Organic Process Research & Development 2007, 11, 903–906
A Chemoenzymatic Synthesis of an Androgen Receptor Antagonist‡
Rajappa Vaidyanathan,* Lynsey Hesmondhalgh, and Shanghui Hu
Chemical Research and DeVelopment, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, U.S.A.
Abstract:
chiral column chromatography to furnish the desired API 1.
This route was utilized to synthesize multiple grams of the target
to satisfy initial bulk requests.
A new scalable enzymatic resolution approach to both
enantiomers of trans-2-hydroxycyclohexanecarbonitrile (9
and 11) was developed. Treatment of the racemic mixture
Several issues were foreseen if this chemistry were to be
used for further scale-up. Lithium hydride is difficult to use on
scale due to safety concerns around its reactivity and propensity
to generate hydrogen gas. Although large-scale chiral column
chromatography is possible, it is not preferred because of the
cost of the stationary phase, high solvent usage, and loss of
50% of the material (the undesired enantiomer) in the last step.
Furthermore, material isolated by chromatography is generally
ultrapure and would likely not produce API with a purity profile
representative of a future commercial process.
(
4) with succinic anhydride in the presence of Novozym 435
led to selective acylation of one enantiomer to the corre-
sponding hemisuccinate, which was separated from the
unreacted enantiomer by a simple basic extraction. This
procedure produced the desired enantiomer in high ee, while
obviating the need for chromatography or expensive catalysts
and ligands. The application of this protocol to the large-
scale synthesis of an androgen receptor antagonist (1) is
described.
Process Development Efforts
Introduction
Step 1. Subsequently, several alternative routes were evalu-
ated as part of early process research efforts. Most asymmetric
3
Alopecia, or baldness, is a commonly observed trait that is
not yet medically well understood or easily treated. Although
the physiological mechanism by which balding occurs has not
been unequivocally established, it is known that androgens are
associated with this phenomenon. Compound 1 is an androgen
receptor antagonist that was being developed for the treatment
syntheses of TMS ether 8 and hydroxy nitrile 9 suffered from
4
either insufficient ee’s or scalability concerns. Therefore,
alternative routes to optically enriched hydroxy nitrile 9 were
investigated.
1,2
of both alopecia and excess sebum (oily skin). Multiple
kilograms of the active pharmaceutical ingredient (API) 1 were
needed to support preclinical safety evaluation and early clinical
studies. Therefore, the immediate aim of the project team was
to develop a route that could be scaled up effectively to meet
the API demand and possibly form the basis of the long-term
manufacturing route for this compound.
An enzymatic resolution approach seemed to be an attractive
way to achieve the desired optical purity for 1. Typically,
enzymatic acylations are performed using an acetate source such
as vinyl acetate as the acylating agent, but the limitation of this
methodology is that the unreacted alcohol and the product
Early Synthetic Approaches
5
acetate are separable only by chromatography. It was rational-
ized that the use of a cyclic anhydride such as succinic anhydride
(
7) as the acylating agent would result in the formation of the
6
corresponding hemi-ester (Scheme 2). This could then be
separated from the unreacted alcohol through a basic extraction,
thereby obviating the need for chromatography.
Several enzymes were screened for the acylation reaction
of 4 with succinic anhydride. The best activity and selectivity
were seen with Candida antarctica Lipase B (CaLB); hence,
optimization efforts involved the use of immobilized CaLB in
Scheme 1 shows the first-generation route for the synthesis
of 1. The racemic form of the API (6) was synthesized in three
steps from cyclohexene oxide via a Lewis acid catalyzed ring
opening with trimethylsilyl cyanide followed by hydrolysis of
the trimethylsilyl group and subsequent O-arylation with 5 in
the presence of lithium hydride. Racemate 6 was purified by
(
3) Hu, L-Y.; Du, D.; Hoffman, J.; Smith, Y.; Huang, Y.; Kesten, S.; Harter,
W.; Johnson, T. R.; Yue, W. S.; Li, J. J.; Barvian, N.; Mitchell, L.;
Kostlan, C.; Fedij, V.; Krieger-Burke, T.; Samas, B.; Lei, H. J.; Lefker,
B.; Carroll, M.; Dettling, D.; Yalamanchili, R.; Lapham, K.; Pocalyko,
D.; Sliskovic, D.; Ciotti, S.; Stoller, B.; Welgus, W. Manuscript in
preparation.
*
Author to whom correspondence should be addressed. E-mail:
rajappa.vaidyanathan@pfizer.com.
‡
Dedicated to the memory of Prof. G. Sundararajan, Department of Chemistry,
Indian Institute of Technology, Madras.
(
1) Hu, L-Y.; Lei, H.; Du, D. Y.; Lefker, B. A. U.S. Pat. Appl. Publ. (2005),
US 2005182132 A1 20050818.
(4) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001–1004.
(5) Forro, E.; Gyogyszerkemiai, I; Szegedi, T.; Szeged, H. Acta Pharm.
Hung. 2001, 71, 119–126.
(
2) Hu, L-Y.; Lefker, B. A.; Du, D. Y.; Smith, Y. D.; Lei, H.; Harter,
W. G.; Downs, V. L.; Boys, M. L.; Iula, D. M. U.S. Patent US 2006/
(6) Terao, Y.; Tsuji, K.; Murata, M.; Achiwa, K.; Nishio, T.; Watanabe,
N.; Seto, K. Chem. Pharm. Bull. 1989, 37, 1653–1655.
0
09427A1.
1
0.1021/op700146c CCC: $37.00
2007 American Chemical Society
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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Published on Web 09/06/2007