Synthesis of (S)-naproxen-benzotriazole and its application as chiral derivatizing reagent for microwave-assisted synthesis and indirect high performance liquid chromatographic separation of diastereomers of penicillamine, cysteine and homocysteine

Synthesis of three strong UV-absorbing Naproxen-based chiral derivatizing agents and their application for enantioseparation of Baclofen by RP-HPLC

“…Thus, all the three CDRs are equally good for resolution of (RS)-Bac via indirect approach. Nap-Btz (CDR1), being an amide, is more stable than CDR2 and CDR3 [1], the esters, due to higher thermodynamic stability of amides over esters. Synthesizing CDR3 (Nap-Phth) is easier than the other two since H-Phth is neither explosive in nature like benzotriazole nor hygroscopic like H-Suc [4].…”

“…Nucleophilic attack of H-Btz [1] on carbonyl carbon of the carboxylic group of (S)-Nap, in the presence of coupling reagent DCC/DMAP under mild conditions, yielded Nap-Btz (CDR1, an azole derivative of Nap). SINP (CDR2) was obtained by the reaction of (S)-Nap with H-Suc by dropwise addition of DCC in dry THF as per method described by Bhushan and Tanwar [3].…”

“…2), namely, Nap-Btz (CDR1), SINP (CDR2), and Nap-Phth (CDR3), and the corresponding diastereomers were synthesized for enantioseparation of (RS)-Bac according to literature reports [1,2,4]. Characterization and determination of enantiomeric purity of the CDRs were also carried out using literature reports [1,2,4].…”

“…The carboxylic group of Nap becomes activated to produce chiral derivatizing reagents (CDRs), by nucleophilic substitution of hydroxyl group of Nap with attacking nucleophilic species, such as, 1H-benzotriazole (H-Btz) [1,2], N-hydroxysuccinimide (H-Suc) [3], and N-hydroxyphthalimide (H-Phth) [4], in presence of dicyclohexylcarbodiimide (DCC), under mild conditions. Three CDRs, namely, (S)-1-(1H-benzo[d] [1,2,3]triazol-1-yl)-2-(6-methoxynaphthalen-2-yl)propan-1-one (Nap-Btz, CDR1), succinimidyl-(S)-2-(6-methoxynaphth-2-yl) propionate (SINP, CDR2), and N-phthalimidyl-(S)-2-(6-methoxynaphth-2-yl) propionate (Nap-Phth, CDR3) were obtained by introducing the said nucleophiles via substitution reaction. The reagents so obtained have been used for enantioseparation of cysteine, homocysteine, DL-penicillamine A [1], 18 proteinogenic amino acids [2], DLpenicillamine A [3], and selenomethionine [4], respectively.…”

“…Three CDRs, namely, (S)-1-(1H-benzo[d] [1,2,3]triazol-1-yl)-2-(6-methoxynaphthalen-2-yl)propan-1-one (Nap-Btz, CDR1), succinimidyl-(S)-2-(6-methoxynaphth-2-yl) propionate (SINP, CDR2), and N-phthalimidyl-(S)-2-(6-methoxynaphth-2-yl) propionate (Nap-Phth, CDR3) were obtained by introducing the said nucleophiles via substitution reaction. The reagents so obtained have been used for enantioseparation of cysteine, homocysteine, DL-penicillamine A [1], 18 proteinogenic amino acids [2], DLpenicillamine A [3], and selenomethionine [4], respectively. Further, the HBtz, H-Suc, and H-Phth moieties of the CDRs act as good leaving groups under nucleophilic substitution conditions when reacted with a racemic drug containing amino group, in particular.…”