An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride

Article abstract of DOI:10.1002/jhet.2705

The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.

Full text of DOI:10.1002/jhet.2705

Month 2016
An Improved and Efficient Process for the Production of Highly Pure
Dexmethylphenidate Hydrochloride
a
a
a
a
Long-Xuan Xing,a† Cheng-Wu Shen,b† Yuan-Yuan Sun, Lei Huang, Yong-Yong Zheng, and Jian-Qi Li
*
*
aNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1111 North
Zhongshan No.1 Road, Shanghai 200437, People’s Republic of China
bDepartment of Pharmacy, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021,
People’s Republic of China
*
E-mail: zhengyongyong@126.com; lijianqb@126.com
†These authors contributed equally to the work described in this paper.
Additional Supporting Information may be found in the online version of this article.
Received January 3, 2015
DOI 10.1002/jhet.2705
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The present work describes an efficient and commercially viable process for the synthesis of
dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with
~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also
described in this report.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
impurities were formed and identified, and this repre-
sents the first identification of such. To improve the prod-
uct process and quality, identification and characterization
of API impurities is a regulatory requirement. Here, we
report the process optimization and mechanisms for de-
creasing impurities in dexmethylphenidate hydrochloride.
Dexmethylphenidate hydrochloride ((R)-methyl 2-phe-
nyl-2-((R)-piperidin-2-yl)acetate hydrochloride 1; Fig. 1),
a mild central nervous system stimulant, was developed
and marketed for the treatment of pediatric attention deficit
hyperactivity disorder by Celgene Corp (Summit, NJ) [1].
It is primarily used in its racemic form ( )-threo-methyl-
phenidate hydrochloride (2; Fig. 1) [2]. 1 has been reported
to be more active with fewer side effects than the corre-
sponding (2S, 2′S)-(-)-threo-isomer [3].
Several processes are reported for the preparation of
dexmethylphenidate hydrochloride (1) [1,4], but the most
preferable and convenient route for synthesis of 1 mainly
involves SNAr arylation of benzeneacetonitrile (3) with
2-chloropyridine (2), to hydrolyze the nitrile 4 and obtain
the amide 5. Catalytic reduction of 5 was then performed
and afforded 6 as a mixture of threo and erythro forms. This
mixture was treated with a base to epimerize the erythro iso-
mer into the threo isomer 7. Resolution of 7 with acid re-
solving agent then afforded (2R, 2′R)-(+)-threo-isomer 8,
which was converted to the desired dexmethylphenidate
hydrochloride (1) by treatment with concentrated sulfuric
acid, methanol, and hydrochloride (Scheme 1).
RESULTS AND DISCUSSION
Intermediate 4 was prepared according to methods in the
literature [4d] with modifications and improvements
(Scheme 1). The SNAr arylation of benzeneacetonitrile
(3) with 2-chloropyridine (2) under different reaction
conditions was explored. The synthetic processes for
α-arylation of nitriles with different bases and solvents
are reported in the literature, such as KOH/DMSO [6],
tetrabutylammonium fluoride (TBAF)/NaOH/PhMe [7],
sodium bis(trimethylsilyl)amide (NaHMDS)/PhMe-THF
[8], and NaNH2/ PhMe [4d]. In our synthetic process
development of 4, a variety of conditions were examined,
as shown in Table 1. Specifically, by using NaHMDS or
NaNH2 as base, afforded the desired compound 4 in
50–60% isolated yield (entries 4–6). These low yields
may be explained by the simultaneous formation of
product along with ketone 4A as a major impurity (Fig. 2).
This impurity results from oxidative decyanation of
secondary nitrile during SNAr arylation, as proposed in
Active pharmaceutical ingredients (API) can be
contaminated by impurities, which may influence drug
quality and safety [5]. During our process development
of dexmethylphenidate hydrochloride (1), some
© 2016 Wiley Periodicals, Inc.

