Preparative HPLC and HPLC-MS are well established as the methods of choice for purification of pharmaceutical library compounds. Recent advances in supercritical fluid chromatography (SFC) have now made SFC a viable alte...Preparative HPLC and HPLC-MS are well established as the methods of choice for purification of pharmaceutical library compounds. Recent advances in supercritical fluid chromatography (SFC) have now made SFC a viable alternative to HPLC for this application. One of the potential arguments for using SFC in place of, or in addition to, HPLC is that it may offer different selectivity and thus has the potential for improved separation success rates. In this paper, we examine relative success rates for SFC and HPLC in obtaining adequate selectivity for successful separation. Our results suggest that use of SFC in addition to HPLC may result in a slight (1-2%) improvement in success rate compared to use of HPLC alone.
Dou D, Viwanathan P, Li Y
… +6 more, He G, Alliston KR, Lushington GH, Brown-Clay JD, Padmanabhan R, Groutas WC
J Comb Chem
· 2010 Nov · PMID 20882963
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The 1-oxo-1, 2, 3, 4-tetrahydroisoquinoline and 1-Oxo-1, 2-dihydroisoquinoline scaffolds were utilized in the design and solution phase synthesis of focused libraries of compounds for screening against West Nile Virus (W...The 1-oxo-1, 2, 3, 4-tetrahydroisoquinoline and 1-Oxo-1, 2-dihydroisoquinoline scaffolds were utilized in the design and solution phase synthesis of focused libraries of compounds for screening against West Nile Virus (WNV) protease. Exploratory studies have led to the identification of a WNV protease inhibitor (a 1-oxo-1, 2-dihydroisoquinoline-based derivative, 12j) which could potentially serve as a launching pad for a hit-to-lead optimization campaign. The identified hit was devoid of any inhibitory activity toward a panel of mammalian serine proteases.
Rolfe A, Samarakoon TB, Klimberg SV
… +4 more, Brzozowski M, Neuenswander B, Lushington GH, Hanson PR
J Comb Chem
· 2010 Nov · PMID 20879738
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The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S(N)Ar diversification-ODCT(50) scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the react...The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S(N)Ar diversification-ODCT(50) scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.
A general, sustainable and practical process for the sequential cascade one-pot synthesis of library of highly substituted push-pull olefins, phenols and 2-methyl-2H-chromenes was reported through multicatalysis cascade...A general, sustainable and practical process for the sequential cascade one-pot synthesis of library of highly substituted push-pull olefins, phenols and 2-methyl-2H-chromenes was reported through multicatalysis cascade (MCC) reactions. Direct sequential one-pot combination of amine- or amino acid-catalyzed cascade Knoevenagel/Michael/aldol condensation/decarboxylation with other reactions like amine- or amino acid-catalyzed cascade Claisen-Schmidt/iso-aromatization, Claisen-Schmidt/isomerization, Claisen-Schmidt/iso-aromatization/isomerization, Michael addition, Claisen-Schmidt/Michael, ruthenium-base-silica-catalyzed ring closing metathesis/base-induced ring-opening/benzylic oxidation/[1,7]-sigmatropic hydrogen shift, or ruthenium-base-heat-catalyzed ring closing metathesis/base-induced ring-opening/[1,7]-sigmatropic hydrogen shift reactions of alkyl acetoacetates, a variety of aldehydes and alkyl halides furnished the highly functionalized push-pull olefins, phenols and 2-methyl-2H-chromenes with high yields. The yields and regioselectivities were good to excellent. Evidence for a new reaction pathway involving in situ formation of novel push-pull dienamines under amine- or amino acid-catalysis is presented along with examples demonstrating the amenability of the process to MCC chemistry.
On the basis of combinatorial methodology and the idea of an equilateral ingredient triangle, the TiO(2)/ZnO/Fe(2)O(3) composite system including 66 ingredient points was designed. The photocurrents under different light...On the basis of combinatorial methodology and the idea of an equilateral ingredient triangle, the TiO(2)/ZnO/Fe(2)O(3) composite system including 66 ingredient points was designed. The photocurrents under different light sources and bias voltages were measured, and the photocurrent amplitude at 300 s was chosen as a parameter to evaluate the photoelectric response of the composite. To appraise the composition effect of the composite compared with pure materials, the quantitative formula of the composition effect has been provided for the first time in this paper. We found that not all the ingredient points demonstrated the enhanced composition effect in the as-designed ingredient triangle material library. The reasons of different composition effect for different ingredient points have been discussed in detail. X-ray diffraction (XRD) and field emission scanning electron microscopy (FE-SEM) were used to investigate the phase structure and the grain morphology of the composite.
