A convenient method for synthesis of enantiomerically enriched methylphenidate from N-methoxycarbonylpiperidine

Article abstract of DOI:10.1021/ol9905046

(equation presented) This report describes a new method to prepare optically active methylphenidate starting from piperidine. The method consists of a transformation of N-methoxycarbonylpiperidine to the corresponding α-methoxylated carbamate I by utilizing electrochemical oxidation followed by the coupling reaction with optically active Evans imides II to produce optically active methylphenidate derivatives III with high stereoselectivities. threo-(2R,2′R)-Methylphenidate (IV; Ar=Ph; Ritalin) was easily prepared from III in three steps.

Full text of DOI:10.1021/ol9905046

ORGANIC
LETTERS
1999
Vol. 1, No. 2
175-178
A Convenient Method for Synthesis of
Enantiomerically Enriched
Methylphenidate from
N-Methoxycarbonylpiperidine
,†
Yoshihiro Matsumura,* Yasuhisa Kanda,‡ Kimihiro Shirai,‡
Osamu Onomura,‡ and Toshihide Maki‡
Institute for Fundamental Research of Organic Chemistry, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, and Faculty of
Pharmaceutical Sciences, Nagasaki UniVersity,
1-14 Bunkyo-machi, Nagasaki 852-8131, Japan
matumura@ms.ifoc.kyushu-u.ac.jp
Received March 13, 1999
ABSTRACT
This report describes a new method to prepare optically active methylphenidate starting from piperidine. The method consists of a transformation
of N-methoxycarbonylpiperidine to the corresponding r-methoxylated carbamate I by utilizing electrochemical oxidation followed by the coupling
reaction with optically active Evans imides II to produce optically active methylphenidate derivatives III with high stereoselectivities. threo-
(2R,2′R)-Methylphenidate (IV; ArdPh; Ritalin) was easily prepared from III in three steps.
threo-Methylphenidate (methyl threo-2-phenyl-2-(2′-pip-
eridyl)acetate) (threo-1, Figure 1), called Ritalin on the
market, has been used mainly for the treatment of attention
deficit hyperactivity disorder (ADHD) in children in the
USA.1 It has been administered to patients as a racemic form
despite the knowledge that the most active enantiomer is the
d-threo isomer.2 On the other hand, d- and l-erythro-1 (Figure
1) were shown to possess very little therapeutic effect and
had toxic hypertensive effects.3 Accordingly, an exploitation
of efficient methods selectively producing the d-threo isomer
is very much worthwhile.
† Kyushu University.
Figure 1.
‡ Nagasaki University.
(1) Barley, R. A. J. Child Psychol. Psychiatry 1977, 18, 137.
(2) Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese, G. R. J.
Pharmacol. Exp. Ther. 1987, 241, 152.
Existing methods for the practical preparation of racemic
(3) Szporny, L.; Gorog, P. Biochem. Pharmacol. 1961, 8, 263.
threo-1 involve procedures to separate its precursor from the
10.1021/ol9905046 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/04/1999

