A Convenient Method for Synthesis of Optically Active Methylphenidate from N-Methoxycarbonylpiperidine by Utilizing Electrochemical Oxidation and Evans Aldol-type Reaction

Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide

doi:10.1016/s0040-4020(00)00653-0

Cited by 46 publications

(28 citation statements)

References 23 publications

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“…12 The diastereoisomeric ratio was determined by gas chromatography and 1 H NMR analysis of the crude mixture and showed essentialy the same results. Trying to improve stereoselectivity, we tried to use a general methodology based on reduction by metal-hydrides.…”

Section: Thementioning

confidence: 74%

“…In this way, a set of available tertiary amines as bases was investigated. In all cases a variable ratio of compounds 2 and 5 was observed ( Table 1, entries [8][9][10][11][12][13][14] and the use of KOt-Bu furnished the compound 5 as a major product (entry 15). Interestingly, the best yield of compound 2 (60%) was achieved when DBU was employed in the absence of a thiophile (Table 1, entry 14) in which thiazolidinone 5 was not isolated.…”

Section: Thementioning

confidence: 99%

“…3 The activity of Ritalin ® promotes an enhancement of the cognitive performance in both adults and children diagnosed with AD/HD. 4 Although Ritalin ® is available in the market as the racemate, the (2R,2%R)-(+)-threo-methylphenidate has been reported to be up to 38 times 5 more active than (2S,2%S)-(−)-threo-methylphenidate and several racemic [6][7][8][9] and chiral [10][11][12][13] synthesis of threo-methylphenidate were reported previously.…”

Section: Thementioning

confidence: 99%

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A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

Russowsky

Neto

2003

Tetrahedron Letters

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Abstract-A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the b-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%. © 2003 Elsevier Science Ltd. All rights reserved. The(+/−)-threo-methylphenidate hydrochloride (Ritalin ® ), is an indirect catecholamine agonist, 1 and is the drug treatment of choice for the attention deficit/ hyperactivity disorder (AD/HD), 2 one of the most common behavioral disorders of childhood which affects 5-10% of the general population. 3 The activity of Ritalin ® promotes an enhancement of the cognitive performance in both adults and children diagnosed with AD/HD. 4 Although Ritalin ® is available in the market as the racemate, the (2R,2%R)-(+)-threo-methylphenidate has been reported to be up to 38 times 5 more active than (2S,2%S)-(−)-threo-methylphenidate and several racemic 6-9 and chiral 10-13 synthesis of threo-methylphenidate were reported previously.Although the erythro-methylphenidate exhibits very few therapeutic properties and toxic hypertensive effects, 14 the stereoselective synthesis of the erythro-isomer can be helpful due to the possibility of resolution and epimerization of the erythro-isomer. 2,15 This approach was used early in the original synthesis of (+/−)-threomethylphenidate. Close to this, an enantioselective synthesis of (2S,2%S)-erythro-methylphenidate was recently published by Due to this fact and relating to our interest in the synthesis of b-aminocarbonyl compounds 17,18 we would like to communicate in this paper our approach to the synthesis of (+/−)-erythro-methylphenidate 1 applying a new concise stereoselective synthetic strategy.We envisaged obtaining 1 based on a stereoselective reduction of a b-enaminocarbonyl compound 2 which is readily accessible by the Eschenmoser sulfide contraction reaction 19,20 (Scheme 1).The needed piperidine-2-thione (3) was prepared in 91% yield after reaction of piperidine-2-one with Lawesson reagent. 21 The bromoester 4 was obtained by sterification and subsequent a-bromination 22 of 2-phenylacetic acid in 71% overall yield after purufication by horizontal destilation at reduced pressure. Next, the condensation reaction of compounds 3 and 4 was carried out under the Eschenmoser sulfide contraction reaction Scheme 1. The retrosynthetic analysis of 1 based on the eschemoser sulfide contraction reaction.

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Section: Thementioning

confidence: 74%

Section: Thementioning

confidence: 99%

Section: Thementioning

confidence: 99%

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A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

Russowsky

Neto

2003

Tetrahedron Letters

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“…Of these, scientists from Novartis first invented a synthetic route in which the asymmetric aldol reaction was introduced as the key step; they later further improved 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.…”

Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Chen²,

Sun³

et al. 2016

IJC

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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.Keywords: dexmethylphenidate, amino acid ester, free base, high purity IntroductionThe 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 in which the asymmetric aldol reaction was introduced as the key step; they later further improved 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...

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“…[4][5][6][7] We developed a new facile method for a copper ion-catalyzed asymmetric introduction of a bis(methoxycarbonyl)methyl group into the 2-position of 1 through 3,4-didehydro-2-methoxypiperidines 3, which are easily prepared from 1 to afford optically active 2-substituted 3,4-didehydropiperidines 4* (path b in Scheme 1), and reported the preliminary result.…”

Section: Introductionmentioning

confidence: 99%