6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid, e.g. 6-methyl-2-amino-isonicotinic acid and its methyl ester or N,N-dimethyl amide (WO 2010115836, WO 2012045803 and WO 2013149926), are important intermediates in the manufacture of pharmaceutically active ingredients.
The known chemical syntheses of 2-amino-pyridines offer only limited access to 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid and all face severe drawbacks that do not allow for supply of these important intermediates at larger or industrial scale. Therefore, there has been a need to develop a novel approach to these compounds. The present invention provides a simple and selective approach to these intermediates which in addition is scalable.
Up to date, the following methods for the preparation of 2-amino-pyridines have been described:
One of the most widely used amination methods for construction of 2-aminopyridine moiety is substitution of 2-halopyridines and analogues with ammonia or an equivalent under high temperature (150-250° C.) and pressure, or under palladium or copper catalyzed conditions with involvement of sealed autoclave or tube. These conditions limit the use of this protocol at large or industrial scale.
6-methyl-2-amino-isonicotinic acid can be prepared in moderate yield by converting 6-methyl-2-chloro-isonicotinic acid into 6-methyl-2-amino-isonicotinic acid under high pressure and high temperature in an autoclave (WO 2012045803 and SCHEME 1). The disadvantages are high pressure, high temperature and use of an autoclave.

Although the Chichibabin Reaction gives 2-aminopyridines directly from pyridines, it is rarely used in industrial scope because of low yields and poor functional group tolerance.
Another synthetic approach to 2-aminopyridines employs pyridine-N-oxides (SCHEME 2). Treatment of pyridine-N-oxides with activating agents enhances the electrophilic character of the 2-position, thus allowing for nucleophilic addition of ammonia (Org. Lett., 2010, 12, 5254-5257) or its equivalent (like tert-butylamine, J. Org. Chem., 2007, 72, 4554-4557). Disadvantages of this approach are that pyridines have to be converted to the corresponding pyridine-N-oxides constituting an additional synthesis step and that 4-amino-pyridines are formed as side products.

Another method is to construct the 2-aminopyridine moiety using 1,3-dione derivatives or equivalents and 3-amino-3-imino-propanoic ester or amide (Heterocycles, 1976, 5, 255-260; Tetrahedron Lett., 1994, 35, 5775-5778; WO 2006059103; Tetrahedron, 2007, 63, 4491-4496). However, this method has only been applied to the synthesis of 4-,6-alkyl substituted nicotinic acid derivatives and not to the synthesis of 2-amino-isonicotinic acid derivatives (SCHEME 3).

The present invention provides a general process for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid that overcomes the disadvantages of these methods known in the prior art.
The process according to the present invention does not require the use of ammonia or equivalents, high temperature or high pressure and selectively delivers 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid in a short reaction sequence with good yields and without transition metal wastes.