Tetrahedron Letters
New catalytic route for the synthesis of an optically active
tetralone-derived amine for rotigotine
⇑
Christopher J. Cobley , George Evans, Tamara Fanjul, Shaun Simmonds, Amy Woods
Chirotech Technology Centre, Dr. Reddy’s Laboratories, Unit 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Rotigotine is a launched drug for the treatment of Parkinson’s disease and restless legs syndrome. The key
steps of an alternative route for the synthesis of rotigotine have been demonstrated. Formation of a
prochiral enamide, asymmetric hydrogenation of the enamide with high enantioselectivity, and reduc-
tion of the resulting amide to an amine have been proved to work successfully. The best conditions
screened to date for the asymmetric hydrogenation of enamide 9 to amide 10 were with [(RuCl((R)-T-
Received 10 December 2015
Revised 11 January 2016
Accepted 18 January 2016
Available online xxxx
BINAP))2(
Reduction of amide 10 to amine 5 was best achieved with Red-Al giving 95% conversion.
Ó 2016 Elsevier Ltd. All rights reserved.
l-Cl)3][NH2Me2] at 25 bar H2 and 30 °C (500:1 S/C ratio, 99% conversion, 91% ee S).
Keywords:
Rotigotine
Chiral amine
Asymmetric hydrogenation
Introduction
The key elements of the overall alternative process are a highly
selective asymmetric hydrogenation reaction that uses a directing
group of relevance to the downstream product of interest, a con-
cise overall route where each step is high yielding with an efficient
amide reduction as the final step, minimising any loss of
enantioselectivity.
Rotigotine is a launched drug of the non-ergoline class of med-
ications that acts as a dopamine agonist for the treatment of
Parkinson’s disease and restless legs syndrome. It was developed
by Aderis Pharmaceuticals and licensed by UCB S.A. and it has been
in use in Europe since 2006.1 Currently, the majority of reported
syntheses of the chiral amine intermediates used in the prepara-
tion of this drug involve the classical resolution of racemic ami-
nes1,2 (and hence a maximum theoretical yield of 50%) as shown
in Scheme 1.
Results and discussion
The reaction between a substituted b-tetralone and a primary
amide to yield the corresponding enamide has been widely
reported.6 In this case, the specific combination shown in Scheme 3
is required.2b,7
Enamide 9 was prepared on a 16 g scale showing quantitative
conversion by 1H NMR spectroscopy. Water was removed under
Dean–Stark conditions using pTSA as an acidic catalyst. Recrystal-
lization was achieved from the reaction solvent in an unoptimized
80% isolated yield.
The development of an efficient asymmetric synthesis would
lead to obvious cost and yield benefits. One approach, reported
in a recent publication, is the synthesis of a chiral tetralone pri-
mary amine as a key intermediate via a multi-enzymatic approach
of ene-reductases (ERs) and alcohol dehydrogenases (ADHs).3
A
different strategy that has been patented is a chiral auxiliary based
route using
a
-methylbenzylamine.4 Herein, we report the prepara-
tion of a prochiral enamide (9), from the appropriately substituted
tetralone (3) and propionamide, followed by asymmetric hydro-
genation which gives access to a chiral amide (10) in high yield
and enantioselectivity. Subsequent reduction of this chiral amide
yields the necessary secondary amine intermediate (5) in a highly
efficient and selective fashion (Scheme 2). The remaining down-
stream steps to rotigotine, as shown in Scheme 1, have been previ-
ously reported.5
The asymmetric hydrogenation of tetralone-derived enamides
has been reported in recent years.8 However, the reduction of the
preferred enamide 9 leading to rotigotine (8) had not been
reported prior to this work7 (Scheme 4).
A screen of Rh and Ru catalyst was undertaken (Table 1 shows
representative results of a total of 4 Rh and 26 Ru precatalysts).
Hydrogenation of 9 with Rh complexes such as [((R,R)-Ph-BPE)Rh
(cod)]BF4 and [((R)-PhanePhos)Rh(cod)]BF4 showed good conver-
sion, albeit at a low enantioselectivity (entries 1 and 2). On the
other hand, the hydrogenation carried out with Ru dimer species
showed a low conversion at 10 bar hydrogen pressure, but a very
⇑
Corresponding author. Tel.: +44 1223 728010; fax: +44 1223 506701.
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