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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