Claims:1. One pot synthesis for the preparation of Carbimazole of formula-1,
comprising: reacting imidazole of formula-2 with dimethyl sulphate in presence of potassium carbonate in hydrocarbon solvent followed by reaction with ethyl chloroformate and sulfur in presence of diisopropylethylamine to provide Carbimazole of formula-1.

2. The process as claimed in claim 1, hydrocarbon solvent selected from toluene
or xylene or mixture thereof.

3. A process for the purification of Carbimazole of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.

4. The process as claimed in claim 3, solvent used in step-a) is selected from dichloromethane. , Description:Field of the invention:
The present invention relates to an improved one pot synthesis for the preparation of Carbimazole.

Formula-1
Background of the invention:
Carbimazole is a thioamide derivative, chemically known as Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate.
Carbimazole is an anti-thyroid agent. It is indicated in all conditions where reduction of thyroid function is required.

US2671088 patent discloses the process for the preparation of Carbimazole by reacting 1-methyl-2-mercaptoglyoxaline with ethyl chloroformate in pyridine to give Carbimazole.
Process described in US’088 patent is shown in the following scheme

The above said process has some disadvantages including the usage of excess pyridine in the reaction and also requires low temperature (0°C) to control impurities and also obtaining lower yield. Formations of impurities are more in this process and it is difficult to control in commercial scale.
Journal of Medicinal Chemistry, 2008, 51(22), 7313-7317 discloses the process for the preparation of Carbimazole by reacting 1-methylimidazole with ethyl chloroformate in tetrahydrofuran (THF) followed by reaction with elemental sulfur in presence of triethylamine to give Carbimazole, which was further purified by column chromatography using ethyl acetate/petroleum ether as eluents.
Process described in the above is shown in the following scheme.

The above said process has some disadvantages i.e. using huge volumes of costly solvent, longer reaction time and also product was purifying in column chromatography. Column chromatography purifications result in the consumption of excess solvents which increases the production cost. By considering all the above demerits, this process is not viable in commercial scale.
IN201841020459 patent discloses the process for the preparation of Carbimazole by reacting 1-methylimidazole with sulfur, ethyl chloroformate in tetrahydrofuran (THF) in presence of triethylamine to give Carbimazole.
The above said process has some disadvantages i.e. requires longer reaction time (24 hours) for the completion of reaction and low yield (63.80%). By considering the above demerits, the above said process is not viable on commercial scale.
Thus, there remains a need to develop an improved process for the preparation of Carbimazole, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Carbimazole, which is one pot, simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.

Summary of the invention
The first embodiment of the present invention provides one pot synthesis for the preparation of Carbimazole of formula-1.
The second embodiment of the present invention provides a process for the purification of Carbimazole of formula-1.

Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term "organic base" used in the present invention selected from but not limited to dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide mixtures thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the compound of formula-1 is substantially free from the impurities and having purity ranges from about 99.0% to 99.9% as measured by a liquid chromatography method.

The first embodiment of the present invention provides one pot synthesis for the preparation of Carbimazole of formula-1, comprising: reacting imidazole of formula-2 with methylating agent in presence of inorganic base and in hydrocarbon solvent followed by reaction with ethyl chloroformate and sulfur in presence of organic base to provide Carbimazole of formula-1.

and optionally purifying the compound to provide substantially pure compound of Carbimazole of formula-1.
In first aspect of first embodiment, methylating agent is selected from dimethyl sulphate, methyl iodide, methyl bromide, dimethyl carbonate, preferably dimethyl sulphate; inorganic base is selected from metal carbonates or metal bicarbonates; hydrocarbon solvent is selected from toluene or xylene or mixture thereof; organic base selected from diisopropylethylamine or triethylamine or mixture thereof; the reaction temperature ranges from about 0-50°C.
In second aspect of first embodiment, the amount of methylating agent used in range from 1.0 to 2.0 with respect to compound of formula-2; inorganic base used in the range from 2.0 to 3.0 with respect to compound of formula-2;
the amount of ethyl chloroformate used in range from 1.5 to 3.0 mole equivalent with respect to compound of formula-2; sulfur used in range from 1.0 to 1.5 mole equivalent with respect to compound of formula-2.
In third aspect of first embodiment of present invention provides one pot synthesis for the preparation of Carbimazole of formula-1, comprising: reacting imidazole of formula-2 with dimethyl sulphate in presence of potassium carbonate in toluene followed by reaction with ethyl chloroformate and sulfur in presence of diisopropylethylamine to provide Carbimazole of formula-1.

The second embodiment of the present invention provides a process for the purification of Carbimazole of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.

Dissolving compound in step-a) can be done by optionally heating the mixture to a temperature ranging from about 35°C to reflux temperature of the solvent used.
The solvent used in step-a) selected from chloro solvents or any of the mixtures thereof; “isolating” in step-b) refers to solvent removal by known techniques which are selected from distillation, decanting, filtration, centrifugation, evaporation, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, by combining with an anti-solvent; wherein anti-solvent is different from the solvent used in step-a), or by any other conventional methods known in the art. Dried the obtained solid, Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and thereof, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperature less than about 70°C, less than about 50°C, less than about 25°C, less than about 10°C, less than about 5°C, or any other suitable temperature, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

In first aspect of second embodiment of the present invention provides a process for the purification of Carbimazole of formula-1, comprising:
a) dissolving compound of formula-1 in dichloromethane,
b) filtering the substantially pure compound of formula-1.

