FORM 2
THE PATENT ACT 1970
&
The Patents Rules, 2003
PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
An improved process for preperation of New Methylene Blue.
2. APPLICANT
(a) NAME : Sudarshan chemical Industries Ltd.
(b) NATIONALITY.: Indian Company, registered under the provisions of
Companies Act, 1956
(c) ADDRESS : 162,WeIlesley Road, Pune 411001.
Maharastra state, India..
3. PREAMBLE TO THE DESCRIPTION

PROVISIONAL
The following specjfieationdescribes the invention.

COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

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Title: An improved process for preparation of New Methylene Blue. TECHNICAL FIELD:
The present invention relates to a process for the preparation of New Methylene Blue. More particularly, the present invention relates to a process for the preparation and isolation of New Methylene Blue by reacting N-ethyl ortho toluidine with its thiosulphonic acid derivatives insitu in presence of a suitable oxidizing agent. The expression NMB used in the specification means the compound of the present invention.
BACKGROUND AND PRIOR ART:
NMB is a valuable compound used for viral disinfection of whole blood [compare: Wainwright M, FEMS Microbiologicals 1994; 22:227-231] and also used in phenothiazine photosensitizes application [compare: M. Wainwright, Dyes and Pigments 57 (2003) 245 - 257.].
New Methylene blue is Phenothiazine derivative. The Phenothiazine derivatives have been prepared by several known methods. One such known method is described in Fundamental Process of Dye Chemistry, p. 311, New York, Interscience Publishers, Inc., 1949 - that involves nitrosation of N, N'-dimethylaniline followed by reduction using zinc in presence of dil HC1. The resultant intermediate product is reacted with sodium thiosulphite and another molecule of N, N'-dimethylaniline followed by oxidization in acid solution by potassium dichromate to obtain desired product. Another general method for substituted Phenothiazines is disclosed by Kehrmann in Ber. 49, 53 (1916),
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where in 3,7-dibromophenothiazinium bromide is reacted with excess bromine followed with N, N'-dimethyl amine gives methylene blue as bromide.
Further, an effort was made to improve purity of the product obtained from above methods. In Patent WO 2006/032879A2 described purification process of various Phenothiazine derivatives except new methylene blue, where in, purification was carried out by treatment of Sodium sulphide, Sodium carbonate, EDTA, HC1 and THF with water. These above processes do not described preparation of new methylene blue (NMB).
The preparation of New Methylene Blue is disclosed in FIAT Final Report No. 1313 and PB Report 85172, Vol. II, p. 373. In the process, it is prepared in three steps, by nitrosation of N-ethyl-o- toluidine followed by reduction of resultant 4-nitroso-N-ethyl-o- toluidine using iron in dil. HC1. The formed 4 -amino-N-ethyl-o- toluidine is oxidized with sodium dichromate and further reacted with N-ethyl o- toluidine, subsequently reacted with thiosulphonic acid and cyclized to give product. The product thus obtained having 15- 20% ash content is isolated by separating inorganic sludge followed by addition of sodium chloride from aqueous filtrate.
It has now been found that the above process described in FIAT Final Report No. 1313 and PB Report 85172, Vol. II, p. 373. can be further improved replacing Iron powder which is being used for reduction of 4- nitroso-N-ethyl o-toluidine by Zinc powder to decrease amount of inorganic salts that generates in process as a by products and inventing purification process to obtain high purity product with free from inorganic salt.
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Deficiencies of Prior Art:
(i) The prior art processes either generates more inorganic salts or
provide product contains high amount of ash contents.
(ii) The prior art processes does not provide simple purification
technique.
Object of invention
The main object of the present invention is to provide a simple process for the preparation of New Methylene Blue. Another object of the present invention is to isolate inorganic salts free material using polar organic solvents.
Still further object of the present invention is to make high purity New Methylene Blue (NMB).
Summary of invention
Accordingly invention relates to an improved process for preparation of New Methylene Blue.Invention process comprises of nitrosation of N-ethyl-ortho-toluidine to give N-Nitroso-N-ethyl-ortho-toluidine which is further converted into 4-Nitroso-N-ethyl-ortho-toluidine in presence of cone HC1. 4-Nitroso-NEOT is then reduced to give 4-amino-NEOT. This formed compound is again reacted with starting compound NEOT. Reaction product is cyclized to obtain New Methylene Blue. Formed NMB is having no or very less ash content. Thus, purification is easy.
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Description of the Present Invention:
Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or matter. Formulas of compounds used are as shown below.
The present invention relates to improved process for the preparation of NMB of formula (I) with high purity. More particularly, the present invention relates to a simple process for the preparation of New Methylene Blue. The present invention also discloses a process for the preparation of New Methylene Blue of formula (I) involves (i) nitrosation of N- Ethyl o- toluidine of formula (V) using aqueous sodium nitrite 1.1 to 1.2 mole equivalent in presence of dil. HCl 1.1 to 1.2 mole equivalent at -5°C to 10°C followed by migration of resultant product formed N-nitroso-N-ortho-toluidine of formula (IV) at -5° to 5°C in presence of Conc.HCl 4 to 5 mole equivalent to provide 4-nitroso-N-ethyl-o-toluidine of formula (III), (ii) Reduction of 4-nitroso-N-ethyl-o-toluidine in presence of Zinc powder 4-6 mole equivalent in water at 25-40°C to afford 4-amino-N-ethyl-o-toluidine of formula (II) and (iii) Reaction of 4-amino-N-ethyl-o-toluidine formula (II) without isolation from reaction mixture
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with sodium thiosulfite and N- Ethyl o- toluidine at 0-10°C followed by oxidation using sodium or potassium dichromate in presence of sulphuric acid and subsequently thiosulphonic acid derivative thus formed is further cyclized without isolating at 70-90°C in presence of copper sulphate and additional dichromate to get New Methylene Blue as shown in below scheme. The formed product NMB is then purified by dissolving in methanol at 40-45°C, filtered to remove inorganic salts, distilled off methanol to get pure product and dried under vaccum at 30-80°C till constant weight.

