JPH06228123A - Production of 2-nitroimidazole derivative - Google Patents

Abstract

PURPOSE:To produce a 2-nitroimidazole derivative useful as a radiation sensitizer in high yield and purity by using an inexpensive tartaric acid diester as a raw material. CONSTITUTION:A compound of formula 2 [Y is COOR<1> (R<1> is alkyl) or CH2OR<2> (R<2> is aliphatic or aromatic acyl)] is made to react with a catalytic amount to equal amount of a Lewis acid (e.g. boron trifluoride or anhydrous aluminum chloride) at room temperature or under heating to obtain a 1,3-dioxolan derivative of formula 3. The compound of formula 3 is made to react with a nitroimidazole compound of formula 4 (R<3> to R<5> are alkyl) preferably in the presence of a Lewis acid at -30 to +50 deg.C (usually under ice cooling or at room temperature) to obtain the objective 2-nitroimidazole derivative of formula 5, e.g. (1'S,2'S)-1-[(3'-acetoxy-1'-acetoxymethyl-2'-hydroxy)propoxy]methyl-2- nitroimidazole. The compound of formula 4 is easily producible by reacting 2-nitroimidazole with excess silylation agent such as N,O- bistrialkylsilylacetamide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a 2-nitroimidazole derivative useful as a radiation sensitizer, an intermediate for producing the derivative in a high yield, and a method for producing the intermediate. Regarding

[0002]

2. Description of the Related Art The following equation (6)

[0003]

[Chemical 13]

The 2-nitroimidazole derivative represented by ## STR1 ## has an effect of enhancing the radiosensitivity of hypoxic cells in the tumor, that is, an excellent radiosensitizing effect, and is highly safe, so that it is a radiotherapy for tumors. It is known to be useful as a drug to be used in combination in the case of (1)
3258).

This 2-nitroimidazole derivative (6)
As a manufacturing method of, a method shown in the following reaction formula is known.

[0006]

[Chemical 14]

This method includes a step of selectively acylating a total of 3 hydroxyl groups, 2 primary hydroxyl groups and 1 secondary hydroxyl group, out of 4 hydroxyl groups of erythritol as a raw material compound. In order to make the difference in the reactivity between the secondary hydroxyl group and the secondary hydroxyl group, a reaction at a low temperature is necessary, but the solubility of the raw material compound is poor and a large amount of solvent is required. Further, the products of this step are tetraacylated products, triacylated products,
It is obtained as a mixture of a diacylated product, a monoacylated product and an unreacted product, and purification by column chromatography or the like is necessary to obtain only the target triacylated product.
Further, since the isolation yield of this step is low, there is also a drawback that the overall yield is low. Furthermore, the optically active 2-
In order to produce the nitroimidazole derivative (6),
There is also a problem that expensive raw materials such as D-erythritol and L-erythritol must be used.

[0008]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a novel method for producing a 2-nitroimidazole derivative (6) useful as a radiation sensitizer and an intermediate for producing the same.

[0009]

[Means for Solving the Problems] Therefore, the inventors of the present invention have variously studied a method for producing a novel 2-nitroimidazole derivative (6) which does not use erythritol as a raw material. It was found that the 2-nitroimidazole derivative (6) and its optically active substance can be industrially advantageously obtained at a high yield by passing the compound as an intermediate, and completed the present invention.

The present invention is represented by the following reaction formula.

[0011]

[Chemical 15]

[Wherein Y is -COOR¹(Where R¹Is
Represents an alkyl group) or -CH₂OR²(Where R²Is fat
A group represented by an aliphatic or aromatic acyl group) is represented by R
³, R^Four And R^FiveRepresents an alkyl group]

That is, according to the present invention, a compound (2) obtained by reacting the compound (1) with dimethoxymethane in the presence of phosphorus pentoxide is reacted with a Lewis acid. A 1,3-dioxolane derivative (3 ) Is provided. The present invention also provides a method for producing a 2-nitroimidazole derivative (5), which comprises reacting the 1,3-dioxolane derivative (3) with a nitroimidazole (4).

