Organic Process Research & Development 2010, 14, 1364–1372
A Mechanistic Insight into a Simple C-N Bond Formation via SN2 Displacement: A
Synergistic Kinetics and Design of Experiment Approach
Luca Massari,†,* Laura Panelli,‡ Mark Hughes,§ Federica Stazi,† William Maton,† Pieter Westerduin,† Federico Scaravelli,† and
Sergio Bacchi†,*
Chemical DeVelopment, Synthetic Chemistry, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy,
Chemical DeVelopment, Particle and Process Science and Engineering, GlaxoSmithKline Medicine Research Centre, Via
Fleming 4, 37135 Verona, Italy, and Continuous Processing, Particle and Process Science and Engineering, GlaxoSmithKline,
Gunnels Wood Road, SteVenage SG1 2NY, U.K.
Abstract:
It is common understanding that the objective of process
development is simply to deliver drug substances. While this
can be viewed as the output, the input of Chemical Development
is the research of robust synthetic procedures. In order to
quantify the reliability of a manufacturing process the ICH Q8
Guidance3 has introduced the key-concept of Design Space. The
ICH Q8 defines the “Design Space” as “the multidimensional
combination and interaction of input variables and process
parameters that have been demonstrated to provide assurance
of quality”. The actual construction of a Design Space requires
a quantitative methodology to simultaneously incorporate the
following: correlation among process responses (attributes) at
each fixed operating condition, model parameter uncertainty,
many sources of input and process variation, and a measure of
assurance for meeting process specifications. The intention of
this paper is to provide an overview of how we manage to
deliver the Design Space of the key SN2 displacement step
between the 1,2,4-triazol-3-yl-halide derivative and variously
substituted azabicyclo[3.1.0]hexanes for the reliable synthesis
of a novel class of selective dopamine DA D3 receptor
antagonists.
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes was
recently identified as new highly potent and selective dopamine
(DA) D3 receptor antagonists. This class of molecules deserved the
Chemical Development special attention to quantify the reliability
and robustness of the pivotal SN2 displacement step between the
1,2,4-triazol-3-yl-halide derivative (4) and variously substituted
azabicyclo[3.1.0]hexanes (5). To reach this goal we applied the
classical Design of Experiment (DoE) approach, simultaneously
trying to build up a descriptive kinetic model of the chemistry.
The synergistic use of these two techniques allowed us to select
new, higher-yielding and more robust reaction conditions and, at
the same time, to identify their Design Space.
Introduction
Scientists at GlaxoSmithKline (GSK) recently discovered a
series of novel 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, po-
tent and selective modulators of dopamine (DA) D3 receptors.1
This new class of compounds has potential for the treatment
of drug addiction, wherein antagonism of the D3 receptor might
be beneficial.2 An alternate take on dopamine must stabilise
DA levels in order to disconnect the linkage between drug use
and dopaminergic reward. A mouse study using the D3
antagonist SB-277011 (from GSK) found that D3 antagonism
was superior to that of naltrexone or acamprosate in reducing
alcohol self-administration. The consequence of this exciting
piece of science was the need to rapidly enter in Chemical
Development with a substantial number of New Chemical
Entities.
Discussion
The pivotal stage in the synthesis of the 1,2,4-triazol-3-yl-
azabicyclo[3.1.0]hexanes (1) was a nucleophilic displacement
of the primary alkyl halide 3-chloropropylthio-triazole (4) by
the aryl azabicyclo[3.1.0]hexane derivative (5) (Scheme 1).
The synthesis of the alkyl halide started with the com-
mercially available 4-methyl-1,3-oxazole-5-carboxylic acid (2)
which was subjected to amidation with the 4-methyl-3-thio-
semicarbazide by means of the coupling agent T3P (propane
phosphonic acid anhydride) as a solution in ethyl acetate. The
resulting thioamide was dehydrocyclised using an organic base
and the subsequent thiotriazole derivative 3 was almost regio-
* To whom the correspondence should be addressed. Private e-mails:
giobacchi@hotmail.com, luca.m.massari@googlemail.com.
† Chemical Development, Synthetic Chemistry, Italy.
‡ Chemical Development, Particle and Process Science and Engineering, Italy.
§ Continuous Processing, Particle and Process Science and Engineering, U.K.
(1) Micheli, F.; Arista, L.; Bonanomi, G.; Blaney, E. F.; Braggio, S.;
Capelli, A. M.; Checchia, A.; Damiani, F.; Di-Fabio, R.; Fontana, S.;
Gentile, G.; Griffante, C.; Hamprecht, D.; Marchioro, C.; Mugnaini,
M.; Piner, J.; Ratti, E.; Tedesco, G.; Tarsi, L.; Terreni, S.; Worby,
A.; Ashby Jr, C. R.; Heidbreder, C. J. Med. Chem. 2010, 53, 374–
391.
(3) The ICH Guidance Q8 represents the U.S. Food and Drug Administra-
tion (FDA) current thinking on Pharmaceutical Development manu-
facturing process. This guidance describes the suggested contents to
input in a regulatory submission providing an opportunity to present
the knowledge gained through the application of scientific approaches
and quality risk management to the development of a product and its
manufacturing process. This guidance is part of a set of Guidance for
Industry developed within the Expert Working Group (Quality) of the
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH). ICH Q8
Pharmaceutical Development, (R2); U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER): Rockville, MD, Aug 2009.
(2) (a) Arista, L.; Bonanomi, G.; Capelli, A. M.; Damiani, F.; Di-Fabio,
R.; Gentile, G.; Hamprecht, D.; Micheli, F.; Tarsi, L.; Tedesco, G.;
Terreni, S. PCT Int. Appl. WO/2005/080382, 2005. (b) Bonanomi,
G.; Checchia, A.; Fazzolari, E.; Hamprecht, D.; Micheli, F.; Tarsi,
L.; Terreni, S. PCT Int. Appl. WO/2006/108701, 2006. (c) Arista, L.;
Cardullo, F.; Cecchia, A.; Hamprecht, D.; Micheli, F.; Tedesco, G.;
Terreni, S. PCT Int. Appl. WO/2006/133946, 2006.
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Vol. 14, No. 6, 2010 / Organic Process Research & Development
10.1021/op100176u 2010 American Chemical Society
Published on Web 10/04/2010