葛兰素史克公司利用QbD原理设计的关于甲磺酸卡索匹坦合成中间体分离的动态动力学方法
200 浏览量
2024-04-25
19:22:42
上传
评论
收藏 1.12MB PDF 举报
Development of a Dynamic Kinetic Resolution for the Isolation of an Intermediate in
the Synthesis of Casopitant Mesylate: Application of QbD Principles in the
Definition of the Parameter Ranges, Issues in the Scale-Up and Mitigation
Strategies
Fernando Bravo,*
,†
Zadeo Cimarosti,
†
Francesco Tinazzi,
†
Gillian E. Smith,
†
Damiano Castoldi,
†
Stefano Provera,
‡
and
Pieter Westerduin
†
GlaxoSmithKline R&D, Chemical DeVelopment, Analytical Chemistry, Via Fleming 4, Verona, Italy
Abstract:
Process development towards the improvement of the manufac-
turing process of casopitant mesylate (a drug developed by
GlaxoSmithKline with activity on the central nervous system)
identified a dynamic kinetic resolution opportunity for the im-
provement of the yield. In this paper, the application of quality
by design principles to the DKR is presented together with the
issues that were faced during different scale-ups and the at-scale
solutions that were implemented.
1. Introduction
For the pharmaceutical industry, the isolation of solid
intermediates is used as a means to purify compounds.
1
When
a racemic mixture is obtained, precipitation of one of the
enantiomers via kinetic resolution (KR) may be preferred over
other resolution techniques because good enantioselectivities
may be achieved from relatively simple solvent and resolving
agent screening. The KR approach is more general than
substrate-specific asymmetric synthesis Via chiral catalysis, Via
the use of biological methods (e.g., enzymes), or Via chiral
auxiliary-driven synthesis, and the cost and environmental
impact related to this technique are contained compared to, for
example, preparative chiral chromatography.
2
KR, however, is burdened by the fact that a maximum of
50% yield may be achieved, and the other half of the material
is lost, or under the best hypothesis, isolated separately to be
recycled. In this sense, the one-pot interconversion of the
undesired enantiomer into the desired one by epimerization of
the stereogenic center under certain reaction conditions is a
much desired objective. This approach is known as dynamic
kinetic resolution (DKR),
3
and it is of particular appeal to the
pharmaceutical industry when the driving force for the inter-
conversion of enantiomers is pulled by the precipitation of only
one of the enantiomers from the reaction medium. In this paper,
an example of such a process of DKR, and the issues faced in
different scale-ups (up to manufacturing scale, 250 kg input),
will be described in detail.
2. Discussion
2.1. Initial Synthetic Route. The commercial process to
synthesize casopitant mesylate (1) is a multistage convergent
process. The original synthesis from which we started to work
in Chemical Development at GlaxoSmithKline is summarized
in Scheme 1. The mesylate salt 1 is obtained after nine stages,
including two intermediate isolations.
Crude racemic 4 is purified by crystallization from the
reaction mixture as the racemate camphorsulfonate salt 3, which
is thereafter resolved by KR using
L-(S)-mandelic acid (∼0.5
mol equiv) in 2-propanol. The total yield of these two
transformations is in the range of 35-40%. Initial process
studies successfully obtained intermediate 2 without isolation
of the intermediate 3, demonstrating that the isolation of the
racemic salt 3 was not necessary, i.e. stages 3 and 4 can be
telescoped into one single stage, furnishing 2 directly from 4
without detriment to the overall yield. So it was decided to focus
the process studies on this approach.
2.2. Screening of a Suitable Reagent for Epimerization
of the Stereogenic Center. The epimerization of the stereogenic
center in (R)-4 was tested with several different reagents. The
mechanism that operates in the racemization attempts can be
classified as the following.
2.2.1. Redox Processes. (i.e., oxidation to form the cyclic
imine followed by reduction to the amine, as depicted in Scheme
2).
4
Different metal-based catalysts (PtO
2
, [Rh(COD)Cl]
2
,
[Ir(COD)Cl]
2
, Ru(PPh
3
)
3
Cl
2
, catASium D(R) Rh) were screened
in the presence of a reducing atmosphere. Typical reaction
conditions were 10% molar ratio of catalyst, 2 bar hydrogen of
pressure, at 25 or 50 °C temperature and using ethyl acetate or
* Author to whom correspondence may be sent. E-mail: fbravo@iciq.es.
†
Chemical Development.
‡
Analytical Chemistry.
(1) Bamforth, A. W. Industrial Crystallization; Leonard Hill: London
(UK), 1965.
(2) Collins, A. N., Sheldrake, G. N., Crosby, J., Eds. Chirality in Industry
II: DeVelopments in the Manufacture and Applications of Optically
ActiVe Compounds; John Wiley & Sons Ltd.: Chichester (UK), 1997.
(3) Reviews on racemization methods and on DKR: (a) Pellissier, H.
Tetrahedron 2008, 64, 1563–1601. (b) Brands, K. M. J.; Davies, A. J.
Chem. ReV. 2006, 106, 2711–2733. (c) Farina, V.; Reeves, J. T.;
Senanayake, C. H.; Song, J. J. Chem. ReV. 2006, 106, 2734–2793. (d)
Fogassy, E.; No´gra´di, M.; Kozma, D.; Egri, G.; Pa´lovics, E.; Kiss, V.
Org. Biomol. Chem. 2006, 4, 3011–3030. (e) Pellissier, H. Tetrahedron
2003, 59, 8291–8327. (f) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall,
J.-E. Chem. Soc. ReV. 2001, 30, 321–331. (g) Ebbers, E. J.; Ariaans,
G. J. A.; Houbiers, J. P. M.; Bruggink, A.; Zwanenburg, B. Tetrahe-
dron 1997, 53, 9417–9476. (h) Caddick, S.; Jenkins, K. Chem. Soc.
ReV. 1996, 25, 447–456. (i) Ward, R. S. Tetrahedron: Asymmetry 1995,
6, 1475–1490.
(4) Some selected examples: (a) Paetzold, J.; Ba¨ckvall, J. E. J. Am. Chem.
Soc. 2005, 127, 17620–17621. (b) Blacker, A. J.; Stirling, M. J.; Page,
M. I. Org. Process Res. DeV. 2007, 11, 642–648.
Organic Process Research & Development 2010, 14, 1162–1168
1162 • Vol. 14, No. 5, 2010 / Organic Process Research & Development 10.1021/op100121s 2010 American Chemical Society
Published on Web 07/08/2010
Downloaded via LANZHOU UNIV on April 25, 2024 at 11:21:45 (UTC).
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
资源评论
