Nipecotic acid ethyl ester

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

Methyl-2-bromothiophene Ethyl nipecotate Nipecotic acid ethyl ester Sodium hydroxide... 

A suspension of 5.0 g of l-bromo-4,4-bis(3-methylthien-2-yl)but-3-ene, 3.4 g of nipecotic acid ethyl ester and 3.3 g of potassium carbonate in 150 ml of dry acetone was kept under reflux for 15 h. The reaction mixture was evaporated and, after addition of 30 ml of water, the resulting solution was extracted twice with 50 ml of ethyl acetate. The ethyl acetate extracts were dried and evaporated leaving 7.3 g of an oil. By column chromatography on silica gel using methanol as eluent, N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid ethyl ester was isolated. 

The most striking examples for the positive confinement effect of supports on enantioselectivity have been provided by Thomas and Johnson s research group [13, 14, 16], who demonstrated that even nonenantioselective catalysts can show significant asymmetric induction when anchored onto a suitable support. The Pd catalyst 14 covalently supported within the pores of MCM-41 affected the hydrogenation of ethyl 1,4,5,6-tetrahydronicotinate (16) to afford nipecotic acid ethyl ester (17) at 17% ee (turnover number (TON) = 291), whereas the use of 15, the... 

Lipophilic prodrugs can also be derived from a carboxylic function, the most commonly used derivatives being carboxylic esters. Simple esters of aliphatic alcohols are attractive as they are cheap to prepare, chemically stable, and yield harmless hydrolysis products." Typical representatives of such prodrugs are tyrosine methyl ester," levodopa ethyl ester," nipecotic acid ethyl ester," enala-prilat ethyl ester," " " trandolapril," y-aminobutyric acid cetyl ester" " and methotrexate cetyl ester." ... 

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. 

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. ... 

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