Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 2,4-DINITROIMIDAZOLE(2,4-DNI)

Abstract

An improved process for the preparation of 2,4-Dinitroimidazole (2,4-DNI) comprising the steps of: a) Nitrating imidazole to obtain 4-nitroimidazole using nitric acid and sulphuric acid b) Nitrating 4-nitroimidazole to 1,4-Dinitroimidazole (1,4-DNI) c) Rearrangement of 1,4-DNII to 2,4-Dinitroimidazole characterized in that by the use of microwave irradiation conditions at a power level selected up to 100% in different solvents.

Full Text

FORM 2 THE PATENTS ACT 1970 COMPLETE SPECIFICATION (See Section 10) TITLE An Improved Process for the Preparation of 2,4-Dinitroimidazole(2,4-DNI) APPLICANT Prof. Akamanchi. Krishnacharya Govindacharya, Department of Pharmaceutical Sciences and Technology, Mumbai University Institute of Chemical Technology, Matunga, MUMBAI 400 019 State of Maharashtra, India, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- Original 209/MUM/2002 05/03/2002 15MAR2004 Field of Invention: The present process deals with, microwave assisted rearrangement of 1,4-dinitroimidazole (1,4-DNI) to 2,4-dinitroimidazole (2,4-DNI), a less sensitive explosive, high energy propellant and is also a useful pharmaceutical intermediate. Background and prior art: In modern ordnance there is a strong requirement for explosives having both good thermal stability, impact sensitivity, and explosive performance. However, these requirements are to some extent mutually exclusive. Those explosives having good thermal stability and impact sensitivity exhibit poorer explosive performances and vice versa. Damavarapu et ai (US Patent No: 5,387,297, 1995) found crystalline 2,4-DNI, a energetic material, to have both good thermal stability and impact insensitivity. The explosives of the prior art are generally less attractive and, unwanted because of many unintentional initiations of munitions by either impact or shock aboard cargo ships, aircraft carriers, ammunition trains, and nuclear warheads. Apart from the high energetic value, 2,4-DNI and its derivatives are well documented in the literature and studied exclusively for their pharmacological medicinal chemistry. Agrawal et. al (J. Med.chem., Vol.22, No.5, 1979, 583-586) have reported 2,4-DNI and its derivatives to be radiosensitizing agents. In the radiotherapy of cancer, the relative resistance of hypoxic cells present in solid tumors is a serious limitation in attempts to increase the therapeutic ratio between tumor and normal tissue damage. Asquith et. al (Radiat.Res., 60, -1974, 108), reported misonidazole, a nitroimidazole derivative to be an effective radiosensitizer of hypoxic cells in at least 16 different animal tumors. However, the high doses of misonidazole required were the limiting factor because of resulting neurotoxicity, convulsions, and peripheral neuropathy in relatively large number of patients. In a systematic approach to design and synthesize various analogues of nitroimidazoles, Agrawal et. al discovered 2,4-DNI as the most promising agent mainly because it exhibited good radiosensitization coupled with low toxicity and mutagenicity, which selectively sensitize hypoxic cells to lethal effects of radiation. 2,4-DNI is a valuable starting material for the synthesis of many potent chemotherapeutic agents belonging to the class of nitroimidazoxazine and nitroimidazoxazole. Stover et. al {Nature, 405, 2000, 962-966) synthesized a series of nitroimidazoxazines and found that more than 100 of these compounds exhibited, specific activity against the tubercle bacilli. PA-824 is one of the most potent compound (Figure 1). Significantly none of the active compounds have any indication of mutagenicity. Ashtekar et. al {Antimicrob. Agents. Chemother., Vol.37. 