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WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

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(WO2016016766) A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM OR ITS SALT THEREOF

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to a process for the preparation of stable Isavuconazonium or its salt thereof. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, Isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide has purity more than 90%. The process is directed to preparation of solid amorphous form of isavuconazonium sulfate, isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide. The present invention process of Isavuconazonium or its salt thereof is industrially feasible, simple and cost effective to manufacture of isavuconazonium sulfate with the higher purity and better yield.

Habil Khorakiwala, chairman of Indian generic drugmaker Wockhardt

Isavuconazonium sulfate is chemically known l-[[N-methyl-N-3-[(methylamino) acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-lH-[l,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-[(lR,2R)-(2,5-Difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l ,2,4-triazol-l-yl)propyl]-l ,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II

US Ppatent 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 patent describes the process of preparation of Isavuconazonium chloride hydrochloride.

The US Pat. ‘238 described the process for the Isavuconazonium chloride hydrochloride, involves the condensation of Isavuconazole 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.

Moreover, 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.

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.

 

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

Formula I

Formula-IA

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 l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3 – [4-(4-cyanophenyl)thiazol-2-yl]butyl] – 1 H-[ 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).

Yield: 84.5 %

HPLC Purity: 87%

Mass: m/z 817.4 (M- 1)+

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

l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,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.

Yield: 93 %

HPLC Purity: 86%

Mass: m/z 717.3 (M-HC1- 1)

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 l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride in 200 ml deminerahzed 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.

Yield: 93 %

HPLC Purity: > 90%

Mass: m/z 717.4 (M- HS04) +

 

 

////////WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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