DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
SYNTHESIS OF STRUCTURAL ANALOGS
OF THE 16 – 19 SOMATOLIBERIN SEQUENCE
Yu. P. Shvachkin,
S. M. Funtova,
A. P. Smirnova,
T. M. Khrabrova,
and V. V. Knyazeva
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 38, No. 11, pp. 33 – 34, November, 2004.
Original article submitted June 28, 2004.
Within the framework of investigations devoted to the
peptide stimulation of insulin secretion, we have developed a
method of synthesis and obtained a previously unreported
peptide sequence representing a structural analog of the
16 – 19 somatoliberin sequence [1, 2].
In solving this task, we have studied three possible ap-
proaches. In the first case, we used carbonyldiimidazole as a
condensing agent. The second method stipulated the forma-
tion of peptide bonds with the aid of 1,2-dihydroquinoline
derivatives. In particular, we have studied the variants of
peptide synthesis using N-ethyloxycarbonyl-2-ethyloxy-
1,2-dihydroquinoline (EEDQ) and N-isobutyloxycarbonyl-
2-isobutyloxy-1,2-dihydroquinoline (IIDQ). The third ap-
proach was based on the use of activated esters of N-pro
tected amino acids.
After experimental assessment and comparative analysis
of possible variants, it was concluded that the most promis
ing synthetic pathway to the target peptide is offered by the
third approach. This method ensures a high yield of the target
compounds, excludes undesired side reactions, allows effec
tive control over racemization processes, and is less tedious
than the other possible schemes. As a result, we have devel
oped an effective method for the synthesis of previously un
reported structural analogs of the 16 – 19 somatoliberin pep
tide sequence, which is a part of the amino end of
The distinguishing features of the proposed method are
(i) Benzyl esters of amino acids and peptides play the
role of amino components;
(ii) Pentafluorophenyl esters of N-protected amino acids
play the role of carboxy components;
(iii) An acid-labile tert-butyloxycarbonyl protection is
used for masking a-amino acids in the carboxy components.
(iv) p-Nitrophenyl esters are used in the case of
w-amides of dicarboxylic acids;
(v) Stepwise construction of peptide chains in the C ® N
An important advantage of the proposed method is the
possibility of using protected derivatives of trifunctional
amino acids for the synthesis of hydrophobic analogs of
It was also established that the isolation of target com-
pounds from the reaction mixtures is considerably simplified
by conducting the condensation stage in DMF. In this case,
the target peptides can be isolated in a crystalline state and
purified by recrystallization. The structure of peptides ob
tained using the proposed scheme is uniquely determined by
the scheme of synthesis. The synthetic analogs of the termi
nal region of somatoliberin can be obtained in an analytically
The proposed method was used to obtain previously un
reported peptides (I – VI), which are structural analogs of the
16 – 19 somatoliberin peptide sequence, representing a part
of the amino end of somatoliberin.
The initial compounds in our syntheses were L-alanine
benzyl ester tosylate (VII), N-tert-butyloxycarbonyl-
O-benzyl-L-serine (VIII), N-tert-butyloxycarbonyl-O-ben
zyl-L-leucine pentafluorophenyl ester (IX); and N-tert-butyl
oxycarbonyl-O-benzyl-L-glutamine p-nitrophenyl ester (X).
Particular procedures involved in the synthesis of previously
unreported peptides (I – VI) are described in detail below.
The synthesis of the structural analogs of the 16 – 19
somatoliberin peptide sequence provides the necessary pre
0091-150X/04/3811-0618 © 2004 Springer Science+Business Media, Inc.
Pharmaceutical Chemistry Journal Vol. 38, No. 11, 2004
Institute of Experimental Endocrinology, Scientific Endocrinological
Center, Russian Academy of Medical Sciences, Moscow, Russia.