L.-X. Xing, C.-W. Shen, Y.-Y. Sun, L. Huang, Y.-Y. Zheng, and J.-Q. Li
Vol 000
[4c]) have been described in the literature for this
hydrogenation process. Based on price, Pd/C was chosen
for further investigation. Experiments were first performed
using 5% Pd/C as catalyst, under different pressures and
solvents and this resulted in poor conversion even after
20h (Table 2, entries 1–2). Compound 5 was hydrogenated
using 10% Pd/C as a catalyst to give 6 in moderate to good
yields (entries 3–7). Optimal reaction condition are given
in entry 3. This reaction afforded the compound 6 as a
mixture of threo and erythro forms, and the ratio (threo/
erythro: 20/80) was established by HPLC.
Figure 1. Structures of 1 and 2.
Scheme 2 [9]. Impurity 4A is an oxidative decyanation
product, so the oxygen in the solvent may be a factor.
Thus, oxygen-free solvents were used to synthesize
intermediate 4, and yields were greater (Table 1, entries
7–8) compared with reactions with solvents without
pretreatment (entries 4–6). The best reaction conditions
among those tabulated include oxygen-free toluene as
solvent and NaNH2 as a base for SNAr arylation (entries 7).
Compound 4 was a light-yellow solid, and purity could be
improved to > 98%. Impurity 4A could be reduced to
≤ 0.1% after recrystallization.
Next, the nitrile 4 was hydrolyzed using concentrated
sulfuric acid to obtain the amide 5 with good yield [4d].
After compound 5 was obtained, catalytic hydrogenation
conditions, such as catalysts, pressure, time, and solvents
were investigated as summarized in Table 2. Various
catalysts (Pt/C [6], PtO2/C [4d], Rh/C [10], and Pd/C
With compound 6 in hand, the threo and erythro mixture
was then treated with potassium tert-butoxide to epimerize
the erythro stereoisomer into threo form 7 with about 80%
yield and this agrees with published yields [4d].
In the next step, the resolution of ( )-threo-2-phenyl-
2-(piperidin-2-yl)acetamide (7) was explored. Three
commercially available acids (D-tartaric acid (D-TA),
dibenzoyl-D-tartaric acid (D-DBTA), and ditoluoyl-D-
tartaric acid(D-DTTA)) were selected and tested for
resolution of 7 as shown in Table 3. Among these acids,
resolution with D-DBTA in methanol, although
successful, produced 8 at only 25.2% yield (entry 2).
Also, the solvent had significant effects on resolution
yield. Resolution with isopropyl alcohol produced
Scheme 1. Synthesis route of 1.
Table 1
Variation of conditions for the arylation step.
HPLC (%)
Entry
Base
Solvent
DMSO
PhMe
DMF
PhMe/THF
PhMe
PhMe/THF
PhMe (O2 free)
PhMe/THF (O2 free)
2
3
4
4A
1
2
3
4
5
6
7
8
KOH
30.4
44.6
43.2
13.5
1.0
12.3
0.5
11.5
32.5
47.3
46.3
15.8
1.3
15.2
0.8
13.1
10.5
1.0
0.5
50.1
60.4
50.2
91.2
65.4
15.6
0.5
0.1
15.2
32.5
24.6
3.2
aq. NaOH/TBAF(as phase transfer catalyst)
t-BuOK
KHMDS
NaNH2
NaNH2
NaNH2
KHMDS
4.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride
Figure 2. Structure of impurities.
Scheme 2. The mechanism of formation impurity 4A.
Table 2
Reaction conditions for the hydrogenation step.
Entry
Catalyst
Solvent
Pressure (MPa)
Time (h)
Yield (%)
1
2
3
4
5
6
7
5% Pd/C
5% Pd/C
AcOH
AcOH/TFA
AcOH
AcOH/TFA
MeOH/H2SO4
AcOH
2
3
2
2
2
1
3
20
20
4
4
4
Trace
Trace
99a
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
90a
50a
20
3
95a
AcOH
98a
aIsolated yield.
Table 3
Resolution of compound 7.
a
Entry
Resolving agent
Solvent
Crystallization temperature (°C)
ee (%)
Yield (%)
1
2
3
4
5
6
7
8
D-TA
MeOH
MeOH
MeOH
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
25
25
25
25
25
20
30
35
85.3
98.3
95.6
97.3
96.7
76.4
99.5
99.6
17.5
25.2
26.3
35.0
45.7
48.2
44.4
40.8
D-DBTA
D-DTTA
D-DBTA
D-DBTA
D-DBTA
D-DBTA
D-DBTA
aIsolated yield.
