Scalable Synthesis of High-Purity ( R , R )-Dexmethylphenidate Free Base

A practical method for the preparation of high-purity (R, R)-dexmethylphenidate free base was developed. The method involves a substitution reaction of 2-chloropyridine and phenylacetonitrile via hydrolysis followed by hydrogenation, configuration inversion, chiral resolution, methyl esterification, and salification to give high-purity dexmethylphenidate hydrochloride. The hydrochloride salt was then neutralized by powder sodium hydroxide overnight to give dexmethylphenidate free base with over 99% purity. This method can be used for the industrial production of the dexmethylphenidate patch API, which could also be further applied for the preparation of other types of amino acid ester free bases.


Introduction
The dexmethylphenidate hydrochloride slow-release capsule was developed by Novartis Inc. (Har et al., 2000), and it was approved by the US Food and Drug Administration (FDA) in May 2005 for the treatment of attention deficit hyperactivity disorder (ADHD) (Volkmar et al., 2003), which is the most commonly diagnosed behavioral disorder in children.In July of 2010, the FDA approved the methylphenidate patch developed by Shire Plc inc, Inc.It was the first non-oral drug for the treatment of ADHD and provided a more convenient treatment choice for children.The APIs used in the capsule or patch treatments have two major differences, dexmethylphenidate chloride is a chiral, optically pure molecule, where as methylphenidate is the racemic isomer.Furthermore, the hydrochloride salt of dexmethylphenidate is used in the capsule, but it is too hydrophilic to be used in the patch because of the hydrophobic property of skin, for which only the free base could be effective.The main functional groups on both dexmethylphenidate and methylphenidate are amino acid esters (Figure 1).Amino acid esters are not very stable and can be easily hydrolyzed when neutralizing the hydrochloride salt to free base, while there is no publication to report the synthesis method of high purity free base of this kind of compound.Thus, the development of high-purity dexmethylphenidate free base could be deemed as the key step for enabling the entire API development process to meet the safety and quality requirements currently accepted by the International Conference on Harmonization (ICH).As an effective therapeutic molecule, the synthesis of dexmethylphenidate has long attracted the attention (Prashad et al., 2001) of chemists around the world, and different synthetic methods have been invented and reported in the past decades.Of these, scientists from Novartis first invented a synthetic route (Prashad et al., 1999) in which the asymmetric aldol reaction was introduced as the key step; they later further improved (Prashad et al., 1999) upon this route.Following Novartis, additional scientists reported different methods (Gutman et al., 2007& Davies et al., 1999), such as the use of Evans amide as the key intermediate for the synthetic route by Matsumura (Matsumua et al., 1999& Matsumura et al., 2000) and coworkers.Moreover, Fox (Fox et al., 2000) and coworkers made an effective improvement on the basis of Matsumura's route by using methylbenzylamine as the key chiral auxiliary.For the purpose of future API industrialization, a concise method (Axten et al., 1998, Chan et al., 2010, Hu et al., 2000, Kumar et al., 2008, Prashad et al., 2000& Zhang et al., 2016) was finally confirmed as the synthetic route to dexmethylphenidate.Herein, we report our work towards the convenient and high efficient synthesis of high-purity dexmethylphenidate free base.

Results and Discussion
The synthetic route began from the commercially available starting materials 2-chloropyridine (2) and phenylacetonitrile (3), which were treated with sodium amide to give 2-pyridyl-2-yl-phenylacetonitrile (4) in 78% yield.The cyano group on 4 was hydrolyzed by concentrated sulfuric acid to the amide group of intermediate 5 in 85% yield.Owing to the aromatic property of the pyridine ring on compound 5, which had to be hydrogenated under pressure (above 1.0 mPa) to give 2-pepridyl-2-yl-phenacetamide (6) in 95% yield.Compound 6 had two chiral centers with both syn-form and anti-form, the anti-from was converted to the syn-form under the treatment of potassium tert-butoxide in 83% yield to give intermediate 7 with syn-form only.Then, 7 as a racemic mixture was resolved by anhydrous D-dibenzoyl tartaric acid in isopropanol to give the optically pure product 8 in 35% yield with over 99% ee values.Scheme 1. Synthesis of (R,R)-2-piperidyl-2-yl-phenylacetamide (8) With highly optically pure compound 8 in hand, the condition screening of the methyl esterification reaction was then processed.Concentrated sulfuric acid was used as catalyst, and the reaction was carried out in refluxing methanol for various times.The excess sulfuric acid was neutralized with sodium hydroxide aqueous solution after the reaction was completed to give compound 9 as light yellow oil, which was the crude dexmethylphenidate free base.Different reaction times were investigated to ensure that the conversion of the methyl esterification reaction was as high as possible.The results are listed in Table 1.Approximately half of reactant 8 was converted to 9 after 12 hours (Table 1, entry 1).After 1 d, the conversion increased to 78% (Table 1, entry 2).Two days later, 94.2% of product 9 had been synthesized (Table 1, entry 3).The reaction time was further extended to 3 d, and the conversion reached 96% (Table 1, entry 4).Unfortunately, reactant 8 did not completely disappear after the reaction had been processed for 7 d; at least 1.1% of reactant 8 could not be converted to 9 in this system (Table 1, entries 5-7).The results shown in Table 1 indicated that the crude free base product was not qualified for API purity because of the residue of reactant 8, so a purification procedure was needed.Consequently, concentrated hydrochloride acid was charged into the ethyl acetate solution of crude product 9.The dexmethylphenidate hydrochloride salt was precipitated and filtered from the mother solution; then it was recrystallized from deionized water to give a white solid with up to 99.8% purity.Different neutralization methods were tried to obtain a high-purity free base form of dexmethylphenidate.There are two requirements for high-purity free base, one is that no other impurity is formed or introduced and the second is that the hydrochloride acid must be neutralized completely in the neutralization process.As the piperidine on methylphenidate is a strong organic base, a stronger base is needed to neutralize hydrochloride acid completely from piperidine.Our attempts (Table 2) began with using 10% sodium hydroxide aqueous solution to neutralize hydrochloride acid, the result (Table 2, entry 1) indicated that only 90.7% purity of the product was obtained, and the main by-product (Figure 2) 2-piperdyl-2-yl-phenylacetatic acid (11) was identified in this process.Though the purity was improved to 94.2% by using 10% lithium hydroxide aqueous solution, it still remained unattractive (Table 2, entry 2) because the methyl ester group was still easily hydrolyzed in aqueous solution.Anhydrous conditions were introduced using sodium methoxide and potassium tert-butoxide, but the results (Table 2, entries 3 and 4) were less suitable because many unidentified impurities were observed.An alternative method was subsequently developed, anhydrous sodium hydroxide powder and dexmethylphenidate hydrochloride solids were mixed as slurry into dichloromethane under a nitrogen atmosphere and stirred vigorously overnight, followed by filtration of the insoluble solid and concentration of the solution in vacuo.The high-purity methylphenidate free base was successfully prepared using this method in 99.8% purity and 90% yield (Table 2, entry 5).The purity of the free base also up to 99.7% and 99.5% when using the anhydrous solids of lithium hydroxide and potassium hydroxide, respectively (Table 2, entries 6 and 7).