1993, 183-186.) also reported number of nitroimidazoxazoles, such as CGI-17341 to be potent anti-tubercular agent (Figure 1). Few methods are reported in the domain literature for the preparation of 2,4-DNI. Most of them are based on the thermal rearrangement of 1,4-DNI to 2,4-DNI. Damavarapu et. al (US Patent No. 5,387,297, 1995) reported the smooth transformation of 1,4-DNI to amorphous 2,4-DNI, by placing 1,4-DNI in an open beaker and heating slowly to 95-98°C for 25 mins followed by cooling to room temperature to give amorphous 2,4-DNI which was recrystallized from hot acetonitrile. S.Bulusu et.al {J.Phys.Chem., 99, 1995, 5009-5015) reported the preparation of 2,4-DNI by thermal rearrangement of 1,4-DNI at 115°C in chlorobenzene overnight, using anhydrous conditions. K. Nagarajan et. al {Indian Journal of chemistry. Vol 21B, 1982, 1022-1026) synthesized 2,4-DNI by heating a mixture of 1,4-DNI and chlorobenzene with stirring at 120-125°C for 50hours. Agrawal et.al (J.Med.Chem., Vol.22, No.5, 1979, 583-586) reported the prepration of 2,4-DNI by nitration of 2-nitroimidazole. Objective: The thermal rearrangement of 1,4-DNI to 2,4-DNI by conventional heating is well documented. However, the process suffers with the drawbacks of longer reaction times. Also the molten state rearrangement of 1,4-DNI to 2,4-DNI at 95-98°C is often not reproducible and yields amorphous form of 2,4-DNI. Our main object was to improve the prior art process overcoming the difficulties mentioned above. Summary of Invention: Accordingly, the present invention relates to an improved process for the preparation of 2,4-DNI comprising A) Nitration of imidazole to 4-nitroimidazole using nitric acid and sulphuric acid B) Nitration of 4-nitroimidazole to 1,4-dinitroimidazole (1,4-DNI) using fuming nitric acid, acetic acid, and acetic anhydride C) Microwave assisted rearrangement of 1,4-DNI to 2,4-dinitroimidazole (2,4-DNI) using different solvents. Detailed description of the invention: The above process of the invention will now be described with details of each of the above steps A) Nitration of imidazole to 4-nitroimidazole (Scheme 1) as a white solid by (Scheme 1) (i) Taking a mixture of imidazole and potassium nitrate in a round bottom flask (RBF) followed by the addition of sulphuric acid. Pouring the resultant mixture over ice, filtering the precipitated solid at pump and washing thoroughly with ice-cold water, Drying the solid and dissolving in hydrochloric acid, clarifying the solution with charcoal, followed by filtration and precipitating the 4-nitroimidazole as a white solid by addition of water. OR (ii) Taking imidazole in a round bottom flask (RBF) and cooling to 0°C. Nitrating it with sulphuric acid and nitric acid. Reaction is exothermic. Refluxing the contents for 2 hours. Isolating the formed 4-nitroimidazole by pouring the contents of the RBF in to ice-cold water with vigorous stirring. Filtering the precipitated solid at pump, washing thoroughly with ice-cold water and drying at 50°C to give 4-nitroimidazole as a white solid. B) Nitration of 4-nitroimidazole to 1,4-DNI (Scheme 2) was carried out by (Scheme 2) Taking 4-nitroimidazole in glacial acetic acid and cooling to 0°C; followed by addition of fuming nitric acid and acetic anhydride and continuing the reaction to completion by overnight stirring. Isolating the product formed by pouring the contents of flask in to ice-cold water followed by filtration. Dissolving the collected solid in solvents esters like ethyl acetate (EtOAc), ketones like methyl isobutyl ketone, halogenated solvent like chloroform. Ethyl acetate is the preferred solvent. Drying the organic layer over sodium sulphate and concentrating under reduced pressure at 40°C to give 1,4-DNI as a white solid which can be further purified by crystallization from benzene or carbontetrachloride to white needles. C) Rearrangement of 1,4-DNI to 2,4-DNI (Scheme 3) as a crystalline solid was carried out by (Scheme 3) Taking 1,4-DNI in organic solvents, hydrocarbons like xylene, toluene, halogenated solvents like chloroform, carbon tetrachloride, chlorobenzene, esters like ethyl acetate, nitriles like acetonitriie, benzonitrile, and combination of solvents chlorobenzene and benzonitrile in different ratios; chlorobenzene, benzonitrile and in combinations are the preferred solvents, irradiating in a microwave oven (Household Purpose) at 20%, 50% and 90% power level; 90% and 50% are the preferred power levels respectively, wherein the said rearrangement occurs within 10 minutes. Cooling the reaction mass to room temperature and filtering to give 2,4-DNI. Re-precipitating the mother liquor with hydrocarbons like hexanes, benzene, toluene, halogenated solvents like chloroform, "carbon tetrachloride; hexane and chloroform are the preferred solvents; to give after filtration second crop of 2,4-DNI, which can be further purified by silica gel column chromatography with EtOAc: hexane (9:1 by