45.7% yield (entry 5), but offered less resolution
efficiency than methanol. The resolution efficiency was
affected by crystallization temperature, too, and the
optimal temperature was 30 C (entry 7) with 99.5%
enantiomeric excess (ee) and 44.4% yield.
Next, in an esterification reaction, amide 8 was reacted
with methanol in the presence of concentrated sulfuric acid
to form the free base methyl ester product. This was then
reacted with concentrated hydrochloric acid to obtain the
desired 1 with 99.50% purity and 99.70% ee. Three major
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L.-X. Xing, C.-W. Shen, Y.-Y. Sun, L. Huang, Y.-Y. Zheng, and J.-Q. Li
Vol 000
points were determined on an electrothermal melting point
apparatus. Solvents and reagents were used without any pre-
treatment. Reaction progress and chemical purity were eva-
luated by HPLC analysis using a Waters Symmetry C18
(Waters, Milford, MA) (5μm, 250mm×4.6mm)with a mo-
bile phase A (acetonitrile) and B (0.015mol/L KH2PO4),
5:95→60:40v/v; and detection at 220nm; flow: 1.0mL/
min; temp. 30°C. Chiral purity was evaluated by HPLC
analysis using a Daicel Chiralpak AD-H chiral column
(5μm, 250mm×4.6mm) with isocratic mobile phase N-
hexane/ethanol/trifluoroacetic acid/diethylamine, 95:5:0.1:
0.1v/v/v/v; and detection at 220nm; flow: 1.0mL/min; and
temp. 35°C.
Figure 3. Single crystal X-ray structure of 1. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
2-phenyl-2-(pyridin-2-yl)acetonitrile (4).
A 3 L multi-
neck glass reactor was charged with toluene (720mL). In
this reaction system, nitrogen purging is required for
0.5 h. Sodium amide powder (138g, 3.54mol) was added
to this solution at room temperature, then benzyl cyanide
(217 g, 1.85mol) and 2-chloropyridine (200g, 1.77 mol)
were added dropwise successively. The reaction mixture
was stirred at the same temperature for 2 h. After cooling
to 10°C, the reaction mixture was quenched with water
(620 mL). Ethyl acetate (600mL) was added to the
solution, and the organic layer was separated and washed
with brine (600mL). The solvent was removed under
reduced pressure, and toluene (100 mL), followed by
n-hexane (1.1 L), were added to this residue. The mixture
was stirred for 1h, and filtered. The filter cake was dried
under vacuum to afford the desired 4 as a light-yellow
solid. This crude product was further purified by
recrystallization from ethyl acetate (600mL) to obtain 4
as a white solid (289g, 84.2% yield) with 99.10%. Mp
84-86°C; MS m/z 195 [M + H]+. 1H NMR (400MHz,
DMSO-d6) δ 8.59-8.58 (d, J =4.4Hz, 1H), 7.85-7.81 (dt,
J1 = 1.6Hz, J2 = 7.6Hz, 1H), 7.46-7.45 (m, 3H), 7.42-7.38
(m, 2H), 7.36-7.31 (m, 2H), 5.93 (s, 1H). 13C NMR
(100.6 MHz, DMSO-d6) δ 155.4, 149.7, 137.9, 135.6,
129.1, 128.2, 127.4, 123.3, 122.4, 119.7, 43.6.
impurities in the range of 0.06–0.15% each were separated
and characterized as 1A, 1B, and 1C (Fig. 2). 1A, the
erythro stereoisomer of 1, was believed to arise from the
process for epimerization of compound 6. Impurity 1B is
the ethyl ester homologue of compound 1. It is generally
believed that there is small amount of ethanol in methanol,
by which the ethyl ester moiety can be introduced as
byproduct of the esterification reaction in this step.
(S)-methyl 2-phenyl-2-((S)-piperidin-2-yl)acetate (1C)
was derived from the resolution of 7.
