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PROCESSES FOR THE PREPARATION OF REGORAFENIB AND AN INTERMEDIATE THEREOF

IP.com Disclosure Number: IPCOM000243674D
Publication Date: 2015-Oct-09

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides processes for the preparation of regorafenib of Formula I and an intermediate of regorafenib 4 4 amino 3 fluorophenoxy N methylpyridine 2 carboxamide of Formula VI The present disclosure further provides a process for the purification of regorafenib of Formula I

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PROCESSES FOR THE PREPARATION OF REGORAFENIB AND AN INTERMEDIATE THEREOF

Abstract

The present disclosure provides processes for the preparation of regorafenib of Formula I

Formula I

and an intermediate of regorafenib, 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide of Formula VI. The present disclosure further provides a process for the purification of regorafenib of Formula I.

Reported herein is a process for the preparation of a compound of Formula VI

Formula VI

comprising the steps of:

a)      treating a compound of  Formula II

Formula II

with a compound of Formula VIII

Formula VIII

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl

to obtain a compound of Formula III

Formula III

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl; and

b)   treating the compound of Formula III with a compound of Formula V

Formula V

to obtain the compound of Formula VI.

Further, reported herein is a process for the preparation of regorafenib of Formula I

Formula I

comprising the steps of:

a)      treating a compound of  Formula II

Formula II

with a compound of Formula VIII

Formula VIII

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl

to obtain a compound of Formula III

Formula III

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl;

b)   treating the compound of Formula III with a compound of Formula V

Formula V

to obtain a compound of Formula VI; and

Formula VI

c)   treating the compound of Formula VI with a compound of Formula VII

Formula VII

to obtain regorafenib of Formula I.

Further, reported herein is a process for the purification of a compound of Formula VI

Formula VI

comprising the steps of:

a)   treating a crude compound of Formula VI with an acid;

b)   adjusting the pH of the reaction mixture obtained in step a) with a base; and

c)   isolating the pure compound of Formula VI.

Further, reported herein is a process for the preparation of regorafenib of Formula I

Formula I

comprising the steps of:

a)      treating a crude compound of Formula VI

Formula VI

with an acid;

b)   adjusting the pH of the reaction mixture obtained in step a) with a base;

c)   isolating a pure compound of Formula VI; and

d)   treating the pure compound of Formula VI with a compound of Formula VII

Formula VII

to obtain regorafenib of Formula I.

Further, reported herein is a process for the preparation of regorafenib of Formula I

Formula I

comprising the steps of:

a)      treating a compound of  Formula II

Formula II

with a compound of Formula VIII

Formula VIII

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl

to obtain a compound of Formula III

Formula III

wherein R3 is C1-6 alkyl, phenyl, or substituted phenyl and R4 is phenyl or substituted phenyl;

b)   treating the compound of Formula III with a compound of Formula V

Formula V

to obtain a cru...