CLIAMS:1. A process for the preparation of (R)-2-(2,5-difluorophenyl)-3-
(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol compound of Formula II,

Formula II
the process comprises the steps of,
a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent,
b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step (a),
c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture thereof.

2. The process of claim 1, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone, tetrahydrofuran and mixture thereof.

3. The process of claim 2, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide, tetrahydrofuran and mixture thereof.

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 7, wherein base is potassium t-butoxide.

9. The process of claim 1, wherein (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is converted to Isavuconazole and Isavuconazonium.

10. The process of claim 9, wherein (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 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 (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (referred hereinafter as “triazole intermediate”). In a particular aspect of the present invention relates to one pot process for the preparation of triazole intermediate, which is a key intermediate for the preparation of Isavuconazole and isavuconazonium or its salt thereof.

Background of the invention

Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole 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 (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol involves the formation of epoxide intermediate in the dimethyl sulfoxide solvent and subsequently obtains triazole compound by using strong base sodium hydride.

The reported process for the preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol involves the use of dimethyl sulfoxide solvent, which is difficult to remove by simple distillation. 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 intermediate of azole derivative.

Summary of the Invention

The present invention provides an improved process for the preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compound of Formula II,

Formula II
the process includes the steps of,
a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent,
b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step a),
c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture thereof.

In an aspect, the present invention provides conversion of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.

Description of the Invention

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

In an aspect, the present invention provides an improved process for the preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compound of Formula II,

Formula II
the process includes the steps of,
a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent,
b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step a),
c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture thereof

The 1,2,4-triazole is added with trimethylsulfoxonium iodide in a aprotic solvent at temperature between in range of 10 °C to 30 °C, then base is added to the reaction mixture. The reaction is performed in aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone, tetrahydrofuran and mixture thereof.

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.

To the above solution, 2,4-difluoro propiophenone solution in aprotic solvent at temperature between in range of 60 °C to 85 °C is added. The aprotic solvent comprises one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane, tetrahydrofuran and N-methyl-2-pyrrolidone, and mixture thereof. After completion of the reaction, the reaction mixture is quenched with water at temperature between in range of 10°C to 20°C and finally extracted with ethyl acetate. The ethyl acetate is removed under reduced pressure to get the (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol 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 (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol obtained 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 (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol to Isavuconazole and subsequently to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be carried out by know method, e.g. 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: The preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Charged (400 ml) tetrahydrofuran, (500 ml) dimethylformamide, 33.1 gm 1,2,4-triazole and 105.6 gm trimethyl sulfoxonium iodide in a flask. The reaction mixture was cooled at temperature between in range of 8 °C - 10 °C and potassium t-butoxide (102.9 gm) was added lot wise. After addition of potassium t-butoxide reaction mixture was stirred for 1 hour at room temperature. The solution of 2,4-difluoro propiophenone (108.0gm) in dimethylformamide (100 ml) was added drop wise over period of 10 minutes into the reaction mixture. The reaction mixture was further stirred for 40 minutes at room temperature and then heated to temperature between in range of 80°C - 85 °C for 6 hours.

After completion of the reaction, it was cooled to temperature 10°C and quench with water (1.2 L). Aqueous layer was extracted with ethyl acetate (1.2 L). The ethyl acetate was distilled out under reduced pressure. The crude product (140 gm) was purified by column by silica gel to get light yellowish oily of tiled compound.

Yield: 120 gm.