Synthesis ritalin

The full potential of this C-H activation process, as a surrogate Mannich reaction, was realized in the direct asymmetric synthesis of threo-methylphenidate (Ritalin) 217 (Eq. 28) [140]. C-H insertion of N-Boc-piperidine 216 using second-generation Rh2-(S-biDOSP)2 and methyl phenyldiazoacetate resulted in a 71 29 diastereomeric mixture, where the desired threo-diastereomer was obtained in 52% yield with 86% enantiomeric excess. Winkler and co-workers screened several dirhodium tetracarboxami-dates and found Rh2(R-MEPY)4 to be the catalyst that gives the highest diastereoselec-tivity for this reaction [142]. 

Keywords attention deficit hyperactivity disorder enantioselective synthesis enzymatic hydrolysis (27J,2 / )-Z/ireo-methylphenidate resolution ritalin... 

Despite the fact that piperidines seem to yield less selective reactions than pyrrolidines, they have been successfully used as substrates for the synthesis of ///reo-methy]phenidate (Ritalin) and analogs (Scheme 35) [108-110], For the synthesis of Ritalin itself, A-Boc-piperidine 146 was treated with methyl phenyl-diazoacetate 99 and a chiral catalyst. Davies and coworkers found that bridged prolinate Rh2(.S -biDOSP)4 (27) provided the desired product in 86% ee, although in moderate diastereoselectivity, providing threo-147 in 52% yield [109]. Winkler obtained the same product in a maximum of 69% ee (recrystallized to 95%), but with 94% de using carboxamidate Rh2(5R-MEPY)4 (5R-28b) in 44% yield, 26% after recrystallization [108],... 

I Synthesis of various drugs like dicyclonine, phenoperidine, oxaladine, ritaline, etc. 

A research group at Novartis also utilized Evans aldol reaction in a straightforward synthesis of (/ ,/ )-methylphenidate hydrochloride (ritalin hydrochloride), the drug well known for the treatment of attention deficit hyperactivity disorder (AD HD). In the key step, displayed in Scheme 4.58, N-acylated oxazolidinone 249, the standard boron enolate addition to 5-chloropentanal, yielded 250 as a single diastereomer that was transformed in several steps into Ritalin hydrochloride. In the aldol step, temperatures lower than -20 °C could be avoided, what makes the procedure applicable in a manufacturing scale [130]. 

Scheme 4.58 Evans aldol protocol as the key step in Novartis synthesis of ritalin.

Methylphenidate hydrochloride (Ritalin and Concerta [Novartis, Basel, Switzerland]) (11, Scheme 2.1) is a mild nervous system stimulant that is primarily prescribed for treatment of attention deficit hyperactivity disorder in children. Although it is marketed in its racemic form, it has been reported that the (+) enantiomer is 5 to 38 times more active than its racemate.Although previous syntheses of (+)-methylphenidate involved classic resolution, researchers at Novartis reported an enantioselective synthesis of (+)-methylphenidate in 1997. As depicted in Scheme 2.1, the synthesis began with a diastereoselective... 

The ability to conduct enantioselective C-H insertion chemistry substantively impacts the strategies available for chemical synthesis. Thus, for example, an application of this reaction was documented independently by Davies [97] and Winkler [98] in their routes to ritalin (186), the most commonly prescribed psychotropic medication for children in the USA (Scheme 15.21). 

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