JP4849855B2 - Method for producing 2-chloro-4-nitroimidazole - Google Patents

Description

  The present invention relates to a method for producing 2-chloro-4-nitroimidazole.

  Formula (1)

2-chloro-4-nitroimidazole is a compound useful as a synthetic intermediate for various pharmaceuticals, agricultural chemicals and the like, particularly as an intermediate for producing antituberculosis drugs.

  Conventionally, as a method for producing 2-chloro-4-nitroimidazole, for example, methods shown in the following reaction formula-1 and reaction formula-2 are known (see Non-Patent Document 1).

  However, these methods have various disadvantages and are not suitable as industrial production methods.

  For example, in the method shown in Reaction Formula-1, compound (4) and compound (5), which are reaction intermediates, are chemically unstable compounds, and there is a risk of explosion due to impact such as dropping or friction. In this method, the TNR temperature (Temperature of No Return) of the compound (4) is safely handled in the reaction (around 130 ° C.) leading to the compound (5) by heating the compound (4). For example, it has been extremely dangerous to industrially mass-produce the target compound.

The method shown in Reaction Formula-2 is a reaction in which the compound (6) is nitrated, but this nitration is only industrially disadvantageous because the compound (1) is only obtained in a low yield.
Swinski et al., Polish Journal of Chemistry, 56, 1261-1272 (1982) (Jerzy SUWINSKI, Ewa SALWINSKA, Jan WATRAS and Maria WIDEL, Polish Jounal of Chemistry, 56, 1261-1272 (1982 ))

  It is an object of the present invention to provide a method for producing 2-chloro-4-nitroimidazole having a high yield and high purity by a simple operation in a safer method with less risk of explosion or the like.

  In order to solve the above-mentioned problems, the present inventor conducted intensive studies on a safer and easier-to-handle method for producing 2-chloro-4-nitroimidazole, and as a result, 1- represented by the following general formula (7): It has been found that the above problem can be solved by reacting an alkoxyalkyl-2-bromo-4-nitroimidazole compound with hydrogen chloride. The present invention has been completed based on such findings.

  The present invention provides a general formula

[Wherein R ¹ represents a lower alkyl group. n shows the integer of 1-3. ]
1-alkoxyalkyl-2-bromo-4-nitroimidazole represented by the formula

A method for producing 2-chloro-4-nitroimidazole represented by the formula:

  In the present invention, examples of the lower alkyl group include straight chain having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl group. Mention may be made of branched alkyl groups.

Process for producing 2-chloro-4-nitroimidazole The reaction leading to 2-chloro-4-nitroimidazole from the compound represented by the general formula (7) is carried out in the presence of hydrogen chloride in an appropriate solvent or without solvent. Done.

  The amount of hydrogen chloride used in the above reaction is not particularly limited, but it is usually at least a 2-fold mole or more, preferably a large excess with respect to the compound of general formula (7).

  Examples of the solvent used include lower alcohols such as water, methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as ethyl ether, dimethoxyethane, dioxane, tetrahydrofuran and ethylene glycol dimethyl ether; acetic acid, Examples include fatty acids such as formic acid; esters such as methyl acetate and butyl acetate; N, N-dimethylacetamide, N-methylpyrrolidone, and mixed solvents thereof.

  The above reaction usually proceeds suitably at about 0 to 150 ° C., preferably about room temperature to 100 ° C., and is generally completed in about 5 minutes to 40 hours.

  In the present invention, the compound of the general formula (7) used as the starting material compound is produced, for example, by the method shown below.

[Wherein, R ¹ and n are the same as defined above. X ¹ represents a halogen atom. X ² represents a halogen atom or a lower alkoxy group. ]
Here, as the lower alkoxy group, for example, a straight chain or branched chain having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy group and the like. A branched alkoxy group can be exemplified.

In the reaction between the compound (8) and the compound (9), when X ² represents a halogen atom, the reaction is generally carried out in a suitable solvent in the presence or absence of a basic compound.

  Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, and halogenated compounds such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Hydrocarbons, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, esters such as acetic acid, ethyl acetate, methyl acetate, butyl acetate, ketones such as acetone, methyl ethyl ketone, acetonitrile, pyridine, 2, 4,6-collidine, dimethyl sulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone (NMP), hexamethyl phosphate Amide or a mixed solvent thereof and the like.

