An efficient large scale resolution of (±)-threo-methylphenidate hydrochloride (Ritalin hydrochloride)

Article abstract of DOI:10.1016/S0957-4166(99)00335-3

An efficient and large scale preparation of (2R,2'R)-(+)-threo-methylphenidate hydrochloride (3) by the resolution of (±)-threo-methylphenidate hydrochloride (1) salt with O,O'-dibenzoyl-D-(+)-tartaric acid in the presence of 4-methylmorpholine is described.

Full text of DOI:10.1016/S0957-4166(99)00335-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3111–3116
An efficient large scale resolution of (ꢀ)-threo-methylphenidate
hydrochloride (Ritalin® hydrochloride)
Mahavir Prashad,∗ Denis Har, Oljan Repic, Thomas J. Blacklock and Peter Giannousis
Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research,
59 Route 10, East Hanover, New Jersey 07936, USA
Received 21 June 1999; accepted 29 July 1999
Abstract
An efficient and large scale preparation of (2R,20R)-(+)-threo-methylphenidate hydrochloride (3) by the resolu-
tion of (ꢀ)-threo-methylphenidate hydrochloride (1) salt with O,O0-dibenzoyl-D-(+)-tartaric acid in the presence
of 4-methylmorpholine is described. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
(ꢀ)-threo-Methylphenidate hydrochloride (1, Ritalin® hydrochloride) is a mild nervous system stimu-
lant. It is marketed for the treatment of children with attention deficit hyperactivity disorder (ADHD).
(2R,20R)-(+)-threo-Methylphenidate hydrochloride (3) has been reported to be five1 to 38 times2 more
active than the corresponding (2S,20S)-(−)-threo-methylphenidate hydrochloride (5). We recently re-
ported the first enantioselective synthesis of 3.3 Original synthesis of 3 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 to afford 3.1,4
A
recent synthesis of 3 also utilized an enantiopure amino acid (D-pipecolic acid) as the starting material,
which in turn was prepared by the resolution of (ꢀ)-pipecolic acid with tartaric acid.5 Both of these
routes were unattractive for a scale-up in comparison to the direct resolution of (ꢀ)-methylphenidate
itself. Resolution of 1 by enzymatic hydrolysis has also been investigated.6–8 A classical resolution
method was reported for the resolution of (ꢀ)-threo-methylphenidate free base using expensive (R)-
(−)-1,10-binaphthyl-2,20-diyl hydrogenphosphate as the resolving agent.9 Recently, patent literature dis-
closed the use of O,O0-di-p-toluoyl-D-(+)-tartaric acid and (−)-menthoxyacetic acid to give satisfactory
resolution,10,11 however, they require the preparation and isolation of the (ꢀ)-threo-methylphenidate free
base, which makes large scale preparation cumbersome. Also, further details on the conversion of the
∗
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)00335-3

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diastereomeric salt to 3 were not disclosed. Thus, the necessity of a more efficient method for the prepa-
ration of 3 on a commercial scale prompted us to investigate the resolution of (ꢀ)-threo-methylphenidate
hydrochloride (1) in detail. In this paper we describe an efficient and large scale preparation of (2R,20R)-
(+)-threo-methylphenidate hydrochloride (3) by the resolution of (ꢀ)-threo-methylphenidate hydrochlo-
ride (1) with O,O0-dibenzoyl-D-(+)-tartaric acid in the presence of 4-methylmorpholine, which avoids
the isolation of (ꢀ)-threo-methylphenidate free base (Scheme 1).
Scheme 1.
2. Results and discussion
Our objective was to develop a process for the direct resolution of (ꢀ)-threo-methylphenidate hydro-
chloride salt, thus eliminating the necessity for the preparation and isolation of the corresponding free
base. Because (ꢀ)-threo-methylphenidate hydrochloride (1) was soluble in a mixture of methanol and
water, we selected this solvent system for the direct resolution of the salt. To test this solvent mixture,
we initially studied the resolution of the free base with different diaroyl-D-tartaric acids (1 equivalent).
The crystalline diastereomeric salts were isolated by filtration and the enantiopurities were determined by
HPLC using a Daicel Chiralpak AD column. The results are summarized in Table 1. The resolution of the
free base was most satisfactory with di-p-isopropylbenzoyl-D-tartaric acid in a 2:1 mixture of methanol
and water, and with dibenzoyl-D-tartaric acid in a 1:1 mixture of these solvents. Because dibenzoyl-D-
tartaric acid is a cheap and commercially available material, it was chosen to study the direct resolution of
the hydrochloride salt. O,O0-Diaroyltartaric acids are well documented resolving agents for amines.12,13
Intuitively, the presence of a base should be necessary for the direct resolution of the HCl salt (1) with
dibenzoyl-D-tartaric acid, however, this is not always the case when thermodynamics are favorable. Thus,
interestingly, resolution of 1 in a 1:1 mixture of methanol and water at 0°C, without any base, yielded the
diastereomeric salt with excellent enantiopurity but in only 18% yield. Use of aqueous sodium hydroxide
Table 1
Resolution of (ꢀ)-methylphenidate free base

