Methods for producing viloxazine salts and novel polymorphs thereof

Patent metadata

Field	Value
Publication number	US-2016304475-A1
Application number	US-201615192098-A
Country	US
Kind code	A1
Filing date	Jun 24, 2016
Priority date	Apr 12, 2010
Publication date	Oct 20, 2016
Grant date	—

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

1 . A method of manufacturing N-benzyl 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 the diol compound in a solvent system with a base to generate a basic system; and,
(c) contacting the basic system with a cyclization agent to produce N-benzyl viloxazine having the following formula:

wherein Et is an ethyl group and Bn is a benzyl group.

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

3 . The method according to claim 2 , wherein the phase transfer catalyst is benzyltriethylammonium chloride.

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

5 . The method according to claim 4 , wherein the solvent system is a liquid-liquid biphasic system.

6 . The method according to claim 5 , wherein the liquid-liquid biphasic system comprises water.

7 . The method according to claim 4 , wherein the solvent system is a monophasic liquid system.

8 . The method according to claim 7 , wherein the monophasic liquid system comprises toluene.

9 . The method according to claim 1 , wherein the base is a solid.

10 . The method according to claim 9 , wherein the base is sodium hydroxide.

11 . The method according to claim 1 , wherein the cyclization agent is a sulfonyl halide selected from the group consisting of tosyl chloride, brosyl chloride, nosyl chloride, and mesyl chloride.

12 . The method according to claim 1 , wherein the cyclization agent is toluenesulfonyl chloride and the solvent system is a liquid-liquid biphasic system.

Assignees

• 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

• A61P25/26

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

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/32

  Alcohol-abuse · CPC title