CLIAMS:1. A stable amorphous form of Isavuconazole base, compound of Formula I,

Formula I
having purity more than 90 % when measured by HPLC

2. The stable amorphous form of Isavuconazole base of claim 1, characterized by powder X-ray diffraction pattern in accordance of Figure 1.

3. The Isavuconazole base prepared according to claim 1 may converted to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.

4. A process for the preparation of stable amorphous form of Isavuconazole base, comprising,
a) reacting thioamide compound of formula-III

Formula-III

with 4-cyano phenacyl bromide in alcohol solvent
b) removal of alcohol solvent,
c) treating residue of step b) with water and acetate solvent followed by adjusting the pH of step c) at 7 to 7.5,
d) separating and concentrating acetate solvent layer,
e) isolating Isavuconazole by adding ether solvent.

5. The process of claim 4, wherein the alcohol solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixtures thereof.

6. The process of claim 5, wherein the alcohol solvent is ethanol.

7. The process of claim 4, wherein the acetate solvent is selected from the group comprising ethyl acetate, methyl acetate, t-butyl acetate, and mixtures thereof.

8. The process of claim 7, wherein the acetate solvent is ethyl acetate.

9. The process of claim 4, wherein the ether solvent is selected group comprising methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and water or mixtures thereof .

10. The process of claim 9, wherein the ether solvent is methyl tert-butyl ether.
,TagSPECI:Field of Invention

The present invention relates to novel stable amorphous form of Isavuconazole base, having purity more than 90 %. In particular of the present invention relates to process for the preparation of novel stable amorphous form of Isavuconazole base, having purity more than 90 %.
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 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

Summary of the Invention

The present invention also provides a stable amorphous form of Isavuconazole base, compound of Formula I,

Formula I
having purity more than 90 %.

The present invention also provides a process for the preparation of stable amorphous form of Isavuconazole base, having purity more than 90 %.

The present invention also provides the conversion of Isavuconazole base to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of stable amorphous form of Isavuconazole base prepared according to Example 1.

Description of the Invention

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

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

In one another, aspect of the present invention provides a stable amorphous form of Isavuconazole base, compound of Formula I,

Formula I
having purity more than 90 % when measured by HPLC.

In another aspect, the present invention provides a stable amorphous form of Isavuconazole base, having an X-ray diffraction pattern as depicted in Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source.

The stable amorphous form of Isavuconazole base obtained as per Example 1 to the present invention was stored at 25°C for a period of 3 months and no conversion in the polymorphic form was observed.

In one another, aspect of the present invention provides the process for the preparation of stable amorphous form of Isavuconazole base, which includes the steps of
a) reacting thioamide compound of formula-III

Formula-III

with 4-cyano phenacyl bromide in alcohol solvent
b) removal of alcohol solvent,
c) treating residue of step b) with water and acetate solvent followed by adjusting the pH of step c) at 7 to 7.5,
d) separating and concentrating acetate solvent layer,
e) isolating Isavuconazole by adding ether solvent.

The process involves reaction of thioamide compound of formula-II with and 4-cyano phenacyl bromide in alcohol solvent. The reaction mixture is heated to temperature of 500C to 1000C under stirring for 1-5hours. After completion of the reaction, solvent is removed under vacuum and the reaction mass is treated with water and acetate solvent.

The pH of the reaction mixture is adjusted to 7 to 7.5 by using 10% sodium bicarbonate solution. After pH adjustment, organic layer is separated and washed with saturated solution of sodium chloride. Further organic layer is concentrated under vacuum and thus residue obtained treated with methyl tert-butyl ether. The reaction mass stir for an hour at about 400C to 500C and then cooled to temperature below 350C and product is filtered, isolated and dried to get off white to pale yellow amorphous Isavuconazole.

The alcohol solvent is selected from the group comprising methanol, ethanol, isopropyl alcohol, butanol and the like, preferably ethanol.

The acetate solvent is selected from the group comprising ethyl acetate, methyl acetate, t-butyl acetate and the like.

The ether solvent is selected from the group comprising methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like.

The reaction may be conducted at a temperature of about 40°C to about 50 °C. The reaction may be performed for a period of about 1hour to about 5 hours.

The isolation step may be performed by removal of solvent, addition of anti-solvent, cooling the reaction mixture and filtration and drying to obtain the product.

The anti-solvent includes of tertiary butyl methyl ether, hexane, pentane and the solvent having lower polarity index.

The present invention provides Isavuconazole base produced by the process of preparation of the present invention is characterized by purity greater than 90 % when measured by HPLC.

In one another, aspect of the present invention also provides the conversion of Isavuconazole base to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.

The Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be prepared according to known methods, e.g. pending Indian Patent Applications IN 2424/MUM/2014 and IN 2588/MUM/2014.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Preparation of Amorphous Isavuconazole

In a round bottomed flask charged ethanol (250 ml), thioamide compound of formula-II (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 0C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product.
Yield: 26.5 gm
HPLC purity: 92.7%