Concise and facile synthesis of (R,R)-dexmethylphenidate hydrochloride and its three stereoisomers

Article abstract of DOI:10.1080/00397911.2017.1293109

A new and concise route is reported for the first time for the preparation of four stereoisomers of dexmethylphenidate hydrochloride starting from a single reactant, 2-benzyolpyridine, through an eight-step reaction process, which includes hydrogenation,

Full text of DOI:10.1080/00397911.2017.1293109

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A Concise and Facile Synthesis of (R,R)-
Dexmethylphenidate Hydrochloride and Its Three
Stereoisomers
Chunzheng Li, Yuanbo Ji, Qing Cao, Jianqi Li & Bonan Li
To cite this article: Chunzheng Li, Yuanbo Ji, Qing Cao, Jianqi Li & Bonan Li (2017): A Concise
and Facile Synthesis of (R,R)-Dexmethylphenidate Hydrochloride and Its Three Stereoisomers,
Synthetic Communications, DOI: 10.1080/00397911.2017.1293109
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1293109
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Date: 29 March 2017, At: 07:46

A Concise and Facile Synthesis of (R,R)-Dexmethylphenidate Hydrochloride and Its
Three Stereoisomers
Chunzheng Li1,2, Yuanbo Ji1,2, Qing Cao1, Jianqi Li1, Bonan Li1
1Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical
Industry, Shanghai, P. R. China,
2School of Engineering, China Pharmaceutical University, Nanjing, P. R. China
CONTACT Bonan Li. E-mail: pkuthulbn@gmail.com
Abstract
A new and concise route is reported for the first time for the preparation of four
stereoisomers of dexmethylphenidate hydrochloride starting from a single reactant,
2-benzyolpyridine, via an eight-step reaction process which includes hydrogenation,
protection, oxidation, chiral separation, Wittig reaction, hydroboration, PDC oxidation
and methyl esterification. The absolute configuration of the two chiral centers of each
stereoisomer was confirmed by X-ray and chiral HPLC analysis.
Graphical Abstract
KEYWORDS: Synthesis; Methylphenidate; Dexmethylphenidate; Stereoisomer
INTRODUCTION
Methylphenidate was developed seven decades ago as the first effective drug for the
treatment of attention deficit hyperactivity disorder (ADHD), a neuro-developmental
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disorder [1,2] that begins in childhood [3]. To date, research on methylphenidate [4] and its
optical isomers remains attractive to scientists from universities and drug companies. The
methylphenidate molecule contains two chiral centers that generate four possible
stereoisomers (Figure 1) which are divided into two pairs of racemic isomers: the
syn-form (R,R-1a and S,S-1c) and the anti-form (R,S-1b and S,R-1d). The first marketed
formulations [1] of methylphenidate, such as centerin, contained a mixture of all four
isomers. In the 1980s, the drug Ritalin only contained the racemic isomers of the
syn-form (R,R-1a and S,S-1c) because previous research [5 7] indicated that only syn-form
–
isomers were associated with central stimulant effects. In 2000, the dexmethylphenidate
hydrochloride slow-release capsule (brand name Focalin) was developed by Novartis Inc.
[8,9] and was approved by the US Food and Drug Administration (FDA) in May of 2005.
The active pharmaceutical ingredient (API), which only contained the (R,R-1a)
configuration isomer[10 12] was eventually identified as the active species. In recent years,
–
many structural-activity relationship (SAR) studies[13 17] for finding more active
–
derivatives have been reported and working on the further development of novel
preparation methods for these four stereoisomers is of great value.
As an effective therapeutic API, the synthesis of dexmethylphenidate and three
stereoisomers has long attracted the attention [18] of chemists around the world and
different synthetic methods have been reported in the past years. Scientists from Novartis
first presented a synthetic route in which the asymmetric aldol reaction was introduced as
2

the key step, where only one stereoisomer of the (R,R) or (S,S) configuration was
synthesized by a nine-step tedious route [19] and the synthesis of the (R,S) or (S,R)
configuration was accomplished by another six-step route [20] with very low yield.
Following Novartis, additional scientists reported different methods [21 25], such as the use
–
of Evans amide as the key intermediate for the synthetic route by Matsumura and
coworkers [26, 27]. Fox and coworkers [28] made an effective improvement based on
Matsumura’s route by using methylbenzylamine as the key chiral auxiliary. Though these
four stereoisomers were successfully synthesized by different methods in the past years,
there is no publication to report a method for synthesizing them using a single starting
material via a concise route with high efficiency. For the purposes of future SAR research
and quality control of the API industrialization process, we have developed a concise
route for this synthesis. Here, we report our work towards the convenient and high
efficiency synthesis of (R,R)-Dexmethylphenidate hydrochloride and its three
stereoisomers.
RESULTS AND DISCUSSION
Our study of the synthesis of four stereoisomers of dexmethylphenidate hydrochloride
(Scheme 1) began with the commercially available compound 2-benzyolpyridine (2), the
pyridine ring of which was hydrogenated under 2.0 MPa pressure at 60 °C to give the
piperidine ring of cis/trans-rac-2-piperidin-2-yl-phenylmethanol (3) in 98% yield. The
secondary hydroxyl group of compound 3 was oxidized by treatment with the
3