mixture of diastereomers at an appropriate stage of the
synthetic scheme.4 A new method through â-lactam inter-
mediates for a stereoselective preparation of racemic threo-1
has recently been reported.5 Also, there has been only one
report concerning on an asymmetric synthesis of d-threo-1,
though the method uses expensive L-pipecolinic acid as the
starting material together with an excess amount of (+)-IPC‚
BH2 at the key step to produce the d-threo isomer with high
diastereoselectivity, and it also requires multistage proce-
dures.6
forming reaction of Evans imides with carbonyl compounds10
and O,O-acetals11 has been reported.12
We found that the C-C bond forming reaction between
3 and 4a-c was successfully achieved by using a combina-
tion10 of TiCl4 and diisopropylethylamine (DIPEA) to give
the coupling products 5a-c with high stereoselectivity. The
configuration of 5a-c was determined at the stage of 7 and
1. Namely, the diastereoselectivity of 5a-c was determined
by HPLC analysis of 7 which was derived from 5a-c
through 6, and the absolute configuration of a main stereo-
isomer of 7 was identified by converting a main diastereo-
isomer of 7 to 1, of which absolute stereochemistry is
known.6 The results, shown in Table 1, which indicates that
We report herein a very convenient method for the
stereoselective synthesis of the d-threo isomer of 1 starting
from easily available N-methoxycarbonylpiperidine 2. Scheme
1 illustrates our method which consisits of only five steps:
Table 1. Reaction of R-Methoxycarbamate 3 with
Phenylacetyloxazolidinones (4a-c)
Scheme 1a
a 3a was not recovered. Overall yield of 7 from 4a-c. b Determined by
CSP HPLC analysis. c The absolute configuration was determined by
converting 7 to hydrochloride salts of each stereoisomer of methyl phenidate
1 followed by comparison of the salts with the authentic samples.6
a (a) 85%, 2.3F/mol of electricity in MeOH containing Et4NBF4;
(b) TiCl4 (1.1 equiv to 4) and DIPEA (1.2 equiv to 4) at -78 °C
for 1.5 h in CH2Cl2, then 3 (1.2 equiv to 4) at -78 °C, and overnight
at room temperature; (c) LiOOH (4.0 equiv to 4) in H2O/THF
overnight at room temperature; (d) CH2N2 for 2 h at room
temperature in ether; (e) Me3SiI (2.5 equiv to 7) in CH2Cl2 at room
temperature overnight; 75%.
the C-C bond forming reaction proceeds with very high
diastereo- and enantioselectivities.
The ratios of erythro-7 to threo-7 obtained in the reaction
of 3 with 4a and 4b were 6.9/93.1 and 5.3/94.7, respectively
(entries 1 and 2), and the ee of threo isomer from 4b was
excellent (99.6%) (entry 2). Also, the high stereoselectivities
(erthro/threo ) 1.6/98.4, the ee of threo isomer ) 81.8%)
were observed in the reaction of 3 with 4c (entry 3), of which
product 7 possessed the absolute configuration (2S,2′S)
opposite to that (2R,2′R) of 7 obtained by the reaction of 3
with 4b.
These stereoselectivities can be explained by considering
the reaction intermediates as exemplified by the mechanism
of the reaction of 3 with 4b. Two routes, (a) coordinated
route (Scheme 2) and (b) noncoordinated route (Scheme 3),
are conceivable for the mode of the attack of a titanium
enolate generated from 4b on an acyliminium ion generated
(a) an electrochemical R-methoxylation of 2 to afford
R-methoxypiperidine 3, (b) a C-C bond formation at the
R-position of 3 with Evans imides 4a-c,7 (c) a removal of
the chiral auxiliary from the products 5a-c, (d) the esteri-
fication of an acid 6, and (e) the deprotection of the
N-methoxycarbonyl group of the resulting ester 7 to give
d-threo-1.
Since the first step has been well established by us as a
promising method for introducing nucleophiles to the R-posi-
tion of carbamates,8 the key step in this scheme is a C-C
bond forming reaction (step 2) between Evans imides and
N,O-acetals such as 3,9 whereas the Ti-promoted C-C bond
(8) (a) Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1984, 63,
206. (b) Shono, T.; Matsumura, Y.; Fujita, T. Chem. Lett. 1991, 81. (c)
Matsumura, Y.; Terauchi, J.; Yamamoto, T.; Konno, T.; Shono, T.
Tetrahedron 1993, 49, 8503.
(9) The C-C bond forming reaction of Sn-enolates of 1,3-thiazololidine-
2-thiones with cyclic acyl imines derived from lactams has been reported:
(a) Nagao, Y.; Kumagai, T.; Tamai, S.; Abe, T.; Kuramoto, Y.; Taga, T.;
Aoyagi, S.; Nagase, Y.; Ochiai, M.; Inoue, Y.; Fujita, E. J. Am. Chem.
Soc. 1986, 108, 4673. (b) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi,
S.; Fujita, E. J. Am. Chem. Soc. 1988, 110, 289.
(4) (a) Panizzon, L. HelV. Chim. Acta 1944, 27, 1748. (b) Deutsch, H.
M.; Shi, Q.; Gruszecka-Kowalik, E.; Schweri, M. M. J. Med. Chem. 1996,
39, 1201.
(5) Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. J. Org. Chem.
1998, 63, 9628.
(6) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M.
J. Med. Chem. 1998, 41, 591.
(7) (a) Evans, D. A.; Bartroli, J.; Shih, T. L.J. Am. Chem. Soc. 1981,
103, 2127. (b) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56,
2489.
(10) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(11) Kanno, H.; Osanai, K. Tetraheron: Asymmetry 1995, 6, 1503.
176
Org. Lett., Vol. 1, No. 2, 1999