In the above reaction formula, R ¹ , R ³ , R ⁴
The alkyl group represented by R ⁵ and R ⁵ is not particularly limited, and examples thereof include a linear or branched alkyl group having 1 to 24 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-octyl group and a palmityl group. Examples of the aliphatic acyl group or aromatic acyl group represented by R ² include acetyl group, propionyl group, stearoyl group, benzoyl group and the like.

The reaction for obtaining the compound (2) from the compound (1) is preferably carried out by adding phosphorus pentoxide to a mixture of the compound (1) and dimethoxymethane at room temperature or under heating.

Examples of the Lewis acid to be reacted with the compound (2) include boron trifluoride, boron trifluoride etherate, anhydrous zinc chloride, anhydrous aluminum chloride and anhydrous tin chloride. The reaction between the compound (2) and the Lewis acid may be carried out by adding a catalytic amount of the Lewis acid to the compound (2) and stirring the mixture at room temperature or under heating. In the reaction of compound (1) with dimethoxymethane, a partial ring-closure reaction occurs due to the action of phosphorus pentoxide, and progresses to 1,3-dioxolane derivative (3). Can be added to complete the ring closure reaction.

In general, in order to introduce a diol into a 1,3-dioxolane ring, paraformaldehyde or 1,3,5-
Trioxane or the like is used, but in the case of compound (1),
Almost no 1,3-dioxolane ring is formed with these reagents, or the yield is very low. On the other hand, according to the method of the present invention, the 1,3-dioxolane derivative (3) can be obtained from the compound (1) in a high yield of 90% or more in total.

The nitroimidazoles (4) can be easily prepared by stirring 2-nitroimidazole with an excess of a silylating agent such as N, O-bistrialkylsilylacetamide at room temperature or under heating. If the unreacted silylating agent is distilled off under reduced pressure, it can be used as it is as a raw material. The reaction of the nitroimidazoles (4) with the 1,3-dioxolane derivative (3) is preferably carried out in the presence of a Lewis acid. As the Lewis acid, the same ones as described above are used, and it is preferable to use the same amount as the 1,3-dioxolane derivative (3) from the catalytic amount. 1,3-Dioxolane derivative (3) and nitroimidazoles (4)
Although the use ratio of can be arbitrarily determined, it is usually preferable to use the former in an equimolar to small excess with respect to the latter. Various reaction solvents can be used, and for example, acetonitrile, methylene chloride, benzene, toluene and the like are used. The reaction can be carried out at -30 to 50 ° C, usually under ice-cooling to room temperature. The reaction time depends on the reaction reagent,
Although it depends on the temperature, reaction solvent, catalyst, etc., it is usually 30
Minutes to 6 hours are preferred.

Further, 1,3-dioxolane derivative (3)
Among them, the compound in which Y is —CH ₂ OR ² can also be produced by the following reaction.

[0020]

[Chemical 16]

[In the formula, R ¹ and R ² have the same meanings as above]

That is, after reducing the compound (3a),
The compound (3b) can be produced by reacting an aliphatic or aromatic carboxylic acid or its reactive derivative. The reduction reaction uses lithium aluminum hydride,
It is preferable to use a reducing agent such as sodium borohydride. The acylation reaction is carried out according to a conventional method, for example, using an acid halide, an acid anhydride or the like as a reactive derivative of an aliphatic carboxylic acid or an aromatic carboxylic acid, in the presence of a base such as pyridine, from room temperature to under heating. Is preferred. The compound (3a) is a novel compound not described in the literature.

Of the 2-nitroimidazole derivative (5) obtained by the above reaction, the compound (5a) in which Y is —CH ₂ OR ² can be prepared by general deacylation, for example, as shown in the following formula. The compound (6) useful as a radiation sensitizer can be obtained by subjecting it to a reaction.

[0024]

[Chemical 17]

[In the formula, R ² has the same meaning as described above.]

Deacylation is carried out, for example, by treatment in anhydrous alcohol containing sodium alcoholate or in anhydrous alcohol saturated with ammonia gas at 0 ° C. to room temperature for several hours to overnight, or triethylamine in hydrous alcohol. It is carried out by a method such as hydrolysis with an organic base such as pyridine at room temperature to 80 ° C.

