Synthesis method of valsartan - Patent - Europe PMC

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

A process for the synthesis of valsartan - Patent - …

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Document (19) is a textbook concerned with the synthesis of optically active alpha-amino acids. In a section with the title "Asymmetric Derivatization of Glycine" it describes an approach using oxazolidinones as a temporary protective group for the stereogenic centre of amino acids during alpha-alkylation. This approach was mainly developed by Seebach and co-workers and allows alpha-alkylation with a high degree of diastereoselectivity. Subsequently, the oxazolidinone is cleaved via hydrolysis to yield the desired optically active alpha-alkylated amino acids. This strategy is illustrated in reaction schemes 82-84 of document (19). The Board does not deny that a skilled person working in the field of amino acid synthesis is likely to be familiar with this concept. However, it fails to see any convincing reasons why the skilled person trying to find an alternative for the valsartan benzyl ester of example 54 would have taken document (19) into consideration. Although an amino acid moiety forms part of its structure, valsartan is not an amino acid; nor is it, with respect to the starting material in example 54, i.e. valine, a valine derivative further alkylated in alpha-position. Moreover, while the Board can appreciate that the skilled person would consider documents in the field of protective groups in organic synthesis, where he could reasonably expect to find suggestions regarding an alternative protected intermediate, for example document (18), the same cannot be said for document (19), which is not concerned with this subject-matter.

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The Board accepts the Appellant's argument that a skilled person trying to find an alternative protected intermediate for the benzyl ester of example 54 would have considered a standard textbook on protective groups in organic synthesis (document (18)). However, there he would have searched for alternative protective groups for carboxylic acids removable under the same reaction conditions as in example 54, rather than for just any alternative. In document (18) oxazolidinones are mentioned as protective groups for a carboxylic acid, in particular an amino acid, in which both functional groups are protected by incorporating them into the oxazolidinone ring. However, document (18) is entirely silent as to any possible deprotection step via hydrogenolysis, let alone via hydrogenation as described in example 54 of document (1). Nor is such a reaction disclosed in document (16), to which document (18) refers as the original paper. On the contrary, according to documents (18) and (16) removal of the protective group takes place via hydrolysis. By that means the oxazolidinone is cleaved and the unprotected alpha-amino acid with its free amino and carboxyl group is regenerated. Such a hydrolytic cleavage would be of no use for the skilled person, even if he had considered applying the chemistry outlined in document (18) and (16) to the imine intermediate of document (1) as alleged by the Appellant, since it would remove the biphenyl unit, which is an essential part of valsartan.

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Greening the Valsartan Synthesis: ..

5.3 According to the patent in suit, the problem to be solved in view of document (1) is the provision of an improved industrial process for the preparation of valsartan, which reduces costs, avoids the conversion of the cyano group in one of the last synthetic steps, and avoids the use of highly toxic butyltin derivatives.

Greening the Valsartan Synthesis: Scale-up of Key …

Concerning the reversal of steps, the reaction sequence allegedly describing the disclosure in document (1) could not be found in that document. Furthermore, starting from a compound with an unprotected carboxylic acid group completely ignored the starting point for the assessment of inventive step, namely the hydrogenation in example 54, which allegedly motivated the skilled person to look for an alternative synthesis involving hydrogenation. Hydrogenation was necessary only to remove the protecting group. Without the presence of a protective group, hydrogenation was not necessary. A combination of example 54 with the alleged reaction sequence was thus not even possible.

Patent CA2474424C - Salts of valsartan - Google Patents

5.4 However, the patent in suit does not contain any evidence of improved cost-effectiveness in the presently claimed process vis-Ã -vis document (1). Nor is the conversion of cyano in the last synthesis step avoided. According to claim 1 of the present main request, the substituent W can be cyano, which is converted after hydrogenolysis into the tetrazolyl group to yield the final product valsartan. Furthermore, since claim 1 is not restricted to specific reaction conditions, the use of highly toxic butyltin derivatives for the conversion of the cyano group is not excluded.