The impurities we identified can be removed with the
following purification process. The hydrochloric acid salt
1 was recrystallized from water, and this offered a qualified
API with 99.92% purity and 99.98% ee and single impurity
of less than 0.1%. A single crystal X-ray structure of 1 was
obtained (Fig. 3), which confirmed the identity and
absolute stereochemistries.
CONCLUSION
2-phenyl-2-(pyridin-2-yl)acetamide (5). A 5 L multi-neck
glass reactor was charged with concentrated sulfuric acid
(570 mL). After cooling to 10°C, compound 4 (457g,
2.36 mol) was added portion-wise, then the mixture was
stirred at room temperature for 12 h. The reaction mixture
was cooled to 10°C, water (1.7 L) was added dropwise, and
adjusted to pH 12 by 30% sodium hydroxide solution. The
precipitate was isolated and washed with water (200 mL).
The filter cake was dried under vacuum to afford 5 as a
light-yellow solid (478 g, 95.8% yield). Mp 134-135°C; MS
An efficient and commercially viable process has been
developed for the synthesis of 1 with an overall yield of
23% and ~99.9% purity. The impurities produced in this
process were well controlled and removed.
EXPERIMENTAL
Nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker NMR AVANCE 400 (400MHz)
spectrometer (Bruker Daltonics Inc., Billerica, MA) with
TMS as an internal standard. Chemical shift (d values)
and coupling constants (J values) are given in ppm and
Hz, respectively. ESI mass spectra were performed on an
Agilent 6210 TOF spectrometer. Uncorrected melting
1
m/z 213 [M+ H]+. H NMR (400 MHz, DMSO-d6) δ 8.49-
8.48 (d, J= 4.4Hz, 1H), 7.76 (br, 1H), 7.74-7.69 (dt,
J1 =1.6Hz, J2 = 7.6Hz, 1H), 7.38-7.36 (m, 3H), 7.33-7.30
(m, 2H), 7.26-7.22 (m, 2H), 7.16 (br, 1H), 5.09 (s, 1H). 13C
NMR (100.6 MHz, DMSO-d6) δ 172.3, 159.6, 148.8, 139.3,
136.6, 128.7, 128.3, 126.8, 123.0, 122.0, 59.3.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride
( )-erythro/threo-2-phenyl-2-(piperidin-2-yl)acetamide
(6). A 5L hydrogenation reactor was charged with Pd/C
(10% Pd content, 20 g), AcOH (2.4 L) and compound 5
(220 g, 1.04 mol). The reactor was pressurized with
hydrogen (2MPa) and then heated to 70°C for 10h. The
reaction mixture was filtered to remove catalyst, and the
solvent was concentrated under reduced pressure
(~30 mmHg). Water (1.9 L) was added to this residue, the
mixture was cooled to 10°C, and adjusted to pH 12 with
a 30% sodium hydroxide solution. The precipitate was
isolated and washed with water (100 mL). The filter cake
was dried under vacuum to afford 6 as a white solid
(223 g, 99.5% yield). Mp 156-157°C; MS m/z 219 [M
1H), 7.29-7.21 (m, 5H), 6.86 (br, 1H), 3.26-3.24 (d,
J = 9.6Hz, 1H), 2.96-2.92 (m, 2H), 2.46 (m, 1H), 1.84
(br, 1H), 1.59-1.56 (J= 12.0Hz, 1H), 1.46-1.43
(J = 12.0Hz, 1H), 1.28-1.22 (m, 1H), 1.19-1.07 (m, 2H),
0.87-0.79 (m, 1H). 13C NMR (100.6 MHz, DMSO-d6) δ
174.1, 138.8, 128.4, 128.2, 126.7, 58.5, 58.1, 46.4, 29.8,
25.9, 24.2.
(R)-methyl 2-phenyl-2-((R)-piperidin-2-yl)acetate hydrochloride
(1). A 5 L multi-neck glass reactor was charged with 8
(100 g, 0.46 mol), concentrated sulfuric acid (130 mL),
and methanol (1.1 L), and heated to 65°C for 40 h. The
reaction mixture was cooled to room temperature, and
the solvent was concentrated under reduced pressure
(~30 mmHg). Water (800 mL) and isobutyl acetate
(1.5 L) were added to this residue. The mixture was
cooled to 10°C, and adjusted to pH 12 using 30%
sodium hydroxide solution. The organic layer was
separated and dried with anhydrous magnesium sulfate,
and the solution was filtered. Concentrated hydrochloric
acid (38 mL) was added to this filtrate, and stirred for
2 h. The precipitate was isolated and washed with
isobutyl acetate (100 mL). The filter cake was dried
under vacuum to afford 1 as a white solid (107.6 g,
87.3% yield) with 99.50% purity and 99.70% ee.
