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PREPARATION OF DIMETHYL FUMARATE

IP.com Disclosure Number: IPCOM000248534D
Publication Date: 2016-Dec-14

Publishing Venue

The IP.com Prior Art Database

Abstract

The present publication relates to processes for preparation of Dimethyl fumarate or crystalline form thereof. It further relates to uniform dimethyl fumarate particles and process thereof.

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PREPARATION OF DIMETHYL FUMARATE

Abstract

The present publication relates to processes for preparation of Dimethyl fumarate or

crystalline form thereof. It further relates to uniform dimethyl fumarate particles and

process thereof.

Introduction

Aspects of the present publication relate to processes for the preparation of

dimethyl fumarate or its crystalline form with uniform particle size distribution. The drug

compound having the adopted name “Dimethyl fumarate” has chemical name: dimethyl

(E) butane-1,4-dioate.

Dimethyl fumarate have been shown to activate the Nuclear factor (erythroid-

derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. Dimethyl

fumarate is approved for the treatment of patients with relapsing forms of multiple

sclerosis and is available in the market under the brand name TECFIDERA™ in the

United States and Europe in the form of a hard gelatin delayed-release capsules for oral

administration, containing 120 mg or 240 mg of dimethyl fumarate.

Various methods are reported for the synthesis of dimethyl fumarate in the art

such as isomerization of corresponding maleate esters or esterification of fumaric acid.

Isomerization of maleate esters can be carried out in the presence of suitable reagents

such as triphenylphosphine, PhSeSePh, PhSSPh, Al2O3, triethylamine, Co(OAc)2 and

Aminals.

Esterification of fumaric acid is the widely explored method for the synthesis of

dimethyl fumarate. Suitable catalysts that are used in esterification method include

suitable acids such as sulfuric acid, sulfonic acid or its derivatives, hydrogen halides;

Boron trifluoride-etherate complex; trialkyloxonium salts; acyl chloride; Organo-

phosphorus reagents; FeCl3; and SOCl2. Alternatively, esterification methods using other

methylation agents such as diazomethane has been employed.

The processes for the preparation of dimethyl fumarate described in the literature

do not describe or emphasize on the techniques to obtain dimethyl fumarate with desired

particle sizes or particle size distribution. There remains a need to provide economically

and industrially viable process, which avoids lengthy procedures for the preparation of

dimethyl fumarate with desired particle size and other attributes to use it directly to

prepare pharmaceutical formulations.

2

Description

Aspects of the present publication provide processes for the preparation of

dimethyl fumarate or its crystalline form with uniform particle size distribution, which are

suitable for consistent handling for drug product processing.

In an aspect, the present publication provides a process for preparing dimethyl

fumarate with uniform particle size distribution, which comprises:

a) providing a mixture of dimethyl fumarate and a suitable solvent or mixture

thereof;

b) milling the reaction mixture of step a) under suitable milling conditions;

c) subjecting the mixture of step a) or b) to ultra sound sonication and

d) recovering dimethyl fumarate with uniform particle siz...