Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors

Patent metadata

Field	Value
Publication number	US-9802931-B2
Application number	US-201614997207-A
Country	US
Kind code	B2
Filing date	Jan 15, 2016
Priority date	Jul 15, 2011
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

The present invention relates to salts of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, to methods for making them or their precursors, to pharmaceutical compositions comprising them, and to their use as medicaments.

First claim

The invention claimed is:

1. A process for the production of a compound of formula I

or a salt thereof, the process comprising:
reacting a compound of formula II

or a salt thereof, with a compound of formula V

or a salt thereof, at elevated temperature in the presence of a base and an inert dipolar aprotic solvent,
wherein the base is (M 2 )OC(R) 3 , wherein M 2 is sodium or potassium and each R independently is C 1-6 alkyl or two R together with the carbon atom they are bound to form C 4-6 cycloalkyl, or the base is a hydroxide base,
to form the compound of formula I; and
optionally converting the compound of formula Ito a salt thereof.

2. The process according to claim 1 , wherein the base is gradually added to the reaction mixture.

3. The process according to claim 1 , wherein the base is sodium tert-butanolate or potassium tert-butanolate.

4. The process according to claim 1 , wherein the inert dipolar aprotic solvent is dimethylsulfoxide.

5. The process according to claim 4 , wherein the reaction mixture further comprises toluene.

6. The process according to claim 1 , further comprising producing the compound of formula II or the salt thereof

according to a process comprising:
a) reacting a compound of formula III

with a compound of formula IV

and/or with a compound of formula IVA

wherein M 1 is alkali and n is 1, or M 1 is earth alkali and n is 2;
in the presence of a palladium catalyst; a base selected from a carbonate base, a phosphate base, a hydroxide base, and an alcoholate base; water and an inert solvent;
to form the compound of formula II; and
b) optionally converting the compound of formula II to a salt thereof.

7. The process according to claim 6 , wherein the reaction of the compound of formula III with the compound of formula IV and/or the compound of formula IVA is carried out at a pH from 10.5 to 13.

8. The process according to claim 6 ,
wherein the inert solvent is a partly water soluble solvent;
wherein cysteine is added to the biphasic reaction mixture after formation of the compound of formula II; the phases are separated; and the compound of formula II is isolated from the non-aqueous phase.

Assignees

• Novartis Ag

Inventors

• Marterer Wolfgang
• Prashad Mahavir
• Villhauer Edwin Bernard
• Waykole Liladhar Murlidhar
• Vivelo James Anthony
• Sutter Bertrand
• Bianchi Jean-Claude
• Wu Raeann
• Har Denis
• Karpinski Piotr H
• Pignone Massimo
• Stingelin Doris
• Buerger Eckart

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title