9628
J . Org. Chem. 1998, 63, 9628-9629
the phenyl ring is oriented on the convex face of the bicyclic
A Ster eoselective Syn th esis of
ring system. Hydrolysis of 6 with acidic methanol provides
the hydrochloride salt of threo-methylphenidate 1 as a single
diastereomer, in which the relative stereochemistry of the
â-lactam 6 is completely preserved.
d l-th r eo-Meth ylp h en id a te: P r ep a r a tion a n d
Biologica l Eva lu a tion of Novel An a logu es†
J effrey M. Axten,‡,1 Lori Krim,‡ Hank F. Kung,*,§ and
J effrey D. Winkler*,‡
Departments of Chemistry and Radiology, The University of
Pennsylvania, Philadelphia, Pennsylvania 19104
Received November 5, 1998
Methylphenidate (Ritalin, 1) is the most commonly pre-
scribed psychotropic medication for children in the United
States. It is used primarily for the treatment of hyperactive
children with attention deficit disorder (ADD). Both 1 and
cocaine 2 have similar binding affinities for the dopamine
transporter (DAT; Ki ) 640 nM for (-)-cocaine and 390 nM
for d-threo-methylphenidate), and both inhibit the reuptake
of dopamine. However, it is not known whether the two
drugs bind to the DAT in the same manner since X-ray
structural information for the DAT is not available. Since
changes in synaptic dopamine levels have been linked to a
number of neurological disorders2 as well as to cocaine
abuse, the discovery of how dopamine uptake inhibitors bind
to the transporter is an important goal, and the results of
such studies could lead to new drug candidates to combat
cocaine abuse and dependence.
Recently, Froimowitz and co-workers proposed a phar-
macophore common to methylphenidate and the cocaine
analogue CFT, 3, a high-affinity ligand for the DAT, in which
the â-amino ester moieties of each are superimposed (Figure
1).3 The six-atom sequence from the ammonium group
through the methyl ester includes two asymmetric centers
in methylphenidate and one of the four asymmetric centers
in 3.
F igu r e 1.
This reaction sequence has proven to be highly efficient
and amenable to modification of both the piperidine and the
aryl moieties of methylphenidate. The role of the piperidine
ring in binding to the DAT can be evaluated by replacing it
with other secondary amines (Scheme 1). Similarly, replace-
ment of ethyl phenylglyoxylate with other arylketoacid
esters leads to the incorporation of other aryl groups into
the methylphenidate framework. The requisite ketoesters
are available by addition of an aryllithium to diethyloxalate.7
Using this procedure, the aryllithiums derived from 1- and
2-bromonaphthalene led to the formation of 7 and 8,
respectively (see Figure 2). The homologated phenidate
analogue 9 was prepared by stereoselective alkylation of
1-azabicyclo[4.2.0]octan-8-one8 with benzyl bromide, followed
by reaction of the resulting substituted â-lactam with acidic
methanol.
SAR studies on methylphenidate have been limited to
modifications of the ester and substitutions on the phenyl
ring due to the limitations of the previously reported
syntheses of methylphenidate.4 We describe herein a highly
flexible and efficient synthesis of methylphendiate and
analogues that should facilitate the establishment of the
structural and functional requirements for methylphenidate
binding to the DAT.
Reaction of ethyl phenylglyoxylate 4 with piperidine
affords the R-ketoamide,5 which on condensation with to-
sylhydrazine gives the tosylhydrazone 5 (Scheme 1). Treat-
ment of 5 with potassium tert-butoxide in refluxing toluene
gave 6, which was obtained in 60% yield on crystallization
of the crude reaction mixture. This procedure represents a
significant improvement over previously reported work.6 The
equilibrating reaction conditions allow for the stereoselective
formation of 6 (6:1 mixture of exo/endo products), in which
The results of the biological evaluation of the meth-
ylphenidate analogues using [125I]-IPT 149 to determine
inhibition constants are shown in Table 1. While only the
Sch em e 1
† Dedicated to our friend and colleague Professor Ralph F. Hirschmann,
the 1999 recipient of both the Arthur C. Cope Award and the Edward E.
Swissman Bristol-Myers Squibb Award.
‡ Department of Chemistry.
§ Department of Radiology.
(1) Division of Organic Chemistry of the American Chemical Society
Fellow, sponsored by Abbott Laboratories.
(2) Strange, P. Brain Biochemistry and Brain Disorders; Oxford Uni-
versity Press: Oxford, 1992.
(3) Froimowitz, M.; Patrick, K. S.; Cody, V. Pharm. Res. 1995, 12 , 10,
1430-1434.
(4) (a) Panizzon, L. Helv. Chim. Acta 1944, 27, 1748-1756. (b) Deutsch,
H.; Shi, Q.; Gruszecka-Kowalik, E.; Schweri, M. J . Med. Chem. 1996, 39,
1201-1209.
(5) Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 2646.
10.1021/jo982214t CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/25/1998