In the above reaction, after the reaction is completed, the desired product is separated and purified from the reaction solution by a conventional method. For example, the desired product can be obtained by concentrating the reaction solution and then adding a solvent to the residue to precipitate crystals, or by separating and purifying the residue by chromatography or the like.

In the reaction of the present invention, if an optically active substance is used as the starting compound (1), the compounds (2), (3), (5) and (6) having the retained steric configuration can be obtained.

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to produce a 2-nitroimidazole derivative which is useful as a radiation sensitizer with a high yield and a high purity by using an inexpensive tartaric acid diester as a raw material.

[0030]

EXAMPLES The present invention will now be described with reference to examples, but the present invention is not limited thereto.

Example 1 Synthesis of diethyl (S, S) -bis (O-methoxymethyl) tartrate: 25.76 g of D-(-)-diethyl tartrate was completely mixed and dissolved in 50 ml of dimethoxymethane. While stirring at room temperature, phosphorus pentoxide was added little by little and reacted. TLC (developing solvent; CHCl ₃ : CH ₃
OH = 19: 1, detection; iodine) and added phosphorus pentoxide until Rf value 0.88 to a single spot. After completion of the reaction, the reaction solution was transferred to a separating funnel and extracted with 700 ml of a mixed solution of ethyl acetate: benzene = 5: 1. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated with an evaporator to give the title compound as an oily substance. NMR (CDCl ₃ ) δ: 1.30 (6H, t, -OCH ₂ C H ₃ × 2), 3.34 (6H, s, -O
C H ₃ x 2), 4.16-4.30 (4H, m, -OC H ₂ CH ₃ x 2), 4.66-4.79 (6
H, m,> C H O- × 2 and -OC H ₂ OCH ₃ × 2)

Example 2 Synthesis of diethyl (R, R) -bis (O-methoxymethyl) tartrate: 20.6 g of diethyl L-(+)-diethyl tartrate was completely dissolved in 60.8 g of dimethoxane. While stirring at room temperature, phosphorus pentoxide was added little by little and reacted. TLC (developing solvent; benzene: ethyl acetate =
3: 2, detection; iodine), and phosphorus pentoxide was added until an Rf value of 0.63 became a single spot. After the reaction was completed, the supernatant was transferred to a separating funnel and 200 ml of ethyl acetate was added.
Was added for extraction. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate several times, then with water several times, dried, concentrated by an evaporator, and purified by silica gel column chromatography (eluent: benzene) to obtain 23.7 g (yield 80.8%) of the title compound. . MS: 294 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.32 (6H, t, -C H ₃ × 2), 3.35 (6H, s, -OC H ₃
× 2), 4.25 (4H, m, -OC H ₂ CH ₃ × 2), 4.6-4.9 (6H, m, -OC H ₂ OC
H ₃ × 2 and> C H O- × 2)

Example 3 (2R, 3R) -2,3-bis (O-methoxymethyl)
Synthesis of -1,4-O-ditosylerythritol: (2
R, 3R) -1,4-O-ditosylerythritol 8.
6 g was mixed with 20 ml dimethoxmethane. While stirring at room temperature, phosphorus pentoxide was added little by little and reacted. TLC (developing solvent; benzene: ethyl acetate = 3:
2, detection; iodine), and phosphorus pentoxide was added until a single spot was obtained. After completion of the reaction, the reaction solution was transferred to a separating funnel and extracted with 100 ml of ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as an oily substance. Yield 9.1 g (92% yield).

