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

Abstract

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.

Facile Synthesis of Naphtho[2,3‐d]thiazoles, Naphtho[2,3‐e][1,3,4]thiadiazines and Bis(naphtho[2,3‐d]thiazolyl)copper(II) Derivatives from Heteroylthiosemicarbazides

“…It has been reported [26] that the coupling between piperidine-2-thione and 2-bromo-2-phenylmethylacetate afforded the β-enaminocarbonyl in around 60% yield by using Eschenmoser sulfide contraction reaction and in most cases the bicyclic thiazolidinone was produced (4%-41%). [26] However, the possibility of by-product formation is very likely, as described before by Eschenemoser et al, [27] Neto [5,28] and others.…”

Central Nervous System Stimulants

“…Various methods and approaches, such as classical resolution [19,[21][22][23][24] use of enantiomerically pure precursors and enantioselective synthesis approaches, and as well as others, to the preparation of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate are proposed [26][27][28][29][30]. Resolution via enzymatic hydrolysis, which afford (2S,2′S)-(-)-threo and (2R,2′R)-(+)threo methylphenidate, is also described [31] and all have been reviewed [32].…”

Synthesis of New Trisubstituted 4‐Aminopiperidines as PAF‐Receptor Antagonists

“…Published work has revealed that β-enamino esters can easily be reduced into the corresponding β-amino esters. [50][51][52][53] A few methods for the reduction of piperidinic β-enamino esters have been described, [38,[47][48][49] but the free primary amines could not be isolated from the corresponding piperidinic β-amino esters or nitriles in any of the cases. As shown in Scheme 2, the intermediate 3 was successfully reduced to the key compound 4 after treatment with NaBH 3 CN in acidic conditions (HCl or acetic acid) and EtOH at 50°C, affording in good yield a crude mixture of inseparable diastereoisomers.…”