Methods for producing viloxazine salts and novel polymorphs thereof

Patent metadata

Field	Value
Publication number	US-9403783-B2
Application number	US-201113084612-A
Country	US
Kind code	B2
Filing date	Apr 12, 2011
Priority date	Apr 12, 2010
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

Provided here are methods of manufacture of viloxazine and its various salts, as well as viloxazine-related compounds, such as novel intermediate reaction products and polymorphs thereof. In particular, the methods provide a substantially pure API of viloxazine HCl while avoiding undesirable impurities. The methods further provide for separating, identifying, and characterizing novel polymorphs of viloxazine. Further provided are methods for synthesis and identification and characterization of novel intermediates of viloxazine, as well as for some important metabolites and precursors of metabolites of viloxazine.

First claim

What is claimed is:

1. A method of manufacturing viloxazine or a pharmaceutically acceptable salt thereof, the method comprising:
(a) reacting a compound of formula

with N-benzyl-aminoethanol to form a diol compound of formula

(b) contacting said diol compound in a solvent system with a base to generate a basic system;
(c) contacting the basic system with a cyclization agent to produce a 2-substituted morpholine compound having the following formula:

wherein Et is an ethyl group and Bn is a benzyl group; and,
(d) removing the benzyl group from the 2-substituted morpholine compound to generate viloxazine, or a pharmaceutically acceptable salt thereof, with less than 2.5 ppm of an impurity selected from the group consisting of epichlorohydrin, and 1-(2-ethoxyphenoxy)-2,3-epoxypropane.

2. The method of claim 1 wherein a phase transfer catalyst is utilized in step (c).

3. The method according to claim 1 , wherein the solvent system is a liquid-liquid biphasic system or a monophasic liquid system.

4. The method of claim 1 , wherein the base is a solid.

5. The method according to claim 3 , wherein the monophasic liquid system comprises toluene.

6. The method according to claim 4 , wherein said base is sodium hydroxide.

7. The method according to claim 2 , wherein said phase transfer catalyst is benzyltriethylammonium chloride.

Assignees

• Liang Likan
• Bhatt Padmanabh P
• Dain David
• Taquet Jean-Philippe
• Pechenov Aleksandr
• Tchesnokov Alexei
• Mariaux Reynold
• Supernus Pharmaceuticals Inc

Inventors

• Liang Likan
• Bhatt Padmanabh P
• Dain David
• Taquet Jean-Philippe
• Pechenov Aleksandr
• Tchesnokov Alexei
• Mariaux Reynold

Classifications

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/26

  Psychostimulants, e.g. nicotine, cocaine · CPC title

• A61P25/32

  Alcohol-abuse · CPC title