  Examples of the basic compound include metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium, Inorganic bases such as metal alcoholates such as sodium, sodium amide, sodium methylate, sodium ethylate, pyridine, 2,4,6-collidine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [ 4.3.0] Nonene-5 (DBN), 1,8-diazabicyclo [5.4.0. And organic bases such as undecene-7 (DBU) and 1,4-diazabicyclo [2.2.2] octane (DABCO).

  The usage-amount of a basic compound is good to set it as about 1-5 mol normally with respect to 1 mol of compounds (8).

  The amount of compound (9) to be used is generally at least about equimolar, preferably about 1 to 5 mol per 1 mol of compound (8).

  The reaction is usually performed at about -50 to 200 ° C, preferably about -50 to 150 ° C. The reaction time is usually about 1 to 30 hours.

  In the reaction system of this reaction, an alkali metal halide such as sodium iodide may be added.

In the reaction of compound (8) and compound (9), when X ² represents a lower alkoxy group, camphorsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid is used instead of the basic compound under the above reaction conditions. It is preferable to use an acid such as sulfonic acid. Among these, methanesulfonic acid is preferable.

  The amount of the acid to be used is usually a catalytic amount, preferably about 0.01 to 0.2 mol, per 1 mol of compound (8).

Furthermore, P ₂ O ₅ can be present in the reaction system.

  The reaction for converting compound (10) to compound (7) is carried out in a suitable solvent in the presence of a reducing agent.

  Examples of the reducing agent used include metal sulfites such as sodium sulfite and sodium hydrogen sulfite, tetramethylammonium borohydride, tetraethylammonium hydride, tetra-n-butylammonium borohydride, tetracyanoborohydride tetra Examples thereof include hydrogenated reducing agents such as boron lower tetraalkylammonium hydrides such as n-butylammonium, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, diborane and the like.

  Examples of the solvent used include water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, diethyl ether, dimethoxyethane, tetrahydrofuran, diisopropyl ether, diglyme and 1,4-dioxane. Ethers, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, NMP or a mixed solvent thereof Can be mentioned.

  In addition, when diborane etc. are used as a reducing agent, it is good to use an anhydrous solvent.

  The amount of the reducing agent to be used is usually at least equimolar amount, preferably about 1 to 10 mol, per 1 mol of compound (10).

  The reaction is usually carried out at around 0 to 150 ° C., preferably around 0 to 120 ° C., and is generally completed in about 1 to 30 hours.

  The reaction leading compound (10) to compound (7) can be carried out in an appropriate solvent, for example, palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, chromium. It can be carried out in the presence of a catalytic hydrogen reducing agent such as copper acid, Raney nickel and palladium acetate and fatty acids such as formic acid, sodium formate, ammonium formate and sodium acetate, fatty acid ammonium or fatty acid alkali metal salts.

  As the solvent, any of the solvents used in the reaction using the hydrogenation reducing agent can be used.

  The catalytic hydrogen reducing agent is generally used in an amount of about 0.001 to 0.4 times the weight, preferably about 0.001 to 0.2 times the weight of the compound (10). The fatty acid, fatty acid ammonium or fatty acid alkali metal salt is usually used in an amount of at least about 1 mol, preferably about 1 to 20 mol, per 1 mol of the compound (10).

  These reactions usually proceed suitably at about room temperature to about 200 ° C., preferably about room temperature to about 150 ° C., and are generally completed in about 1 to 30 hours.

  In these reaction systems, amines such as triethylamine, phosphorus compounds such as tri-ortho-tolylphosphine, and the like may be added.

  The reaction for converting the compound (10) to the compound (7) can be performed in a suitable solvent in the presence of a catalytic hydrogen reducing agent.

  Examples of the contact hydrogen reducing agent include palladium, palladium acetate, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, and Raney nickel. Such a catalytic hydrogen reducing agent is usually used in an amount of about 0.02 to 1 times the weight of the compound (4).

  Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, 1,4 -Ethers such as dioxane, dimethoxyethane, tetrahydrofuran, diethyl ether, monoglyme and diglyme, esters such as methyl acetate, ethyl acetate and butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, NMP and the like Examples thereof include a protic polar solvent or a mixed solvent thereof.

  These reactions usually proceed suitably at about -20 to 100 ° C, preferably about 0 to 80 ° C, and are generally completed in about 0.5 to 20 hours. The hydrogen pressure is usually about 1 to 10 atm.

  An amine such as triethylamine is preferably added to these reaction systems, and the reaction proceeds advantageously by the addition of amines.

  Further, the reaction for converting the compound (10) to the compound (7) can be carried out in a suitable solvent in the presence of a catalyst.