Dess-Martin periodinane reagent to give rac-2-piperidin-2-yl-phenylmethanone (4) in
95% yield, which was a racemic mixture with both R and S configurations. Each of the
configuration was treated with anhydrous D- or L-dibenzoyl tartaric acid to afford
(R)-2-piperidin-2-yl-phenylmethanone (4a) or (S)-2-piperidin-2-yl-phenylmethanone (4b)
in 37% or 35% yield, respectively. To confirm the absolute configuration from the chiral
resolution process, compound 4a was treated with the solution of hydrochloride gas in
ethyl acetate to give (R)-2-piperidin-2-yl-phenylmethanone hydrochloride salt, which was
easier to crystallize. The crystal structure [29] (Figure 2) showed that the chiral center of
compound 4a is in the R configuration. Following this, the secondary amine group of
compound 4a or 4b was protected by tert-butyloxycarbonyl anhydride to give
(R)-N-(tert-butyloxycarbonyl) -2-piperidin-2-yl-phenylmethanone (5a) and
(S)-N-(tert-butyloxycarbonyl)-2-piperidin-2-yl- phenylmethanone (5b) in 97% or 95%
yield, respectively. The intermediates
(R)-1-[N-(tert-butyloxycarbonyl)piperidin-2-yl]-1-phenylethene (6a) and
(S)-1-[N-(tert-butyloxycarbonyl) piperidin-2-yl]-1-phenylethene (6b) were synthesized
from compounds 5a and 5b, respectively, via the Wittig reaction in the presence of
methyl triphenylphosphonium bromide and potassium tert-butoxide in 90% or 89% yield,
respectively. At this point, one absolute configuration of the four stereoisomers of
dexmethylphenidate was successfully confirmed using a five-step conversion of the
starting material 2.
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Next, compound 6a (Scheme 2) was treated with a solution of borane-dimethyl sulfide to
give (R,R) and (R,S)-2-[N-(tert-butyloxycatbonyl)piperidin-2-yl]-2-phenylethanol (7a, 7b)
in 66% or 25% isolation yield, respectively. The two compounds were easily separated by
flash column chromatography due to their diastereoisomeric properties. The primary
hydroxyl group of compound 7a or 7b was oxidized by pyridinium dichromate (PDC) in
N, N-dimethyl formamide solution to give (R, R)/(R,
S)-2-[N-(tert-butyloxycarbonyl)piperidin-2-yl]-1-phenylacetic acid (8a or 8b) in 90% or
91% yield, respectively. The final product, (R,R)/(R,S)-methyl
2-piperidin-2-yl-phenylacetate hydrochloride (1a or 1b), was obtained via three
consecutive reactions of de-protection, methyl esterification and salification in 82% or
84% yield, respectively.
In the next step, compound 6b (Scheme 3) was treated with a solution of borane-dimethyl
sulfide complex to give (S, S) and (S,
R)-2-[N-(tert-butyloxycarbonyl)piperidin-2-yl]-2-phenylethanol (7c, 7d) in 58% or 33%
isolation yield, respectively. Each compound was separated by flash column
chromatography and the primary hydroxyl group of compound 7c or 7d was oxidized by
pyridinium dichromate in N, N-dimethyl formamide solution to give
(S,S)/(S,R)-2-[N-(tert-butyloxycatbonyl) piperidin-2-yl]-1-phenylacetic acid (8c or 8d) in
92% or 91% yield, respectively. The final product, (S,S)/(S,R)-methyl
2-piperidin-2-yl-phenylacetate hydrochloride (1a or 1b), was obtained via three
5

