JPH07242668A - Novel azetidine derivative - Google Patents

Abstract

PURPOSE:To provide the novel compound expected as an antiviral agent, a carcinostatic agent or a reagent. CONSTITUTION:This compound is expressed by formula I (B is nucleide group derivative; R1, R2 are H, hydroxyl group-protecting group) and its salt, e.g. 9-[2,3-bishydroxymethyl-1-azetidinyl]aclenine. The compound is obtained e.g. by reacting a compound of formula II with a compound of formula III, subjecting the reaction product to a ring-closing reaction, and subsequently reducing the product. The compound of formula II is obtained e.g. by cyclizing a compound of formula IV (Ms is mesyl) such as (2S, 3R)-1,4bis(benzyloxy)-3- azido-2-mesyloxybutane by a catalytic reduction method using Raney nickel, treating the product with isoamyl nitrite in a solvent, and subsequently reducing the obtained nitroso compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel nucleic acid derivative expected as a medicine such as an antiviral agent and an anticancer agent.

[0002]

2. Description of the Related Art Nucleic acid is a substance that controls genetic information of an organism and has a very close relationship with differentiation and proliferation. Therefore, a naturally-occurring or non-natural nucleic acid derivative that controls the proliferation of organisms (including viruses) Many are known. In fact, some of them are clinically used as effective drugs against cancers that repeat disorderly growth and viral infections that cause various diseases by growing only in human cells. From the standpoint of antiviral agents, most nucleic acid derivatives are pharmaceuticals. For example, vidarabine, acyclovir, azidothymidine and the like are known as antiviral agents. In addition, 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C) and the like are known as anticancer agents.

[0003]

However, the above-mentioned antiviral agents have drawbacks such as a narrow application range for viruses and a limited administration method due to factors such as solubility, oral absorbability and metabolism. Further, side effects such as bone marrow toxicity may limit the dose and administration period. On the other hand, acquired immunodeficiency disease (AIDS), which has a very poor prognosis,
There are many viral diseases without effective medicines and vaccines such as human adult T-cell leukemia (ATL) and highly infectious cold syndrome. Therefore, development of new antiviral agents is strongly desired in the future. In addition, the effect of the above anticancer agent,
It is not always sufficient in terms of side effects and the development of new anticancer agents is desired.

[0004]

The present invention is based on the general formula (1)

[Chemical 9] [Wherein B is a nucleobase derivative, and R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group], and a novel azetidine derivative and salts of these compounds. In the general formula (1), examples of the nucleobase derivative of B include purine bases and pyrimidine bases, and those having a protecting group attached thereto. Examples of purine bases include the following formula

[0005]

[Chemical 10]

[Wherein Y represents a hydrogen atom, a hydroxyl group or a halogen atom, and R ₃ represents an alkyl group having 1 to 20 carbon atoms, a benzyl group which may have a substituent, or an aryl group]. Included are the compounds shown. Examples of the pyrimidine base include the following formulas

[0007]

[Chemical 11]

[Where R ₄ is a hydrogen atom and has 1 to 4 carbon atoms]
To a lower alkyl group, a substituted vinyl group, or a halogen atom].

Examples of the halogen atom include chlorine, bromine, fluorine and iodine, and examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group and isobutyl group. Examples of the benzyl group which may have a substituent include (C1-C4 alkoxy) benzyl groups such as benzyl group and 4-methoxybenzyl group, and examples of the aryl group include phenyl group and tolyl group. , A xylyl group and the like.
Examples of the substituted vinyl group include a 2-halogenated vinyl group such as a 2-iodovinyl group and a 2-bromovinyl group, and a vinyl group substituted with an alkoxycarbonyl group such as a methoxycarbonyl group.

R ₁ and R ₂ in the general formulas (1) to (3)
The protective group for the hydroxyl group represented by is not particularly limited as long as it is generally used as a protective group, and ester type protective groups such as acetyl group, acyl groups such as benzoyl group, or ether type protective groups such as tert-butyl. Dimethylsilyl group, substituted silyl group such as tert-butyldiphenylsilyl group, (C1-C4 alkoxy) C1-C4 alkyl group such as methoxymethyl group, cyclic acetal group such as tetrahydropyranyl group, or benzyl group, 4-methoxy Examples thereof include a methyl group substituted with one or more substituted or unsubstituted phenyl groups such as a benzyl group and a trityl group.