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Example
Preparation of N-nitroso-N-ethyl-o-toluidine of formula (IV)
In a 4 necked round bottom flask, equipped with dropping funnel and over head stirrer were placed 3-4 parts of water per mole of NEOT of formula (V) and l.l-1.2moles of commercial NaN02, stirred till dissolution and cooled it to 5-10 °C. 1 mole of N-Ethyl ortho toluidine (NEOT) was added under stirring at 5 - 10 °C. To the reaction mass, 1.1 to 1.2 moles of hydrochloric acid (35%) in 3 part water per mole of HC1 was added maintaining reaction at 5 - 10 °C during 1.5-2 hours and stir reaction mass for further 2 hours at same temp. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction; product was separated as liquid by adding 0.68 mole of sodium chloride in 98% yield of theory.
Preparation of 4-nitroso-N-ethyl-o-toluidine of formula (III)
In a 4 necked round bottom flasks equipped with dropping funnel and over head stirrer were placed 4.5 moles of 36% HC1, cooled it to -3°C to 0°C and added lmole N-nitroso-N-ethyl-o-toluidine through dropping funnel in 1- 2 hours at 0-5°C. The reaction mass was stirred for 5-6 hrs. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction; product was used for next step without isolation from reaction mass.
Preparation of New methylene blue (NMB)
In a 4 necked round bottom flasks equipped with dropping funnel and over head stirrer were placed 10 -12 part of water per lmole of 4-nitroso-N-ethyl-o-toluidine (III) and 4.4 -4.6 mole of zinc dust powder. To this mixture, abovesaid reaction mass containing 1 mole of 4-nitroso-N-ethyl-o-toluidine (III) was added drop wise at 30 to 40 "during 1 hour and stirred for further 1-2 hours at same temperature. The progress of the reaction was monitored by thin layer
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chromatography (TLC). After completion of reaction, Zinc residue filtered and washed with four times 2-3 parts of water. The combined clear filtrate was placed in another 4 necked round bottom flasks equipped with dropping funnel and over head stirrer, make up to 60-70 parts by addition of water per mole of 4-nitroso-N-ethyl-o-toluidine (III) and cooled to 0 -10 °C. In to mixture, 0.85 moles of NEOT (V), 0.17 mole cone. HC1 followed by 0.93 moles Na2S203 dissolved in 1.4 to 1.5 parts of water per 1 mole of Na2S203 were added at 5°C. Then added 1.06 mole sodium dichromate dissolved in 2-3 part water per mole of Na2Cr207 and 180gm cone. H2S04 during 15 miniatures. The reaction mass was stirred for 30 min at 10 to 20 °C and raised temperature to 25°C. Then 0.27 mole sodium dichromate dissolved in 54gm water followed 0.1 moles copper sulphate dissolved in 96gm of water were added at 25 °C. The reaction mass then heated to 80- 90 °C and stirred for 0.5 to 2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction, reaction mass filtered at 70°C through suction and washed with 500-600 ml hot water.
The combined filtrate was placed in another round bottom flask equipped with overhead stirrer. 1.23 mole HC1 (35 %) and 30 % w/v NaCl were added at 30°C and stirred for 5 hours at same temperature. The product thus obtained was filtered through suction and dried at 70 - 80 °C to get crude 240 gm. The crude product was then purified by dissolving in methanol (5ml per gm) at 40 to 45 °C, filtered to remove inorganic salts, distilled off methanol to get pure product and
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dried under vacuum at 30-80 deg C till constant weight. The NMB product weighed 206 gm which was analyzed by High performance liquid chromatography (HPLC) for its purity. The product obtained NMB of formula (I) in 85% purity along with its 15% isomer was characterized by elementary analysis, IR, UV and spectrophotometry analysis.
