FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
LITTLE OF THE INVENTION:
Process for the preparation of Nimorazole
2. APPLICANT (S)
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur Pharmaceuticals Pvt. Ltd.
Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. Tel No. 91-22-66499144 Fax No. 91-22-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Process for the preparation of Nimorazole
FIELD OF THE INVENTION
The present invention relates to the novel process for preparation of Nimorazole (N-2-morpholinoethyl-5-nitroimidazole). The said invention further relates to an effective isolation process for Nimorazole in highly pure form.
BACKGROUND OF THE INVENTION
Nimorazole (N-2-morpholinoethyl-5-nitroimidazole) (I) is a known as antiprotozoal drug described in Arzneimittel-Forschung (1970), 20(1), 52-55

Also known under the trade name Naxogin (Pfizer). There are various processes used in the prior art for the preparation of Nimorazole using different synthetic routes.
BE667262 disclose the reaction of sodium salt of 4(5)-nitroimidazole with 2-chloroethylmorpholine in toluene reflux for 50 hrs gives mixture of N-2-morpholinoethyl-5-nitroimidazole and N-2-morpholinoethyl-4-nitroimidazole (Scheme I), The mixture is further crystallized from water. The product isolated by such processes, invariably has the undesired isomer (N-2-morpholinoethyl-4-nitroimidazole), which is difficult to control as per ICH guideline for residual impurity. The main drawback of the process is the purity of the final product. The said process is more time and energy consuming.


US3458528 disclose the reaction of 4(5)-nitroimidazole with ethylene oxide to give l-(2'-hydroxyethyl)-5-nitroimidazole. It is further reacted with p-toluene sulfonyl chloride in pyridine to give l-(2'-p-toluenesulfonyloxyethyl)-5-nitroimidazoIe. This intermediate is further treated with morpholine to give Nimorazole (Scheme II). The reactant used in the said processes such as p-toluenesulfonyl chloride and pyridine are hazardous in nature hence such processes are environmentally unsuitable for large scale preparation.

JP49051276 disclose the reaction of sodium salt of 4(5)-nitroimidazole and chlorohydrine in N, N'-dimethylformamide at 100°C for 3 hrs followed by reaction with thionyl chloride to give a mixture of 2-chloroethyl-5-nitroimidazole and 2-chloroethyl-4-nitroimidazole. The mixture is treated with morpholine in toluene to give N-2-morphoIinoethyl-5-nitroimidazole and N-2-morpholinoethyl-4-nitroimidazole (from mother liquor) (Scheme III). The main drawback of the process is the purity of the final product. The usage of thionyl chloride and chlorohydrins on large scale preparation are environmentally hazardous.


JP51143680 disclose the reaction of 4(5)-nitroimidazole with ethylene oxide to give l-(2'~ hydroxyethyl)-5-nitroimidazole. It is further treated with phosphorous tribromide to give 2-bromoethyl-5-nitroimidazole. The 2-bromoethyl-5-nitroimidazole is treated with morpholine in N, N'-dimethylformamide to give Nimorazole (Scheme IV). The overall yield of the process is 13.7%.The final product is isolated by column chromatography on silica gel and crystallized from Isopropyl alcohol. The large scale usage of phosphorous tribromide is undesired and large scale purification by column chromatography is not feasible.

The present invention provide the novel process for preparation of Nimorazole, which is commercially viable and allows the desired product to be obtained in improved yield without using any chromatographic technique. Also it avoids the usage of any environmentally hazardous chemicals.
SUMMARY OF THE INVENTION
It is principal object of the present invention to provide the novel process for producing N-2-morpholinoethyl-5-nitroimidazole (Nimorazole) (1), wherein the drawback associated in the prior art processes are avoided.
The present invention further relates to an improved process for isolation of N-2-morpholinoethyl-5-nitroimidazole (I) in good yield (85%W/W) without using any chromatographic technique.

