Pivalaldehyde → HCID 135505743, compound

Participants

Reaction Steps

Substituted thiazolines, such as, for example, 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2,3-di-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxy-3-methoxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(4-carboxy-2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(3-hydroxyquinolin-2-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxynaphth-1-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(3-hydroxynaphth-2-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxyphenylmethyl)-4-methylthiazole-4-(S)-carboxylic acid, etc. are potential iron chelators. The preparation of these compounds is carried out via the coupling of (S)-α-methylcysteine or of a salt thereof with the appropriate nitrile or imidoester compound and has already been described in the literature. Thus, the coupling of (S)-α-methylcysteine hydrochloride with 2,4-dihydroxy-benzonitrile is carried out, for example, according to J. Med. Chem. 1999, 42, 2432-2440 in degassed methanol by heating at 71° C. for 3 days with addition of degassed phosphate buffer to achieve a pH of 6, whereby, after working up the reaction mixture, 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid is obtained in 57% yield. Analogously, 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid is prepared in a yield of only 32%. An important intermediate compound for the synthesis of the abovementioned target compounds is in this case (S)-α-methylcysteine, which is obtained, for example, according to Tetrahedron 1993, 49 (24), 5359-5364 in a Seebach-analogous synthesis by acidic hydrolysis of 2S,4S-methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-methyl-4-carboxylate. 2S,4S-Methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-methyl-4-carboxylate is in this case prepared starting from (S)-cysteine methyl ester and pivaldehyde via 2S-methyl 2-tert-butyl-1,3-thiazolidine-4-carboxylate, introduction of a formyl protective group to give 2S,4S-methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate, reaction at −78° C. with lithium diisopropylamide to give the corresponding enolate and quenching of the enolate with methyl iodide. The yield of (S)-α-methylcysteine starting from (S)-cysteine methyl ester is in this case only 29%. In addition to the low yield of (S)-α-methylcysteine, the laborious process steps and especially the starting material (S)-cysteine methyl ester hydrochloride, a compound which is unnatural, commercially unavailable and therefore not to be taken into consideration for industrial syntheses, are significant disadvantages of this preparation variant.

Provenance & Evidence