DESC:FIELD OF THE INVENTION
The present invention relates to process for the preparation of Itraconazole intermediate having the structural formula (I).

BACK GROUND OF THE INVENTION
Itraconazole is an antifungal medication used for the treatment of fungal infections.

Itraconazole intermediate of formula (I) is chemically known as 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methane sulfonate.

Itraconazole and its process for preparation is first disclosed in US 4,267,179. The Itraconazole intermediate compound of formula I and its process for preparation is first disclosed in US 4,160,841.

Various synthetic routes for the preparation of Itraconazole intermediate of formula I were disclosed in US 4358449, US 4607045, WO 2000043390, CN 101302213 and KR 2009049001, Journal of medicinal chemistry 26(4), 1983, 611-613, Tetrahedron asymmetry 6(9), 1995, 2365-2368, Jingxi Huagong 22(4), 2005, 317-320. The reported process for preparation of Itraconazole intermediate of formula I suffer from many disadvantages which includes difficulty in achieving desired purity and yield. All these disadvantages effect the overall yield as well as the quality of the final product.

In view of all these disadvantages, there is a significant need in the art to develop a novel process for the preparation of highly pure Itraconazole intermediate of formula I with good yield and purity.

SUMMARY OF THE INVENTION
The present invention provides process for the preparation of Itraconazole intermediate compound of formula (I).

a) reacting cis bromo ester of compound of formula (1)

with 1,2,4-triazole compound of formula (2) in presence of base and solvents to obtain 1,2,4-triazole derivative compound of formula (3);

b) reacting 1,2,4-triazole derivative compound of formula (3) with acid salt in presence of base and solvents to obtain acid salt of 1,2,4-triazole derivative compound of formula (4);

c) converting acid salt of 1,2,4-triazole derivative compound of formula (4) in presence of base into pure 1,2,4-triazole derivative compound of formula (5);

d) reacting pure 1,2,4-triazole derivative compound of formula (5) with methane sulfonyl chloride in presence of base and solvents to obtain methane sulfonate 1,2,4-triazole derivative compound of formula (6);

e) reacting of 1,2,4-triazole derivative compound of formula (6) with acid salt in presence of base and solvents to obtain acid salt of methane sulfonate 1,2,4-triazole derivative compound of formula (7);

f) converting acid salt of 1,2,4-triazole derivative compound of formula (7) in presence of base into pure methane sulfonate 1,2,4-triazole derivative compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides the process for the preparation of Itraconazole intermediate compound of formula I.

Scheme-I illustrates the process for the preparation of Itraconazole compound of formula I.

Step I:
Reacting cis bromo ester of compound of formula (1) with 1,2,4-triazole compound of formula (2) in presence of base and solvents to obtain 1,2,4-triazole derivative compound of formula (3).
The base used in the reaction is selected from potassium carbonate, sodium carbonate or sodium hydroxide, preferably potassium carbonate.

The solvent used in the reaction is selected from dimethyl sulfoxide, water, DMF, NMP, xylene or mixture thereof, preferably dimethyl sulfoxide, toluene and water.

Step II:
Reacting 1,2,4-triazole derivative compound of formula (3) with acid in presence of solvents to obtain acid salt of 1,2,4-triazole derivative compound of formula (4).

The acid used in the reaction is selected from oxalic, maleic, acetic, fumaric, tartaric, succinic or p-toluene sulfonic acid, preferably oxalic acid.

The solvent used in the reaction is selected from from water, methanol, ethanol, aetone, IPA, toluene, chloroform or dichloromethane, preferably water and toluene.

Step III:
Converting acid salt of 1,2,4-triazole derivative compound of formula (4) in presence of base into pure 1,2,4-triazole derivative compound of formula (5).

The solvent used in the reaction is selected from water, toluene, IPA, methanol or acetone, preferably water, toluene.

The base used in the reaction is selected potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate or aqueous ammonia, preferably potassium hydroxide or potassium carbonate.

Step IV:
Reacting pure 1,2,4-triazole derivative compound of formula (5) with methane sulfonyl chloride in presence of base and solvents to obtain methane sulfonate 1,2,4-triazole derivative compound of formula (6).
The solvent used in the reaction is selected from pyridine, acetone, benzene, toluene, chloroform or dichloromethane, preferably pyridine and acetone;

The base used in the reaction is selected from pyridine and triethylamine.