M. Prashad et al. / Tetrahedron: Asymmetry 10 (1999) 3111–3116
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Table 2
Optimization of direct resolution of (ꢀ)-methylphenidate hydrochloride salt
as a base yielded the diastereomeric salt with poor enantiopurity. Use of ammonium hydroxide and
triethylamine, while leading to good enantiopurity, always contaminated the diastereomeric salt with
ammonium or triethylammonium salt of the resolving agent and was undesirable for scale-up puposes.
We found that 4-methylmorpholine gave the diastereomeric salt which was not contaminated with the 4-
methylmorpholinium salt of the resolving agent. Thus, the resolution of 1 was studied using varying
compositions of methanol and water at different temperatures in the presence of 1 equivalent of 4-
methylmorpholine as a base to afford crystalline diastereomeric salts which were isolated by filtration.
The results are summarized in Table 2. A 1.5:1 ratio of methanol and water gave satisfactory resolution
at room temperature. Further cooling to 0°C led to poor enantiopurity of the diastereomeric salt 2 (entries
7 and 8). A 2:1 ratio of methanol and water was optimal for this resolution. With this ratio the resolution
was satisfactory at room temperature as well as at 0°C. Cooling to 0°C increased the yield from 38%
to 44% (entries 13 and 18). These conditions were selected for a further scale-up. A preformed salt of
4-methylmorpholine with dibenzoyl-D-tartaric acid also led to a satisfactory resolution of 1.
With successful resolution conditions in hand, our next objective was to convert the D-(+)-DBTA
salt (2) to 3. Basification of the salt (2) with aqueous sodium hydroxide in isopropyl acetate yielded
a solution of the (2R,20R)-(+)-threo-methylphenidate free base in isopropyl acetate. Treatment of this
solution with concentrated hydrochloric acid furnished the crude (2R,20R)-(+)-threo-methylphenidate
hydrochloride. Finally, the crude material was recrystallized from water and concentrated hydrochloric
acid and isolated by filtration to afford 40.3% of crystalline 3 with 99.9% enantiopurity (it contained
<0.1% of the (2S,20S)-enantiomer).
The resolving agent was also recovered by combining the filtrate from the resolution step and the
aqueous layer from the basification step of the diastereomeric salt 2, treatment with aqueous sodium
hydroxide to basify the combined solution, extraction with isopropyl acetate and acidifying the aqueous