consecutive reactions of de-protection, methyl esterification and salification in 85% or
84% yield, respectively.
The absolute configuration of product 1c [30] was confirmed (Figure 3) by X-ray analysis,
and the crystal structures of products 1a and 1d were also confirmed by our group [31]
.
Though the crystal structure of product 1b failed to be obtained after multiple attempts
using different solvents, the absolute configuration of which also was indirectly
confirmed by HPLC analysis with both C18 column and chiral column according to the
X-ray analysis of other three stereoisomers, more details about the above experiments
were put on the supporting information of this article.
EXPERIMENTAL
Synthesis Of (R,R)/(R,S)
2-[N-(Tert-Butyloxycatbonyl)Piperidin-2-Yl]-2-Phenylethanol (7a, 7b)
Compound 6a (3.0 g, 10.4 mmol) was dissolved into tetrahydrofuran (10 mL), 1.0 M
tetrahydrofuran solution of borane-dimethyl sulfide complex was added drop wise over
10 min. the reaction was reacted for 5 hours, and then water (5 mL), 2 M sodium
hydroxide aqueous solution (5 mL) and 30% hydro-peroxide solution (5 mL) was added
into the solution consecutively. When the reaction mixture was stirred overnight, ethyl
acetate (50 mL) and water (20 mL) was added in one portion for dilution purpose, the
aqueous layer was separated and extracted by ethyl acetate (30 mL, twice), and the
6

combined organic layer was dried by saturated brine, magnesium sulfate and
concentrated in vacuum. The residual oil was purified by flash column chromatography
(eluted by hexane/ethyl acetate 5:1 v/v). 7a. low polar, white solid, 2.1 g, 66% yield; 78.0
– 81.0 0C; [α]D20 – 50.5 (c = 1, MeOH) [-11.1 (c = 1.32, CH2Cl2)][14]; 1H NMR (600 MHz,
CDCl3): δ 1.25 -1.34 (m, 2H), 1.38 – 1.47 (m, 3H), 1.50 (s, 9H), 1.64 (d, J = 12.0 Hz, 1H),
2.85 (t, J = 12.0 Hz, 1H), 3.07 (d, J = 11.6 Hz, 1H), 3.47 – 3.61 (m, 2H), 3.71 – 3.78 (m,
1H), 4.04 (d, J = 12.9 Hz, 1H), 4.65 (dd, J1 = 11.5 hz, J2 = 4.3 Hz, 1H), 7.21 – 7.25 (m,
1H), 7.29 – 7.32 (m, 2H), 7.35 – 7.39 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 18.9, 25.4,
26.1, 28.5, 39.9, 45.9, 50.4, 63.5, 80.4, 126.7, 128.5, 128.8, 141.3, 156.4. HRMS (ESI)
C18H28NO3 [M+H]+: Calcd for 306.2064, found: 306.2065. 7b. high polar, colorless oil,
0.8 g, 25% yield; [α]D20 + 25.4 (c = 1, MeOH);1H NMR (600 MHz, CDCl3): δ 1.28 (s,
9H), 1.33 – 1.89 (m, 7H), 2.59 (s, 1H), 3.23 (s, 1H), 3.74 (s, 1H), 3.79 – 3.87 (m, 1H),
4.52 (s, 1H), 7.16 – 7.31 (m, 5H); 13C NMR (150 MHz, CDCl3): δ 19.2, 25.1, 26.9, 28.3,
39.9, 48.9, 50.7, 64.9, 79.1, 126.9, 128.3, 128.9, 139.5, 154.9. HRMS (ESI) C18H28NO3
[M+H]+: Calcd for 306.2064, found: 306.2064.
CONCLUSION
In summary, a concise and facile synthetic route for the synthesis of four stereoisomers of
dexmethylphenidate chloride is presented in this work. All intermediates were fully
characterized and the absolute configuration of each stereoisomer was confirmed by
7

X-ray and chiral HPLC analysis. This synthetic methodology study described above can
be further applied for the preparation of novel dexmethylphenidate derivatives.
FUNDING
This project was supported by the 2016 Shanghai Pujiang Talent Program (No.
16PJ1432800).
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR spectra for all new compounds, Chiral HPLC
traces for compound 4a, 4b, 1b and 1d. X-ray analyusis for compound 4a and 1c. This
material can be found via the “Supplementary Content” section of this article’s webpage.
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Scheme 1. Synthesis of intermediates 6a and 6b.
11

Scheme 2. Synthesis of (R, R) /(R, S) products 1a and 1b from intermediate 6a.
12

Scheme 3. Synthesis of (S, S) /(S, R) products 1c and 1d from intermediate 6b.
13

Figure 1. Structures of Dexmethylphenidate hydrochloride (1a) and its three
stereoisomers (1b-1d).
14

Figure 2. The crystal structure of compound 4a as its hydrochloride salt.
15

Figure 3. The crystal structure of compound 1c.
16