Step V:
Reacting 1,2,4-triazole derivative compound of formula (6) with acid in presence of solvents to obtain acid salt of methane sulfonate 1,2,4-triazole derivative compound of formula (7).

The acid used in the reaction is selected from oxalic, maleic, acetic, fumaric, tartaric, succinic or p-toluene sulfonic acid, preferably acetic acid.

The solvent used in the reaction is selected from water, acetic acid, methanol, ethanol, toluene, chloroform or dichloromethane, preferably water, acetic acid.

Step VI:
Converting acid salt of 1,2,4-triazole derivative compound of formula (7) in presence of base into pure methane sulfonate 1,2,4-triazole derivative compound of formula (I).

The base used in the reaction is selected from aqueous potassium carbonate, sodium bicarbonate or ammonia solution.

EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example: Preparation of 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methane sulfonate

Step 1: Preparation of 1,2,4-triazole derivative compound
Cis bromo ester (100 grams, 0.22 mole), anhydrous potassium carbonate (50 grams, 0.36 mole) and 1,2,4 triazole (32.5 grams, 0.47 mole) were added to 100 mL dimethyl sulfoxide. The reaction mass was heated to 140-150 °C for 4-5 hours. After completion of the reaction, the contents were cooled to 70-80 °C. Charged 500 mL of water and 17.9 grams of NaOH and stirred the reaction for 3-4 hours. Charged 100 mL of toluene and stirred the mass for 30 minutes. After that the reaction mixture was cooled to 25-30 °C and stirred for 2 hours. Filtered and washed the wet cake with 100 mL water. The content was 86.78%, and the isomer content was 10.03%. The wet compound was purified by converting into oxalate salt by using 10% aqueous oxalic acid. Oxalate salt was converted into free base by using aqueous KOH solution to obtain “1,2,4-triazole derivative compound”. Yield: 60%.

Step 2: Preparation of 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate
Step 1 compound of 1,2,4 Triazole derivative (90 grams, 0.272 mole) was added to 90 mL Pyridine. Add methane sulfonyl chloride (37.4 grams, 0.327 mole) to the reaction mass was at 20-25 °C. The reaction mass was stirred for 1-2 hours at the same temperature. After completion of the reaction, charged 900 mL of water and stirred the mass for 2-3 hours. Filtered and washed the wet cake with 100 mL water. The wet compound was purified by converting into acetate salt by using 270 mL of Acetic acid. Acetate salt was converted into free base by using aqueous NaHCO3/K2CO3/NH3 solution to obtain “2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methane sulfonate”. Yield: 86%.
,CLAIMS:

1. A process for the preparation of Itraconazole intermediate compound of formula (I).

which comprises:
a) reacting cis bromo ester of compound of formula (1)

with 1,2,4-triazole compound of formula (2) in presence of base and solvents to obtain 1,2,4-triazole derivative compound of formula (3);

b) reacting 1,2,4-triazole derivative compound of formula (3) with acid in presence of base and solvents to obtain acid salt of 1,2,4-triazole derivative compound of formula (4);

c) converting acid salt of 1,2,4-triazole derivative compound of formula (4) in presence of base into pure 1,2,4-triazole derivative compound of formula (5);

d) reacting pure 1,2,4-triazole derivative compound of formula (5) with methane sulfonyl chloride in presence of base and solvents to obtain methane sulfonate 1,2,4-triazole derivative compound of formula (6);

e) reacting 1,2,4-triazole derivative compound of formula (6) with acid in presence of solvents to obtain acid salt of methane sulfonate 1,2,4-triazole derivative compound of formula (7);

f) converting acid salt of 1,2,4-triazole derivative compound of formula (7) in presence of base into pure methane sulfonate 1,2,4-triazole derivative compound of formula (I).

2. The process as claimed in claim 1, wherein, base is selected from the group consisting
of selected potassium hydroxide, potassium carbonate, sodium hydroxide, sodium
carbonate or aqueous ammonia, preferably potassium hydroxide or potassium
carbonate.

3. The process as claimed in claim 1, wherein, solvent is selected from the group
consisting of pyridine, acetone, benzene, toluene, chloroform or dichloromethane.

4. The process as claimed in claim 1, acid is selected from the group consisting of oxalic
acid, maleic acid, acetic acid, fumaric acid, tartaric acid, succinic acid or p-toluene
sulfonic acid.