Example 4 Synthesis of (RS, SR) -bis (O-methoxymethyl) diethyl tartrate: 20.6 g of meso-diethyl tartrate was completely mixed and dissolved in dimethoxymethane. While stirring at room temperature, phosphorus pentoxide was added little by little and reacted. TLC (developing solvent; benzene: ethyl acetate =
3: 2, detection; iodine), Rf value 0.63
Phosphorus pentoxide was added until a single spot was added. After the reaction was completed, the reaction solution was transferred to a separating funnel, and ethyl acetate 300 was added.
It was extracted with ml. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off with an evaporator to obtain the title compound as an oily substance. Yield 29.0 g (99% yield). MS: 294 (M ⁺ )

Example 5 (4S, 5S) -4,5-bis (ethoxycarbonyl)
Synthesis of -1,3-dioxolane: Obtained in Example 1 (S,
S) -bis (O-methoxymethyl) diethyl tartrate 3
To 0.07 g of benzene (300 ml) was added and dissolved, and boron trifluoride etherate (16.12 g) was added, and the mixture was stirred and reacted at room temperature. After reacting overnight, ethyl acetate 500
ml was added for extraction, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. Then, it was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. Although it can be used as it is in the next reaction, purification by silica gel column chromatography gave the title compound as a colorless transparent oil almost quantitatively.

Example 6 (4R, 5R) -4,5-bis (ethoxycarbonyl)
Synthesis of -1,3-dioxolane: Obtained in Example 2 (R,
R) -bis (O-methoxymethyl) diethyl tartrate 2
3.7 g was dissolved in 50 ml benzene. Boron trifluoride etherate (11.5 g) was added and the mixture was reacted with stirring. After reacting overnight at room temperature, the mixture was transferred to a separating funnel, and ethyl acetate was added to 200
ml was added for extraction. The solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, dried and then concentrated with an evaporator. Although it can be used in the next reaction as it is, it was purified by eluting with benzene using a silica gel column to obtain the title compound. Yield 17.6 g (yield 99.8%). MS: 218 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.35 (6H, t, -CH ₂ C H ₃ × 2), 4.30 (4H, q, -C H
₂ CH ₃ x 2), 4.75 (2H, s,> C H O- x 2), 5.25 (2H, s, -OC H ₂ O-)

Example 7 Synthesis of (4RS, 5SR) -4,5-bis (ethoxycarbonyl) -1,3-dioxolane: (RS, SR) -bis (O-methoxymethyl) tartaric acid obtained in Example 4. To 29.0 g of diethyl was added 100 ml of benzene to dissolve it, and 14.0 g of boron trifluoride etherate was added thereto, and the mixture was reacted with stirring at room temperature. After reacting overnight, ethyl acetate 2
00 ml was added for extraction, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. Then, it was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. Although it can be used as it is in the next reaction, purification by silica gel chromatography gave the title compound as a colorless transparent oil almost quantitatively. Yield 21.0g. MS: 218 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.35 (6H, t, -CH ₂ C H ₃ × 2) 4.25 (4H, q, -C H ₂ C
_{H 3 × 2), 4.80 (} 2H, s,> C H O- × 2), 5.2 (1H, s, -OC H 2 O -), 5.
4 (1H, s, -C H ₂ O-)

Example 8 (4R, 5R) -4,5-bis (tosyloxymethyl)
Synthesis of -1,3-dioxolane: Obtained in Example 3 (2
R, 3R) -2,3-bis (O-methoxymethyl)-
9.1 g of 1,4-O-ditosylerythritol was dissolved in 50 ml of benzene. Boron trifluoride etherate 2.
6 g was added and the reaction was carried out with stirring all day and night. 100 ml of ethyl acetate
Was added for extraction, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. Then, it was washed with water, dried, and then concentrated by an evaporator.
Although it can be used as it is in the next reaction, it was purified by silica gel column chromatography to obtain 8.0 g of the title compound as an oily substance (yield 99%). MS: 442 (M ⁺ ) NMR (CDCl ₃ ) δ: 2.50 (6H, s, -φ-C H ₃ × 2), 4.05 (2H, m,> C H
O- × 2), 4.3 (4H, m, -C H ₂ O- × 2), 7.2-7.4 (4H, d, aromatic proton), 7.7-7.9 (4H, d, aromatic proton)

