Dexmethylphenidate: An efficient process for the racemization of Unwanted (2 S,2 S or l - Threo)-α-Phenyl-α-(2-piperidyl)acetamide

Article abstract of DOI:10.1021/op100197g

(2R,2 R)-d-threo-α-Phenyl-α-(2-piperidyl)acetamide (3), an advanced intermediate for dexmethylphenidate hydrochloride synthesis, is prepared by the resolution of dl-threo-α-phenyl-α-(2-piperidyl) acetamide (2) with dibenzoyl-d-tartaric acid in isopropanol with % yield and 99% ee. Although this process is efficient, there is a need to recycle the unwanted l-threo-amide and uncrystallized d-threo- amide from the mother liquor. The purpose of this study is 2-fold, first being the pollution issue to discard large amounts of unwanted isomer and the second to reduce the cost of (1). This aspect of recovery of unwanted isomer 4 formed the basic objective of this study. We have developed a new, simple, and cost-effective process for the racemization in which 4 was treated with potassium carbonate and N-chlorosuccinimide in DMF followed by treatment with DBU to afford the olefinic intermediate (5). Subsequent hydrogenation of the double bond provided dl-erythro-α-phenyl-α-(2-piperidyl)acetamide (6); the latter intermediate has already been converted into 1.

Full text of DOI:10.1021/op100197g

Organic Process Research & Development 2010, 14, 1473–1475
Dexmethylphenidate: An Efficient Process for the Racemization of Unwanted (2S,2′S
or l-threo)-r-Phenyl-r-(2-piperidyl)acetamide
Anil B. Chavan,* Sachin S. Gundecha, Pramod N. Kadam, Golak C. Maikap,* and Mukund K. Gurjar
Emcure Pharmaceuticals Ltd., R & D Centre, Plot No.12/2, F-II Block, M.I.D.C., Pimpri, Pune - 411018, India
Scheme 1
Abstract:
(2R,2′R)-d-threo-r-Phenyl-r-(2-piperidyl)acetamide (3), an ad-
vanced intermediate for dexmethylphenidate hydrochloride syn-
thesis, is prepared by the resolution of dl-threo-r-phenyl-r-(2-
piperidyl)acetamide (2) with dibenzoyl-d-tartaric acid in isopropanol
with % yield and 99% ee. Although this process is efficient, there
is a need to recycle the unwanted l-threo-amide and uncrystallized
d-threo- amide from the mother liquor. The purpose of this study
is 2-fold, first being the pollution issue to discard large amounts
of unwanted isomer and the second to reduce the cost of (1). This
aspect of recovery of unwanted isomer 4 formed the basic objective
of this study. We have developed a new, simple, and cost-effective
process for the racemization in which 4 was treated with potassium
carbonate and N-chlorosuccinimide in DMF followed by treatment
with DBU to afford the olefinic intermediate (5). Subsequent
hydrogenation of the double bond provided dl-erythro-r-phenyl-
r-(2-piperidyl)acetamide (6); the latter intermediate has already
been converted into 1.
reported by several routes which include classical resolutions,4-8
enzymatic hydrolysis9,10 and enantioselective synthesis.11-15
Recently, the synthesis of 1 has also been reported by Thai who
utilized d-pipecolic acid as a chiral pool precursor.16
Khetani and Ramaswamy patented the resolution process
of 2 (Scheme 1) by using dibenzoyl-d-tartaric acid in isopro-
panol. They also demonstrated the transformation of 3 to 1 with
methanol and sulfuric acid.17
Introduction
Dexmethylphenidate hydrochloride 1, a mild nervous system
stimulant, is marketed in its racemic form essentially to treat
children with attention deficit hyperactivity disorder (ADHD).
Subsequent studies revealed that the (2R,2′R) or d-threo-isomer
of methylphenidate is considerably more active than the cor-
responding (2S,2′S) or l-threo-isomer and this led to the
introduction of dexmethylphenidate hydrochloride 1 into the
consumer’s market.1,2
Results and Discussion
The resolution of (2RS,2′RS or dl-threo-R-phenyl-R-(2-
piperidyl)acetamide 2 by using dibenzoyl-d-tartaric acid in
(4) Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese, G. R.
J. Pharmcol. Exp. Ther. 1987, 241, 152–158.
(5) Faulconbridge, S.; Zavareh, H. S.; Evans, G. R.; Langsten, M. World
Patent Application No. WO/98/25902, 1998.
