ChemInform Abstract: Synthesis and Analgesic Activity of Pemedolac (cis‐1‐Ethyl‐1,3,4,9‐tetrahydro‐4‐(phenylmethyl)pyrano(3,4‐b)indol‐1‐ylacetic Acid).

Abstract

206 ChemInform Abstract Several methods of preparing the title compound (X) from indole derivatives are described. One key intermediate is the (hydroxymethyl)phenylethylindole (IV) which is obtained from isatin (I) and the phenylpropionate (II) or from the indolylacetate (V) and benzyl chloride (VI). (IV) undergoes cyclocondensation with the methoxypentenoate (VIII), forming the dihydropyranoindolylacetates (IX). Saponification of the main diastereomer (IXa) yields pemedolac (X). An alternative pathway to (IX) starts with the oxime (XI) which is hydrogenated and reduced, giving the amino alcohol (XII). This is N-protected and then cyclized with (VIII), producing the fused aminodihydropyran derivative (XV) which is subjected to a complex formylation, dehydration, cleavage, and rearrangement procedure, followed by coupling with benzylmagnesium bromide (XVII), to yield (IX). Pemedolac (X) has analgesic activities. (X-ray analysis of (X) and its (S)-borneol ester).

The chemistry of isatins: a review from 1975 to 1999

“…The analgesic drug pemedolac [122][123][124] , analogues of etodolac 125,126 and the synthesis of the alkaloids hobartine and aristoteline 127 were initiated by the C-3 alkylation of isatins to yield dioxindoles that were then reduced to the corresponding indoles by the use of lithium aluminum hydride (Schemes 36 and 37). In a similar manner, 1-acylisatins can be reduced to 1-alkylindoles by BH 3 .THF in high yields 99 (Scheme 38).…”

The Oxa-Pictet-Spengler Cyclization: Synthesis of Isochromans and Related Pyran-Type Heterocycles

“…The use of ketones in place of aldehydes gives rise to 1,1disubstituted oxacycles. In addition to the example provided by Guiso ( 41 Among other 1,1-disubstituted pyran-type heterocycles with the same activity, etodolac (7) 42 and pemedolac (56) 43 have prominent importance ( Figure 5). These are clinically effective as antiinflammatories, with the activity related to the presence of the dihydropyran acetic subunit.…”

Synthesis of Oxacyclic Scaffolds via Dual Ruthenium Hydride/Brønsted Acid‐Catalyzed Isomerization/Cyclization of Allylic Ethers

“…The 1,3,4,9‐tetrahydropyrano[3,4‐ b ]indole (THPI) skeleton (Figure 1) is of considerable interest in the field of medicinal chemistry, as exemplified by pharmaceuticals such as etodolac (a nonstereoidal anti‐inflammatory drug),1 pemedolac (an effective analgesic agent),2 and HCV‐371 (which displays potent antiviral activity) 3…”