volume) or by recrystallization using nitriles like acetonitriie, halogenated solvents like chloroform, alcohols like ethanol, acetonitriie alone and in combination with chloroform is the preferred solvent to give 2,4-DNI as a crystalline solid. Proof of Energetic Character was carried out by Taking the purified sample and dropping a 2.5 kg weight object at various heights. At heights above 100 cm, a powerful detonation was observed of this material. This proves that said 2,4-DNI prepared by the process of present invention is an energetic material, which can be used as explosive or propellant material. Examples: The invention will now be illustrated with the help of example. Example is by way of illustration only and in no way restrict the scope of the invention. Example: Process for the synthesis of 2,4-DNI Following chemicals, reagents, and solvents used in these examples were obtained from S.D.Fine Chemicals, Mumbai Imidazole L.R. grade Nitric acid 70% Sulphuric acid 98% Glacial acetic acid Acetic anhydride Ethyl acetate Chloroform Xylene Toluene Chloroform Carbontetrachloride Chlorobenzene Acetonitrile Benzonitrile Hexane Sodium sulphate (Anhydrous) Fuming nitric acid was prepared freshly from cone, sulphuric acid and cone, nitric acid In this example the progress of all the reactions was monitored using Precoated TLC aluminium sheets silica gel F254 procured from Merck. Example 1: Preparation of 4-nitroimidazole A mixture of imidazole (10.00g, 147.00 mmotes) and potassium nitrate (29.70g, 585.29 mmoles) were charged in a 100 ml RBF. Cone. Sulphuric acid (30.00 ml) was .added slowly with stirring to the above mixture. The resultant syrupy mixture was poured over ice with vigorous stirring, and the residue washed with ice-cold water, dried and taken up in cone, hydrochloric acid. The acid solution was clarified with charcoal, filtered and the 4-nitroimidazole was precipitated by addition of water. The yield of 4-nitroimidazole is 9.64g. Melting point: 304°C, NMR (1H NMR, in DMSO-d6 + CDCI3, 11.2, 8.3, 7.8), and Mass (M+ 113). The data clearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Example 2: Preparation of 4-nitroimidazole Imidazole (10.00g, 147.00 moles) was charged in a 100 ml RBF and cooled to 0°C by external cooling in an ice-bath. Cone, nitric acid (25.00 ml) was added slowly to it, reaction is exothermic. On complete addition cone, sulphuric acid (25.00 ml) was slowly added and the colored solution was refluxed for 2hours in an efficient fume cupboard. On completion, the contents of the RBF poured in to 250.00 ml of ice-cold water with vigorous stirring. The solid precipitated was filtered at the pump and washed thoroughly with ice-cold water to give after drying 10.50 g of 4-nitroimidazole as a white solid. Melting point: 304°C, NMR (1H NMR, in DMSO-d6 + CDCI3, 11.2, 8.3, 7.8), and Mass(M+ 113). The data clearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Example 3: Preparation of 1,4-dinitroimidazole (1,4-DNI) A stirred solution of 4-nitroimidazole (10.00g, 88.5 mmoles) in 20.00 ml of glacial acetic acid was cooled to 0°C by external cooling in an ice-bath. Freshly prepared fuming nitric acid (6.50 ml) was added slowly followed by addition of 18.00 ml of acetic anhydride. Contents of the flask stirred at this temperature till complete dissolution of solid takes place and solution becomes brown (about 2 hours). Reaction mixture stirred at room temperature over night. Reaction quenched by pouring the contents in to 125.00ml of ice-cold water with vigorous stirring and the solid precipitated was filtered at the pump and washed with about 100.00ml of ice-cold water. The solid is dissolved in 50.00 ml of ethyl acetate, organic layer dried over sodium sulphate and concentrated under reduced pressure at 40°C to give 9.45g of 1,4rDNI as a white solid which can be further purified by recrystallization from benzene or carbontetrachloride to give white fine needles. Melting Point: 92°C, NMR (1H NMR, in CDCI3, 9.4 and 9.0), Mass (M+ 158) The data clearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Example 4: Preparation of 2,4-dinitroimidazole (2,4-DNI) 1,4-DNI (1.0g, 6.329 mmoles) was taken in 10.00ml of benzonitrile and irradiated in a microwave oven at 50% power level for 2mins. The reaction mixture cooled to room temperature and the solid precipitated was filtered to give 