δ: 0.40
(t, J = 5.1Hz, 1H), 0.88 (dd, J = 4.8,8.7Hz, 1H), 1.23 (m, 1
H), 3.24-3.37 (m, 2H), 3.41 (dd, J = 6.0,12.6Hz, 1H), 3.58 (d
t, J = 12.0,6.0Hz, 1H), 3.81 (d, J = 14.1Hz, 1H), 4.00 (d, J = 1
4.1Hz, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 6.38 (bs, 2H), 7.71
(s, 1H), 10.49 (bs, 1H); high resolution mass spectrum (C ₁₁
H ₁₆ O ₃ N ₅ , M + H): calculated value 266.1253, found value 266.1263; melting point: 285 ° C. (decomposition); UVma
x: 253 nm (ε = 10500).

Example 10 9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl]
Preparation of methylguanine 2-acetylamino-6- (N, N obtained in Example 4
-Diphenylcarbamoyloxy) -9- (4 ', 4'
-Dimethyl-3 ', 5'-dioxabicyclo [5,1,
0] octyl-1 ′-] methylpurine 11.1 g (2
0.4 mmol) was dissolved in 150 ml of methanol, 30 mg of paratoluenesulfonic acid was added, and the mixture was stirred at room temperature for 1 hour. 100 ml of 29% ammonia water was added dropwise, the mixture was allowed to stand at 30 ° C. for 24 hours, the reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with chloroform to obtain 5.0 g (92%) of the title compound. Further, the crystals were recrystallized from methanol to obtain white crystals. The physical properties were the same as in Example 9.

Example 11 9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl]
Preparation of methylguanine 2-Amino-6-chloro-9-obtained in Example 7
4.5 g (10.05 mmol) of (4 ′, 4′-diphenyl-3 ′, 5′-dioxabicyclo [5,1,0] octyl-1 ′-] methylpurine was suspended in 40 ml of 80% formic acid. The mixture was heated at 100 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1N aqueous sodium hydroxide solution, washed with ethyl acetate, and then neutralized with 1N aqueous hydrochloric acid solution. The powder was collected by filtration and 2.05 g (7
8%) of the title compound was obtained. The physical properties were the same as in Example 9.

Example 12 9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl]
Preparation of methylguanine 2-acetylamino-6- (N, N obtained in Example 8
-Diphenylcarbamoyloxy) -9- (4 ', 4'
-Diphenyl-3 ', 5'-dioxabicyclo [5,5
1,0] octyl-1 ′-] methylpurine 5.38 g
(8.07 mmol) was dissolved in 74 ml of methanol, 50 mg of paratoluenesulfonic acid was added, and the mixture was stirred at room temperature for 1 hour. 50 ml of 29% ammonia water was added dropwise, and the mixture was added at 30 ° C for 2
After standing for 4 hours, the reaction solution was concentrated to dryness, and the residue was washed with chloroform to obtain 1.58 g (5.96 mmol, 74%) of the title compound. The physical properties were the same as in Example 9.

Example 13 (-) 9- [1'R, 2'S
Preparation of -bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine In step 1 of Example 1, R-(-)-epichlorohydrin was used as a raw material and was obtained in the same manner as in Examples 2 and 3 below. 2-amino-6-chloro-9-[(1'R,
4.5 g (10 mmol) of 2'S) -4 ', 4'-diphenyl-3', 5'-dioxabicyclo [5,1,0] octyl-1 '-] methylpurine was suspended in 40 ml of 80% formic acid. It was turbid and heated at 100 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution.
After washing with ethyl acetate, the mixture was neutralized with a 1N aqueous hydrochloric acid solution.
The white powder precipitated here was collected by filtration and recrystallized from methanol to obtain 1.90 g (yield 72%) of the title compound. White crystals. [Α] _D (20 ° C.) = − 11 ° (C =
0.5%, DMSO). The other physical properties were the same as in Example 9.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Naoshi Tsuji 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Central Research Institute of Ajinomoto Co., Inc. (72) Seiichi Nishi Nishi 1-cho, Suzuki-kawa, Kawasaki-ku, Kanagawa 1 Central Research Institute of Ajinomoto Co., Inc.

Claims (5)

[Claims] 1. A cyclopropane derivative represented by the following chemical formula 1 and an optically active form thereof. [Chemical 1] (In the formula, B ¹ represents a protected purine derivative residue, and R ¹
Represents an optionally substituted alkoxymethylene group or an optionally substituted methylene group in which two are taken together to form a ring. ) 2. B ¹ is 2-amino-6-chloropurine-
9-yl, 2-acetamino-6-chloropurine-9-
2-acetoamino-6- (N, N-diphenylcarbamoyl) oxypurin-9-yl, 2-amino-6
-Benzyloxypurin-9-yl or 2-amino-
The cyclopropane derivative according to claim 1, which is 6- (methoxyethoxy) purin-9-yl. 3. A cyclopropane derivative represented by the following chemical formula 2 and an optically active form thereof. [Chemical 2] (In the formula, X ¹ represents a leaving group, and R ¹ is the same as above.) 4. The method for producing a cyclopropane derivative according to claim 1, which comprises reacting the cyclopropane derivative according to claim 3 with a protected purine derivative. 5. A process for producing the compound represented by Chemical formula 3, which comprises deprotecting the cyclopropane derivative according to claim 1. [Chemical 3] (In the formula, B ² represents a purine derivative residue.)