Process for the introduction of hydroxyethoxy side chain in bosentan
AssigneeGenerics [UK] Limited
InventorsAbhay Gaitonde, Bindu Manojkumar, Sandeep Sonawane, Dattatrey Kokane, Sandeep Mekde, Dattatraya Shinde, Prakash Bansode
Life of this patent
Estimating the term…
Abstract
The present invention relates to an improved process for the preparation of bosentan. In particular it relates to a process for preparing bosentan substantially free from the dimer impurity of formula (II) and the 6-hydroxy impurity of formula (III). The invention also relates to a pharmaceutical composition comprising bosentan and its use in the treatment of endothelin-receptor mediated disorders.
Claims44
A process for the preparation of bosentan (I), comprising the steps of:
- (a) providing a mixture of ethylene glycol and hydroxide ions;
- (b) adding 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide to the mixture from step (a) or vice versa;
- and
- (c) isolating bosentan (I) from the mixture obtained in step (b).
A process according to any one of the preceding claims, wherein the mixture from step (b) is heated to dissolve the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide.
A process according to any one of the preceding claims, wherein the hydroxide ions are provided by an alkali metal hydroxide, an alkali earth metal hydroxide, or an ammonium hydroxide.
A process according to any one of the preceding claims, wherein the mixture from step (b) is cooled.
A process according to any one of the preceding claims, wherein an organic or inorganic acid is added to the mixture from step (b).
A process for the preparation of bosentan (I), comprising the steps of:
- (a) heating a mixture of ethylene glycol and sodium hydroxide in tetrahydrofuran until the ethylene glycol has substantially dissolved;
- (b) adding to the solution from step (a) 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide or vice versa, and heating the mixture;
- (c) cooling the mixture from step (b) and adding a solution of tartaric acid;
- and
- (d) isolating the resulting solid.
Bosentan (I) comprising less than about 0.1% of the dimer impurity (II):
Bosentan (I) comprising less than about 5% of the 6-hydroxy-sulfonamide impurity (III):
Dependencies are inferred from the claim text.