  As the solvent, any of the solvents used in the reaction using the hydrogenation reducing agent can be used.

  As the catalyst, for example, palladium compounds such as palladium acetate-triphenylphosphine and tetrakis (triphenylphosphine) palladium can be used. Such a catalyst is generally used in an amount of about 0.01 to 5 mol, preferably about 0.01 to 1 mol, per 1 mol of compound (10).

  These reactions usually proceed suitably at about room temperature to about 200 ° C., preferably about room temperature to about 150 ° C., and are generally completed in about 1 to 10 hours.

  An alkylsilane compound such as triethylsilane is preferably added to these reaction systems, and the reaction proceeds advantageously by the addition of the alkylsilane compound.

  In each of the above reduction reactions, the 5-position of the imidazole ring is selectively dehalogenated to obtain the desired compound of the general formula (7).

  The target compound obtained by the method of the present invention is easily isolated and purified from the reaction mixture according to the usual isolation and purification means.

  According to the present invention, 2-chloro-4-nitroimidazole having a high yield and high purity can be produced by a simple operation by a safer method with less risk of explosion or the like.

  The following reference examples and examples will further clarify the present invention.

Reference example 1
Synthesis of 1-ethoxymethyl-2,5-dibromo-4-nitroimidazole 2,5-Dibromo-4-nitroimidazole (20.0 g, 73.8 mmol), ethylal (100 ml) and methanesulfone A mixture of acids (1.42 g, 14.8 mmol) was heated and stirred (bath temperature: 65-70 ° C., internal temperature 60 ° C., 1.5 hours). The reaction mixture was further concentrated to dryness under reduced pressure over 2 hours (using a fractionating tube). The residue was allowed to cool to room temperature, ice water (200 g) was added, and the mixture was stirred for 10 min. The crystals collected by filtration were washed with cold water and then air-dried (room temperature 3 days). Thus, 1-ethoxymethyl-2,5-dibromo-4-nitroimidazole was produced.
Yield 23.5 g (Yield 96.8%)
IR spectrum (KBr);
1532, 1491, 1464, 1397, 1365, 1344, 1315, 1273, 1248, 1127, 1106, 1054, 1020, 830.740 cm ^-1
1 H-NMR spectrum (CDCl ₃ ) δ ppm:
1.25 (t, J = 7.0 Hz, 3H), 3.64 (q, J = 7.0 Hz, 2H), 5.50 (s, 2H).

Reference example 2
Synthesis of 1-methoxymethyl-2,5-dibromo-4-nitroimidazole 2,5-Dibromo-4-nitroimidazole (20.0 g, 73.8 mmol), methylal (100 ml) and methanesulfone A mixture of acids (1.42 g, 14.8 mmol) was stirred with water cooling, and P ₂ O ₅ (21.0 g, 148 mmol) was added thereto at 42 ° C. or lower. Furthermore, the mixture was heated to reflux (43 ° C., 3 hours). The reaction mixture was concentrated to dryness under reduced pressure. The residue was allowed to cool to room temperature, ice water (200 g) was added, and the mixture was stirred for 10 min. The precipitated crystals were collected by filtration, dispersed and washed (cold water 100 ml, 0.5 hour) and air-dried (room temperature 3 days). In this way, 1-methoxymethyl-2,5-dibromo-4-nitroimidazole was produced.
Yield 21.8 g (Yield 93.8%)
IR spectrum (KBr), 1543, 1530, 1486, 1458, 1439, 1367, 1318, 1260, 1194, 1119, 1104, 1053, 1013, 912, 833, 743 cm ^-1
1 H-NMR spectrum (CDCl ₃ ) δ ppm:
3, 46 (s, 3H), 5.46 (s, 2H).

Reference example 3
Synthesis of 1-methoxymethyl-2-bromo-4-nitroimidazole 1-methoxymethyl-2,5-dibromo-4-nitroimidazole (12.5 g, 39.7 mmol) was added to dimethylformamide (100 ml). It melt | dissolved and stirred under ice-cooling (12 degreeC). Furthermore, water (50 ml) and sodium sulfite (10.0 g, 79.3 mmol) were added, and the mixture was stirred at room temperature (23-24 ° C.) for 72 hours. 5% aqueous sodium bicarbonate (50 ml) and cold water (250 ml) were added, and the mixture was extracted with ethyl acetate (250 ml, twice). The organic layer was washed with 5% brine (250 ml, twice), then dried (MgSO ₄ ) and concentrated to dryness (crystallization). In this way, 1-methoxymethyl-2-bromo-4-nitroimidazole was produced.
Yield 8.17 g (Yield 87.2%)
Light yellow crystalline HPLC 99.69%
IR spectrum (KBr);
3138, 1543, 1504, 1455, 1405, 1354, 1338, 1272, 1192, 1146, 1108, 1087, 1035, 989, 915, 824, 739, 668, 538 cm ^-1
1 H-NMR spectrum (CDCl ₃ ) δ ppm:
3.42 (s, 3H), 5.34 (s, 2H), 7.93 (s, 1H).

