CLIAMS:1. A process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-1H-1,2,4-triazole, compound of Formula II,

Formula II
the process includes the steps of,
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butane-2,3-diol with base in the organic solvent,
b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting aqueous solution of base with the reaction mixture of step b),
d) isolating 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-
1H-1,2,4-triazole from the reaction mixture thereof.

2. The process of claim 1, wherein organic solvent is selected from the group comprising one or more of chloroform, dichloromethane, dichloroethane, carbon tetrachloride and water mixture thereof.

3. The process of claim 1, wherein organic solvent is dichloromethane.

4. The process of claim 1, wherein step (a) is carried out in presence of base.

5. The process of claim 4, wherein base comprises one or more of organic base and inorganic base.

6. The process of claim 5, wherein base is organic base such as dimethylamine, diethylamine ammonia and triethylamine.

7. The process of claim 5, wherein base inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide.

8. The process of claim 1, wherein base is triethylamine and potassium carbonate.

9. The process of claim 9, wherein (1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-1H-1,2,4-triazole, is converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.
,TagSPECI:Field of Invention

The present invention relates to an improved process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (referred hereinafter “oxirane intermediate”). In a particular aspect of the present invention relates to one pot process for the preparation of oxirane intermediate, which is a key intermediate for the preparation of Isavuconazole or its salt and isavuconazonium or its salt thereof.

Background of the invention

Isavuconazole, Isavuconazonium are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US Patent Numbers 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.

The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; and has the structural formula I

Formula I
The reported process for the intermediate of triazole intermediate formula II is disclosed in the Scheme 1,

The reported process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole involves the formation of mesylate intermediate by means of mesyl chloride in dichloromethane solvent, followed by formation of oxirane intermediate using strong base sodium methoxide in methanol solvent.

The reported process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole involves additional workup and distillation step for the isolation of mesylate intermediate. However, reported process is very tedious and cumbersome. The reported process suffers one or the other problems like yield and purity due to the reagents and reaction condition.

Hence, there is a need for a simple process for making large-scale quantities of oxirane intermediate.

Summary of the Invention

The present invention provides an improved process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole, compound of Formula II,

Formula II
the process includes the steps of,
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol with base in the organic solvent,
b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting aqueous solution of base with the reaction mixture of step b),
d) isolating 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole from the reaction mixture thereof.

In an aspect, the present invention provides conversion of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole to Isavuconazole, Isavuconazonium or its salt thereof.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole, intermediates and starting materials of the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

In an aspect, the present invention provides an improved process for the preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole, compound of Formula II,

Formula II
the process includes the steps of,
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol with base in the organic solvent,
b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting aqueous solution of base with the reaction mixture of step b),
d) isolating 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole from the reaction mixture thereof.

The (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol is dissolved in a organic solvent with base at temperature between in range of 20 °C to 30 °C, followed by drop wise addition of mesyl chloride at temperature between in range of 10 °C to 15 °C. The reaction is stirred for 1 to 2 hour at temperature between in range of 15 °C to 30 °C, wherein organic solvent is selected from the group comprising one or more of chloroform, dichloromethane, dichloroethane, carbon tetrachloride and water mixture thereof.

The step (c) of the present invention involves the addition of 10% to 20 % aqueous solution of base in the reaction mixture, followed by stirring the biphasic reaction for period of 2 to 4 hour at temperature between in range of 15 °C to 30 °C.

The base may be selected from the group comprising one or more of organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably potassium t-butoxide.

Isolation involves the removal of organic solvent by means of distillation under reduced pressure to get the 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-1H-1,2,4-triazole as light yellowish oil.

In an embodiment of the invention, the step (a) to (c) may be carried out using a one-pot procedure.

After completion of the reaction, the reaction mixture may be subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like.

After completion of the reaction, the reaction mixture may be quenched quenching agent such as water. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.

In particular aspect of present invention triazole intermediate obtained 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-1H-1,2,4-triazole according to process of the invention converted to converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.

The conversion of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole to Isavuconazole and subsequently to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be carried out know method, e.g. US 6,300,353; US 6,812,238; IN 2424/MUM/2014; IN 2588/MUM/2014 and IN 3189/MUM/2014.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example-1: Preparation of 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole

Charged dichloromethane (400 ml) and (2R,3R)-2-(2,5-difluoro phenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol (40 gm) in a round bottom flask. Followed triethylamine (30 gm) was added dropwise at room temperature. Then reaction mixture was cooled at temperature between in range of 10°C to 15°C and mesyl chloride (21.2 gm) was added drop wise at temperature between in range of 10°C to 15°C to the said reaction mixture. After addition of mesyl chloride reaction was stirred for 1-2 hours at temperature between in range of 15°C to 25°C. After completion of the reaction 10 % aqueous Potassium carbonate solution (400 ml) was added in to the reaction mixture and furhter stirred for 1-2 hours at temperature between in range of 15°C to 25°C. Then dichloromethane layer was separated and dichloromethane was distillation out to get the title compound as light yellowish oily product.

Yield: 33.5 gm
HPLC Purity: > 80 %