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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) Concise and facile synthesis of (R,R)-dexmethylphenidate hydrochloride and its three stereoisomers, Synthetic Communications, 47:14, 1301-1306, DOI: 10.1080/00397911.2017.1293109 To link to this article: https://doi.org/10.1080/00397911.2017.1293109
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SYNTHETIC COMMUNICATIONS® 2017, VOL. 47, NO. 14, 1301–1306 https://doi.org/10.1080/00397911.2017.1293109
none defined
Concise and facile synthesis of (R,R)-dexmethylphenidate hydrochloride and its three stereoisomers Chunzheng Lia,b, Yuanbo Jia,b, Qing Caoa, Jianqi Lia, and Bonan Lia a
Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China; bSchool of Engineering, China Pharmaceutical University, Nanjing, P. R. China ABSTRACT
ARTICLE HISTORY
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, protection, oxidation, chiral separation, Wittig reaction, hydroboration, pyridinium dichromate oxidation, and methyl esterification. The absolute configuration of the two chiral centers of each stereoisomer was confirmed by X-ray and chiral HPLC analyses.
Received 28 November 2016 KEYWORDS
Dexmethylphenidate; methylphenidate; stereoisomer; synthesis
GRAPHICAL ABSTRACT
Introduction Methylphenidate was developed seven decades ago as the first effective drug for the treatment of attention deficit hyperactivity disorder, a neurodevelopmental 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 (Fig. 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 in May 2005. The active pharmaceutical ingredient CONTACT Bonan Li
[email protected] Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, P. R. China. Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc. Supplemental data (full experimental details, 1H and 13C NMR spectra for all new compounds, Chiral HPLC traces for compound 4a, 4b, 1b and 1d. X-ray analysis for compound 4a and 1c) can be accessed on the publisher’s website. © 2017 Taylor & Francis
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Figure 1. Structures of dexmethylphenidate hydrochloride (1a) and its three stereoisomers (1b–1d).
(API), which only contained (R,R-1a) configuration isomer,[10–12] was eventually identified as an 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 a key step, where only one stereoisomer of (R,R) or (S,S) configuration was synthesized by a nine-step tedious route[19] and the synthesis of (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 et al.[26,27] Fox et al.[28] made an effective improvement based on Matsumura’s route using methylbenzylamine as a 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 through 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 toward 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 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-ylphenylmethanone hydrochloride salt, which was easier to crystallize. The crystal structure[29] (Fig. 2) showed that the chiral center of compound 4a is in R configuration. Following this, the secondary amine group of compound 4a or 4b was protected by tert-butyloxycarbonyl
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Scheme 1.
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Synthesis of intermediates 6a and 6b.
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]-1phenylethene (6a) and (S)-1-[N-(tert-butyloxycarbonyl) piperidin-2-yl]-1-phenylethene (6b) were synthesized from compounds 5a and 5b, respectively, through 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. 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
Figure 2. The crystal structure of compound 4a as its hydrochloride salt.
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Scheme 2.
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Synthesis of (R,R)/(R,S) products 1a and 1b from intermediate 6a.
dichromate 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 through three consecutive reactions of deprotection, methyl esterification, and salification in 82 or 84% yield, respectively. In the next step, compound 6b (Scheme 3) was treated with a solution of boranedimethyl sulfide complex to give (S,S) and (S,R)-2-[N-(tert-butyloxycarbonyl)piperidin2-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 through three consecutive reactions of deprotection, methyl esterification, and salification in 85 or 84% yield, respectively. The absolute configuration of product 1c[30] was confirmed (Fig. 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.
Scheme 3.
Synthesis of (S,S)/(S,R) products 1c and 1d from intermediate 6b.
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Figure 3. The crystal structure of compound 1c.