Solid-phase synthesis of bisheterocyclic compounds that contain purine and the 3-hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure is described. The reaction sequence s...Solid-phase synthesis of bisheterocyclic compounds that contain purine and the 3-hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure is described. The reaction sequence started from the primary amines immobilized on aminomethylated polystyrene resin equipped with an acid-labile linker (4-(4-formyl-3-methoxyphenoxy)butyric acid). After the arylation of amines with 2,6-dichloropurine via its C(6), purine N(9) was alkylated and subsequently the chlorine at purine C(2) was substituted with aliphatic diamines. The resulting terminal amino group was used as the starting point for the synthesis of 3-hydroxyquinolin-4(1H)-one precursors based on the acylation with 3-amino-4-(methoxycarbonyl)benzoic acid followed by the saponification of the methyl ester and esterification of the resulting carboxylic acid with various haloketones. The intermediates were cleaved from the resin, and their cyclization to the target purine-hydroxyquinolinone bisheterocycles was accomplished by heating in acetic or trifluoroacetic acid.
A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinato...A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic compounds library.
A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages su...A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave-assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields. Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis.
A direct and efficient approach to 1-aminoindolizines through three-component one-pot reaction of heteroaryl aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF(4) has been developed. Desired products wer...A direct and efficient approach to 1-aminoindolizines through three-component one-pot reaction of heteroaryl aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF(4) has been developed. Desired products were obtained in moderate to excellent yields. Similar aminoindolizines products were afforded from trimethylsilyl protected alkyne substrates as well. This methodology provides a rapid access to construct a diversity-oriented library of indolizines.
J Comb Chem
· 2010 Sep · PMID 20831265
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Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic analogues from bromo arylcarboxylates and o-hydroxyarylboronic acids via Suzuki-Miyaura cross coupling reaction is d...Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic analogues from bromo arylcarboxylates and o-hydroxyarylboronic acids via Suzuki-Miyaura cross coupling reaction is described. Spontaneous lactonization gave dibenzopyranones and heterocyclic analogues bearing electron-donating and -withdrawing groups on both aromatic rings in good to excellent yields.
The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-catalyzed...The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-catalyzed cross-coupling of aryl boronic acids with a fluorous tagged N-hydroxyphthalimide, and (2) a supported aminolysis was designed and optimized using Taguchi's method. A library of O-aryloxyamines was synthesized in high yields with high purity and diversity.
A facile and highly efficient method for one-pot four-component synthesis of triazolyl methoxy phenylquinazolines is described. A mixture of aromatic propargylated aldehydes, different azides, 2-aminobenzophenone derivat...A facile and highly efficient method for one-pot four-component synthesis of triazolyl methoxy phenylquinazolines is described. A mixture of aromatic propargylated aldehydes, different azides, 2-aminobenzophenone derivatives, and ammonium acetate were condensed in the presence of catalytic amounts of acidic ionic liquid, 1-methylimidazolium trifluoroacetate, ([Hmim]TFA), and Cu(OAc)(2)/sodium ascorbate to afford the corresponding products in excellent yields. This methodology is highly efficient for structurally diverse azides.
In this work, a novel one-pot multicomponent reaction of 2-aminophenols, Meldrum's acid, and isocyanides leads to the synthesis of tetrahydrobenzo[b][1,4]oxazepine or malonamide derivatives using 1 or 2 equiv of 2-aminop...In this work, a novel one-pot multicomponent reaction of 2-aminophenols, Meldrum's acid, and isocyanides leads to the synthesis of tetrahydrobenzo[b][1,4]oxazepine or malonamide derivatives using 1 or 2 equiv of 2-aminophenols, respectively, in good to excellent yields at ambient temperature.
A catalyst-free one-pot four component methodology for the synthesis of 1,2,4,5-substituted imidazoles under conventional heating and microwave irradiation using 1-butyl-3-methylimidazolium bromide, [Bmim]Br, as a neutra...A catalyst-free one-pot four component methodology for the synthesis of 1,2,4,5-substituted imidazoles under conventional heating and microwave irradiation using 1-butyl-3-methylimidazolium bromide, [Bmim]Br, as a neutral reaction media is described. A broad range of structurally diverse aldehydes (aromatic aldehydes bearing electron withdrawing and/or electron releasing groups as well as heteroaromatic aldehydes) and primary amines (aromatic and aliphatic) were applied successfully, and corresponding products were obtained in good to excellent yields without any byproduct.
A convenient and highly efficient multicomponent protocol has been developed for the synthesis of various poly-substituted 2-(pyridin-2-yl)imidazoles from 2-cyanopyridine, corresponding aromatic aldehydes, and NH(4)OAc/p...A convenient and highly efficient multicomponent protocol has been developed for the synthesis of various poly-substituted 2-(pyridin-2-yl)imidazoles from 2-cyanopyridine, corresponding aromatic aldehydes, and NH(4)OAc/primary amine. Notably, tri-substituted 2-(pyridin-2-yl)imidazoles were highly yielded when aromatic primary amines were used as substrates, but both di- and tri-substituted 2-(pyridin-2-yl)imidazoles were obtained in one pot when some aliphatic primary amines were used as substrates.