Enantioselective synthesis of (2S,2'R)-erythro-methylphenidate

Article abstract of DOI:10.1016/S0957-4166(99)00384-5

A new approach towards the enantioselective synthesis of (2S,2'R)- erythro-methylphenidate (1) is described. The key step in the synthesis utilizes Evans' 4-substituted-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hyd

Full text of DOI:10.1016/S0957-4166(99)00384-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3479–3482
Enantioselective synthesis of (2S,20R)-erythro-methylphenidate
Mahavir Prashad,∗ Yugang Liu, Hong-Yong Kim, Oljan Repic and Thomas J. Blacklock
Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research,
59 Route 10, East Hanover, New Jersey 07936, USA
Received 16 August 1999; accepted 17 August 1999
Abstract
A new approach towards the enantioselective synthesis of (2S,20R)-erythro-methylphenidate (1) is described.
The key step in the synthesis utilizes Evans’ 4-substituted-2-oxazolidinone chiral auxiliary to control the dia-
stereofacial selectivity in the hydrogenation of enamine intermediate 6, yielding the hydrogenated product 7 with
excellent diastereoselectivity. Methanolysis of 7 afforded 1 with excellent enantiopurity. © 1999 Elsevier Science
Ltd. All rights reserved.
(ꢀ)-threo-Methylphenidate hydrochloride (Ritalin® hydrochloride) is a mild nervous system sti-
mulant marketed for the treatment of children with attention deficit hyperactivity disorder (ADHD).
(2R,20R)-threo-(+)-Methylphenidate hydrochloride has been reported to be five times1 to thirty-eight
times2 more active than the corresponding (2S,20S)-threo-(−)-methylphenidate hydrochloride. Ori-
ginal synthesis of (2R,20R)-threo-(+)-methylphenidate hydrochloride utilized the resolution of (ꢀ)-
erythro-α-phenyl-α-(2-piperidyl)acetamide to obtain enantiomerically pure l-erythro-α-phenyl-α-(2-
piperidyl)acetamide, which was subjected to epimerization, hydrolysis, and esterification.1,3 Resolution
of (ꢀ)-threo-methylphenidate hydrochloride by enzymatic hydrolysis as well as classical resolution
methods have recently been reported.4–11 A synthesis of (2R,20R)-threo-(+)-methylphenidate hydrochlo-
ride using D-pipecolic acid as the starting material was also reported, however, D-pipecolic acid had
to be prepared by resolution.12 We recently reported the first enantioselective synthesis of (2R,20R)-
threo-(+)-methylphenidate hydrochloride,13 which is now followed by other reports.14–16 We were also
interested in an enantioselective synthesis of (2S,20R)-erythro-(−)-methylphenidate because it could
be epimerized to (2R,20R)-threo-(+)-methylphenidate, as the epimerization of l-erythro-α-phenyl-α-(2-
piperidyl)acetamide to the corresponding threo-isomer was known.1 In this communication, we wish to
report our results on the enantioselective synthesis of (2S,20R)-erythro-methylphenidate (1).
Our strategy towards (2S,20R)-erythro-methylphenidate (1), as depicted in Scheme 1, utilizes Evans’
(S)-4-substituted-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hy-
drogenation of enamine intermediate I. We envisioned that in enamine intermediate I, the possible
∗
Corresponding author. E-mail: mahavir.prashad@pharma.novartis.com
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00384-5

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hydrogen bonding between the carbonyl oxygen and N-H hydrogen would probably lock the geometry
of the double bond as Z, and the dipole–dipole interaction between the two carbonyl groups would
further regulate the geometry of I as shown in Scheme 1. Accordingly, hydrogenation of I would
occur in the face opposite to that of the 4-substituent in the chiral auxiliary, providing hydrogenation
product Ia with the (2S,20R) configuration. Further manipulations of Ia would afford (2S,20R)-erythro-
methylphenidate. Similarly, (R)-4-substituted-2-oxazolidinone chiral auxiliary would yield the (2R,20S)-
erythro-methylphenidate.
Scheme 1.
Synthesis of the key enamine intermediate 6 is depicted in Scheme 2. It is based on the acylation of (S)-
4-benzyl-N-phenylacetyl-2-oxazolidinone (2) with the mixed anhydride 4, followed by the deprotection
of the t-butyloxycarbonyl group with simultaneous cyclization to give enamine intermediate 6. Com-
pound 2 was obtained in 85% yield by acylation of (S)-4-benzyl-2-oxazolidinone with phenylacetic acid
using the procedure developed in our laboratories.17 Mixed anhydride 4 was synthesized quantitatively
by acylation of carboxylic acid 3 with pivolyl chloride and triethylamine. The acylation of 2 with 4 in
the presence of LiHMDS in THF afforded the desired C-acylated product 5 along with the O-acylated
products. Such an O-acylation problem has been observed before.18 Compound 5 could not be completely
purified from other by-products and was used directly in the next step. Cleavage of the t-butyloxycarbonyl
group in 5 with trifluoroacetic acid, and neutralization of the reaction mixture with aq. NaHCO3 furnished
the desired enamine intermediate 6 in 30% combined yield over two steps (Scheme 2) after a silica gel
1
chromatography. H NMR confirmed the structure of 6 and that it was a single isomer.19 Chemical shift
of the NH proton indicated an intramolecular H-bonding with the carbonyl group of the chiral auxiliary.
Hydrogenation of 6 in ethyl acetate yielded 7 in 95% yield with an excellent diastereoselectivity (97:3).19
The amount of Pd–C (10%) varied from 2% to 20% depending on the purity of 6, but it had no impact
on the diastereoselectivity of the reaction. We found that 6 had to be rigorously purified by silica gel
chromatography before hydrogenation. Treatment of 7 with methanol20 in the presence of LnI3 afforded
(2S,20R)-erythro-methylphenidate (1)12 in 85% yield after a silica gel chromatography. The enantiopurity
of 1 was excellent (2S,20R:2R,20S 97:3).21
Interestingly, use of (S)-4-phenyl-2-oxazolidinone chiral auxiliary furnished the enamine intermediate
which was a mixture of H-bonded and non-H-bonded conformers, as suggested by 1H NMR. As expected,
hydrogenation of this enamine over Pd–C yielded a mixture of diastereoisomers.
In summary, a novel approach towards an enantioselective synthesis of (2S,20R)-erythro-
methylphenidate (1) is described. The key step in the synthesis utilizes Evans’ 4-substituted-2-
oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine
intermediate 6, yielding the hydrogenated product 7 with excellent diastereoselectivity. Methanolysis of 7

M. Prashad et al. / Tetrahedron: Asymmetry 10 (1999) 3479–3482
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Scheme 2. (a) t-BuCOCl, Et3N, PhCH3, 80°C, 12 h (85%); (b) t-BuCOCl, Et3N, PhCH3, rt, 4 h (100%); (c) LiHMDS, THF,
0°C, 1 h; (d) (i) CF3CO2H, CH2Cl2, 0°C to rt, 4 h, (ii) NaHCO3 (30% in two steps); (e) 10% Pd–C, EtOAc, rt, 24 h (95%); (f)
MeOH, LnI3, THF, rt, 16 h (85%)
afforded 1 with excellent enantiopurity. This approach could also be used to synthesize the corresponding
(2R,20S)-erythro-methylphenidate by using (R)-4-benzyl-2-oxazolidinone chiral auxiliary.
Acknowledgements
We thank Dr. Bin Hu for chiral HPLC analysis of compound 1.
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