Christopher R. Schmid

Synergistic methodologies for the synthesis of 3-aroyl-2-arylbenzo[b]thiophene-based selective estrogen receptor modulators. Two concise syntheses of raloxifene

Difunctionalized benzo[b]thiophene intermediates are prepared which allow fully independent elaboration of the 2-aryl position or the tether position of benzo[b]thiophene-based selective estrogen receptor modulators (SERMs). Two concise syntheses of the SERM raloxifene (Evista®) are presented.

Nucleophilic aromatic substitution on 3-aroyl-2-arylbenzothiophenes. Rapid access to raloxifene and other selective estrogen receptor modulators

Versatile, mild and high yielding methods for nucleophilic aromatic substitution of 2-dialkylamino-1-ethoxides and related nucleophiles on 3-aroyl-2-arylbenzothiophene nuclei are presented. A short synthesis of raloxifene is detailed.

Acid liability of allylic esters: use of methallyl esters as acid-labile protecting groups for car☐ylic acids

Abstract Substituted allylic esters are cleaved in refluxing 90% formic acid to afford car☐ylic acids. The scope and generality of the reaction is investigated, and several examples using methallyl esters as an acid-labile protecting group for car☐ylic acids are presented.

Synthesis and biological activity of trans-2,3-dihydroraloxifene.

The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the compound to be a potent selective estrogen receptor modulator (SERM).

Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene.

Compounds were synthesized where oxygen in the ethoxypiperidine region of raloxifene is replaced with carbon, sulfur, or nitrogen linkages. Thia- and aza-substituted compounds were prepared by novel methodology. The compounds were evaluated in vitro as selective estrogen receptor modulators (SERMs). Calculations suggested the compounds exhibit an ER-alpha binding affinity/conformational energy relationship.