2,4-DNI. The mother liquor was precipitated with 25.00ml of hexane to give second crop of 2,4-DNf. The combined yield of 2,4-DNI is 0.88g. The solid 2,4-DNI was further purified by silica gel chromatography using ethyl acetate : hexane (9:1 by volume) to give crystalline solid The solid 2,4-DNI was also purified by recrystallization from hot acetonitrile and also by using a mixture of acetonitrile and chloroform. Melting point: 264-267°C, NMR (1H NMR, in CDCI3) 11.7 and 8.6), Mass (M+ 158) The purified material of 2,4-DNI was tested for its energetic character by dropping a 2.5 kg weight object at various heights. At heights above 100 cm, a powerful detonation was observed of this material. This proves that said 2,4-DNI prepared by the process of present invention is an energetic material, which can be used as explosive or propellant material. The data clearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Example 5: Preparation of 2,4-dinitroimidazole (2,4-DNI) 1,4-DNI (1.0g, 6.329 mmoles) was taken in 10.00ml of chlorobenzene and irradiated in a microwave oven at 90% power level for 10mins. The reaction mixture cooled to room temperature and the solid precipitated was filtered to give 2,4-DNI. The mother liquor was precipitated with 25.00ml of hexane to give second crop of 2,4-DNI. The combined yield of 2,4-DNI is 0.57g. The solid 2,4-DNI was further purified by silica gel chromatography using ethyl acetate : hexane (9:1 by volume) to give crystalline solid. The solid 2,4-DNI was also purified by recrystallization from hot acetonitrile and also by using a mixture of acetonitrile and chloroform. Melting point: 264-267°C, NMR (1H NMR, in CDCI3, 11.7 and 8.6), Mass (M+158) The purified material of 2,4-DNI was tested for its energetic character by dropping a 2.5 kg weight object at various heights. At heights above 100 cm, a powerful detonation was observed of this material. This proves that said 2,4-DNI prepared by the process of present invention is an energetic material, which can be used as explosive or propellant material. The data dearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Example 6: Preparation of 2,4-dinitroimidazole (2,4-DNI) 1,4-DNI (1.0g, 6.329 mmoles) was taken in 10.00ml of benzonitrile : chlorobenzene (3:7) and irradiated in a microwave oven at 90% power level for 5mins. The reaction mixture cooled to room temperature and the solid precipitated was filtered to give 2,4-DNI. The mother liquor was precipitated with 25.00ml of hexane to give second crop of 2,4-DNI. The combined yield of 2,4-DNI is 0.79g. The solid 2,4-DNI was further purified by silica gel chromatography using ethyl acetate : hexane (9:1 by volume) to give crystalline solid. The solid 2,4-DNI was also purified by recrystallization from hot acetonitrile and also by using a mixture of acetonitrile and chloroform. Melting point: 264-267°C, NMR (1H NMR, in CDCI3, 11.7 and 8.6), Mass (M+ 158) The purified material of 2,4-DNI was tested for its energetic character by dropping a 2.5 kg weight object at various heights. At heights above 100 cm, a powerful detonation was observed of this material. This proves that said 2,4-DNI prepared by the process of present invention is an energetic material, which can be used as explosive or propellant material. The data clearly shows that the compound formed by the process of present invention is similar to that reported by earlier workers. Advantages of the invention: The improved process of the present invention is simple, fast and less tedious compared to earlier prior art process. This is mainly because of the improvements made in the process; particularly, microwave assisted rearrangement of 1,4-DNI to crystalline 2,4-DNI which is safe, non-infringing, and requires shorter reaction times, and is simple to operate with consistent reproducible results. We claim: 1) An improved process for the preparation of 2,4-Dinitroimidazole (2,4-DNI) comprising the steps of: a) Nitrating imidazole to obtain 4-nitroimidazole using nitric acid and sulphuric acid b) Nitrating 4-nitroimidazole to 1,4-Dinitroimidazole (1,4-DNI) c) Rearrangement of 1,4-DNII to 2,4-Dinitroimidazole characterized in that by the use of microwave irradiation conditions at a power level selected up to 100% in different solvents. 