(6) Harris, M. C. J.; Zavareh, H. S. World Patent Application No. WO/
97/27176, 1997.
(7) Zavareh, H. S. World Patent Application No. WO/97/32851, 1997.
(8) Prasad, M.; Har, D.; Repic, O.; Blacklock, T. J. Tetrahedron:
Asymmetry 1999, 10, 3111–3116.
(9) Prasad, M.; Har, D.; Repic, O.; Blacklock, T. J. Tetrahedron:
Asymmetry 1998, 9, 2133–2136.
(10) Zeitlin, A. L.; Stirling, D. I. U.S. Patent No. 5,733,756, 1998.
(11) Prasad, M.; Liu, Y.; Kim, H. Y.; Repic, O.; Blacklock, T. J.
Tetrahedron: Asymmetry 1999, 10, 3479–3482.
The first synthesis of (2R,2′R)-methylphenidate hydrochlo-
ride 1, reported in 1958 by Rometsch,1,3 had utilized the
resolution of dl-erythro-R-phenyl-R-(2-piperidyl)acetamide to
obtain the enantiopure l-erythro-R-phenyl-R-(2-piperidyl)ac-
etamide. The latter isomer was subjected to epimerization,
hydrolysis and esterification to obtain dl-threo-methylphenidate.
The concept of resolution of dl-threo-methylphenidate has been
(12) Prasad, M.; Kim, H. Y.; Lu, Y.; Har, D.; Repic, O.; Blacklock, T. J.;
Giannousis, P. J. Org. Chem. 1999, 64, 1750–1753.
(13) Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J. D. J. Am. Chem. Soc.
1999, 121, 6511–6512.
(14) Matsumura, Y.; Kand, Y.; Shirai, K.; Onomura, O.; Maki, T. Org.
Lett. 1999, 1, 175–178.
(15) Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panarao, S. A. J. Am.
Chem. Soc. 1999, 121, 6509.
(16) Thai, D. L.; Sapko, M. T.; Reifer, C. T.; Bierer, D. E.; Perel, J. M.
J. Med. Chem. 1998, 41, 591–601.
(17) Khetani, V.; Ramaswamy, S. World Patent Application No. WO/1998/
52921, 1998.
* Authors for correspondence. E-mail: golak.maikap@emcure.co.in.
(1) Rometsch, R. U.S. Patent 2,957,880, 1960.
(18) Elati, C. R.; Kolla, N.; Gangula, S.; Naredla, A.; Vankawala, P. J.;
Avinigiri, M. L.; Chalamala, S.; Sundaram, V.; Mathad, V. T.;
Bhattacharya, A.; Bandichhor, R. Tetrahedron Lett. 2007, 48, 8001–
8004.
(2) Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J. R.; Hite, G.
J. Pharmcol. Exp. Ther. 1970, 173, 158–165.
(3) Rometsch, R. U.S. Patent 2,838,519, 1958.
10.1021/op100197g  2010 American Chemical Society
Published on Web 10/15/2010
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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Scheme 2
Table 1. Study of various bases for formation of 5
time
isolated
rxn solvent
base
temp (°C) (h) yield (%)a
1
2
3
4
5
6
DMF diisopropylamine 0-5 °C
3
3
3
3
3
3
no reaction
no reaction
no reaction
37
DMF triethylamine
DMF piperidine
DMF NaOH
0-5 °C
0-5 °C
0-5 °C
0-5 °C
0-5 °C
DMF KOH
DMF KOtBu
46
23
a Product was isolated by column chromatography over silica gel (60-120
mesh) using n-hexane and ethyl acetate (9.5:0.5).
Table 2. Optimization of DBU for formation of 5
mol equiv
(DBU)
time
(h)
isolated
yield (%)
rxn
solvent
temp (°C)
1
2
3
4
0.25
0.50
1.25
1.70
DMF
DMF
DMF
DMF
0-5
0-5
0-5
0-5
3
3
3
3
54a
62a
82
isopropanol, as reported in the literature,17 was successfully
repeated in our laboratory to give (2R,2′R)-isomer 3 in quantita-
tive yield. The analysis of the mother liquor after the resolution
and basification of 3 by HPLC revealed that it contained
typically the (2R,2′R)-isomer 3 in 15-20% and the unwanted
(2S,2′S)-isomer 4 in 80-85%.