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layer with concentrated hydrochloric acid, extraction with isopropyl acetate, followed by recrystallization
from isopropanol and heptane. The recovered O,O0-dibenzoyl-D-(+)-tartaric acid was of comparable
purity to that of the commercial material. A resolution of 1 with the recovered material yielded the
D-(+)-DBTA salt (2) with the desired enantiopurity ((2R,20R):(2S,20S)=95.5:0.5). These results indicate
that the resolving agent is recyclable, making this process even more economical.
We also needed to prepare the (2S,20S)-(−)-threo-enantiomer of methylphenidate (5) as a reference
standard (Scheme 2). Compound 5 was prepared in 38% yield using the same procedure but replacing
O,O0-dibenzoyl-D-(+)-tartaric acid with O,O0-dibenzoyl-L-(−)-tartaric acid in the resolution step.
Scheme 2.
In summary, an efficient and large scale synthesis of (2R,20R)-(+)-threo-methylphenidate hydrochlo-
ride (3) by direct resolution of (ꢀ)-threo-methylphenidate hydrochloride (1) with O,O0-dibenzoyl-D-(+)-
tartaric acid in the presence of 4-methylmorpholine was developed. The resolving agent was recyclable.
(2S,20S)-(−)-threo-Methylphenidate hydrochloride (5) was also prepared by the resolution of (ꢀ)-threo-
methylphenidate hydrochloride with O,O0-dibenzoyl-L-(−)-tartaric acid.
3. Experimental
Melting points were measured on a Büchi 535 melting point apparatus. 1H NMR spectra were recorded
on a Bruker 300 instrument. The enantiopurities were determined either by capillary electrophoresis on
a Beckman P/ACE 5000 series instrument (capillary: fused silica, 75 µm (ID)×361 µm (OD)×77 cm
(70 cm effective separation length), 800 µm aperture; detection: 214 nm; injection: 4.5 seconds, run
voltage: 28 kV (363 V/cm); run time: 32 min; polarity: positive; temperature: 23°C; current: 115–130
µamps; separation electrolyte: 100 mM phosphate, pH 2.0, 10% methanol, 5 mM heptakis-(2,6-di-O-
methyl)-β-cyclodextrin, or by chiral HPLC on a Rainin Dynamax system using a Daicel Chiralpak AD
column (4.6×250 mm) and a mixture of hexane:ethanol:methanol:TFA (96:2:2:0.1) as the mobile phase
(isocratic at a flow rate of 0.8 mL/min and UV detector at 230 nm). O,O0-Dibenzoyl-D-(+)-tartaric acid
and O,O0-di-p-toluoyl-D-(+)-tartaric acid were commercially available. The other diaroyl-D-tartaric acids
were prepared from D-tartaric acid using a reported procedure.14
3.1. (2R,20R)-(+)-threo-Methylphenidate hydrochloride (3)
A 3 L, four-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer,
and heating mantle was charged with (ꢀ)-methylphenidate hydrochloride (129.5 g; 0.48 mol), O,O0-
dibenzoyl-D-(+)-tartaric acid (172.0 g; 0.48 mol), and methanol (624 mL). The mixture was stirred at
room temperature (23–25°C) and to the resulting solution was added 4-methylmorpholine (48.55 g; 0.48
mol) over a period of 5–10 min while maintaining an internal temperature of 29–31°C. The resulting
clear solution was heated to an internal temperature of 40–45°C, and water (312 mL) was added over

