Synthesis of Pure p-Chlorophenyl-L-alanine form L-Phenylalanine Article

Houghten, RA, Rapoport, H. (1974). Synthesis of Pure p-Chlorophenyl-L-alanine form L-Phenylalanine . Journal of Medicinal Chemistry, 17(5), 556-558. 10.1021/jm00251a025

cited authors

  • Houghten, RA; Rapoport, H

abstract

  • It has long been known that p-chlorophenylalanine (IV) inhibits serotonin (5-hydroxytryptamine) formation in the tissues of laboratory animals.1 This fact has lead to a large number of publications on the effects of this inhibition, a few of which include altered sleep patterns in cats,2 variations in learning in rats,3 changes in social behavior in rats,4 and alteration of normal sexual patterns in rats, cats, and rabbits.5 The resolution of this physiologically important compound did not appear until 1971,6 and the method used gave poor yields of the optical isomers of IV. We sought a simple, direct method of preparation using L-phenylalanine as the optically active starting material, thus avoiding a resolution step, and we now present the details of such a method. A simple means for obtaining IV, which appeared quite attractive, was the direct chlorination of L-phenylalanine (I) with molecular chlorine in acidic medium, the acid functioning as an amine protecting group. The difficulties encounted with this method were the production of other isomers (ortho, meta, and dichlorinated) and the complete separation of these isomers from the desired product (IV). The isomeric composition varied little with the solvent or the ratio of chlorine to phenylalanine employed (Table I). The components of the isomer mixture were identified through amino acid analysis by comparison with authentic samples prepared by the method of Burchalter and Stevens7 (Table II). All attempts to separate pure IV in practical yield from the mixture, using cation exchange resins with aqueous acid as eluent, failed. A recent procedure,8 which has been used to separate isomeric bromophenylalanines on Sephadex, was considered and rejected because the separation and yields were poor for the bromophenylalanines, and the differences between isomeric chlorophenylalanines are smaller than for the corresponding bromophenylalanines. © 1974, American Chemical Society. All rights reserved.

authors

publication date

  • May 1, 1974

published in

Digital Object Identifier (DOI)

start page

  • 556

end page

  • 558

volume

  • 17

issue

  • 5