Claims:1. A process for the preparation of (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile, compound of Formula II,

Formula II
the process comprises the steps of;
a) dissolving 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl) -1H-1,2,4-triazole and magnesium oxide in toluene,
b) adding the trimethylsilyl cyanide in the reaction mixture of step a),
c) treating the reaction mixture of step b), with the solution of tetra-n-butylammonium fluoride in tetrahydrofuran,
d) isolating (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol -1-yl)butanenitrile from the reaction mixture of step (c).

2. The process of claim 1, wherein (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile has the purity more than 99 %, when measured by HPLC.

3. The process of claim 1, wherein step (a) and (b) are carried out at temperature in between range of 100 ?C to 115?C.

4. The process of claim 1, wherein step (c) is carried out at temperature in between range of 5 ?C to 10 ?C.

5. The process of claim 1, 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.

, Description:Field of Invention

The present invention relates to an improved process for the preparation of (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile (referred hereinafter “hydroxyl-nitrile”). In a particular aspect of the present invention relates to one pot process for the preparation of hydroxyl-nitrile 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 preparation of (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile (referred herein after “hydroxyl-nitrile”) is depicted in Scheme-1, which involves reaction higher temperature at 135?C to 140?C in xylene solvent.

Scheme-1

However, reported process is very tedious and cumbersome. The reported process suffers one or the other problems like yield and purity due to higher temperature. Hence, there is a need for a simple process for making large-scale quantities of hydroxyl-nitrile intermediate.

Summary of the Invention

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

Formula II
the process includes the steps of,
a) dissolving 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole and magnesium oxide in toluene
b) adding the trimethylsilyl cyanide in the reaction mixture of step a),
c) treating the reaction mixture of step b), with the solution of tetra-n-butylammonium fluoride in tetrahydrofuran
d) isolating (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol -1-yl)butanenitrile from the reaction mixture of step (c)

In an another aspect, the present invention provides the (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile has purity more than 99%, when measured by HPLC.

In an aspect, the present invention provides conversion of (2S,3R)-3-(2,5-difluoro phenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile to Isavuconazole, Isavuconazonium or its salt thereof.

Description of the Invention

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

The (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butane nitrile, 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.

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

Formula II
the process includes the steps of;
a) dissolving 1-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole and magnesium oxide in toluene,
b) adding the trimethylsilyl cyanide in the reaction mixture of step a),
c) treating the reaction mixture of step b), with the solution of tetra-n-butylammonium fluoride in tetrahydrofuran,
d) isolating (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol -1-yl)butanenitrile from the reaction mixture of step (c).

The process for the preparation of (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile involve the dissolving oxirane compound and magnesium oxide in toluene at temperature between range of 25?C to 35?C. The trimethylsilyl cyanide is added under stirring to the reaction mixture. The reaction mixture is heated at temperature in between range of 105°C to 110°C with stirring for the period of 14 hours to 20 hours. After completion of reaction it is cooled to 35?C to 40 ?C temperature, filtered and washed with toluene. The filtrate is concentrated under reduced pressure and mass is dissolved in tetrahydrofuran. Further it is cooled to 5?C to 10?C, followed by addition of (1M) tetra-n-butylammonium fluoride solution in tetrahydrofuran (400 ml) at temperature of about 5?C to 10?C. The reaction mixture is further stirred for the period of 1 to 2 hours at temperature 25?C to 30 ?C. The solvent is distilled out, followed it is treated with ethyl acetate and water. The ethyl acetate layer is concentrated to get the solid mass, which further washed with hexane and dried under vacuum get the compound of invention.
In an another embodiment of present invention provides the (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile has purity more than 99%, when measured by HPLC.

In an another embodiment of present invention provides the conversion of (2S,3R)-3-(2,5-difluoro phenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile to Isavuconazole, Isavuconazonium or its salt thereof.

The conversion of (2S,3R)-3-(2,5-difluoro phenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile 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, IN 253/MUM/2015, IN 254/MUM/2015.

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 (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile

Charged 100 gm of oxirane compound (0.398 mol) and 80.2 gm magnesium oxide light (1.99 mol) in toluene 1.0 L. The reaction mixture was stirred, followed by addition of 168 gm (1.69 mol) of trimethylsilyl cyanide. The reaction mixture was heated to 105°C to 110°C with stirring for 14 to 20 hours. After that, reaction mixture was cooled to 35?C to 40 ?C, filtered it through hylfobed and wash it with toluene. The filtrate was distilled out to get the residue. The residue was dissolved in 800 ml of tetrahydrofuran and cooled it at temperature of about 5?C to 10?C, followed by slowly addition of (1M) tetra-n-butylammonium fluoride solution in tetrahydrofuran (400 ml) at temperature of about 5?C to 10?C. The reaction mixture was stirred for the period of 1 to 2 hours at temperature 25?C to 30 ?C. The solvent was distilled out, followed addition of ethyl acetate and water. The reaction mixture was stirred and organic layer was collected to distilled out solvent to get the solid, which further washed with hexane and dried under vacuum get the titled compound.

Yield: 110 gm
HPLC Purity: > 99.1%