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 in tetrahydrofuran (10 mL), 1.0M tetrahydrofuran solution of borane-dimethyl sulfide complex was added dropwise over 10 min, the reaction reacted for 5 h and then water (5 mL), 2M sodium hydroxide aqueous solution (5 mL), and 30% hydro peroxide solution (5 mL) were added into the solution consecutively. While the reaction mixture was stirred overnight, ethyl acetate (50 mL) and water (20 mL) were added in one portion for dilution purpose, the aqueous layer was separated and extracted by ethyl acetate (30 mL, twice), and the combined organic layer was dried by saturated brine and 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 °C; ½a�20 50.5 (c ¼ 1, MeOH) [ 11.1 (c ¼ 1.32, CH2Cl2)][14]; 1H NMR D (600 MHz, CDCl3): δ 1.25–1.34 (m, 2H), 1.38–1.47 (m, 3H), 1.50 (s, 9H), 1.64 (d, J ¼ 12.0 Hz, 1H), 2.85 (t, J ¼ 12.0 Hz, 1H), 3.07 (d, J ¼ 11.6 Hz, 1H), 3.47–3.61 (m, 2H), 3.71–3.78 (m, 1H), 4.04 (d, J ¼ 12.9 Hz, 1H), 4.65 (dd, J1 ¼ 11.5 hz, J2 ¼ 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 [MþH]þ: Calcd for 306.2064, found: 306.2065. 7b. high polar, colorless oil, 0.8 g, 25% yield; ½a�20 D þ 25.4 (c ¼ 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 [MþH]þ: 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
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characterized and the absolute configuration of each stereoisomer was confirmed by 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).
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]
Panizzon, L. Helv. Chin. Acta. 1944, 27, 1748. Thapar, A.; Cooper, M. Lancet 2016, 387, 1240. Wenthur, C. J. ACS Chem. Neurosci. 2016, 7, 1030. Steinberg, A.; Froimowitz, M.; Parrish, D. A. J. Org. Chem. 2011, 76, 9239. Rudolf, R. U. S. Patent, 1958, US 2838519. Rudolf, R. U. S. Patent, 1960, US 2957880. Markowitz, J. S.; Straughn, A. B.; Patrick, K. S. Pharmacotherapy 2003, 23, 1281. Har, D.; Prashad, M. U.S. Patent, 2000, US 6100401 A. Novartis; Celgene. Drugs R&D 2002, 3, 279. Patrick, K. S.; Caldwell, R. W.; Ferris, R. M. J. Pharm. Exp. Therap. 1986, 241, 152. Prashad, M.; Har, D.; Repic, O. Tetrahedron. Asym. 1998, 9, 2133. Patrick, K. S.; Williard, R. L.; Vanwert, A. L. J. Med. Chem. 2005, 48, 2876. Deutsch, H. M.; Shi, Q.; Gruszecka-Kowalik, E. J. Med. Chem. 1996, 39, 1201. Thai, D. L.; Sapko, M. T.; Reiter, C. T. J. Med. Chem. 1998, 41, 591. Davies, H. M. L.; Hopper, D. W.; Hansen, T. Bioorg. Med. Chem. Lett. 2004, 14, 1799. Froimowita, M.; Gu, Y.; Dakin, L. A. J. Med. Chem. 2007, 50, 219. Misra, M.; Shi, Q.; Ye, X. Bioorg. Med. Chem. 2010, 18, 7221. Prashad, M. Adv. Synth. Catal. 2001, 343, 379. Prashad, M.; Kim, H. Y.; Lu, Y.; Giannousis, P. J. Org. Chem. 1999, 64, 1750. Prashad, M.; Liu, Y.; Kim, H. Y. Tetrahedron. Asym. 1999, 10, 3479. Davies, H. M. L.; Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 1999, 121, 6509. Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. J. Org. Chem. 1998, 63, 9628. Prashad, M.; Hu, B.; Repic, O. Org. Process Res. Dev. 2000, 4, 55. Chan, A. B.; Gundecha, S. S.; Kadam, P. N. Org. Process Res. Dev. 2010, 14, 1473. Hu, B.; Prashad, M. U.S. Patent, 2000, US 6162919. Matsumura, Y.; Kanda, Y.; Shirai, K. Org. Lett. 1999, 1, 175. Matsumura, Y.; Kanda, Y.; Shirai, K. Tetrahedron. 2000, 56, 7411. Fox, M. E.; Paul, J. M. PCT Patent, 1997, WO 9735836. CCDC No. 1507254. CCDC No. 1507253. Zhang, F.; Li, B.; Sun, Y.; Li, J. Chin. J. Org. Chem. 2016, 36, 2162.
