CLIAMS:1. Isavuconazonium iodide hydrochloride compound of Formula IA

Formula IA

2. The compound of claim 1, wherein the purity of isavuconazonium iodide hydrochloride is more than 99 % by as measured HPLC.

3. A process for the preparation isavuconazonium iodide hydrochloride compound of Formula IA, which comprises

Formula IA
a) reacting isavuconazole compound of formula (II) or salt thereof

Formula II
with [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridine-
2-yl] carbamic acid 1-chloro-ethyl ester or salt thereof compound of formula (III)

Formula III
in presence of iodide salt, in the suitable solvent to obtain protected isavuconazonium iodide compound of formula (IV)

Formula IV
b) deprotection of protected isavuconazonium iodide compound of formula (IV) with hydrochloric acid in suitable solvent to obtain isavuconazonium iodide hydrochloride compound of Formula IA.
4. The process of claim 3, wherein the suitable solvent used in step (a) is selected from the group comprising nitrile, ether, amides, alcohol, acetates, hydrocarbon, water or mixture thereof.

5. The process of claim 3, wherein the suitable solvent used in step (b) is selected from the group comprising acetates, alcohols, amides, ether, chlorinated solvents, water or mixture thereof.

6. The suitable solvent of claim 5, contains hydrochloric acid 12% to 20% w/v.

7. The process of claim 3, wherein the iodide salt is selected from the group comprising potassium iodide and sodium iodide.

8. The process of claim 3, wherein the purity of isavuconazonium iodide hydrochloride Formula IA, having the purity more than 99 % by as measured HPLC.

9. The process according to claim 3, wherein isavuconazonium iodide hydrochloride compound of formula-IA subsequently converted to isavuconazonium or a pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of isavuconazonium iodide hydrochloride, having purity more than 99%. A further aspect of the present invention relates to conversion of isavuconazonium iodide hydrochloride to isavuconazonium sulfate. The new 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 or a pharmaceutically acceptable salt thereof having 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 don’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.

The US Pat. '238 describes the process for the preparation Isavuconazonium hydrochloride, which may be used as the key intermediate for the synthesis of isavuconazonium sulfate, compound of formula I. There are several drawbacks in the said process, which includes the use of anionic resin to prepare Isavuconazonium chloride hydrochloride, consequently it requires multiple time lyophilization, which makes the said prior art process industrially, not feasible.

The inventors of the present invention surprisingly found that Isavuconazonium or a pharmaceutically acceptable salt thereof in yield and purity could be prepared by using substantially pure intermediates in suitable solvent.

The US Pat. '238 described the process for the Isavuconazonium or a pharmaceutically acceptable salt thereof, involves the condensation of Isavuconazonium and [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1-chloro-ethyl ester.

The prior art reported process require almost 15-16 hours, whereas the present invention process requires only 8-10 hours. Inter alia prior art reported process requires too many step to prepare isavuconazonium sulfate, whereas the present invention process requires fewer steps.

Thus, an object of the present invention is to provide a process to overcome aforesaid problems and to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate.

Inventors of the present invention surprisingly also found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity as comparison to isavuconazonium sulfate prepared from Isavuconazonium chloride hydrochloride.

Summary of the Invention

The present invention provides isavuconazonium iodide hydrochloride, compound of Formula IA,

Formula IA

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 iodide hydrochloride compound of Formula IA, which includes steps of reacting isavuconazole compound of formula (II) or salt thereof with [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1-chloro-ethyl ester or salt thereof compound of formula (III) in presence of iodide salt, in the suitable solvent to obtain compound of protected isavuconazonium iodide compound of formula (IV). Deprotection of protected isavuconazonium iodide compound of formula (IV) with hydrochloric acid in suitable solvent to obtain isavuconazonium iodide hydrochloride compound of Formula IA.

In another aspect, the present invention provides isavuconazonium iodide hydrochloride, having purity greater than or equal to 99%.

Description of the Invention

In one aspect, the present invention provides isavuconazonium iodide hydrochloride, compound of Formula IA,

Formula IA

In another aspect, the present invention provides isavuconazonium iodide hydrochloride compound of Formula IA having purity more than 99 % by as measured HPLC.

In another aspect, the present invention provides a process for the preparation of isavuconazonium iodide hydrochloride compound of Formula IA,

Formula IA
which includes steps of
a) reacting isavuconazole compound of formula (II) or salt thereof

Formula II
with [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridine-
2-yl] carbamic acid 1-chloro-ethyl ester or salt thereof compound of formula (III)

Formula III
in presence of iodide salt, in the suitable solvent to obtain protected isavuconazonium iodide compound of formula (IV)

Formula IV
b) deprotection of protected isavuconazonium iodide compound of formula (IV) with hydrochloric acid in suitable solvent to obtain isavuconazonium iodide hydrochloride compound of Formula IA.

Suitable solvent used in the step (a) includes but are not limited to nitrile, ether, amides, alcohol, acetates, hydrocarbon, water or mixture thereof. The nitriles such as acetonitrile and propionitrile and the like; the ether such as methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, dioxane and the like; the amides such as dimethyl acetamide and dimethyl formamide and the like; the alcohol such as methanol, ethanol, isopropyl alcohol 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;

Suitable solvent used in the step (b) includes but are not limited to acetates, alcohols, amides, ether, chlorinated solvents, water or mixture thereof. The acetate such as ethyl acetate, propyl acetate, butyl acetate and the like; the alcohol such as methanol, ethanol, isopropyl alcohol and the like; the ether such as methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, dioxane and the like; the amides such as dimethyl acetamide and dimethyl formamide and the like; chlorinated solvents such as dichloromethane, chloroform, chlorobenzene and the like.

The used hydrochloric gas is purged in suitable solvent, wherein the percentage of hydrochloric acid in the suitable solvent is 12 to 20 % w/v.

Iodide salt used for the reaction includes but is not limited to potassium iodide and sodium iodide.

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

The isavuconazonium iodide hydrochloride compounds of formula IA can be converted into isavuconazonium sulfate compound of formula I according to general known methods in the art.

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 (compound of Formula IV)

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 followed by potassium iodide (9.9 g) was added. The reaction mixture was stirred at 47-50°C for 10-13 hour for completion after completion of the reaction the reaction mixture was to room temperature. and 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: 98%

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)
The product obtained in Example-1 was dissolved in ethyl acetate (600 ml) and reaction mixture was cooled to -5 to 0 °C. The ethyl acetate containing hydrochloric acid (150 ml, Hydrochloric acid content 14.2% w/v) solution was added in 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: 99%