M. Prashad et al. / Tetrahedron: Asymmetry 10 (1999) 3111–3116
3115
a period of 10 min while maintaining the same internal temperature to obtain a clear solution. To this
solution were added seeds of O,O0-dibenzoyl-D-(+)-tartrate salt (2) of (2R,20R)-methylphenidate (60
mg). The reaction mixture was allowed to cool to room temperature (23–25°C) over a period of 1 h,
and the stirring was continued at the same temperature for an additional 1 h. The heterogeneous mixture
was cooled to an internal temperature of 0–5°C over a period of 15 min and stirred at 0–5°C for an
additional 2 h (at the 25 kg scale this cooling step was eliminated). The solids were collected by filtration,
washed with a precooled mixture (0–5°C) of methanol and water (2:1 v/v) in three equal 70 mL portions,
and dried at 50–55°C (100 mmHg) to afford 125.5 g of O,O0-dibenzoyl-D-(+)-tartrate salt of (2R,20R)-
methylphenidate (4): mp=138–140°C; [α]D25 +107.7 (c=1.0, MeOH); (2S,20S):(2R,20R)=99.54:0.46.
O,O0-Dibenzoyl-D-(+)-tartrate salt of (2R,20R)-(+)-threo-methylphenidate (2, 125.3 g) was suspended
in isopropyl acetate (400 mL), and a solution of sodium hydroxide (21.2 g) in water (400 mL) was added
over a period of 15 min while maintaining an internal temperature of 20–25°C. The addition funnel
was washed with water (5 mL), which was added to the mixture. The suspension was stirred efficiently
until all the solids dissolved (15–20 min). The organic layer was separated, and the aqueous layer was
extracted with isopropyl acetate (200 mL). The aqueous layer was saved to recover the resolving agent.
The combined organic layers were washed with water (30 mL) and filtered. The filtrate was cooled
to 0–2°C (internal temperature), and concentrated hydrochloric acid (34.9 g; 31%) was added over a
period of 10 min while maintaining an internal temperature of <10°C. The heterogeneous mixture was
warmed to room temperature over a period of 45 min. The solids were collected by filtration, washed with
isopropyl acetate (2×50 mL), and dried at 50–55°C (100 mm Hg) to afford 55.2 g of crude (2R,20R)-(+)-
threo-methylphenidate hydrochloride. This solid was added to hot water (64 g; preheated to an internal
temperature of 74–75°C). The mixture was heated to an internal temperature of 80–82°C to obtain a clear
solution. The solution was cooled to room temperature (20–22°C) over a period of 45 min to obtain a
suspension. To the resulting suspension was added concentrated hydrochloric acid (24.0 g; 31%) over
a period of 10 min while maintaining an internal temperature of <25°C. The mixture was cooled to
0–5°C over a period of 15 min and was allowed to stir at this temperature for an additional 30 min.
The solids were collected by filtration, washed with cold water (2×7.5 mL; precooled to 0–5°C) and
dried at 50–55°C (100 mmHg) for 16 h to obtain a constant weight of 52.2 g of pure (2R,20R)-(+)-
25
threo-methylphenidate hydrochloride (3) as a white powder. Yield 40.3%; mp=222–224°C; [α]D +84
25
(c=1.0, MeOH); (2R,20R):(2S,20S)=99.9:<0.1). Lit.1 mp=210–211°C; [α]D +88 (1% in MeOH); IR
1
(KBr, cm−1) 1739; H NMR (CD3OD, δ) 1.35–1.58 (m, 3H), 1.65–1.93 (m, 3H), 3.11 (dt, 1H, J=3.5
and 12.6 Hz), 3.4–3.5 (m, 1H), 3.7 (s, 3H), 3.84 (dt, 1H, J=3.5 and 10.0 Hz), 3.99 (d, 1H, J=10.0 Hz),
7.25–7.44 (m, 5H); 13C NMR (CD3OD, δ) 22.78, 23.23, 27.54, 46.63, 53.4, 55.2, 59.18, 129.59, 129.62,
130.36, 135.25, 173.22; MS (m/e) 234 (MH+). Anal. calcd for C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19;
Cl, 13.14. Found: C, 62.31; H, 7.36; N, 5.15; Cl, 13.11.
3.2. (2S,20S)-(−)-threo-Methylphenidate hydrochloride (5)
Compound 5 was prepared in a similar manner as described above for 3 except O,O0-dibenzoyl-L-
(−)-tartaric acid was used for the resolution step. This afforded the O,O0-dibenzoyl-L-(−)-tartrate salt of
25
(2S,20S)-(−)-threo-methylphenidate (4) in 41.7% yield; mp=138–140°C; [α]D −107 (c=1.0, MeOH);
(2S,20S):(2R,20R)=99.73:0.27.
25
Compound 5: Yield 38%; mp=222–224°C; [α]D −87 (c=1.0, MeOH); (2S,20S):(2R,20R)=99.9:0.1.
Lit.1 mp=209–210°C; [α]D20 −75 (1% in MeOH); IR (KBr, cm−1) 1739; 1H NMR (CD3OD, δ) 1.33–1.55
(m, 3H), 1.64–1.92 (m, 3H), 3.1 (dt, 1H, J=3.5 and 12.6 Hz), 3.4–3.5 (m, 1H), 3.7 (s, 3H), 3.83 (dt, 1H,
J=3.5 and 10.0 Hz), 3.96 (d, 1H, J=10.0 Hz), 7.25–7.44 (m, 5H); 13C NMR (CD3OD, δ) 22.79, 23.27,

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M. Prashad et al. / Tetrahedron: Asymmetry 10 (1999) 3111–3116
27.58, 46.64, 53.4, 55.23, 59.2, 129.59, 129.64, 130.38, 135.25, 173.24; MS (m/e) 234 (MH+). Anal.
calcd for C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19; Cl, 13.14. Found: C, 62.21; H, 7.32; N, 5.44; Cl,
13.16.
Acknowledgements
We thank Dr. Yugang Liu for preparing non-commercial diaroyl-D-tartaric acids.
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