Reference example 4
Synthesis of 1-ethoxymethyl-2-bromo-4-nitroimidazole 1-ethoxymethyl-2,5-dibromo-4-nitroimidazole (13.1 g, 39.7 mmol) was added to dimethylformamide (100 ml). It melt | dissolved and stirred under ice-cooling (12 degreeC). Furthermore, water (50 ml) and sodium sulfite (10.0 g, 79.3 mmol) were added, and the mixture was stirred at room temperature (23-24 ° C.) for 72 hours. 5% aqueous sodium bicarbonate (50 ml) and cold water (250 ml) were added, and the mixture was extracted with ethyl acetate (250 ml, twice, 100 ml, once). The organic layer was washed with 5% brine (250 ml, twice), then dried (MgSO ₄ ) and concentrated to dryness. In this way, 1-ethoxymethyl-2-bromo-4-nitroimidazole was produced.
Yield 8.74 g (Yield 88.0%)
Slightly yellow crystalline HPLC 98.51%
IR spectrum (KBr) 3139, 2983, 1540, 1507, 1455, 1400, 1340, 1279, 1264, 1163, 1138, 1096, 1038, 1009, 991, 828, 813, 741, 671 cm ^−1
1 H-NMR spectrum (CDCl ₃ ) δ ppm:
1.25 (t, J = 7.0 Hz, 3H), 3.60 (q, J = 7.0 Hz, 2H), 5.37 (s, 2H), 7.92 (s, 1H).

Example 1
Synthesis of 2-chloro-4-nitroimidazole (one-pot method from N-protected body)
A mixture of 1-methoxymethyl-2-bromo-4-nitroimidazole (1.41 g, 5.96 mmol), concentrated hydrochloric acid (7.0 ml, concentration 35%) and water (7.0 ml) was heated and stirred ( (Bath temperature 95-100 ° C. for 15 hours). While maintaining the temperature of the reaction mixture at 50 ° C., the mixture was concentrated to dryness under reduced pressure, water (8.4 ml) was added to the residue, and the mixture was cooled and stirred (1 hour at 5 ° C.). The crystals were collected by filtration and dried by blowing (at 60 ° C. for 15 hours) to obtain 0.641 g (yield 72.9%) of the desired 2-chloro-4-nitroimidazole.
¹ H-NMR spectrum (DMSO-d ₆ ) δ ppm:
8.43 (s, 1H), 14.1 (br.s, 1H).

Example 2
Synthesis of 2-chloro-4-nitroimidazole (one-pot method from N-protected body)
A mixture of 1-ethoxymethyl-2-bromo-4-nitroimidazole (4.05 g, 16.2 mmol), concentrated hydrochloric acid (20.3 ml, concentration 35%) and water (20.3 ml) was heated and stirred ( Bath temperature 97-102 ° C. for 12 hours). The reaction mixture was concentrated to dryness under reduced pressure while maintaining the temperature at 70 ° C. Water (20 ml) was added to the residue and concentrated to dryness under reduced pressure. Furthermore, water (20 ml) was added to the residue, and the mixture was cooled and stirred (1 hour at 5 ° C.). The precipitated crystals were collected by filtration and dried (at 60 ° C. for 16 hours) to obtain 1.41 g (yield 59.0%) of the desired 2-chloro-4-nitroimidazole.
¹ H-NMR spectrum (DMSO-d ₆ ) δ ppm:
8.43 (s, 1H), 14.1 (br.s, 1H)
Further, the filtrate was concentrated to obtain 0.186 g (yield 7.8%) of 2-chloro-4-nitroimidazole.
Total yield: 66.8%

Claims (1)

General formula

[Wherein, R ¹ represents an alkyl group having 1 to 6 carbon atoms . n shows the integer of 1-3. ]
1-alkoxyalkyl-2-bromo-4-nitroimidazole represented by the formula

A method for producing 2-chloro-4-nitroimidazole represented by the formula: