CLIAMS:We Claim:

1. A isolated solid form of stable isavuconazonium sulfate compound of Formula I

Formula I

2. The isavuconazonium sulfate compound of claim 1, wherein the purity of isavuconazonium sulfate is more than 90 % by as measured HPLC.

3. A process for the preparing isavuconazonium sulfate compound of Formula I,

Formula I
comprises
a) contacting isavuconazonium iodide hydrochloride compound of Formula IA

Formula IA
with anion exchange resin in the suitable solvent
b) isolation of isavuconazonium sulfate in the suitable solvent.

4. The process of claim 3, wherein the suitable solvent is selected from the group comprising alcohol, amides, ether, acetates, hydrocarbon, water or mixture thereof.

5. The process of claim 3, wherein the anion exchange resin but are not limited to selected from the group comprising Diaion™ SA10A, Diaion™ SA11A, Diaion™ SA12A, Diaion™ NSA100, Diaion™ PA308, PA306, Amberjet 4000 Cl, Amberjet 4400 Cl and Amberjet 4600 Cl.

6. The process of claim 3, wherein the purity of isavuconazonium iodide hydrochloride Formula IA, having the purity more than 86 % by as measured HPLC.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of stable isavuconazonium sulfate. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, having purity more than 90%. The process is directed to improvement in the manufacture of isavuconazonium sulfate, which would be industrially feasible and facilitate simple and cost effective manufacture of isavuconazonium sulfate with the better purity and yield.

Background of the invention

Isavuconazonium sulfate is chemically known 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium Sulfate and is structurally represented by formula (I):

Formula I
Isavuconazonium sulfate (BAL8557) is indicated for the treatment of antifungal infection. Isavuconazonium sulfate is a prodrug of Isavuconazole (BAL4815), which is chemically known 4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II
US Pat. No. 6,812,238 (referred to herein as ‘238); 7,189,858 (referred to herein as ‘858); 7,459,561 (referred to herein as ‘561) describe Isavuconazonium and its process for the preparation thereof.

The US Pat. '238 doesn’t exemplify the process of preparation of Isavuconazonium sulfate. The said patent describes the process of preparation of Isavuconazonium chloride hydrochloride. Isavuconazonium sulfate is not prepared in anywhere in the reported literature.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate. Inventors of the present invention surprisingly found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity.

Summary of the Invention

The present invention provides a solid form of isavuconazonium sulfate, compound of Formula I,

Formula I
The present invention also provides a process for the preparation of isavuconazonium iodide hydrochloride. A further aspect of the present invention relates to conversion of isavuconazonium iodide hydrochloride to isavuconazonium sulfate.

The present invention provides the process for the preparation of isavuconazonium sulfate compound of Formula I, which includes contacting isavuconazonium iodide hydrochloride compound of Formula IA with anion exchange resin in the suitable solvent and followed by isolation of isavuconazonium sulfate compound of Formula I in the suitable solvent.

In another aspect, the present invention provides isavuconazonium sulfate compound of Formula I, having purity greater than or equal to 90%.

Description of the Invention

In one aspect of the present invention provides a solid form of isavuconazonium sulfate, compound of Formula I,

Formula I

In another aspect, the present invention provides isavuconazonium sulfate, compound of Formula I, having purity more than 90 % by as measured HPLC.

In one of the embodiment the isavuconazonium Sulfate obtained by the process of present invention shown stability under standard condition of stability as described in United States Pharmacopoeia 2014.

In another aspect, the present invention provides a process for the preparation of isavuconazonium sulfate, compound of Formula I,

Formula IA
which includes steps of
a) contacting isavuconazonium iodide hydrochloride compound of Formula IA

Formula IA
with anion exchange resin in the suitable solvent
b) isolation of isavuconazonium sulfate in the suitable solvent.

In another aspect, the present invention provides isavuconazonium sulfate, compound of Formula I, having purity greater than or equal to 90%.

Suitable solvent includes but are not limited to alcohol, halogenated solvent, acetates, ether, hydrocarbon, water or mixture thereof. The alcohol such as methanol, ethanol, isopropyl alcohol and the like; the halogenated solvent such dichloromethane; the ether such as methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; the amides such as dimethyl acetamide and dimethyl formamide and the like; the acetate such as ethyl acetate, propyl acetate, butyl acetate and the like; hydrocarbon such as toluene, n-hexane, benzene, heptane and the like;

The anion exchange resin includes but are not limited to Diaion™ SA10A, Diaion™ SA11A, Diaion™ SA12A, Diaion™ NSA100, Diaion™ PA308, PA306, Amberjet 4000 Cl, Amberjet 4400 Cl and Amberjet 4600 Cl.

The isavuconazonium iodide hydrochloride compound of Formula IA can be prepared according to known methods, e.g. pending Indian Patent Application IN 2424/MUM/2014.

The process of the present invention is depicted in the following scheme:

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: Synthesis of 1-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium iodide

Isavuconazole (20 g) and [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxy methyl)pyridine-2-yl]carbamic acid 1-chloro-ethyl ester (24.7 g) were dissolved in acetonitrile (200ml). The reaction mixture was stirred to add potassium iodide (9.9 g). The reaction mixture was stirred at 47-50°C for 10-13 hour. The reaction mixture was cooled to room temperature. The reaction mass was filtered through celite bed and washed acetonitrile. Residue was concentrated under reduced pressure to give the crude solid product (47.7 g). The crude product was purified by column chromatography to get its pure iodide form (36.5 g).
Mass: m/z 817.4 (M- I)+
Yield: 84.5 %
Purity: 87%

Example-2: Synthesis of 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium iodide hydrochloride (compound of Formula IA)

1-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium iodide (36.5 g) was dissolved in ethyl acetate (600 ml). The reaction mixture was cooled to -5 to 0 °C. The ethyl acetate hydrochloride (150 ml) solution was added to reaction mixture. The reaction mixture was stirred for 4-5 hours at room temperature. The reaction mixture was filtered and obtained solid residue washed with ethyl acetate. The solid dried under vacuum at room temperature for 20-24 hrs to give 32.0 gm solid.
Mass: m/z 717.3 (M-HCl- I)+
Yield: 93 %
Purity: 86%

Example-3: Preparation of Strong anion exchange resin (Sulfate).

Indion GS-300 was treated with aqueous sulfate anion solution and then washed with DM water. It is directly used for sulfate salt.

Example-4: Synthesis of 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium iodide hydrochloride in 200 ml demineralized water and 30 ml methanol. The solution was cooled to about 0 to 5°C. The strong anion exchange resin (sulfate) was added to the cooled solution. The reaction mixture was stirred to about 60-80 minutes. The reaction was filtered and washed with 50ml of demineralized water and methylene chloride. The aqueous layer was lyophilized to obtain (8.0 g) white solid.
Mass: m/z 717.4 (M- HSO4) +
Yield: 93 %
Purity: > 90%