The inventors of present invention have also carried out the preparation of
Carbimazole in tetrahydrofuran solvent and in presence triethylamine base. But these reactions have some disadvantages including low production yield and also formation of impurities was observed during the reaction which were not easily removed by simple purification processes.

By the synthetic process of present invention impurities are well controlled during the synthesis of the Carbimazole of formula-1, along with these impurities, the starting materials are also well within the controlled limit.
Further embodiment of the present invention the obtained Carbimazole of formula-1 is having the purity more than 99% by HPLC, preferably more than 99.5% by HPLC, more preferably about 99.8% by HPLC and controlled all the impurities below ICH limits.

Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Carbimazole of formula-1 on commercial scale with a high reproducibility.
• One pot synthesis for the preparation of Carbimazole of formula-1 provides environment friendly and cost-effective process which avoids the usage of excess solvent and avoids the additional workup process, filtration and drying procedures. This makes the process suitable on commercial scale.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Solvent(s) used in the present invention are recycled and reused in the process.
• Usage of low cost reactants provides cost-effective process.

The other embodiment of the present invention provides a method of treating a patient suffering from hyperthyroidism comprising administering to the patient with a therapeutically effective amount of Carbimazole obtained by the process of the present invention.

Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.

High Performance Liquid Chromatography (HPLC) analysis method:
Carbimazole and its related substances of present invention were analyzed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: end-capped octadecylsilyl silica; 5μm (or) equivalent; Wavelength: 254 nm; Flow rate: 1.0 mL/min; Injection volume: 10μL; Elution: Gradient; Mobile phase: acetonitrile, water (10:90 V/V). Test solution: Dissolve 25mg of the substance to be examined in the solvent mixture of acetonitrile, water (20:80 V/V) and dilute to 50 mL with the solvent mixture.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.

Examples:
Example-1: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and toluene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated and water was azeotropically distillated from organic layer. Ethyl chloro formate (208 g, 1.3 mole equivalent) was added to the above organic layer at 0-5°C and stirred for 1 hour at same temperature. Diisopropylethylamine (248 g, 1.3mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 261.79 g (95.69%); HPLC purity: 98.1%.
Example-2: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and toluene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated and water was azeotropically distillated from organic layer. Ethyl chloro formate (208 g, 1.3 mole equivalent) was added to the above organic layer at 0-5°C and stirred for 1 hour at same temperature. Triethylamine (194 g, 1.3 mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 249.29 g (91.12%); HPLC purity: 95.3%.
Example-3: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and toluene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated. Organic layer was completely distillated from the mixture. Tetrahydrofuran (700 ml) and ethyl chloroformate (208 g, 1.3 mole equivalent) were added to the above aqueous layer at 0-5°C and stirred for 1 hour at same temperature. Triethylamine (194 g, 1.3 mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 232.82 g (85.10%); HPLC purity: 93.5%.
Example-4: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and toluene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated. Organic layer was completely distillated from the mixture. Tetrahydrofuran (700 ml) and ethyl chloroformate (208 g, 1.3 mole equivalent) were added to the above aqueous layer at 0-5°C and stirred for 1 hour at same temperature. Diisopropylethylamine (248 g, 1.3 mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 239.55 g (87.56%), HPLC purity: 97.6%.
Example-5: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and xylene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated and water was azeotropically distillated from organic layer. Ethyl chloro formate (208 g, 1.3 mole equivalent) was added to the above organic layer at 0-5°C and stirred for 1 hour at same temperature. Diisopropylethylamine (248 g, 1.3 mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 227.70 g (83.23%); HPLC purity: 92.1%.

Example-6: Preparation of Carbimazole of formula-1
Dimethyl sulphate (278 g, 1.5 mole equivalent) and potassium carbonate (407 g, 2.0 mole equivalent) were added to the mixture of imidazole (100 g, 1 mole equivalent) and xylene (1000 ml) at room temperature and stirred for 3 hours at same temperature. Water was added to the above reaction mixture. Layers separated and water was azeotropically distillated from organic layer. Ethyl chloro formate (208 g, 1.3 mole equivalent) was added to the above organic layer at 0-5°C and stirred for 1 hour at same temperature. Triethylamine (194 g, 1.3 mole equivalent) and Sulfur (62 g, 1.3 mole equivalent) were added to the reaction mixture at room temperature and stirred for 10 hours at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 219.61 g (80.27%); HPLC purity: 91.3%.
Example-7: Purification of Carbimazole of formula-1
Carbimazole (100 g) was dissolved in dichloromethane (300 ml) at 35-40°C.
Water was added to above solution at 35-40°C and stirred for 10 minutes at the same temperature. Layers separated. Organic layer decolorized by using activated carbon. Toluene was added to the above obtained clear filtrate and stirred for 10 minutes at room temperature. Filtered the solid and dried to get the pure compound.
Yield: 95.27g (95.27%); HPLC purity: 99.9%.