Tetrazole-containing derivatives of 4-amino-3-phenylbutanoic acid

The molecule 4-amino-3-phenylbutanoic acid contains amino and carboxy terminal groups. The reactivity of both groups was utilized for preparation of corresponding tetrazole-containing derivatives. The terminal amino group was directly replaced by a tetrazol-1-yl fragment through reaction of 4-amino-3-phenylbutanoic acid hydrochloride with triethyl orthoformate and sodium azide in acetic acid. 4-Amino-3-phenylbutanoic acid was converted into 4-(tetrazol-1-yl)-3- phenylbutanoic acid and also methyl 4-(5-methyltetrazol-1-yl)-3-phenylbutanate in 79 and 45% yields, respectively.


Introduction
The tetrazole ring as an analog and metabolically stable substitute of a carboxy group is extensively used in molecular design and in the synthesis of modified amino acids and peptidomimetics. 1 Certain analogs of natural amino acids containing one or several tetrazole rings have been synthesized.4-Aminobutanoic acid (GABA) was historically the first nootropic drug. 34-Amino-3phenylbutanoic 1, the corresponding hydrochloride 1а (Phenibutium), and some other derivatives of acid 1 belong to a new generation of nootropic drugs. 4The introduction of a tetrazole ring into the molecule of 4-amino-3-phenylbutanoic acid 1, and also of some derivatives of this substrate might afford promising metabolically stable analogs.We report here on the synthesis of 4-(tetrazol-1-yl)-3-phenylbutanoic acid and methyl 4-(5-methyltetrazol-1-yl)-3-phenylbutanoate, the first tetrazole-containing derivatives and analogs of 4-amino-3-phenylbutanoic acid 1.

Results and Discussion
The conversion of an amino group of a primary amine into a tetrazole ring effected by a triethyl orthoformate -sodium azide system in acetic acid is well documented. 5However, this procedure was not formerly applied to the conversion of amino acids into the corresponding tetrazolecontaining derivatives.We demonstrated that the amino group of compound 1 reacted with the above-mentioned reagents to afford a tetrazole derivative, 4-(tetrazol-1-yl)-3-phenylbutanoic acid 2. We also carried out an alternative way of tetrazol-1-yl substituent introduction into the structure of an ester of 4-amino-3-phenylbutanoic acid.The corresponding synthesis route was based on the conversion of primary amides into 1,5-disubstituted tetrazoles. 2 In the first stage acid chloride 3 was obtained in situ and subsequently subjected to esterification into ester 4.
Scheme 2 In the second stage, acylation of the terminal amino group was performed in pyridine transforming ester 4 into amide 5.

Scheme 3
Following the procedure, 2 we succeeded in converting amide 5 into tetrazole derivative 6.
Scheme 4 Hence in this study we obtained the first representatives of tetrazole-containing analogs of 4amino-3-phenylbutanoic acid.

Experimental Section
General Procedures. 1 Н and 13 С NMR spectra were recorded on a Bruker DPX-300 spectrometer.IR spectra were recorded on a SHIMADZU FTIR-8400 spectrophotometer.Elemental analysis was performed on a Hewlett-Packard 185 C,H,N-analyzer semi-automatic instrument.Reaction progress was monitored by TLC on Merck Kieselgel 60F 254 plates, and spots were visualized under UV light.