Scheme 2
Scheme 4
Since the determination of the configuration of the initially
formed C-C bond forming products 11a,b-13a,b was
difficult, it was achieved at the stage of 14-16. The reaction
was also found to possess very high stereoselectivities as
shown in Table 2.
from 3. Those routes may involve intermediates A-D, in
which the acyliminium ion approaches the thermodynami-
Scheme 3
Table 2. Reaction of R-Methoxycarbamate 3 with a Variety of
p-Substituted Phenylacetyloxazolidinones 8a,b-10a,b
a Overall yields from 8a,b-10a,b. b Determined by CSP HPLC analysis.
cally stable Z-form13 of the titanium enolate from the Si face.
The fact that (2R,2′R)-isomer was predominantly formed
strongly suggests the participation of A or C among A-D.
Large steric repulsion between the acyliminium ion and the
substituents (especially, phenyl group) of the titanium enolate
can be envisioned in B and C, while A and D may be less
crowded than B and C. Thus, we suppose that the reaction
might proceed through A via the coordinated intermediates.
Our method was successfully applied to the preparation
of p-substituted methylphenidates 14-16 by using p-sub-
stituted phenylacetyloxazolidinones 8a,b-10a,b (Scheme 4).
Among these products, p-trifluoromethyl-substituted meth-
ylphenidate derivative 16 was a new compound which could
not be prepared by the conventional method.4b
The configuration of 14 and 15 (entries 1-4, Table 2)
was determined by the deprotection of 14 and 15 followed
by the comparison of hydrochloride salts of the resulting
amino compounds with authentic samples.6 The configuration
of 16 was estimated on the basis of the proposed reaction
mechanism described above (entries 5 and 6, Table 2).
Furthermore, our method was applied to the preparation
of five- and seven-membered analogues5 (19, 22) of meth-
ylphenidate derivative 7 from pyrrolidine and hexameth-
yleneimine derivatives 17 and 20 (Schemes 5 and 6). The
coupling products 18a,b and 21a,b were converted without
isolation to 19 and 22, and the configuration of the main
stereo-
isomer of 19 and 22 was assigned by analogy to be (2R,2R′)
on the basis of the proposed reaction mechanism. In those
reactions, high diastereo- and enantioselectivities were also
observed (Table 3).
In conclusion, this paper describes a new efficient method
to prepare optically active methylphenidate 1 and its
(12) A variety of the Evans aldol reactions with other electrophiles have
been reported: (a) Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. J. Am. Chem.
Soc. 1986, 108, 4675. (b) D’Souza, A.; Motevalli, M.; Robinson, A. J.;
Wyatt, P. B. J. Chem. Soc., Perkin Trans. 1 1995, 1. (c) Arvanitis, E.;
Ernst, H.; Ludxig, A. A.; Robinson, A. J.; Wyatt, P. B. J. Chem. Soc., Perkin
Trans. 1 1998, 521.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
Org. Lett., Vol. 1, No. 2, 1999
177

Scheme 5
Table 3. Reaction of a Variety of R-Methoxycarbamates 17
and 20 with Phenylacetyloxazolidinone 4a,b
a See ref 14. b Overall yields from 4a,b. c Determined by CSP HPLC
analysis.
derivative 16. Further study on the mechanistic aspect and
the optimization of yields are currently under investigation.
analogues 19 and 22 starting from easily available N-
protected piperidine, pyrrolidine, and hexamethyleneimine.
The key step was the coupling of Evans imides with
electrochemically prepared R-methoxylated carbamates. It
also shows the preparation of p-substituted methylphenidates
including the first synthesis of trifluoromethyl-substituted
Acknowledgment. One of authors (Y.M.) thanks a Grant-
in-Aid for Scientific Research on Priority Area (No. 283)
(No. 10132254) and Scientific Research (B) (No. 09450335)
from the Ministry of Education, Science and Culture, Japan.
Scheme 6
Supporting Information Available: Full experimental
and analytical data for all new compounds; the conditions
of HPLC analysis for 7, 14-16, 19, and 22; the specific
rotations of 4b,c, 8b, 9b, 10b, threo-19, threo-22, and HCl
salts of threo-1 and its p-methoxy and p-bromo derivitives.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9905046
(14) Those R-methoxylated carbamates were easily obtained in around
85% yields by the electrochemical oxidation of the corresponding carbamates
in methanol.8
178
Org. Lett., Vol. 1, No. 2, 1999