L-DOPA methyl ester

Wulff and his collaborators reported, in 1989, the preparation of imprinted polymers able to perform enantioselective synthesis [11, 12]. The imprinting complex was prepared by reacting 3,4-di-hydroxy-phenyl-alanine methyl-ester (l-DOPA methyl ester) (16) with the 4-vinyl-salicylaldehyde (17) to form the corresponding Schiff s base (18), which was further reacted with the 4-vinyl-phenyl-boronic acid (19) to afford to the corresponding ester (20) (Scheme 4). The imprinting complex obtained was then polymerised and the template removed. The resulting polymers were incubated with sodium glycinate to allow formation... 

The first asymmetric syntheses in the chiral cavity were achieved in our research group [27, 52, 53]. A cavity was made with an l-DOPA methyl ester. After removal of the template, glycine was embedded in the cavity, deprotonated, and alkylated. So far, the highest enantiomeric excesses (36% e.e.) on using imprinted polymers have been with the amino acids formed in this way. This excess is purely a result of the shape of the asymmetric cavity. 

In the case of monomer 7 (60)a 4-vinylphenyl-boronic acid is bound to the two hydroxyl groups of L-DOPA methyl estec In addition, 5-vinylsalicylaldehyde ( ) is linked to the amino-group through an azomethine-bond. Polymerization under the usual conditions and splitting off the template, L-DOPA methyl ester, yielded a polymer that showed a separation factor a = 1.98 for the solution of the racemate of the template. The same polymer did not resolve the racemate of tyrosine methyl ester or... 

As might be expected, methods for measuring exogenous levodopa, L-DOPA methyl ester (LDME) and the DOPA-decarboxylase inhibitor, carbidopa... 

Triethylamine and 10%-Pd-on-carbon added to a soln. of 1.25 g. 0,0,N-triacetyl-6-bromo-L-dopa methyl ester in dioxane, cooled with liq. air, evacuated, tritium added, allowed to warm and liquefy, stirred overnight at room temp, under slightly reduced pressure, the dehalogenation completed with H2, and the crude product (1.03 g.) hydrolyzed by stirring and heating at 100° in 1 iV HCl overnight L-dopa-[6- H]. Y 65-80% spec, activity 100-135 mC/mMol. Also L-dopa-[2,5,6-3H] s. E. Schreier, W. Pacha, and J. Rutschmann, Helv. 46, 954 (1963). 

I. Ester derivatives L-Dopa Carboxyl ester, e.g., methyl catechol mono-o-pivaloyl. 4-6,8-10... 

Chira.lHydrogena.tion, Biological reactions are stereoselective, and numerous dmgs must be pure optical isomers. Metal complex catalysts have been found that give very high yields of chiral products, and some have industrial appHcation (17,18). The hydrogenation of the methyl ester of acetamidocinnamic acid has been carried out to give a precusor of L-dopa, ie, 3,4-dihydroxyphenylalanine, a dmg used in the treatment of Parkinson s disease. 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

The L-dopa esters were also examined for their enzymatic hydrolysis in human plasma and/or by purified pig liver carboxylesterase (EC 3.ELI Table 8.1). In human plasma under the conditions of study, hydrolysis again followed pseudo-first-order kinetics. In all but two cases examined, enzymatic hydrolysis was slightly faster than chemical hydrolysis. For the methyl ester, rates of chemical and enzymatic hydrolysis were comparable, whereas the /erf-butyl ester was not hydrolyzed in plasma and was protected from chemical hydrolysis presumably by becoming bound to plasma proteins. 

Reaction 9.1 has been extensively studied to establish the mechanism of asymmetric hydrogenation. The catalytic cycle proposed for the asymmetric hydrogenation of the methyl ester of a-acetamido cinamic acid with 9.14 as the precatalyst is shown in Fig. 9.3. As mentioned earlier, this reaction is one of the early examples of industrial applications of asymmetric catalysis for the manufacture of L-DOPA (see Table 1.1). 

Aspartame (Enichem/Anic). L-Phenylalanine is an intermediate for the aspartame sweetener. For a few years, it has been produced by Enichem/Anic on a scale of ca. 15 t, using a variant of the L-dopa procedure (36). The Rh/eniphos catalyst was considerably less selective than Rh/dipamp but easier to prepare and much cheaper. Crystallization of the methyl ester gave a product of 97% ee. Owing to the low stability of the ligand (P-N bond cleavage), reaction conditions had to be carefully controlled. 

The synthesis of L-methyl DOPA 80 by the Strecker reaction was straightforward and of course produced racemic material. A conventional resolution by crystallising the menthyl ester 83 from hexane and hydrolysis of acetal, ester and amide in 48% HBr (note that no racemisation by enolisation can occur) gives good yields.19... 

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