A Scaleable Synthesis of Fiduxosin

Abstract

Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described.

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

“…Methods of preparation of the hydrazides 4b-c and aldehydes of choice 6a-b, 6d-f, 7a-b, and 7d-f were adapted from the original literature [54][55][56][57][58][59][60][61][62][63][64]. 4-Methoxy-and 3-hydroxybenzoic acid hydrazides 4b and 4c were prepared in 67-85% yields from the appropriate benzoic acid methyl esters 8b and 8c and hydrazine monohydrate following a literature procedure [63].…”

Highly diastereoselective 1,3-dipolar cycloaddition of nonstabilized azomethine ylides to 3-nitro-2-trihalomethyl-2H-chromenes: synthesis of 1-benzopyrano[3,4-c]pyrrolidines

“…n¼2638, 2568,2440,2245,1607,1580,1490,1470,1456,1412,1344 5,38.8,41.3,57.7,58.1,65.5,117.3,117.5,119.8,122.2,129.1,130.1,153.0. Found: C,62.36;H,6.23;N,10.88 …”

“…3 In view of this, combining benzopyran and pyrrolidine moieties in a single molecule seems a synthetic task of current interest. 4 cis-Benzopyranopyrrolidine I is an antagonist of 5-HT 2C receptors with respect to 5-HT 2A , 4c whereas its more complex derivative II (Fiduxosin) is an a 1 adrenoreceptor antagonist and shows an a 1a /a 1b selectivity for adrenoreceptors; it was suggested as a promising pharmaceutical agent for the treatment of benign prostatic hyperplasia 5 ( Fig. 1).…”

Total Synthesis of Blennolide Mycotoxins: Design, Synthetic Routes and Completion

“…Building blocks for this natural product were salicylaldehyde 51 and the substituted cyclohexenone 52 (Scheme ). The synthesis of aldehyde 51 is possible in two steps from dimethoxybenzene,44 whereas cyclohexenone 52 is accessible through a known, seven‐step synthesis from D ‐quinic acid 45. Both building blocks were used in a domino oxa‐Michael‐aldol condensation and yielded the tetrahydroxanthone scaffold 53 as a mixture of two separable epimers.…”