This work presents an improved eight-step process, leading to
kilogram quantities of high-quality DL-028A, an antihypertensive agent. The improvements include reducing the levels of
toxic reagents and the removal of dangerous processes and
waste gas treatment. Moreover, specification and impurity
profiles were determined.
The exploration of an efficient method for resolving etodolac using either L‐cinchonidinium salt or chiral isopinocamphenol diastereomeric esters is described herein. Furthermore, racemization mechanism of chiral etodolac is rationalized in terms of an isotope labeling experiment.
Condensation of 5-methylthio-2-benzoylpyrrole (1) with spiro[2.5]-5,7-dioxa-6.6-dimethyloctane-4,s-dione (3) using excess amount of NaH in DMF gave an anomalous tetrahydro-2H-oxocine hsed pyrrole (lo), which then undergoes an acid-catalyzed rearrangement in refluxing toluene/methanol (10: 1, v/v) to afford the unexpected anti-aromatic compounds (15 and 16).In the preparation of Ketorolac,' an analgesic markted by Roche Co., for the pharmacological studies, one of the literature procedures was followed by u~.~~A m o n g the multi-step transformations, one of the key steps is the N-alkylation of 5-methylthio-2-benzoylpyrrole (1) with sipro[2.5]-5,7-dioxa-6,6dimethyloctane-4,8-dione (3).5.6 We report herein an anomalous medium-ring fused pyrrole formation during the validation of this transformation and the subsequently rearrangement of one of the resulting fused pyrroleDuring our initial attempt of the deprotonation of 1 using stoichiometry amount of NaH in DMF, we found that the reaction remains incomplete after a long period of stirring (> 72 h). In order to accelerate the deprotonation process, an excess amount of NaH was employed. Under this condition, we found that the reaction of pyrrole anion and reagent (3) gave an unexpected tetrahydro-2H-oxocine fused pyrrole (10) as the major product (40 %).' The desired chain-extension product (6) was obtained in comparable yield .The 'H-NMR peaks attributable to four multiplets ( 4.51, 4.08, 2.91 and 2.48 respectively) of 10 are characteristic of the strained tetrahydrooxocine ring. In order to broaden the scope of this unexpected reaction, 11 was prepared from 2-benzoylpyrrole (2)8 by the similar procedure as that described for the preparation of 10, but the yield is low (17.5 % based on recovered 2). As judged from the structures of the condensation products (10 and l l ) , we proposed that the normal chain-extension intermediate (4) was
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