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

Formula I
having purity more than 95 % when measured by HPLC

2. The stable crystalline form of Isavuconazole base of claim 1, characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a powder X-ray diffraction pattern having peaks at about 13.32, 13.96, 14.35, 14.75, 19.02, 21.32, 25.27 and 25.59 ± 0.2°.
iii. a powder X-ray diffraction pattern having additional peaks at about 7.87, 16.55, 19.72, 20.42, 20.90, 23.82, 24.58, 26.82, 27.35, 27.81

3. A process for the preparation of stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC, comprises the steps of
a) adding Isavuconazole hydrobromide in the halogenated solvent,
b) treating step a) mass with aqueous sodium bicarbonate solution to get clear reaction mixture,
c) separating organic layer and treated it hydrochloric acid solution,
d) isolating Isavuconazole base, having the purity more than 95%.

4. The process of claim 3, wherein the halogenated solvents are dichloromethane, chloroform carbon tetrachloride or mixtures thereof.

5. A stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,

Formula II
having purity more than 95 %

6. The stable crystalline form of Isavuconazole Hydrobromide salt of claim 5, characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 2;
ii. a powder X-ray diffraction pattern having peaks at about 6.96, 7.28, 20.70, 22.09, 23.28 and 25.56
iii. a powder X-ray diffraction pattern having additional peaks at about 11.58, 12.37, 16.43, 17.94, 19.41, 22.70, 24.90, 25.20, 26.11, 28.42 and 31.67.

7. The Isavuconazole and it hydrobromide salt prepared according to claim 1 and 5 may converted to Isavuconazole base, Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.

8. The process for the preparation of stable crystalline form of Isavuconazole Hydrobromide salt, which comprises,

a) treating the compound of Formula III

Formula-III
with 4-cyano phenacyl bromide in alcohol solvent,
b) heating of the reaction mixture,
c) isolating isavuconazole hydrobromide.

9. The process of claim 8, wherein the alcohol solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixtures thereof.

10. The process of claim 9, wherein alcohol solvent is Isopropanol.
,TagSPECI:Field of Invention

The present invention relates to novel stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC. In particular, of the present invention directs to crystalline form Isavuconazole Hydrobromide salt, having purity more than 95 % when measured by HPLC.

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 provides a novel stable crystalline form of Isavuconazole base, compound of Formula I,

Formula I
having purity more than 95 % when measured by HPLC

The present invention also provides a process for the preparation of stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC.

The present invention also provides a stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,

Formula II
having purity more than 95 %

The present invention also provides a process for the preparation of stable crystalline form of Isavuconazole Hydrobromide salt, having purity more than 95 %.

The present invention also relates to the conversion of Isavuconazole Hydrobromide to Isavuconazole base and subsequently converted into Isavuconazonium iodide hydrochloride, which is further converted into Isavuconazonium sulfate.

Brief Description of the Drawings

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

Figure 2 shows an illustrative example of X-ray powder diffraction pattern of a stable crystalline form of Isavuconazole Hydrobromide salt prepared according to Example 2.

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.

The salification is act of combining with an acid to form a salt.

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

Formula I
having purity more than 95 % when measured by HPLC.

In another aspect, the present invention provides a stable crystalline form of Isavuconazole base, having an X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 13.32, 13.96, 14.35, 14.75, 19.02, 21.32, 25.27 and 25.59 ± 0.2°.

The XRPD characteristic peaks of the stable crystalline form of Isavuconazole base, having purity more than 95 %, further defined from the Table 1:

Crystalline XRD Isavuconazole Base
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
7.87 11.22 23.22
13.32 6.64 65.36
13.96 6.34 75.27
14.35 6.16 55.81
14.75 6.00 75.06
16.55 5.35 23.98
19.02 4.66 60.03
19.72 4.50 15.62
20.42 4.34 47.22
20.90 4.24 35.32
21.32 4.16 100.00
23.82 3.73 29.98
24.58 3.62 21.71
25.27 3.52 93.43
25.59 3.48 79.90
26.82 3.32 19.98
27.35 3.26 19.46
27.81 3.20 17.27

The stable crystalline form of Isavuconazole base obtained as per Example 2 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 crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC, includes the steps of :
a) adding Isavuconazole hydrobromide in the halogenated solvent,
b) treating step a) mass with aqueous sodium bicarbonate solution to get clear reaction mixture,
c) separating organic layer and treated it hydrochloric acid solution,
d) isolating Isavuconazole base.

The step b) of the present invention involves treating step a) mass with aqueous solution of about 10 % sodium bicarbonate to get clear reaction mixture.

The step c) of the present invention involves treatment of organic layer with hydrochloric acid solution of about 1 % to about 2 %, followed by treatment with saturated solution of sodium chloride.

The halogenated solvent is selected from the group comprising dichloromethane, dichloroethane chloroform carbon tetrachloride and the like;

The process where 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 purification of the present invention is characterized by purity greater than 95 % when measured by HPLC.

In one another, aspect of the present invention provides the conversion of Isavuconazole Hydrobromide to Isavuconazole base and subsequently converted into Isavuconazonium iodide hydrochloride, which is further converted into Isavuconazonium sulfate.

In one another aspect of the present invention provides a stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,

Formula II
having purity more than 95 %.

In another aspect, the present invention provides a stable crystalline form of Isavuconazole Hydrobromide salt, having an X-ray diffraction pattern according to Figure 2, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 6.96, 7.28, 20.70, 22.09, 23.28 and 25.56 ± 0.2°.

The XRPD characteristic peaks of the stable crystalline form of Isavuconazole Hydrobromide salt further defined from the Table 1:

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
6.96 12.68 100
7.28 12.13 35.43
11.58 7.63 32.97
12.37 7.15 31.57
16.43 5.39 30.14
17.94 4.94 34.62
19.41 4.57 17.48
20.70 4.29 42.48
22.09 4.02 52.72
22.70 3.91 18.41
23.28 3.81 42.41
24.90 3.57 33.87
25.20 3.53 28.76
25.56 3.48 96.21
26.11 3.41 17.20
28.42 3.14 16.31
31.67 2.82 24.34

The stable crystalline form of Isavuconazole Hydrobromide salt obtained as per Example 3 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 crystalline form of Isavuconazole Hydrobromide salt, having purity more than 95%, comprises
a) treating the compound of Formula III

Formula-III
with 4-cyano phenacyl bromide in alcohol solvent,
b) heat of the reaction mixture,
c) isolating isavuconazole hydrobromide.

The alcohol solvent selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, or in combination thereof.

The step b) of the present invention involves heating the reaction mixture of about 30 to about 60 °C for a period of about 1hour to about 5 hours.

The term isolating includes of 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.

In one another, aspect of the present invention provides the conversion of Isavuconazole Hydrobromide salt to Isavuconazole base having HPLC purity more than 95 %.

The present invention provides Isavuconazole Hydrobromide salt produced by the process of preparation of the present invention is characterized by purity greater than 90 % more particularly greater than 95 % when measured by HPLC.

In one another, aspect of the present invention provides the conversion Isavuconazole and its Hydrobromide salt prepared according to the present invention to Isavuconazole base, 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 crystalline Isavuconazole Hydrobromide

Charged isopropanol alcohol (250 ml) followed by thioamide compound of formula-III (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 °C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 ºC to obtain off-white solid product.
Yield: 26.5 gm
HPLC Purity: 97.3%

Example-2: Preparation of crystalline Isavuconazole Base

Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.
Yield: 18.5 gm
HPLC Purity: 97%