Example 9 (4R, 5R) -4,5-bis (acetoxymethyl)-
Synthesis of 1,3-dioxolane: (4S, 5S) -4,5
2.40 g of -bis (ethoxycarbonyl) -1,3-dioxolane was dissolved in 50 ml of ethyl alcohol. Sodium borohydride 1.16 g (3 eq) was added in small portions with stirring. After the addition was completed, the mixture was reacted overnight with stirring. The precipitated white powdery substance was filtered, and the filtrate was concentrated with an evaporator. 20 ml of pyridine and acetic anhydride were added to the concentrated liquid, and at room temperature a gel was formed. Ethyl alcohol was added to decompose excess acetic anhydride, and the mixture was concentrated with an evaporator.
After extraction with 100 ml of ethyl acetate, washing with water and drying, the solvent was distilled off with an evaporator, and the oily substance was subjected to silica gel column chromatography (eluent; ethyl acetate: benzene =).
2.1 g of the title compound (yield 97.7)
%) Was obtained. MS: 218 (M ⁺ ) NMR (CDCl ₃ ) δ: 2.1 (6H, s, -COC H ₃ × 2), 4.0 (2H, m,> C H O-
× 2), 4.2 (4H, m, -C H ₂ -OCO- × 2), 5.0 (2H, s, -OC H ₂ O-)

Example 10 (4S, 5S) -4,5-bis (acetoxymethyl)-
Synthesis of 1,3-dioxolane: 300 ml of tetrahydrofuran was added dropwise to 43.61 g of lithium aluminum hydride while cooling with ice. (4R, 5R) -4,5-bis (ethoxycarbonyl) -1,3-dioxolane 125.3
What melt | dissolved g in 200 ml of tetrahydrofuran was dripped and reacted under ice cooling with vigorous stirring. After completion of dropping, the mixture was reacted under reflux for 1 hour. Then, water under ice cooling was added drop by drop to decompose excess lithium aluminum hydride. 4 mol /
7.5 ml of sodium hydroxide (1) were added dropwise. After completion of dropping, the mixture was stirred for 30 minutes and then suction filtered. 700 ml of ethanol was added to the precipitated portion, and the mixture was heated to 60 to 70 ° C., stirred, and suction filtered three times. All the filtrates were collected and concentrated with an evaporator to obtain a crude diol body. To the crude diol compound, 200 ml of pyridine was added and dissolved, and an excess of 200 g of acetic anhydride was dropped and reacted under water cooling. After reacting for several hours, ethyl alcohol was added dropwise to decompose excess acetic anhydride. The reaction mixture was concentrated with an evaporator, and most of pyridine was distilled off. The concentrate was extracted with 500 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried, and concentrated by an evaporator. The concentrate was purified by silica gel column chromatography (eluted with benzene: ethyl acetate = 9: 1) to obtain 90.0 g (yield 71.8%) of the title compound as a colorless liquid. MS: 218 (M ⁺ ) NMR (CDCl ₃ ) δ: 2.10 (6H, s, -COC H ₃ × 2), 4.02 (2H, m,> C H O
-× 2), 4.25 (4H, m, -C H ₂ OCO- × 2), 5.05 (2H, s, -OC H ₂ O-)

Example 11 (1'S, 2'S) -1-[(3'-acetoxy-1 '
-Acetoxymethyl-2'-hydroxy) propoxy]
Synthesis of methyl-2-nitroimidazole: 5.6 g of 2-nitroimidazole and 30 ml of N, O-bistrimethylsilylacetamide (BSA) are placed in a flask equipped with a calcium chloride tube and stirred at 40-50 ° C. It gradually becomes a transparent liquid, and 2-nitroimidazole becomes a silyl form completely in 1 to 2 hours. Unreacted BSA and by-produced O-trimethylsilylacetamide are distilled off under reduced pressure at 90 ° C. or higher and used as they are in the next reaction. The silyl form of 2-nitroimidazole has (4S, 5S) -4,5-
Bis (acetoxymethyl) -1,3-dioxolane 1
0.9 g and 20 ml of anhydrous acetonitrile were added, and then 10 ml of anhydrous stannic chloride was added dropwise under water cooling, and the mixture was reacted with stirring for 2 to 3 hours. 5 g of ethyl acetate containing 100 g of ice
Pour into 00 ml and stir while adding anhydrous sodium hydrogen carbonate until bubbles of carbon dioxide gas are not generated.
The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate,
The solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of ethyl acetate-benzene as an eluent to obtain 12.8 g (yield: 77.5%) of the title compound. NMR (CDCl ₃ ) δ: 1.9 (6H, d, -COC H ₃ × 2), 2.8 (1H, bs,> CHO
H ), 3.9-4.4 (6H, m,> C H O- × 2, -C H ₂ OCO- × 2), 5.9 (2H, n
q, -OC H ₂ N (ring)), 7.2 (1H, d, ring proton), 7.4 (1H, d, ring proton)

