VALSARTAN « New Drug Approvals

As explained in point 5.2 above, document (1) refers to a broad range of compounds, methods for their preparation and various intermediates. Example 54 describes a multi-step synthesis of valsartan starting from (L)-valine with the carboxylic group being protected by a benzyl group. The last step in this synthesis is the removal of the benzyl group from valsartan benzyl ester to yield valsartan via hydrogenation in the presence of palladium on carbon, which is a commonly known way of removing this particular protective group. However, hydrolysis is an equally well-known method of cleaving an ester, including a benzyl ester. Incidentally, this way of removing a benzyl group is also used in document (1) (example 53). At the same time, the skilled person is well aware of the fact that the use of a different amino acid ester as starting material, for example an alkyl ester as in example 16, does not require hydrogenation in the last step. Those esters are commonly cleaved via hydrolysis. Thus, in the Board's view, no particularly suitable last reaction step in the preparation of valsartan is taught in document (1). The only conclusion which the skilled person can draw from example 54 is that hydrogenation in the presence of palladium on carbon is a suitable last step, if the final intermediate is the benzyl ester of valsartan. Accordingly, the skilled person without the benefit of hindsight has no motive for keeping the hydrogenation conditions of example 54, which are linked to the particular intermediate used therein, and at the same time replacing that particular intermediate as advocated by the Appellant.

Valsartan Intermediates, Intermediate, manufacturer, …

Process for the preparation of valsartan and intermediates thereof ..


5.11 The Appellant argued that the last step of example 54 of document (1) already pointed to hydrogenolyis as a very suitable final step in a reaction sequence leading to the target compound valsartan. According to the Appellant, taking this clear teaching as a starting point the skilled person faced with the problem of providing an alternative process for the preparation of valsartan would therefore have looked for an alternative synthesis involving a hydrogenation reaction as the last step. In particular, he would have considered an approach starting from an alternative protected final intermediate, while retaining the hydrogenation reaction of the prior-art example. To this end the skilled person would have consulted document (18), a well-known standard textbook on protective groups. In view of example 54, where the protective group was an ester, he would have focused his attention on alternative ester protective groups and in particular on those described in the context of the preparation of amino acids, since the starting compound in document (1) was an amino acid, namely valine, and valsartan could be considered as a substituted amino acid. Document (18) contained in the chapter "protection for the carboxyl group" a section called "miscellaneous esters". In this section, on page 267, oxazolidinones were mentioned as suitable protective groups for the carboxylic acid group in amino acids. These were formed via the reaction of the amino acid with an aldehyde leading to a substituted imine (or Schiff base). Addition of benzoyl chloride to the imine resulted in the formation of an oxazolidinone. According to the Appellant, the general applicability of this reaction was easily recognisable for the skilled person and was furthermore confirmed by document (16), to which document (18) referred as the original paper (page 267, second reference below the reaction scheme at the top of the page). Document (16) also explicitly referred to valine as suitable starting material in the aforementioned reaction sequence.

Patent US7378531 - Process for the preparation of valsartan

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.

27/05/2008 · Valsartan and/or its intermediates are ..
Process for the preparation of valsartan and intermediates thereof

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6306-52-1, Valsartan Intermediate, L-Valine methyl …

Other intermediates of Valsartan offered by ..