Process for the preparation of vilanterol and intermediates thereof
AssigneePerrigo Api Ltd.
InventorsVenkata Lakshmi Narasimha Rao Dammalapati, Hari Krishna Mudduluru, Ravindra Aduri
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Abstract
An improved process for the preparation of vilanterol and pharmaceutically acceptable salts thereof is disclosed. More specifically the improved process for preparing intermediates for the preparation of vilanterol is disclosed.
Claims45
An improved process for preparing vilanterol or a pharmaceutically acceptable salt thereof of Formula I;
- comprising:
- a) reacting 2,6-dichlorobenzyl halide
- (X is either F or Cl or Br or I);
- with ethylene glycol in presence of a suitable base to obtain 2-(2,6-dichlorobenzyloxy) ethanol of
- b) reacting the 2-(2,6-dichlorobenzyloxy) ethanol with 1,6-dihalo hexane of formula
- (X is either F or Cl or Br or I);
- in presence of a base and optionally in presence of a phase transfer catalyst in a suitable organic solvent to obtain 2-[2-(6-halo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene Formula XIIA,
- (X is either F or Cl or Br or I)
- c) condensing the resultant compound of Formula XIIA with (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of Formula IX,
- in presence of a suitable base and a solvent to obtain (5R)-3-{6-[2-(2,6-dichloro benzyloxy)-ethoxy]-hexyl}-5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one
- d) cleaving the compound of step (c) in presence of a suitable base and a suitable solvent to obtain 4-(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-di methyl-4H-1,3-benzodioxin-6-yl) ethanol of Formula XIV,
- e) deprotecting the compound of step (d) in presence of an acid and a suitable nonalcoholic solvent to obtain substantially pure vilanterol,
- f) optionally converting vilanterol into a pharmaceutically acceptable salt of vilanterol in a suitable nonalcoholic solvent medium.
An improved process for preparing vilanterol or a pharmaceutically acceptable salt thereof, comprising:
- a) deprotecting 4-(1R)-2-[(6-{2-[(2,6-dichloro benzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-di methyl-4H-1,3-benzodioxin-6-yl)ethanol of Formula XIV
- with a suitable acid in presence of a nonalcoholic solvents to obtain vilanterol, and
- b) optionally converting the vilanterol into a pharmaceutically acceptable salt of vilanterol in a suitable nonalcoholic solvent medium.
An improved process for preparing vilanterol or a pharmaceutically acceptable salt thereof, comprising preparing substantially pure chiral oxazolidinone intermediate of Formula IX,
- comprising:
- i) reaction of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl) ethanone of Formula V with di-tert-butyl iminodicarboxylate
- in the presence of a suitable base and an aprotic solvent to obtain di(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl imidodicarbonate of Formula VI,
- ii) deprotecting the resultant compound from step (i) in the presence of acid to obtain tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate of Formula VII,
- iii) reducing the compound of step (ii) with a suitable reducing agent in the presence of suitable chiral auxiliary to obtain substantially pure tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl carbamate of Formula VIII,
- iv) cyclisation of compound of step (iii) in presence of a suitable base and a solvent to obtain substantially pure (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, and
- v) conversion of substantially pure (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one to vilanterol or pharmaceutically acceptable salts thereof.
A process for purification of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula IX, comprising:
- a) dissolving the crude compound in a suitable solvent
- b) adding suitable anti solvent to precipitation,
- c) filtering to obtain substantially pure desired isomer.
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of Formula IX having less than 0.2% of its corresponding (S)-isomer as measured by HPLC.
Vilanterol or a pharmaceutically acceptable salt thereof having a total purity greater than 98% as measured by HPLC.
Vilanterol or a pharmaceutically acceptable salt thereof having a chiral purity greater than 98% as measured by HPLC.
Vilanterol or a pharmaceutically acceptable salt thereof is having less than 0.2% of its corresponding (S)-isomer as measured by HPLC.
Vilanterol or a pharmaceutically acceptable salt thereof containing less than 0.15% as measured by HPLC of one or more impurities.
Dependencies are inferred from the claim text.