Example 12 (1'R, 2'R) -1-[(3'-acetoxy-1 '
-Acetoxymethyl-2'-hydroxy) propoxy]
Synthesis of methyl-2-nitroimidazole: 5.6 g of 2-nitroimidazole and 30 ml of N, O-bistrimethylsilylacetamide (BSA) are placed in a flask equipped with a calcium chloride tube and stirred at 40-50 ° C. It gradually becomes a transparent liquid, and 2-nitroimidazole becomes a silyl form completely in 1 to 2 hours. Unreacted BSA and by-produced O-trimethylsilylacetamide are distilled off under reduced pressure at 90 ° C. or higher and used as they are in the next reaction. The silyl derivative of 2-nitroimidazole has (4R, 5R) -4,5-
Bis (acetoxymethyl) -1,3-dioxolane 1
0.9 g and 20 ml of anhydrous acetonitrile were added, and then 10 ml of boron trifluoride etherate was added dropwise under water cooling,
Stir for 3 hours. This is poured into 500 ml of ethyl acetate containing 100 g of ice and further stirred with adding anhydrous sodium hydrogen carbonate until bubbles of carbon dioxide gas are not generated. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an ethyl acetate-benzene mixed solution as an eluent to give the title compound 11.
9 g (yield 71.8%) was obtained. NMR (CDCl ₃ ) δ: 1.9 (6H, d, -COC H ₃ × 2), 2.9 (1H, bs, O
H), 3.9-4.4 (6H, m,> C H O- × 2, -C H ₂ OCO- × 2), 5.9 (2H, nq,
-OC H ₂ N (ring)), 7.2 (1H, d, ring proton), 7.4 (1H, d, ring proton)

Example 13 (1'S, 2'S) -1-[(2 ', 3'-dihydroxy-1'-hydroxymethyl) propoxy] methyl-2
Synthesis of -nitroimidazole: obtained in Example 11 (1 '
68.9 g of S, 2 ′S) -1-[(3′-acetoxy-1′-acetoxymethyl-2′-hydroxy) propoxy] methyl-2-nitroimidazole was added to methanol 20
It was mixed and dissolved in 0 ml. 100 g of triethylamine was added, and the mixture was stirred at room temperature. 30 ml of water was added, and the mixture was stirred overnight for hydrolysis to hydrolyze. After checking by TLC (developing UV detection with ethyl acetate) and confirming that the reaction was completed, the reaction mixture was concentrated with an evaporator. Isopropanol and toluene were added to the concentrated solution, and the concentration was repeated. The acetic acid and triethylamine which had been completely formed were distilled off. Ethanol (50 ml) was added to the residue to dissolve it, and the crystals were filtered off with a glass filter, seed crystals were added for crystallization, and the crystals were separated by filtration and dried to obtain 26.2 g (yield 57.0%) of the title compound as pale yellow crystals. It was Melting point: 97.0-98.0 ° C MS: 248 (M ⁺ ) NMR (DMSO) δ: 3.2-3.7 (6H, m, -C H ₂ OH × 2,> C H O- × 2), 4.5
0 (1H, t, -CH ₂ O H ), 4.6-4.7 (2H, m, -CH ₂ O H and> CHO H ), 5.8
5 (2H, s, -OC H ₂ N (ring)), 7.18 (1H, d, ring proton), 7.80 (1
(H, d, ring proton) Optical rotation: [α] _D ²⁵ = + 12.2 ° (c = 1.0, CH ₃ OH); [α] _D
²⁰ = + 9.4 ° (c = 2.0, H ₂ O) Optical purity: 99.5% ee Elemental analysis Actual value (%): C; 16.93 H; 38.88 N; 5.35 Calculated value (%): C; 17.00 H; 38.87 N; 5.30