1
+ H]+. H NMR (400 MHz, DMSO-d6 + D2O) δ 7.37-7.21
(m, 5H), 3.28-3.26 (d, J =10.0Hz, 1H), 2.97-2.93 (t,
J =9.6Hz, 1H), 2.77-2.74 (d, J = 10.8Hz, 1H), 2.36-2.31
(m, 1H), 1.70-1.67 (d, J= 9.2Hz, 2H), 1.42 (m, 1H),
1.28-1.24 (m, 2H), 1.14-1.06 (q, J = 11.2Hz, 1H). 13C
NMR (100.6 MHz, DMSO-d6) δ 175.3, 139.2, 128.9,
128.6, 127.1, 58.9, 58.1, 46.3, 29.6, 26.2, 24.3.
( )-threo-2-phenyl-2-(piperidin-2-yl)acetamide (7).
A
10L multi-neck glass reactor was charged with 6 (200g,
0.91mol), potassium tert-butoxide (205 g, 1.83mol), and
toluene (6L) under a nitrogen atmosphere. The reaction
mixture was heated to 70°C for 6h. After cooling to 10°C,
the reaction mixture was quenched with water
(400 mL). Then, 5 N hydrochloric acid (2.4 L) was added
dropwise and stirred for another 1 h. The water layer was
separated and adjusted to pH12 using 30% sodium
hydroxide solution. The precipitate was isolated and
washed with water (100 mL). The filter cake was dried
under vacuum to afford 7 as a light-yellow solid (165g,
The crude product (107.6 g, 0.4 mol) was further purified
by recrystallization from pure water (100 mL) to obtain the
qualified product 1 (98.3 g, 91.4% yield) with 99.92 purity
and 99.98% ee. [α]D25 +85.6 (MeOH, c 1) (lit [4b]. [α]2D5
+84 (MeOH, c 1)); Mp 222-223 C (lit [4b]. Mp 222–
224°C); MS m/z 234 [M+ H]+. 1H NMR (400Hz,
1
DMSO-d6) δ H NMR (400 MHz, DMSO-d6) δ 9.64 (br,
1H), 8.97 (br, 1H), 7.41-7.26 (m, 5H), 4.18-4.16 (d,
J = 9.2Hz, 1H), 3.77-3.75 (m, 1H), 3.66 (s, 3H), 3.25 (m,
1H), 2.94 (m, 1H), 1.67-1.64 (m, 3H), 1.41-1.25 (m, 3H).
13C NMR (100.6 MHz, DMSO-d6) δ 171.3, 134.2, 129.1,
128.6, 128.2, 56.8, 53.3, 52.6, 44.5, 25.7, 21.5, 21.4.
1
82.5% yield). Mp 173-174°C; MS m/z 219 [M+ H]+. H
NMR (400 MHz, DMSO-d6 + D2O) δ 7.28-7.21 (m, 5H),
3.28-3.25 (d, J = 9.6Hz, 1H), 2.97-2.89 (m, 2H), 2.45 (m,
1H), 1.58-1.55 (m, 1H), 1.45-1.42 (m, 1H), 1.27-1.24 (m,
1H), 1.13-1.07 (m, 2H), 0.87-0.84 (m, 1H). 13C NMR
(100.6 MHz, DMSO-d6) δ 173.6, 138.5, 128.5, 128.1,
126.5, 58.1, 57.8, 46.1, 29.5, 25.7, 24.1.
Acknowledgments. This work is supported by the National
Science and Technology Major Project (Grant No.
2014ZX09507006-002).
(R)-2-phenyl-2-((R)-piperidin-2-yl)acetamide (8). A 5 L
multi-neck glass reactor was charged with 7 (100g,
0.46mol), D-DBTA (164.2g, 0.46mol), and isopropanol
(3.2 L), heated to 60°C for 0.5 h. After cooling to 30°C,
the precipitate was isolated to afford a light-yellow solid.