The embodiments of the invention as described above and the method disclosed of the present invention will suggest further modification and alterations to those skilled in the art. Such further modifications and alterations may be made without departing from the spirit and scope of the invention which is defined by the scope of the following claims.
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We Claim:
1. An improved process for preparation of New Methylene Blue (NMB) of formula (I) comprises of nitrosation of N-ethyl-o-toluidine of formula (V) using aqueous sodium nitrite 1.1 to 1.2 mole equivalent in presence of dil. HC1 1.1 to 1.2 mole equivalent at -5°C to 10°C which gives N-nitroso-N-ethyl-o-toluidine of formula (IV); which on treating with sodium nitrite with inorganic acid viz HC1, HBr, HI, H2S04 4 to 5 mole equivalent which further on treating with concentrated acid gives 4-nitroso-N-ethyl-o-toluidine of formula (III) compound; further 4-nitroso-N-ethyl-o-toluidine,of formula(III) is reduced in presence of Zinc powder 4-6 moles in water at 25-40°C to give 4-amino-N-ethyl-o-toluidine of formula (II) ; without isolation from reaction mixture 4-amino-N-ethyl-o-toluidine is further reacted, with sodium thiosulfite and N-Ethyl o- toluidine (V) at 0-10°C followed by oxidation using potassium dichromate in presence of sulphuric acid and subsequently thiosulphonic acid derivative thus formed is further cyclized without isolating at 70-90°C in presence of copper sulphate and additional dichromate to get desired product New Methylene Blue of formula (I); the collected crude product was then purified by dissolving in methanol 5ml per gm at 40 to 45 °C, filtered to remove inorganic salts, distilled off methanol to get pure product and dried under vacuum at 30-80 deg C till constant weight; the product obtained NMB of formula (I) in 85% purity along with its 15% isomer.
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(II) (I)
2. An improved process of preparing New Methylene Blue (NMB) of formula (I) as claimed in claim 1, wherein the solvent is selected for purification from the group consisting of methanol, Ethanol, IPA, dimethylformamide and dimethyl sulfoxide.
3 An improved process of preparing New Methylene Blue (NMB) of formula (I) as claimed in claim 1, wherein the oxidizing agent is selected from the group consisting of sodium dichromate, potassium dichromate
4. An improved process of preparing New Methylene Blue (NMB) of formula (I) as claimed in claim 1, wherein N-nitroso NEOT of formula (IV) is prepared in good yield using Sodium nitrite in 1.1 to 1.2 mole equivalent and inorganic acid viz. HC1, HBr, HI and H2S04 in 1.1 to 1.2 mole equivalent.
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5. An improved process of preparing New Methylene Blue (NMB) formula (I) as claimed in claim 1, wherein 4-nitroso NEOT of formula (III) is prepared in good yield with cone. HCL in 4 to 5 mole equivalent.
6.An improved process of preparing New Methylene Blue (NMB) formula (I) as claimed in claim 1 substantially as herein described with reference to the example.

Date 24h day of May 2007.

CHETAN V. GUNDECHA. (AGENT FOR THE APPLICANT)
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Abstract
This invention relates to an improved process of preperation of New Methylene Blue.New Methylene Blue is prepered by reacting N-ethyl-ortho-toluidine with its thiosulphonic acid derivatives insitu in presence of a suitable oxidizing agent. Wherein the oxidizing agent is selected from the group comprising of sodium dichromate, potassium dichromate.