Experimental
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Ultrashield-600 spectrometer with TMS as an internal standard.Chemical shifts (values) and coupling constants (J values) are given in ppm and Hz, respectively.ESI mass spectra were obtained using on an Agilent 6210 TOF spectrometer.Reaction progress and chemical purity were evaluated by HPLC analysis using a Waters symmetry C18 column (5 μm, 250 mm × 4.6 mm) with mobile phases A (MeOH + 0.05% TFA) and B (0.3% TEA), 88:12 v/v, and detection at 230 nm; flow rate: 1.0 mL/min, temperature: 25 °C.Palladium content was analyzed by Perkin Emler 800 AAS instrument.TLC analysis was conducted using prepared HSGF254 TLC plates.Solvents and reagents were used as received.All the intermediates and products were characterized by 1H & 13C NMR, high resolution ESI mass spectra, HPLC, melting point apparatus and optical rotation apparatus (if needed).

Synthesis of syn-2-piperidyl-2-yl-phenylacetyl amide (7):
Syn/anti-2-piperidyl-2-yl-phenylacetyl amide (6, 2000.0g, 9.2 mol) and potassium tert-butoxide (2000.0g) were added into toluene solution (50.0 L) in a 100-L double layer reaction vessel and mixed well.The solution was heated to 70 °C for 16 h, quenched by water, and washed by 6 N hydrochloride acid solutions (1.0 L, twice).The aqueous phase was separated and combined.A 30% sodium hydroxide solution was used to neutralize the solution until the pH value was 13.The product was precipitated, filtered, and dried by heating in an oven for 6 h to give the purified product as a white solid (1710 g) in 85.5% yield and 97.76% purity.Mp. 172.9 -173.9 0 C.

Synthesis of (R,R)-2-piperidyl-2-yl-phenylacetyl amide (8):
To a 20-L double layer reaction vessel, syn-2-piperidyl-2-yl-phenylacetyl amide (7, 600.0 g, 2.8 mol) and anhydrous D-dibenzoyl tartaric acid (1002.0g, 2.8 mol) were added into isopropanol solution (12.0 L) and heated to 60 °C until all of the solids were dissolved.Then, the reaction was cooled gradually to 30 °C.White solids were precipitated, filtered, and transferred into the 6 N hydrochloride acid solution and stirred for 1 h; the precipitates were eliminated, and the solution was neutralized using a 30% sodium hydroxide solution until the pH was 13.The product was precipitated, filtered, and dried by heating in an oven for 6 h to give the purified product as a yellow solid (213.7, 26.0, 26.4, 30.2, 58.6, 58.9, 127.1, 128.6, 128.8, 139.9, 174.5 (R,R)-2-piperidyl-2-yl-phenylacetyl amide (8, 200.0 g, 0.92 mol) was added to a methanol solution (500 mL) in a 2-L round bottom flask with four necks.Concentrated sulfuric acid (200 mL) was added dropwise, and the solution was refluxed for 3 d.afterwards, methanol was removed in vacuo.The residue was dissolved into a mixture of ethyl acetate (3.0 L) and water (1.0 L), which was neutralized with a 30% sodium hydroxide solution until the pH of the aqueous layer was 13.The top organic layer was separated and concentrated hydrochloride acid (50 mL) was added into the solution and mixed well.The white solid was precipitated, filtered, recrystallized from deionized water (150 mL), and finally dried by heating in an oven for 2 h to give the purified product as a white solid (186.0 g) in 75.5% yield and 99.82% purity.

Conclusion
In summary, a new, practical method towards high purity free base of methylphenidate was successfully developed via seven steps starting from simple commercially available materials.This innovative method could also be used for the synthesis of high-purity free base of other amino acid esters.

Table 1 .
Condition screening of the methyl esterification reaction