Synthesis of chiral zileuton, a potent and selective inhibitor of 5-lipoxygenase

Hsiao, Chi-Nung; Kolasa, Teodozyj

doi:10.1016/s0040-4039(00)79043-5

Cited by 54 publications

(18 citation statements)

References 10 publications

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“…The organic layer was separated, dried with anhydrous Na 2 SO 4 , and evaporated in vacuum to give compound 3a (31. O-Acetyl-(S)-lactic Acid (4) [4], tert-Butyl O-Acetyl-(S)-lactate (5) [5], tert-Butyl (S)-Lactate (6) [5], and tert-Butyl (2S)-(Trifluoromethylsulfonyloxy)propionate (3b) [6] were prepared by known methods. Their melting points , specific rotations, and spectral characteristics agreed with literature values.…”

Section: Methodsmentioning

confidence: 99%

tert-Butyl (2S)-(p-tolylsulfonyloxy)propionate — a suitable reagent for the direct alkylation of indole derivatives

Kurkin

Belov

Yurovskaya

2008

Chem Heterocycl Comp

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A new method is proposed for the synthesis of indole derivatives containing a chiral substituent at the nitrogen atom, which includes the direct alkylation of indole derivatives with tert-butyl (2S)- (p-tolylsulfonyloxy)propionate, obtained from commercial ethyl (S)-lactate with subsequent conversion to the corresponding p-toluenesulfonyloxy derivative by hydrolysis, and esterification.The leading role of derivatives of indole derivatives among physiologically active compounds of both natural and synthetic sources is well known. A considerable number of indole derivatives have been synthesized with the objective of developing new biologically active compounds and medicinals. The results of investigations associated with the synthesis of derivatives of esters of N-(1H-indolyl)alanines were recently patented and the possibility of using them for the treatment of diabetes, obesity, hyperlipidemia, and atherosclerosis has been demonstrated. The authors paid particular attention to the development of the synthesis of enantiomerically pure compounds, since the optical purity of the substrates determines the biological activity and permits, for example, the use of such derivatives of indole for the combination therapy of diabetes [1]. In this connection especial value is attached to the development of methods for the synthesis of derivatives of indole with chiral substituents in particular, at the nitrogen atom of indole. However the authors of the patent [1] used, in place of asymmetric synthesis to prepare the required chiral structures, the separation of racemic substrates using chromatography on columns with a chiral stationary phase.In our view the use of asymmetric synthesis has considerably greater promise for the preparation of derivatives of indole with chiral substituents at the nitrogen atom. In principle, there are two methods to solve the problem of the synthesis of derivatives of indole with a chiral substituent at the nitrogen atom. The first method -synthesis from a chiral predecessor -was developed by us in detail previously [2]. The second method -introduction of a chiral substituent at the nitrogen atom of an available indole structure -is the subject of this paper. The standard route for the N-alkylation of indole structures is connected with the preliminary generation of an N-anion under basic conditions and its interaction with activated alkylating agents. _______ * Dedicated to Academician B. A. Trofimov on his 70 th birthday. __________________________________________________________________________________________

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Section: Methodsmentioning

confidence: 99%

tert-Butyl (2S)-(p-tolylsulfonyloxy)propionate — a suitable reagent for the direct alkylation of indole derivatives

Kurkin

Belov

Yurovskaya

2008

Chem Heterocycl Comp

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“…Zileuton, N-[ 1-(2-benzo[b]thienyl)ethyl]-Nhydroxyurea, is a selective inhibitor of 5-1ipoxygenase currently undergoing clinical trials (Carter et al, 1991;Israel et al, 1993). During the course of the zileuton development program, many syntheses were investigated, some of which are documented (Hsiao & Kolasa, 1992). These synthetic efforts provided a large number of novel methodology-specific intermediates and by-products.…”

Section: Commentmentioning

confidence: 99%

N-[1-(2-Benzo[b]thienyl)ethyl]-N'-carbamoylurea and 1-[1-(2-Benzo[b]thienyl)ethyl][1,3,5]triazine-2,4,6-trione Methanol Solvate

Henry¹,

Copp²,

Wong³

1996

Acta Crystallogr C

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“…Substituted benzo[ b ]thiophenes represent an important class of heterocyclic compounds because they exhibit a broad range of biological activities and provide useful properties in material science 1a. b, 2 The benzo[ b ]thiophene ring system and its derivatives are the core structures of numerous drug molecules,1a, b such as clinically used raloxifene,3a–c arzoxifene,3d and zileuton 3e–f. Consequently, the synthesis of this privileged structure has attracted much attention in recent years and many efficient methods have been developed 1.…”

Section: Introductionmentioning

confidence: 99%

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

Acharya

Kumar

Ila

2015

Chemistry A European J

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An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium-catalyzed intramolecular oxidative C-H functionalization-arylthiolation of enethiolate salts of α-aryl-β-(het)aryl/alkyl-β-mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one-pot, two-step process in which enethiolate salts [generated in situ through base-mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C-H functionalization-arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N-dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two-step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)2 (or PdCl2) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2- and 3-positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno-fused heterocycles such as thieno[2,3-b]thiophenes, thieno[2,3-b]indoles, thieno[3,2-c]pyrazole, and thieno[2,3-b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd-S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.

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Synthesis of chiral zileuton, a potent and selective inhibitor of 5-lipoxygenase

Cited by 54 publications

References 10 publications

tert-Butyl (2S)-(p-tolylsulfonyloxy)propionate — a suitable reagent for the direct alkylation of indole derivatives

tert-Butyl (2S)-(p-tolylsulfonyloxy)propionate — a suitable reagent for the direct alkylation of indole derivatives

N-[1-(2-Benzo[b]thienyl)ethyl]-N'-carbamoylurea and 1-[1-(2-Benzo[b]thienyl)ethyl][1,3,5]triazine-2,4,6-trione Methanol Solvate

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

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