This solid was crystallized from isopropanol (600 mL)
and dried under vacuum to afford a white solid. The
white solid was added to 6 N hydrochloric acid (330 mL),
and stirred for 4 h. The mixture was filtered, and the
filtrate was cooled to 10°C, and adjusted to pH12 using
30% sodium hydroxide solution. The precipitate was
isolated and washed with water (100 mL). The filter cake
was dried under vacuum to afford 8 as a white solid
(44.4 g, 44.4% yield). Mp 175-176°C; MS m/z 219 [M
REFERENCES AND NOTES
[1] Chavan, A. B.; Gundecha, S. S.; Kadam, P. N.; Maikap, G. C.;
Gurjar, M. K. Org Process Res Dev 2010, 14, 1481.
[2] Kimko, H. C.; Cross, J. T.; Abernethy, D. R. Clin
Pharmacokinet 1999, 37, 457.
[3] (a) Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J. R.;
Hite, G. J. Pharmacol Exp Ther 1970, 173, 158; (b) Zeitlin, A. L.,
Dariani, M. M., Stirling, D. L. Method of Treating Attention Deficit
Disorders with d-Threo Methylphenidate. U.S. Patent 20060030587,
2006.
[4] (a) Prashad, M. Adv Synth Catal 2001, 343, 379; (b) Prashad,
M.; Hu, B.; Repic, O.; Blacklock, T. J.; Giannousis, P. Org Process Res
Dev 2000, 4, 55; (c) Kumar, A.; Singh, D.; Patil, S. H.; Mahale, G. D.;
Sawant, U. A. Manufacturing Process for Methyl Phenidate and
1
+ H]+. H NMR (400 MHz, DMSO-d6 +D2O) δ 7.53 (br,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L.-X. Xing, C.-W. Shen, Y.-Y. Sun, L. Huang, Y.-Y. Zheng, and J.-Q. Li
Vol 000
[6] Herold, F.; Kleps, J.; Anulewicz-Ostrowska, R.; Szczesna, B. J
Heterocyclic Chem 2002, 39, 773.
[7] Dutta, A. K.; Davis, M. C.; Reith, M. E. A. Bioorg Med Chem
Lett 2001, 11, 2337.
[8] Klapars, A.; Waldman, J. H.; Campos, K. R.; Jensen, M. S.;
McLaughlin, M.; Chung, J. Y. L.; Cvetovich, R. J.; Chen, C. Y. J Org
Chem 2005, 70, 10186.
[9] Donetti, A.; Boniardi, O.; Ezhaya, A. Synthesis 1980, 1980, 1009.
[10] Frigerio, M.; Maculan, S.; Vergani, D., Process for the
Preparation of Alpha-Aryl-Alpha-Piperid-2-Yl-Acetamides and the Acid
Hydrolysis Thereof. U.S. Patent 20080269494, 2008.
Intermediates Thereof. U.S. Patent 2005277667, 2008; (d) Khetani, V.;
Konnecke, W.; Ge, C. Methods for Production of Piperidyl Acetamide Ste-
reoisomers. U.S. Patent 6359139, 2002; (e) Harris, M. C. J.; Zavareh, H. Sin-
gle Isomer Methylphenidate and Resolution Process. U.S. Patent 6531489,
2003; (f) Gutman, A.; Zaltsman, I.; Shalimov, A.; Sotrihin, M.; Nisnevich,
G.; Yudovich, L.; Fedotev, I. Process for the Preparation of
Dexmethylphenidate Hydrochloride. U.S. Patent 2004180928A1, 2004;
(g) Prashad, M.; Kim, H. Y.; Lu, Y. S.; Liu, Y. G.; Har, D.; Repic, O.;
Blacklock, T. J.; Giannousis, P.
J Org Chem 1999, 64, 1750;
(h) Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Org Lett
1999, 1, 175.
[5] Zheng, Y. Y.; Shen, C. W.; Zhu, M. Y.; Zhou, Y. M.; Li, J. Q.
Org Process Res Dev 2014, 18, 744.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet