A practical synthesis of [13C4] N-benzylpiperazine from [13C2] glycine

Article abstract of DOI:10.1016/j.tetlet.2012.05.084

A high yielding gram-scale synthesis of [¹³C₄] N-benzylpiperazine for use as a convenient and versatile building block in isotope labeling studies of clinical drug candidates is reported.

Full text of DOI:10.1016/j.tetlet.2012.05.084

Tetrahedron Letters 53 (2012) 3927–3929
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Tetrahedron Letters
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A practical synthesis of [13C4] N-benzylpiperazine from [13C2] glycine
⇑
Fredrik Lake, Christian Linde
Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden
a r t i c l e i n f o
a b s t r a c t
A high yielding gram-scale synthesis of [13C4] N-benzylpiperazine for use as a convenient and versatile
building block in isotope labeling studies of clinical drug candidates is reported.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 3 April 2012
Revised 10 May 2012
Accepted 17 May 2012
Available online 26 May 2012
Keywords:
13C
Isotope labeling
N-Benzylpiperazine
Glycine
Efficient methods for isotope labeling of clinical drug candidates
are very important for metabolic studies in the development of
new drugs.1 It is desirable to have the label located at a relatively
stable part of the molecule to avoid fragmentation of the labeled
moiety as a result of metabolic degradation. Four or more labeled
atoms are normally required for accuracy in spectroscopic mea-
surements, as well as a high isotopic purity of the labeled final
compound. Furthermore, it is advantageous to use a labeling strat-
egy that allows for facile introduction of the labeled moiety with-
out modification of the established synthetic route and that also
allows use of the same labeled moiety for analog structures.
Piperazines are frequent motifs in several drugs, for example
among the antipsychotics AbilifyÒ, SeroquelÒ, ZyprexaÒ, and Geo-
donÒ, which were among the top 40 selling drugs on the US market
in 2010, as well as LevaquinÒ and ViagraÒ (Fig. 1).2 The piperazine
ring is most often a stable part of the molecule and offers a conve-
nient location for the introduction of four 13C atoms. However,
available [13C2] glycine, which provides the title compound in high
overall yield.
There are already some procedures reported for the preparation
of 13C-labeled piperazines. Previous examples suffer from limited
applicability, for example, unsubstituted4 or N-methylpiperazine.3a
We identified the need for a monoprotected unit in order to widen
the scope of piperazine labeling chemistry. We opted for a
UV-active and hydrophobic benzyl substituent as the N-protecting
group, which was to be introduced early in the synthetic sequence,
thus facilitating spectroscopic analysis, and purification and
isolation of intermediates. The benzyl group can be removed later
by catalytic hydrogenation after derivatization of the second piper-
azine nitrogen atom.
We synthesized the target compound 8 by combining two [13C2]
glycine units, one of which was N-benzylated glycine ester 4
(Scheme 1), and the other was N-Boc-protected glycine 5 (Scheme
2). Compound 4 was prepared in four steps via reductive amina-
tion,5 N-Boc-protection,6 esterification, and Boc-removal. The first
two steps were performed in a one-pot, two-step manner to avoid
isolation of the zwitterionic form of 1 and compound 2 was easily
isolated via acid–base extraction. Chromatographic purification
was not required for this or any of the following intermediates 3
and 4, and they could be isolated in good yields by extractive
means.
Compound 5 was prepared in one step via Boc-protection of
glycine and was coupled with compound 4 using standard cou-
pling conditions.7 Compound 6 underwent spontaneous ring-
closure after Boc-deprotection and subsequent treatment with
aqueous base. The resulting diketopiperazine 7 was reduced by
LiAlH4 in refluxing THF,4 affording target compound 8 in nearly
40% overall yield and over 98% isotopic purity. This procedure
could easily be executed on a multigram scale and also provides
[
13C4] piperazine is not commercially available and often requires
difficult monoprotection in order for it to become a useful building
block.
Herein, we report an efficient synthesis of [13C4] N-benzylpiper-
azine as a versatile building block which could be used for facile
introduction of a 13C-labeled piperazine moiety. Common methods
start from acetic acid derivatives and overall yields are generally
modest.3 To our knowledge, the selection of alternative commer-
cially available 13C-labeled starting materials is somewhat limited.
Therefore, we have developed a scheme starting from readily
⇑
Corresponding author. Tel.: +46 8 553 26000; fax: +46 8 553 28892.
E-mail address: christian.linde@astrazeneca.com (C. Linde).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.084

3928
F. Lake, C. Linde / Tetrahedron Letters 53 (2012) 3927–3929
HO
Cl
Cl
N
S
N
O
N
N
N
N
N
N
O
N
H
N
H
S
O
Abilify®
Seroquel® (quetiapine)
Zyprexa® (olanzapine)
(aripiprazole)
Cl
O
N
O
N
O
O
N
CO2H
F
N
N
S
NH
O
N
H
N
N
N
O
N
O
N
N
S
Geodon® (ziprasidone)
Levaquin® (levofloxacin)
Viagra®
(sildenafil)
Figure 1. Top selling drugs containing N,N0-disubstituted piperazines.
OH
O
OH
13C
13C
OH
13C
13C
O
13C
13C
O
O
O
13C
13C
O
13C
13C
H2N
a)
b)
c)
d)
O
Boc
N
Boc
N
HN
N
H
Ph
Ph
Ph
Ph
1
2
3
4
Scheme 1. Synthesis of 4. Reagents and conditions (a) benzaldehyde, Et3N, MeOH, rt, 3 h then NaBH4, overnight, 99%; (b) (Boc)2O, 1,4-dioxane, Et3N, rt, 2 h, 82% (c) MeI,
Cs2CO3, DMF, rt, overnight, 88% (d) TFA, CH2Cl2, rt, 2 h, 99%.
O
O
13C
OH
H
N
OH
H
N
13C
O
O
13C
13C
HN
13C
13C
13C
13C
13C
13C
13C
13C
O
13C
13C
H2N
a)
b)
c)
d)
N
13C
13C
Ph
O
O
N
N
Boc
Ph
NH
Ph
Boc
5
6
7
8
Scheme 2. Synthesis of 8. Reagents and conditions (a) (Boc)2O, 1,4-dioxane/H2O, Et3N, rt, overnight, 83%; (b) HBTU, DIPEA, CH2Cl2, rt, 10 min then 4, rt, 2 h, 80%; (c) TFA,
CH2Cl2, rt, overnight then satd aq NaHCO3, rt, 15 min, 90%; (d) LiAlH4, THF, reflux, 2 h, 73%.
the option of introducing, for example, 15N-labeling from [15N] gly-
Supplementary data
cine or D-labeling by using LiAlD4 in the final reduction step.
In conclusion, we have reported a reliable and simple procedure
for the preparation of [13C4] N-benzylpiperazine, which could serve
as a versatile building block for labeled piperazine-containing drug
candidates.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.084.

F. Lake, C. Linde / Tetrahedron Letters 53 (2012) 3927–3929
3929
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