2) An improved process for the preparation of 2,4-DNI as claimed in claim 1, wherein 1,4-DNI undergoes rearrangement to said 2,4-DNI under microwave irradiation conditions using house-hold microwave oven. 3) An improved process for the preparation of 2,4-DNI as claimed in claims 1 or 2, wherein the said rearrangement of 1,4-DNI to crystalline 2,4-DNI is brought about by A) Taking 1,4-DNI in dry organic solvents hydrocarbons like xylene, toluene, halogenated solvents like chloroform, chlorobenzene, carbontetrachloride, esters like ethylacetate, nitriles like acetonitrile, benzonitrile and combinations therof; and irradiating under microwave conditions at different power levels and filtering the product after cooling to room temperature to obtain said 2,4-DNI B) Purifying 2,4-DNI either by recrystallization or by chromatography such as silica gel column chromatography to obtain pure crystalline 2,4-DNI 4) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-3 wherein, the power level for microwave irradiation is selected up to 100%. 5) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-4 wherein, the solvent for microwave irradiation is selected from hydrocarbons like xylene, toluene, halogenated solvents like chloroform, carbon tetrachloride, chlorobenzene, esters like ethylacetate, nitriles like acetonitrile, benzonitrile, and combinations thereof. 6) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-5 wherein, the preferred power level is 50% for benzonitrile, 90% for chlorobenzene and 90% for mixture of chlorbenzene and benzonitrile. 7) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-6 wherein, the preferred solvent for microwave irradiation is chlorobenzene, benzonitrile and mixture of chlorobenzene and benzonitrile. 8) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-7 wherein, the rearrangement is accomplished at a temperature of reflux in chlorobenzene. 9) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-8 wherein, the rearrangement is accomplished at a temperature of 150-190°C in benzonitrile. 10) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-9 wherein, the rearrangement is accomplished at refluxing temperature of the mixture of chlorobenzene and benzonitrile. 11) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-10 wherein, the rearrangement is brought about within 10 minutes under microwave conditions. 12) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-11 wherein, the rearrangement occurs within 2 minutes under microwave irradiation in benzonitrile. 13) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-12 wherein, the rearrangement occurs within 10 minutes under microwave irradiation in chlorobenzene. 14) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-13 wherein, the rearrangement occurs within 10 minutes under microwave irradiation in a mixture of chlorobenzene and benzonitrile. 15) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-14 wherein, the said 2,4-DNI is purified by recrystallization from hot acetonitrile as crystalline solid. 16) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-15 wherein, the said 2,4-DNI is purified by recrystallization from acetonitrile and chloroform to crystalline solid. 17) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-16 wherein, the said 2,4-DNI is purified by silica gel column chromatography using ethyl acetate : hexane (9 :1 by volume) to crystalline 2,4-DNI. 18) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-17 wherein, the article contains an explosive or propellant and used as ordnance, the improvement comprising microwave irradiation of 1,4-DNI so that said 1,4-DNI undergoes rearrangement to 2,4-DNI in an amount sufficient to provide a thermally stable, shock insensitive, powerful energetic composition as the explosive or propellant. 19) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-18 wherein, the article contains a pharmaceutical substance and is adapted for use as a pharmacological medicinal agent mainly as a radiosensitizing, anti-tubercular agent, etc; comprising microwave irradiation of 1,4-DNI so that said 1,4-DNI undergoes rearrangement to 2,4-DNI in an amount sufficient to provide a pharmacological medicinal agent. 20) An improved process for the preparation of 2,4-DNI as claimed in any claims 1-19, substantially as herein described in the text and in the examples. Date: 5th March 2002.

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