The physiologically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, substituted ammonium salts, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid. Examples thereof include salts, acetic acid, fumaric acid, maleic acid, tartaric acid, and organic acid salts such as methanesulfonate.

Specific examples of the compound represented by the general formula (1) are shown below. The compounds shown here include all existing isomers, optically active substances, and racemates. Also, salt is not shown here.

1-1-1,9- [2,3-bishydroxymethyl-1-azetidinyl] adenine 1-1-2,9- [2,3-bishydroxymethyl-1]
-Azetidinyl] guanine 1-1-3,2,6-diamino-9- [2,3-bishydroxymethyl-1-azetidinyl] purine 1-1-4,9- [2,3-bishydroxymethyl-1
-Azetidinyl] hypoxanthine 1-1-5, 2-amino-6-chloro-9- [2,3-
Bishydroxymethyl-1-azetidinyl] purine 1-1-6,6-chloro-9- [2,3-bishydroxymethyl-1-azetidinyl] purine

1-2-1, 1- [2,3-bishydroxymethyl-1-azetidinyl] cytosine 1-2-2,1- [2,3-bishydroxymethyl-1]
-Azetidinyl] thymine

1-2-3,1- [2,3-bishydroxymethyl-1-azetidinyl] uracil 1-2-4,5- (2-bromovinyl) -1- [2,3
-Bishydroxymethyl-1-azetidinyl] uracil 1-2-5,5-fluoro-1- [2,3-bishydroxymethyl-1-azetidinyl] uracil 1-2-6,5-iodo-1- [2 , 3-Bishydroxymethyl-1-azetidinyl] uracil 1-2-7,5- (2-methyloxycarbonylvinyl) -1- [2,3-bishydroxymethyl-1-azetidinyl] uracil

The purine base type compound represented by the general formula (1) of the present invention is, for example, the general formula (2)

[0017]

[Chemical 12]

A known method (MR Harnden) using a compound represented by the formula [R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group] as a starting material
et al. Med. Chem. , 33, 187-1
96 (1990)), for example, by the reaction route shown in the following scheme 1 or scheme 2.

[0019]

[Chemical 13]

[0020]

[Chemical 14]

Further, the pyrimidine base type compound represented by the general formula (1) of the present invention is represented by the general formula (2).

[0022]

[Chemical 15]

A known method (K. Tadano et al.) Using a compound represented by the formula [wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group] as a starting material.
al, Bull. Chem. Soc. Jp. , 51, 8
97-900 (1978)), for example, by the reaction route shown in the following scheme 3 or scheme 4.

[0024]

[Chemical 16]

[0025]

[Chemical 17]

The compound represented by the general formula (2), which is a starting material for the schemes 1 to 4, can be produced from the compound represented by the general formula (3), for example, by the reaction route shown in the following scheme 5. .

[0027]

[Chemical 18]

That is, the compound represented by the general formula (2) is obtained by reducing the N-nitroso compound represented by the general formula (4) obtained by the nitrosation reaction of the compound represented by the general formula (3). It can be manufactured. The nitrosation reaction is carried out by adding 1 to 1 of isoamyl nitrite in a solvent such as tetrahydrofuran (hereinafter abbreviated as THF), ether, benzene or toluene.
It can be easily obtained by treating with 10 equivalents or with 1 to 3 equivalents of sodium nitrite under acidity of acetic acid or hydrochloric acid. The reaction time is 1 to 30 hours. The reaction temperature is preferably -30 ° C to room temperature.

In addition, the reduction reaction of the nitroso group to the amino group does not affect the protecting group used in the general formula (4), for example, a reduction method using acetic acid or metallic zinc under acidic conditions of hydrochloric acid and aluminum hydride, Any metal hydride reducing agent such as borated hydride can be used. Desirably, 3 to 5 equivalents of lithium aluminum hydride are reacted in a solvent such as THF, ether, benzene or toluene at -30 ° C to room temperature. The reaction time is 1 to 30 hours.

Further, the compound represented by the general formula (3) can be synthesized from the compound represented by the general formula (5) by the reaction route shown in the following scheme 6.
In the general formula (5), Ms represents a mesyl group. That is, when the reaction is performed using a reagent that reduces the azido group of the compound represented by the general formula (5) to an amino group, a cyclization reaction occurs during the reaction to give the target compound represented by the general formula (3). obtain. As the reducing agent, Pd-C, Pd-black, Ra
A catalytic reduction method using a catalyst such as ney-Ni and a method using a metal hydride reducing agent such as aluminum hydride or borated hydride are possible.

As the solvent to be used, lower alcohols such as methanol, ethanol and propanol are used in the catalytic reduction method, and ethers such as diethyl ether and THF are used in the metal hydride reduction method. A tel solvent is used. The reaction temperature is -30 ° C to 50 ° C. The reaction time is 1 to 50 hours. Desirably, the reaction is carried out for 40 hours at room temperature in ethanol under hydrogen gas atmosphere using Raney-Ni as a catalyst.
Scheme 6 is shown below.

[0032]

[Chemical 19]

Further, the compound represented by the general formula (5) can be obtained via the compounds represented by the general formulas (7) and (8), for example, by the reaction route shown in the following scheme 7. .

[0034]

[Chemical 20]

That is, the compound represented by the general formula (5) is produced, for example, by subjecting the compound represented by the general formula (6) to ring-opening with a vinylating agent, followed by azidation and mesyl (methanesulfonyl) formation steps. can do.

As a method of ring opening, for example, a vinylating agent such as vinylmagnesium bromide is used and reacted in ethyl ether in the presence of copper iodide. As a result, the compound represented by the general formula (7) is obtained. Reaction temperature is -15
Desirably, the reaction time is 3 to 5 hours.

As a method for converting the hydroxyl group of the compound represented by the general formula (7) into an azido group, for example, first, mesyl chloride and triethylacyl are reacted preferably at a temperature of 0 ° C. for 4 hours. Sodium azide is then added in dimethylformamide, preferably at a temperature of 98 ° C. to 105 ° C.
Allow to react for ~ 3 hours. As a result, the compound represented by the general formula (8) is obtained.

As a method for mesylating a vinyl group, for example, first, the carbon-carbon double bond of the compound represented by the general formula (8) is subjected to ozonolysis, and then a reducing agent such as sodium tetrahydroborate is used. Are allowed to react overnight at room temperature.
Further, mesyl chloride and triethylamine are reacted at a temperature of 0 ° C. for 4 hours.

Further, the compound represented by the general formula (6) can be prepared by a known method (KC Nicolaou et a.
l. J. Org. Chem. , Vol. 50, No.
9, 1985), and tartaric acid is used as a starting material to carry out an epoxidation reaction.

Further, an optically active substance of the compound represented by the general formula (1) can be produced, for example, as follows. When the starting material is a racemate, each diastereomer salt is obtained by mixing the racemic compound represented by the general formula (2) with various acids such as an optically active carboxylic acid. The stereomers are isolated by chromatographic methods, crystallization and the like. These diastereomers can be converted into an optically active free base represented by the general formula (2) by a usual method, for example, by adding a base to decompose a salt, or by an ion exchange resin method. Or general formula (1),
R in the racemic compound represented by (2) and (3)
_An optically active substituent can be introduced into at least one of R ₁ and R ₂ to form a diastereomer, and the diastereomer can be divided to obtain an optically active compound.

[0041]

EXAMPLES Next, the production of the compound of the present invention will be described in detail with reference to examples. The compounds shown here are optically active compounds.

[0042] Example 1 1- [2,3-bis (benzyloxymethyl) - azetidinyl Production of uracil (1) _2, 3- bis (benzyloxymethyl) azetidine manufacturing _(2S, 3R) _-1, 4 -Bis (benzyloxy) -3
-Azido-2-mesyloxymethylbutane (4.49
g) is dissolved in ethanol (250 ml) and Raney
Add Ni (W-2) (1 g) and stir vigorously for 24 hours in a hydrogen atmosphere. After completion of the reaction, the catalyst is filtered and the filtrate is concentrated under reduced pressure. The resulting oily substance was subjected to silica gel chromatography (silica gel 18 g, developing solvent chloroform /
Purification with methanol = 10: 1) gives the desired product.
(Colorless oil 2.29 g, yield: 92%)

[Α] ²² D +25.0 ° (c 0.63, CHCl ₃ ) υ _max (film) 3340, 3090, 3060, 3030, 2930, 2860, a
nd 1545 cm ^{-1 1} H NMR (270 MHz, CDCl ₃ ) δ 2.76, 1H, tq, J = 7.6, 5.9 Hz, 3-CH 3.43, 1H, t, J = 7.6 Hz, 4-CH H 3.53, 1H , t, J = 7.6 Hz, 4-CH H 3.57, 4H, d, J = 5.9 Hz, CH2 x 2 3.91, 1H, q, J = 5.9 Hz, 1-CH 4.51, 2H, s, Ph-CH ₂ 4.56, 2H, s, Ph-CH ₂ 7.30-7.35, 10H, complex, Ph x 2 ¹³ C NMR (67.8 MHz, CDCl ₃ ) δ 37.3, 47.0, 60.8, 71.7, 73.2, 73.4, 74.0, 127.7
x 4, 127.8 x 2, 128.5x 4, 138.4 x 2

[0044] (2) 1-nitroso _-2 1,3-bis (benzyloxymethyl) azetidine manufacturing (2S, 3S) _-2, 3-bis (benzyloxymethyl) azetidine (8.1 mg) in anhydrous THF (0 .2m
l) In solution, under ice cooling, isoamyl nitrite (0.04 m
l) is added and the mixture is stirred for 16 hours at room temperature. After completion of the reaction, the residue obtained by concentration under reduced pressure is purified by preparative thin layer chromatography (silica gel 0.5 mm, developing solvent n-hexane / ethyl acetate = 3: 1) to obtain the desired product. (Light yellow oil 8.9 mg, yield 98%) [α] ¹⁹ D -29.6 ° (c 1.10, CHCl ₃ ) υ _max (film) 3035, 2930, 2855, and 1490 cm ^-1

[0045] (3) _1-amino-2, 3-bis (benzyloxymethyl) azetidine manufacturing 1N- nitroso - (2S, 3S) - bis in THF (benzyloxymethyl) azetidine (84 mg) (3 ml)
The solution was cooled to -20 ° C, and lithium aluminum hydride hydride (67 mg) was added thereto, so that -14 ° C to -1.
Stir at 0 ° C. for 4 hours. After the reaction was completed, excess reagents were decomposed with ethanol, and then a 1N-NaOH aqueous solution (15 m
l) was added and the reaction mixture was mixed with methylene chloride (20 ml).
x 3 times). The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain the desired product. (67 mg) This substance is unstable and used in the next reaction without purification. υ _max (film) 3340, 3090, 3060, 3030, 2930, 2850, 1
600, and 1495 cm ^-1

[0046] (4) 1- _[2, 3- bis (benzyloxymethyl) - azetidinyl] uracil manufacturing crude 1-amino - (2S, 3S) - anhydrous bis (benzyloxymethyl) azetidine (206 mg) DMF
(N, N-dimethylformamide) (3 ml) solution-
It was cooled to 20 ° C., in which a solution of b-ethoxyacrylic acid isocyanate in benzene (b-ethoxyacrylic acid chloride (257 mg) and silver cyanate (1.19) was added.
g) and benzene (prepared from 7 ml) are added, and the mixture is stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the obtained residue was separated and purified by preparative thin layer chromatography (silica gel, developing solvent n-hexane / ethyl acetate = 1: 4) to give 1- [N ′-( 3-ethoxy-acryloyl) - ureido] _-2, to obtain a 1,3-bis (benzyloxymethyl) azetidine. (258 mg, 64% yield). Next, this substance (46 mg) was dissolved in ethanol (3 ml) and 7% aqueous ammonia (3 ml), and the mixture was stirred in a sealed tube at 80 ° C. for 7.5 hours. After cooling to room temperature, the solvent and excess reagents were distilled off under reduced pressure, and the residue was collected by preparative thin-layer chromatography (silica gel,
Separation and purification with a developing solvent n-hexane / ethyl acetate = 2: 3) gives the desired product. (38 mg, yield 92%)

¹ H NMR (270 MHz, CDCl ₃ ) δ 2.47, 1H, sex, J = 7.0 Hz, 3'-CH 3.56, 2H, d, J = 5.3 Hz, 5'-CH ₂ 3.71, 2H, d , J = 7.0 Hz, 6'-CH ₂ 3.76, 1H, t, J = 7.0 Hz, 4'-CH H 4.39, 1H, t, J = 7.0 Hz, 4'-CH H 4.50, 4H, s, CH2 -Ph x 2 4.76, 1H, dd, J = 7.0, 5.3 Hz, 2'-CH 5.47, 1H, d, J = 7.9 Hz, 5-CH 7.29, 1H, d, J = 7.9 Hz, 6-CH 7.26 -7.33, 10H, complex, Ph x 2 9.34, 1H, br, NHD ₂ O exchangeable

[0048] Example 2 1- _[2, 3- bis (hydroxymethyl) - azetidinyl] uracil (Compound No. 1-
2-3) Preparation of 1- [2,3-bis (benzyloxymethyl) -azetidinyl] -uracil (9.0 mg) in ethanol (0.
A catalytic amount of palladium hydroxide and cyclohexene (0.30 ml) were added to the solution (60 ml) and the mixture was heated under reflux for 3 hours. The reaction mixture is cooled to room temperature, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue is separated and purified by preparative thin layer chromatography (silica gel, developing solvent chloroform / methanol = 4: 1) to obtain the desired product. (3.2
mg, yield 64%)

[Α] ²² D -35.7 ° (c 0.69, MeOH) λ max 263 nm (e 8943, MeOH) υ _max (film) 3440, 1685, 1650, 1590, and 1575 cm
^{-1 1} H NMR (270 MHz, CD ₃ OD) δ 2.45, 1H, sex, J = 7.1 Hz, 3'-CH 3.59, 1H, dd, J = 5.6, 11.9 Hz, 5'-CH H 3.67, 1H , dd, J = 3.6, 11.9 Hz, 5'-CH H 3.74, 1H, t, J = 7.1 Hz, 4'-CH H 3.80, 2H, d, J = 7.1 Hz, 6'-CH ₂ 4.29, 1H , t, J = 7.1 Hz, 4'-CH H 4.59, 1H, ddd, J = 3.6, 5.6, 7.1 Hz, 2'-CH 5.55, 1H, d, J = 8.1 Hz, 5-CH 7.69, 1H, d, J = 8.1 Hz, 6-CH ¹³ C NMR (67.8 MHz, CD ₃ OD) δ 34.1, 56.2, 64.4, 64.8, 72.3, 101.2, 149.6, 15
2.0, and 166.3 HRMS, m / z 227.0905 calcd for C ₉ H ₁₃ O ₄ N ₃ (M ⁺ ) found
227.0886

Reference Example 1 Preparation of (2S, 3R) -1,4-bis (benzyloxy) -3-azido-2-mesyloxymethylbutane

(1) Production of (2R, 3R) -1,4-bis (benzyloxy) -3-vinyl-2-butanol Vinyl magnesium bromide in THF (1M, 26.6).
ml) to copper iodide (2.61 g, 13.7 mmol)
The mixture is added to a suspension of anhydrous diethyl ether (60 ml) under ice-cooling and stirred for 30 minutes. 1,4-bis (benzyloxy) -2,3-epoxide (1.91 g, 6.73 mm)
ol) in anhydrous diethyl ether (20 ml) is added, and the mixture is stirred under ice cooling for 3.5 hours.

After completion of the reaction, the aqueous layer was washed with diethyl ether (1
50 ml × 4 times) and ethyl acetate (150 ml), the organic layers were combined, washed with saturated aqueous ammonium chloride solution (500 ml) and saturated saline (500 ml),
Then it is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (silica gel 60 g,
Purification with an elution solvent n-hexane / ethyl acetate = 4: 1) gives the desired product. (Colorless oil 1.97 g, yield 94
%)

[Α] ²³ D -27.4 ° (c 1.04, CHCl ₃ ) υ _max (film) 3480, 3075, 3040, 2900, 2860, 1640, a
^{nd 1500 cm -1 1 H NMR (} 400 MHz, CDCl 3) δ 2.57, 1H, dddd, J = 5.4, 6.2, 7.5, 8.6 Hz, 3-CH 3.04, 1H, brs, D 2 O exchangeable, O H 3.46 , 1H, dd, J = 7.0, 10.0 Hz, 4-CH H 3.55, 1H, dd, J = 3.5, 10.0 Hz, 4-CH H 3.63, 1H, dd, J = 6.2, 9.5 Hz, 1-CH H 3.67, 1H, dd, J = 5.4, 9.5 Hz, 1-CH H 3.90, 1H, ddd, J = 3.5, 7.0, 7.5 Hz, 3-C H 4.47-4.60, 4H, complex, Ph-C H ₂ x 2 5.11, 1H, dd, J = 1.6, 10.3 Hz, CH = CH H 5.14, 1H, dd, J = 1.6, 17.1 Hz, CH = CH H 5.75, 1H, ddd, J = 8.6, 10.3, 17.1 Hz, C H = CH ₂ 7.22-7.42, 10H, complex, Ph x 2

(2) Production of (2R, 3R) -1,4-bis (benzyloxy) -3-vinyl-2-mesyloxybutane (2R, 3R) -1,4 obtained in the above (1). -Bis (benzyloxy) -3-vinyl-2-butanol (1
1.95 g, 38.3 mmol) and triethylamine (10 ml, 71.7 mmol) in anhydrous dichloromethane (100 ml) were mixed with mesyl chloride (4.0 m).
1, 51.7 mmol) was added under ice cooling and stirred for 4 hours.
Then, acidify with 0.5 M hydrochloric acid (60 ml) and extract with ethyl acetate (100 ml × 3 times).

The organic layer was saturated sodium hydrogen carbonate (200
ml), saturated saline (100 ml), and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purify by column chromatography to obtain the desired product.

(3) Preparation of (2S, 3R) -1,4-bis (benzyloxy) -3-azido-2-vinylbutane Sodium azide (6.76 g, 10.4 mmol) and obtained in (2) above. A solution of the obtained (2R, 3R) -1,4-bis (benzyloxy) -3-vinyl-2-mesyloxybutane (13.33 g, 34.1 mmol) in dimethylformamide at 98 to 105 ° C for 2.5 hours. Stir. After cooling to room temperature, wash with water (100 ml) and extract with ethyl acetate (200 ml × 2 times).

The organic layers were combined, washed with saturated ammonium chloride (100 ml) and saturated saline (100 ml),
Dry over anhydrous sodium sulfate. It is concentrated under reduced pressure and purified by column chromatography (silica gel 620 g, elution solvent n-hexane / ethyl acetate = 10: 1) to obtain the desired product. (Pale yellow oil 10.34 g, 3
0.6 mmol, yield 90%)

[Α] ²³ D -23.9 ° (c 0.98, CHCl ₃ ) υ _max (film) 3080, 3040, 2865, 2100, 1640, and 149
5 cm ^{-1 1} H NMR (270 MHz, CDCl ₃ ) δ 2.57, 1H, ddd, J = 4.4, 5.3, 9.2 Hz, 2-CH 3.41, 1H, dd, J = 5.4, 9.4 Hz, 4-CH H 3.53, 1H, dd, J = 8.1, 9.4 Hz, 4-CH H 3.54, 2H, d, J = 5.3 Hz, 1-CH ₂ 4.00, 1H, ddd, J = 4.4, 5.4, 8.1 Hz, 3-CH 4.49, 2H, s, Ph-CH ₂ 4.49, 1H, d, J = 11.9 Hz, Ph-CH H 4.55, 1H, d, J = 11.9 Hz, Ph-CH H 5.10, 1H, dd, J = 2.1, 10.6 Hz, CH = CH H 5.11, 1H, dd, J = 2.1, 16.8 Hz, CH = CH H 5.66, 1H, ddd, J = 9.2, 10.6, 16.8 Hz, C H = CH ₂ 7.24-7.38, 10H, complex, Ph x 2

(4) Production of (2R, 3R) -1,4-bis (benzyloxy) -3-azido-2-hydroxymethylbutane (2S, 3R) -1,4 obtained in the above (3). -Bis (benzyloxy) -3-azido-2-vinylbutane (10.34 g, 30.6 mmol) in methanol (1
(00 ml) solution, ozone gas (oxygen flow rate 15 ml /
Minute) air bubbles (temperature 75 ° C.). After completion of the reaction for 3 hours, sodium tetrahydroborate (8.17 g, 21
6 mmol), and react overnight at room temperature. Concentrate under reduced pressure (-10 ml) and separate the resulting residue with ethyl acetate (100 ml) and water (100 ml).