Example 14 (1'R, 2'R) -1-[(2 ', 3'-dihydroxy-1'-hydroxymethyl) propoxy] methyl-2
Synthesis of -nitroimidazole: (1'R, 2'R) -1-[(3'-acetoxy-1 ') obtained in Example 12.
-Acetoxymethyl-2'-hydroxy) propoxy]
11.58 g of methyl-2-nitroimidazole was dissolved in 100 ml of methanol and stirred at room temperature. Triethylamine (10 ml) and water (20 ml) were added, and stirring was continued for hydrolysis. TLC (developing solvent; chloroform: methanol =
After completion of the reaction was checked by 9: 1, detection; UV absorption), the solvent was distilled off with an evaporator to crystallize. Recrystallization from ethanol gave 4.30 g of the title compound as yellowish white columnar crystals. Melting point: 99-101.5 ° C MS (m / e): 248 (M + 1) NMR (DMSO) δ: 3.25-3.33 (2H, m, -CH (OH) CH ₂ OH), 3.39-3.
64 (4H, m,> C H OCH _2- × 2 and -CH (OCH _2- ) C H ₂ OH), 4.46 (1H,
t, -CH (OH) CH ₂ O H ), 4.59 (1H, d, -CH (O H )-), 4.64 (1H, t, -C
H (OCH _2- ) CH ₂ O H ), 5.88 (2H, nq, -CH ₂ N (ring)), 7.21 (1H, s,
Ring proton), 7.83 (1H, s, ring proton) IR (cm ^-1 ): 3385 (OH), 1540 (NO ₂ ), 1370 (NO ₂ ) Optical rotation: [α] _D ²⁵ = -12.09 ° (c = 1.0, MeOH); [α] _D
^{20 = -9.2 ° (c = 2.0} , H 2 O)

Claims (5)

[Claims] 1. A compound represented by the general formula (2): [Wherein Y represents a group represented by -COOR ¹ (wherein R ¹ represents an alkyl group) or -CH ₂ OR ² (wherein R ² represents an aliphatic or aromatic acyl group)] A compound represented by reacting a Lewis acid with a general formula (3): [Wherein Y represents the same meaning as described above] 1,
Process for producing 3-dioxolane derivative. 2. A compound represented by the general formula (3a): [Wherein R ¹ represents an alkyl group] is reduced, and then an aliphatic or aromatic carboxylic acid or a reactive derivative thereof is reacted with the compound of the general formula (3b) ] [Wherein R ² represents an aliphatic or aromatic acyl group]. 3. A compound represented by the general formula (3): [Wherein Y represents a group represented by -COOR ¹ (wherein R ¹ represents an alkyl group) or -CH ₂ OR ² (wherein R ² represents an aliphatic or aromatic acyl group)] The 1,3-dioxolane derivative represented is represented by the general formula (4): [Wherein R ³ , R ⁴ and R ⁵ represent an alkyl group] is reacted with a nitroimidazole compound of the general formula (5) [Wherein Y represents the same meaning as described above] 2-
Process for producing nitroimidazole derivative. 4. A compound represented by the general formula (3b): [Wherein Y represents a group represented by —CH ₂ OR ² (wherein R ² represents an aliphatic or aromatic acyl group)], the 1,3-dioxolane derivative represented by the general formula (4) Chemical 9] [Wherein R ³ , R ⁴ and R ⁵ represent an alkyl group] is reacted with a nitroimidazole compound, and the resulting compound of the general formula (5a) [Wherein R ² has the same meaning as described above] is deacylated and a compound of the general formula (6): A method for producing a 2-nitroimidazole derivative represented by: 5. A compound represented by the general formula (3a): [Wherein R ¹ represents an alkyl group] 1,3
-Dioxolane derivatives.