FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
ONE POT SYNTHESIS FOR THE PREPARATION OF CLOTRIMAZOLE
M/S AMOLI ORGANICS PVT. LTD, 407 DALAMAL HOUSE, J.B.ROAD, NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under the companies Act,
1956
The following specification particularly describes and ascertains the nature of this invention and
the manner in which it is to be performed

Field Of Invention
The present invention relates to one pot synthesis for the preparation of Clotrimazole.
Clotrimazole is a broad spectrum antifungal agent that inhibits growth of pathogenic yeasts by altering the permeability of cell membranes. Hence, Clotrimazole is generally indicated for the treatment of oropharyngeal candidiasis and vaginal yeast infections, also used in fungal infection of the skin such as ring worm, athlete's foot and jock itch.
Background of the invention
Clotrimazole is chemically designated as l-(o-chlorophenyl-diphenyl-methyl)-imidazole. Its empirical formula is C22 H17CIN2. Its molecular weight is 344.837 and structural formula is;

The process for preparation of Clotrimazole has been described in few patents such as US 3660577 and US 5091540.
US Patent No. 3660577 describes the process for the preparation of (l-(o-ch!orophenyl-diphenyl-methyl)-imidazole) by reacting silver salts or alkali metal salts of imidazole with trityl halides such as o-chlorophenyl-diphenyl chloromethane in an inert solvent such as benzene, toluene, hexane, cyclohexane or diethyl ether at a temperature from about 20°C to about 110°C. The residue remained after removal of the solvent is recrystallized from benzene/light petrol. The given process is not industrially viable as the solvent benzene is used which is reported to be harmful for its carcinogenicity.

US Patent No. 5091540 describes the process for preparing Clotrimazole by reacting 2-chlorotriphenyl chloride with imidazole in a benzene solution in the presence of a neutralizing agent such as triethylamine, followed by nitration of the product for purification. The nitrate is reconverted into free base which is crystallized from acetone. The purification process in the given process of the patent is quite lengthy.
The present invention provides one pot synthesis for the preparation of Clotrimazole which is more beneficial economically and industrially favorable as compared to the processes reported in the prior art and yields quality product as per pharmacopoeial standards.
Object and Summary of the invention
The principal object of the present invention is to provide an industrially economical process for the preparation of Clotrimazole.
The present invention provides a process for the preparation of Clotrimazole which comprises-

a) Reacting o-chlorophenyl diphenyl chloromethane of Formula 2 with imidazole of Formula 3 in a solvent such as acetone or toluene and triethyl amine at reflux temperature;


a) Optionally washing the organic solvent layer with water;
b) Distilling off the solvent and crystallizing from the respective solvent to obtain Pure Clotrimazole designated as Formula 1.
Detailed Description of the Invention
The present invention provides one pot synthesis for the preparation of Clotrimazole which comprises of steps as follows:
c) Reacting o-chlorophenyl diphenyl chloromethane of Formula 2 with imidazole of Formula 3 in a solvent such as acetone or toluene and triethyl amine at reflux temperature;
d) Optionally washing the organic solvent layer with water;
e) Distilling off the solvent and crystallizing from the respective solvent to obtain Pure Clotrimazole designated as Formula 1.
The above process can be described schematically as below:


The details of the invention are further illustrated in the following examples:
Example 1
Preparation of Clotrimazole
130 g of imidazole is dissolved in 4000 mL Acetone at 25-30°C. To the solution, 194 g of Triethylamine is added and stirred for 30-45 minutes. 500 g of o-chlorophenyl diphenyl chloromethane is added to the prepared solution and reaction mass is stirred for 60-75 minutes and heated at reflux temperature for 2-3 hours. After the completion of reaction, the solution is cooled to 25-30°C and maintained for 30-45 minutes. The reaction mass is filtered and cake is washed with 500 mL acetone. Further, after it is subjected to charcoal treatment, mother liquor is concentrated by atmospheric distillation upto 1500 mL and the reaction mass is gradually cooled at 25-30°C within 2-3 hours and maintained for 1 to 1.5 hours. The reaction mass is further cooled upto 0-5°C gradually and maintained for 1 to 2 hours. The reaction mass is filtered and washed with chilled acetone. To the residue, 1500 mL water is added and reaction mass is heated at 50-55°C and maintained for 30-45 minutes. The residue is further washed with hot water and dried to obtain Pure Clotrimazole.
Yield-0.87 % WAV
% Purity = 99.5%
The X-Ray Diffraction pattern of pure Clotrimazole is shown in Figure 1.

Example 2
Preparation of Clotrimazole
26 g of imidazole is dissolved in 300 mL Toluene. To the solution, 39 g of Triethylamine is added and stirred for 15-30 minutes. 100 g of o-chlorophenyl diphenyl chloromethane is added to the prepared solution and reaction mass is stirred for 15-30 minutes and heated at reflux temperature for 2-3 hours. After the completion of reaction, the solution is cooled to 55-60°C. The reaction mass is filtered and cake is washed with 50 mL toluene. Further, the toluene layer is washed twice with water, after which it is subjected to charcoal treatment, mother liquor is concentrated by vacuum distillation upto 200 mL and the reaction mass is gradually cooled at 25-30°C within 2-3 hours and maintained for 2 to 3 hours. The reaction mass is further cooled upto 0-5°C gradually and maintained for 1 to 2 hours. The reaction mass is filtered and washed with chilled toluene. The mass is dried at 55-60°C to obtain Pure Clotrimazole,
Yield-0.79 % W/W
% Purity = 99.66%
The X-Ray Diffraction pattern of pure Clotrimazole is shown in Figure 2.

We Claim:
1) A process for the preparation of Clotrimazole which comprises-

a) Reacting o-chlorophenyl diphenyl chloromethane of Formula 2 with imidazole of Formula 3 in a solvent such as acetone or toluene and triethyl amine at reflux temperature;

b) Optionally washing the organic solvent layer with water;
c) Distilling off the solvent and crystallizing from the respective solvent to obtain Pure Clotrimazole designated as Formula 1.

2) The process as claimed in claim 1 is one-pot process.
3) The process according to claim 1, where crystallization is carried out by gradually cooling from 58-68°C to 25-30°C, maintaining for 1-1.5 hour and further cool to 0-5°C.
4) The process according to claim 1, where the purity of pure Clotrimazole is greater than 99.5 %.

5) The process according to claim 1, where Clotrimazole can be characterized by X-Ray Diffraction pattern with reflections at about 2θ (± 0.2) values 9.35, 12.63, 18.72, 19.72, 20.87, 22.71, 23.34, 24.35, 25.35, 28.27, 32.93 and 37.74.