The aqueous layer was extracted with ethyl acetate (100 ml × 2 times), the organic layers were combined, washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and perform column chromatography (silica gel 530
g, elution solvent n-hexane / ethyl acetate = 2: 1 →
Purify 6: 1 → 8: 1) to obtain the desired product. (Pale yellow oil 8.05 g, 23.6 mmol, yield 77%)

[Α] ²² D -37.1 ° (c 0.883, CHCl ₃ ) υ _max (film) 3450, 3075, 3040, 2900, 2865, 2100, a
nd 1500 cm ^{-1 1} H NMR (270 MHz, CDCl ₃ ) δ 1.95, 1H, tt, J = 2.3, 3.5, Hz, 2-CH 3.49, 1H, dd, J = 2.3, 9.3 Hz, 1-CH H 3.56, 1H, dd, J = 2.3, 9.3 Hz, 1-CH H 3.60, 1H, dd, J = 6.6, 10.1 Hz, 4-CH H 3.67, 1H, dd, J = 3.3, 10.1 Hz, 4-CH H 3.70, 2H, d, J = 3.5 Hz, C H ₂ OH 3.88, 1H, dt, J = 3.3, 6.6 Hz, 3-CH 4.41, 1H, d, J = 12.0 Hz, Ph-CH H 4.47, 1H , d, J = 12.0 Hz, Ph-CH H 4.49, 1H, d, J = 12.7 Hz, Ph-CH H 4.54, 1H, d, J = 12.7 Hz, Ph-CH H 7.21-7.39, 10H, complex, Ph x 2

(5) Production of (2S, 3R) -1,4-bis (benzyloxy) -3-azido-2-mesyloxymethylbutane (2R, 3R) -1, obtained in (4) above. A solution of 4-bis (benzyloxy) -3-azido-2-hydroxymethylbutane (8.39 g, 24.6 mmol) and triethylamine (6.5 ml, 47 mmol) in anhydrous chloromethane (80 ml) was added with mesyl chloride (3). 0.0 m
1, 38.8 mmol) at a temperature of 0 ° C. The reaction solution was stirred at room temperature for 4 hours, and then 0.5M hydrochloric acid (30 m
Acidify with l) and extract with ethyl acetate (100 ml x 3 times).

The organic layer was washed with saturated sodium carbonate (150 m).
l) and saturated saline (100 ml), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and purify by column chromatography (silica gel 400 g, elution solvent n-hexane / ethyl acetate = 1: 1) to obtain the desired product.
(10.12 g, yield 98%)

[Α] ²¹ D -28.4 ° (c 1.15, CHCl ₃ ) υ _max (film) 3050, 2940, 2880, 2105, and 1500 cm
^{-1 1} H NMR (270 MHz, CDCl ₃ ) δ 2.25, 1H, dddt, J = 5.0, 5.4, 5.6, 6.6 Hz, 2-CH 2.93, 3H, s, SO ₂ CH ₃ 3.47, 1H, dd, J = 5.6, 9.5 Hz, 1-CH H 3.52, 1H, dd, J = 5.4, 9.5 Hz, 1-CH H 3.61, 1H, dd, J = 6.6, 10.2 Hz, 4-CH H 3.70, 1H, dd, J = 3.3, 10.2 Hz, 4-CH H 3.79, 1H, dt, J = 6.6, 3.3 Hz, 3-CH 4.29, 1H, dd, J = 6.6, 9.9 Hz, CH H OSO ₂ 4.38, 1H, dd, J = 5.0, 9.9 Hz, CH H OSO ₂ 4.45, 1H, d, J = 12.0 Hz, Ph-CH H 4.49, 1H, d, J = 12.0 Hz, Ph-CH H 4.52, 1H, d, J = 11.9 Hz, Ph-CH H 4.57, 1H, d, J = 11.9 Hz, Ph-CH H 7.22-7.45, 10H, complex, Ph x 2

[0065]

According to the present invention, antiviral agents, anticancer agents,
A novel azetidine derivative expected as a reagent is obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 473/40 487/04 144 7019-4C // A61K 31/52 ADY 31/53 ADU

Claims (6)

[Claims] 1. A general formula (1): A novel azetidine derivative represented by the formula: wherein B is a nucleobase derivative, and R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group, and salts of these compounds. 2. A general formula (2): A novel azetidine derivative represented by the formula [wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group] and salts of these compounds. 3. A general formula (3): A novel azetidine derivative represented by the formula [wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group] and salts of these compounds. 4. A general formula (3): A compound of the general formula (4) obtained by the nitrosation reaction of the compound represented by The N-nitroso compound represented by the general formula (2): The manufacturing method of the compound represented by. 5. A compound represented by the general formula (5): A compound represented by the general formula (3): The manufacturing method of the compound represented by. 6. The production method according to claim 5, wherein the reduction is carried out by a catalytic reduction method or a method using a metal hydride reducing agent.