Nipecotic acid moiety

Compound 1 was the first cyclopentane-based NK-1 receptor antagonist development candidate at Merck. It contains five stereocenters a central core possessing three contiguous all-trans stereocenters, a pendent bis(trifluoromethyl)-benzyHc ether, and a nipecotic acid moiety (Figure 7.1). Key to the successful preparation of 1 was construction of the trans, trans-cyclopentyl core and installation of the unsymmetrical secondary-secondary (sec-sec) ether. The preparation of 1 is the focus of this chapter. 

Novel sets of lipophilic molecules that do not contain the nipecotic acid moiety, have been shown to have higher affinity for GAT2 and GAT4 than for GATl and GAT3... 

The ethyl ester (13) was saponified with ethanolic sodium hydroxide no racemization of the nipecotic acid moiety accompanied this transformation. The product was extracted with methylene chloride, the solvent was evaporated and residue was redissolved in toluene. Treatment with stoichiometric quantities of methanol followed by chlorotrimethylsi-lane yielded the anhydrous product. This method was demonstrated to be generally useful for the isolation of hydrochloride salts under anhydrous conditions. ... 

Many polar active molecules, selected through in vitro screening tests are unable to cross the biomembranes and their bioavailability is particularly low. Attaching a very lipophilic moiety can sometimes help to overcome this drawback. A typical example is given by the development of the anticonvulsant drug thiagabine starting from nipecotic acid (Fig. 19.48). Cyclic amino acids such as... 

The completion of the synthesis of 1 required installation of the (R)-nipecotic moiety. The original method used (R)-ethyl nipecotate L-tartrate 21, which was commercially available, but the availability of this intermediate on multi-kilogram scale required long lead times and cost was a major factor. In addition, it was also discovered that saponification of the ethyl ester in the final stages of the synthesis, as shown in Scheme 7.3, was accompanied by small amounts of epimerization at the carboxylic acid center of 1, resulting in diastereomeric contamination of the final product. 

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