Browse Prior Art Database

An Efficient Process for the Amide Bond Formation in Basmisanil

IP.com Disclosure Number: IPCOM000244762D
Publication Date: 2016-Jan-11
Document File: 2 page(s) / 539K

Publishing Venue

The IP.com Prior Art Database

Related People

Stefan Hildbrand: AUTHOR

Abstract

An efficient and high yielding process for the amide bond formation in basmisanil using 1,1'-carbonyl-diimidazole for activation and lithium carbonate as base is described.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 54% of the total text.

Page 01 of 2

An Efficient Process for the Amide Bond Formation in Basmisanil

Stefan Hildbrand1

F. Hoffmann-La Roche Ltd., Small Molecules Technical Development, Grenzacherstrasse 124, 4070 Basel, Switzerland

Issued: January 11, 2016

ABSTRACT: An efficient and high yielding process for the amide bond formation in basmisanil using 1,1'-carbonyl-diimidazole for activation and lithium carbonate as base is described.

INTRODUCTION

   Basmisanil (INN) 1 − also known as RG1662 or RO5186582 − is an orally active and highly selective inverse agonist/negative allosteric modulator of α5 subunit-containing GABAA receptors and is currently under development by F. Hoffmann-La Roche for the treatment of cognitive impairment associated with Down syndrome.2

   The last chemical step in the synthesis of basmisanil 1 is the amide bond formation between the nicotinic acid derivative 2 and thiomorpholine-1,1'-dioxide hydrochloride (3) (Scheme 1). In WO 2013/057123 two different reaction conditions − both using 1,1'-carbonyl- diimidazole (CDI) for activation − were described.3

Scheme 1: Two different coupling conditions described for the amide bond formation in 1.

Conditions I:

CDI, DMAP, NEt3 THF, reflux, 50 h (92% yield)

Conditions II:

CDI, LiOtBu THF/DMF, 40 °C, 3 h (97% yield)

   Both conditions have been successfully applied for the production of multi ten kilogram quantities of basmisanil 1 for clinical trials. Nonetheless, both conditions are not suitable for further scale up. While CDI was found to be the best coupling agent, triethylamine or lithium tert-butoxide as base are both not optimal. Triethylamine is not strong enough to completely release thiomorpholine-1,1'-dioxide from its hydrochloride salt 3 and hence leads to in- complete conversions. Lithium tert-butoxide on the other hand, is prone to oxidation and bears the risk of forming the tert-butyl ester of 2 as a side product. Herein, we report improved conditions for this transformation.

1 Corresponding author: stefan.hildbrand@roche.com.


2 WO 2009/071476 (F. Hoffmann-La Roche); WO 2012/059482 (F. Hoffmann-La Roche).
3 WO 2013/057123 (F. Hoffmann-La Roche), example 26 (page 50).

Page 1 of 2

O O

N N

HCl

O

     S
N

O

N

O

N

O

+

H

O

O

        S
N
O

F F

O

O

H

2 3 1


Page 02 of 2

RESULTS

   An extensive base screening revealed that lithium carbonate overcomes the obstacles de- scribed above. Surprisingly, it was found, that only 0.56 equivalents (related to 2) of lithium carbonate are sufficient to drive the coupling to completion. The reaction is conveniently conducted in solvent mixtures of tetrahydrofuran (THF) with...