83
a Product was isolated by column chromatography over silica gel (60-120
mesh) using n-hexane and ethyl acetate (9.5:0.5).
Scheme 3
We believe that the most viable process of racemization of
4 would be to create a double bond across the two chiral centers
as shown in scheme 2. The catalytic reduction of the double
bond of 5 is expected to provide the dl-erythro isomer 6 by the
virtue of cis reduction. The transformation of dl 6 to dl-threo 2
and subsequently to dexmethylphenidate 1 are well docu-
mented17 (Scheme 2).
In order to install the double bond across the chiral centers
of 4, the advantage of the reactive benzylic carbon at C-2 was
explored. The obvious choice would be halogenation at the C-2
carbon followed by dehydrohalogenation. The most suitable
method17 from scale-up and an economy point of view was
N-chlorosuccinimide for chlorination and DBU for elimination.
Therefore, 4 was subjected to the reaction of N-chlorosuc-
cinimide and potassium carbonate in DMF. This step was
carefully monitored by TLC, and after 3 h, the reaction was
complete. The isolation of generated chloro intermediate
was avoided by in situ addition of DBU giving rise to the double
bond intermediate 5.
In order to optimize the elimination reaction, the organic
bases such as piperidine, diisopropyl amine, triethylamine as
well as inorganic bases such as KOtBu, NaOH, and KOH were
also attempted. However, with organic bases the reaction was
found to be very sluggish, and most of the starting material 4
remained unreacted. With metal alkoxides, the elimination
product was formed, but side reactions were also observed
(Table 1).
Subsequently, 6 was converted to 2 by treatment with potassium
tert-butoxide.
Conclusion
In conclusion we believe that we have developed a new,
superior, and cost-effective method (Scheme 3) for racemization
of 4 to 2.
Experimental Section
All materials were purchased from commercial suppliers.
Unless specified otherwise, all reagents and solvents were used
1
as supplied by manufactures. The H NMR spectra were
recorded in CD3OD and DMSO-d6 on Varian 400 MHz; the
chemical shifts were reported in δ ppm relative to TMS. The
FT-IR spectra were recorded in the solid state KBr dispersion
using Perkins Elemer FT-IR spectrophotometer. The mass
spectra were recorded on Applied Biosystems API2000LCMS
mass spectrometer. The melting points were determined by
using Buchi apparatus. The solvents and reagents were used
without purification. Contents of dl-erythro and dl-threo were
recorded on HPLC on Inertsil C8 (250 mm × 4.6 mm) at 210
nm and eluted with buffer (2.72 g KH2PO4 in 1000 mL DM
water and pH adjusted to 3.51 using orthophosphoric acid/
acetonitrile (800:200). Content of d and l isomers of threo-
amide were recorded on chiral HPLC on Chiralcel ODH (250
mm × 4.6 mm) at 210 nm and eluted with n-hexane/ethanol/
TFA/triethyl amine (950:50:0.2:0.1). TLC was performed by
The next investigation was to establish the optimal quantity
of DBU to ensure maximum yield. We conducted many
experiments (Table 2) and observed that 1.25 equiv of DBU
(entry 3) produced best yield of 5.
Our next target was the reduction of 5. In the presence of
Pd-C in methanol at 10 kg/cm2 at 45 °C for 10 h, 5 gave the
dl-erythro isomer 6. Its HPLC analysis indicated that 0.28% of
dl-threo isomer was also formed during the reduction step.
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using silica gel as the stationary phase and methanol/chloroform
(5:5) as the mobile phase.
hydroxide solution. The solid was filtered, washed with cold
DM water (1.1 L), and dried at 50-55 °C to give 0.32 kg
(79.5%) of 6 as a solid. Mp: 140-143 °C, IR (KBr): 3313,
3037, 2966, 2928, 2766, 1670, 1409, 1361, 1024 cm-1, MS
(m/z): 219, 239, 241, 455, dl-erythro/dl-threo content by HPLC:
99.72%:0.28%.
Preparation of 2-Phenyl-2-piperidin-2-ylidene-acetamide
(5). A mixture l-thero-R-phenyl-R-(2-piperidyl)acetamide 4
(containing ∼15% of d-threo amide, 0.500 kg, 2.31 mol) and
dimethylformamide (3.0 L) was cooled to 0-5 °C. Potassium
carbonate (0.100 kg, 0.720 mol) was added and after 0.5 h,
N-chlorosuccinimide (0.428 kg, 3.20 mol) and DBU (0.439 kg,
2.88 mol) added. The reaction was stirred for additional 0.5 h
at 0-5 °C and then warmed to 25-30 °C for 2 h. At this time,
the absence of 4 (by TLC) was noted. It was cooled to 0-5 °C
and diluted with DM water (2.5 L). Toluene (2.5 L) was
introduced and stirred for 1 h. The layers were separated, and
aqueous layer was two times extracted with toluene (2 × 1 L).