This and other objectives of the present invention are further attained and supported by the following embodiment described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one preferred embodiment of the present invention, there is provided a process for producing N-2-morpholinoethy]-5-nitroimidazole (I), wherein the process comprises of condensation of 4(5)-nitroimidazole (II) with 2-chloroethylmorpholine (III) in presence of single or combination of organic bases such as triethylamine, pyridine or inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or ammonia alone or mixture thereof in organic solvent like cyclohexane, toluene, xylene or methylcyclohexane alone or mixture thereof to give mixture of N-2-morphoIinoethyl-5-nitroimidazole (I) and N-2-morpholinoethyl-4-nitroimidazole (IV), followed by insitu salt preparation using organic acids such as benzenesulphonic acid, p-toluenesulphonic acid, methane sulphonic acid, oxalic acid, fumaric acid, formic acid maleic acid, succinic acid, acetic acid or benzoic acid or inorganic acids such as, hydrochloric acid, sulfuric acid or nitric acid to give mixture of acid salt of both isomer (V) and (VI).
The salts are further purified by crystallization in organic solvent such as lower alcohol like methanol, ethanol, isopropyl alcohol, amyl alcohol, n-butanol, isobutanol or lower ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone or aqueous solution or mixture thereof to give acid salt of N-2-morpholinoethyl-5-nitroirnidazole (V). The acid salt is basified to obtain pure N-2-morpholinoethyl-5-nitroimidazole (I) using organic bases such as triehtylamine, ethanolamine, piperidine or inorganic bases such as metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, aqueous ammonia or ammonia gas in single or combination thereof in presence of organic solvents such as lower alcohols like methanol, ethanol, Isopropyl alcohol, amy! alcohol, n-butanol or isobutanol or lower ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone or aqueous solution or mixture thereof. The purity of isolated product from such process is not less than 99.0%. The undesired isomer [N-2-morpholinoethyl-4-nitroimidazole] is not more than 0.15%.

In accordance with another preferred embodiment of the present invention, there is provided a process for producing N-2-morpholmoethyl-5-nitroimidazole (I), wherein the condensation, salt preparation and basification are performed in a single pot.
DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming
that, which is regarded as the invention, it is anticipated that the invention can be more readily
understood through reading the following detailed description of the invention and study of the
included example.
The present invention provides an improved process for producing N-2-morpholinoethyl-5-
nitroimidazole (I).
The process comprises the steps of:
4(5)-Nitroimidazole (II) is condensed with 2-chloroethylmorpholine (III) by employing suitable
base in single or combination of organic bases such as triethylamine, pyridine or inorganic bases
such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or
ammonia alone or mixture thereof under temperature 50- 150°C more preferably under reflux in
suitable organic solvents like cyclohexane, toluene, xylene or methylcyclohexane alone or
mixture thereof. After completion of reaction as monitored by TLC to obtain a mixture of N-2-
morpholinoethyl-5-nitroirnidazole (I) and 3 N-2-morpholinoethyl-4-nitroimidazole (IV).

a) The mixture of compound N-2-morpholinoethyl-5-nitroimidazole (I) and N-2-morpholinoethyl-4-nitroimidazole (IV) is converted in to their corresponding acid salts using organic acids such as benzenesulphonic acid, p-toluenesulphonic acid, methane sulphonic acid, oxalic acid, fumaric acid, formic acid, maleic acid, succinic acid, acetic acid or benzoic acid or

inorganic acids such as hydrochloric acid, sulfuric acid or nitric acid in organic solvents such cyclohexane, toluene, xylene, methylcyclohexane alone or mixture thereof at 0- 130°C more preferably under reflux condition to obtain the mixture of salt of both isomer ( V ) and (VI) compounds.

b) The mixture of salts (V) and (VI) are further purified by crystallization in organic solvents such as lower alcohol like methanol, ethanol, isopropyl alcohol, amyl alcohol, n-butanol, isobutanol, or lower ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone or aqueous solution or mixture thereof at 0 - 100°C to give desire acid salt of N-2-morphol in oethyl -5 -nitroimidazol e (V).
The acid salt of N-2-morpholinoethyl-5-nitroimidazole (V) is basified using organic bases such as triethylamine, ethanolamine, piperidine or inorganic base such as metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and aqueous ammonia or ammonia gas in single or combination thereof in organic solvents such as lower alcohols like methanol, ethanol, Isopropyl alcohol, amyl alcohol, n-butanol, isobutanol or lower ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone or aqueous solution or mixture thereof at 0 -80°C. The solid obtained is collected by filtration and dried to give pure Nimorazole [N-2-morpholinoethyl-5-nitroimidazole] (I) purity by HPLC Not less than 99.0%


Thus in the present invention preparation of Nimorazole [N-2-morpholinoethyl-5-nitroimidazole] (I) consist of condensation, salt preparation and purification are performed in single pot with good yield and quality.
In the process of the present invention preparation of Nimorazole [N-2-morpholinoethyl-5-nitcoimid&zole] (I) allows the desired product to obtain in high yield at least 75% w/w, preferably at least 85% w/w, Further the use of chromatographic techniques is also avoided in the present inventions, which are particularly disadvantageous from a practical point of view. The examples that are not intended to limit the scope of the invention as defined hereinabove or as claimed below:
Example-l
Preparation of Nimorazole [N-2-morpholinoethyl-5-nitroimidazole]
Toluene (30 parts), potassium carbonate (27.5 moles), 4(5)-nitroimidazole (8.85 moles) and 2-chloroethylmorpholine (17.7 moles) were heated till completion of reaction. The maleic acid (41.3 moles) was dissolved in 50% aqueous methanol (10 parts) and added in the reaction mixture. The solid was filtered and purified from 50% aqueous methanol (10 parts). The mother liquor was treated with aqueous ammonia to obtain N-2-morpholinoethyl-5-nitroimidazoIe (Melting point 110-111 °C.) (Yield: 75% w/w) (Purity: 99.0%)

CLAIMS:
l.A process for preparing Nimorazole comprising the steps of:
a) condensation of 4(5)-nitroimidazole (II) with 2-chloroethylmorpholine (III) in presence of base in organic solvent at 50 -150°C to give mixture of N-2-morpholinoethyl-5-nitroimidazole (I) and N-2-morpholinoethyl-4-nitroimidazole (IV);
b) further N-2-morpholinoethyl-5-nitroimidazole (I) and N-2-morpholinoethyl-4-nitroimidazole (IV), followed by insitu salt preparation using acid at 0- 130°C;
c) purification by crystallization of N-2-morpholinoethyl-5-nitroimidazole (I) in solvents at 0-100°C followed by treatment with base in solvent at 0- 80°C to form Nimorazole having purity more than 99.0%;

2. A process for preparing Nimorazole according to claim 1 wherein, base used for condensation is organic base such as triethylamine, pyridine or mixture thereof or inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and ammonia or mixture thereof.
3. A process for preparing Nimorazole according to claim 1 wherein, a condensing base is potassium carbonate.
4. A process for preparing Nimorazole according to claim 1 wherein, organic solvent is
cyclohexane, toluene, xylene, methylcyclohexane or mixture thereof but preferably toluene.
5. A process for preparing Nimorazole according to claim 1 wherein, solvent is toluene at reflux
temperature.

6. A process for preparing Nimorazole according to claim 1 wherein, the salt of crude product is prepared at 0 - 130°C by using organic acid such as benzenesulphonic acid, p-toluenesulphonic acid, methane sulphonic acid, oxalic acid, fumaric acid, formic acid maleic acid, succinic acid, acetic acid, benzoic acid or mixture thereof or inorganic acid such as, hydrochloric acid, sulfuric acid and nitric acid or mixture thereof.
7. A process for preparing Nimorazole according to claim 1 wherein, acid used in preparation for acid salt is maleic acid at reflux temperature.
8. A process for preparing Nimorazole according to claim 1 wherein, acid salt of both isomer N-2-morpholinoethyl-5-nitroimidazole (I) and N-2-morpholinoethyl-4-nitroimidazole (IV), are purified by crystallization at 0- 100°C by using lower alcohols such as methanol, ethanol, isopropyl alcohol, amyl alcohol, n-butanol, isobutanol or lower ketones such as acetone, methyl ethyl ketone , methyl isobutyl ketone, alone or admixture along with water.
9. A process for preparing Nimorazole according to claim 1 wherein, crystallizing solvent is aqueous methanol at reflux temperature.

10. A process for preparing Nimorazole according to claim 1 wherein, the acid salt is basified at 0- 80°C to obtain pure N-2-morphoIinoethyi-5-nitroimidazole (I) using organic base such as triethylamine, ethanolamine, piperidine in single or combinations or inorganic base such as metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and aqueous ammonia or ammonia gas in single or combinations.
11. A process for preparing Nimorazole according to claim 1 wherein, the organic base is ammonia to basify the acid salt.
12. A process for preparing Nimorazole according to claim 1 wherein, the organic solvents used in basification of salt, are lower alcohols like methanol, ethanol, isopropyl alcohol, amyl alcohol,

n-butanol, isobutanol or lower ketones like acetone, methyl ethyi ketone, methyl isobutyl ketone or aqueous solution or mixture thereof.
13. A process for preparing Nimorazole according to claim 1 wherein, organic solvent, which is
used for basification is methanol.
14. A process for preparing Nimorazole according to claim 1 wherein, the process of
condensation, salt preparation and purification by crystallization are carried out in one pot.
15. A process for preparing Nimorazole according to claim 1 wherein, the purity of Nimorazole
isolated product from such process is not less than 99.0% and the isomer, N-2-morpholinoethyl-
4-nitroimidazole (IV) is not more than 0.15%.