Combined toluene layers were concentrated under vacuum at
50-55 °C to give 0.406 kg (82%) of 5. Mp: 132-134 °C, IR
(KBr): δ 3481, 3294, 2956, 1634, 1568, 1339 cm-1, MS (m/z):
172, 200, 217, 239, 344, 455, 1H NMR (DMSO-d6): δ
1.4-1.5(m, 2H) 1.50-1.60 (m, 2 H), 1.80-1.90 (t, 2 H),
3.1-3.2 (t, 2 H), 4.5-5.0 (s, 1H), 5.8-6.2 (s, 1H), 7.0-7.5
(m, 5 H), 10.3 (s, 1H). 13C NMR (100 MHz, DMSO): δ 20.27,
22.51, 27.83, 41.12, 96.41, 127.42, 129.59, 132.95, 139.28,
158.61, 172.68. Anal. for C13H16N2O (after recrystallization):
calcd C, 72.22; H, 7.40; N, 12.96. Found C, 72.35; H, 7.45; N,
13.02.
Preparation of dl-threo-r-Phenyl-r-(2-piperidyl)aceta-
mide (2). The above and predominantly dl-erythro-R-phenyl-
R-(2-piperidyl)acetamide 6 (0.31 kg, 1.42 mol) and potassium
tert-butoxide (0.426 kg, 3.79 mol) in toluene (7.75 L). The
reaction was heated at 70-75 °C for 24 h. After absence of 6
(by TLC), it was cooled to 20-25 °C, and HCl solution
(preparation: 0.620 L aq HCl in 1.55 L DM water) was
introduced and further stirred for 1 h. The layers were separated,
the aqueous layer was basified to pH 12.5 using 30% sodium
hydroxide solution (∼0.70 potassium tert-butoxide (0.426 kg,
3.79 mol). The solid obtained was filtered, washed with DM
water, and dried at 50-55 °C to give 0.25 kg (81%) of 2 as a
solid. Mp: 173-175 °C (lit1 mp, 173 °C), IR (KBr): 3283, 3035,
2951, 2931, 1679, 1397, 1360, 1031 cm-1, MS (m/z): 136, 219,
1
221, 241, 437, 473 H NMR (CD3OD): δ 0.9-1.3(m, 3H)
1.40-1.70 (m, 3H), 2.60-2.70 (dt, 1 H), 3.0-3.1 (d, 1 H),
3.1-3.2 (dt, 1 H), 3.3-3.4 (dt, 1H), 7.2-7.4 (m, 5 H),
dl-erythro/dl-threo content by HPLC 0.60%:99.40%, d-threo/
l-threo content by chiral HPLC: 50.34%:49.66%.
Preparation of dl-erythro-r-Phenyl-r-(2-piperidyl)aceta-
mide (6). 2-Phenyl-2-piperidin-2-ylideneacetamide 5 (0.400 kg,
1.85 mol), 10% Pd/C (40 g) in methanol (4.0 L) were
hydrogenated at 10.0 kg/cm2 pressure at 45 °C for 10 h. After
absence of 5 (by TLC), it was cooled to 30 °C and filtered
through hyflow supercel. The filtrate was concentrated under
Vacuo at 50-55 °C. Acetic acid (2.9 L) was added to the
reaction mass, stirred for 30 min at 60 °C and concentrated
under Vacuo at 55-60 °C. Ethyl acetate (1.45 L) was added to
the concentrated mass and cooled to 0-5 °C. The solid was
filtered, washed with cold ethyl acetate (0.37 L) and dried at
50-55 °C. The solid was dissolved in DM water (1.0 L), cooled
to 0-5 °C, and basified to pH 12-12.5 using 30% sodium
Acknowledgment
We thank Mr. Samit Mehta, our management, and the IPM
group of Emcure Pharmaceuticals Ltd. for their encouragement
and support.
Supporting Information Available
Additional characterization data of compounds 2, 4, 5, and
6. This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review July 19, 2010.
OP100197G
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