Synthesis of dimethyl aryl acylsulfonium bromides from aryl methyl ketones in a DMSO-HBr system.

A new, simplified method for the synthesis of dimethyl aryl acylsulfonium salts has been developed. A series of dimethyl aryl acylsulfonium bromides were prepared by the reaction of aryl methyl ketones with hydrobromic acid and dimethylsulfoxide (DMSO). This sulfonium salt confirms that bromine production and the bromination reaction take place in the DMSO-HBr oxidation system. What's more, it is also a key intermediate for the synthesis of arylglyoxals.

Structure-activity relationships of novel alkylides: 3-O-arylalkyl clarithromycin derivatives with improved antibacterial activities.

A series of novel alkylides, possessing 3-O-arylalkyl group instead of 3-O-cladinose, were designed, synthesized and evaluated for in vitro antibacterial activities. The increased potency clearly ranked by the order of 3-O-(3-aryl-2-propargyl), 3-O-(3-aryl-E-prop-2-enyl), 3-O-(3-aryl-propyl), and 3-O-(3-aryl-Z-prop-1-enyl) groups. Some alkylides, exemplified by 7a, 10a, 21, 22, 26, 27 and 33, showed improved activities against inducible MLS(B) resistance and efflux resistance compared to the second-generation macrolides. Among them, 26 possessed comparable activities against erythromycin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes (MICs of 0.016-0.5 µg/mL). Moreover, 26 displayed dramatically enhanced potency against both efflux resistant and inducibly MLS(B) resistant strains (MICs of 0.125-0.5 µg/mL) resistant to clarithromycin and azithromycin (MICs of 1- >254 µg/mL), independent of methicillin-susceptible and methicillin-resistant phenotypes.

Synthesis and antibacterial activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives.

An allyl group was attached to 3-keto function of ketolides in the presence of allyl bromide and KOtBu. Consequently, the Heck reaction of the resulting 2, 3-dehydro-3-O-allyl-10, 11-anhydroclarithromycin derivatives, in the presence of palladium (II) acetate and tri(o-tolyl)phosphine, afforded a 3-O-(3-aryl-E-prop-2-enyl) sidechain, not the previously reported 3-O-(3-aryl-Z-prop-1-enyl) sidechain. The results suggested that some steric factors in ß-hydrogen elimination might regulate the isomerization. The activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives was low.

Synthesis and antibacterial activities of 6-O-methylerythromycin A 9-O-(3-aryl-2-propenyl) oxime ketolide, 2,3-enol ether, and alkylide analogues.

A facile and efficient route was presented to achieve 3-keto-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 8, 2,3-dehydro-3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 11, and 3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 12. Among them, compound 8, particularly 8d (Ar = 6-quinolyl), exhibited improved antibacterial activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and greatly enhanced activities against the resistant strains encoded by erm and mef genes, as compared to clarithromycin and azithromycin.

Synthesis and antibacterial activities of a novel alkylide: 3-O-(3-aryl-2-propargyl) and 3-O-(3-aryl-2-propenyl)clarithromycin derivatives.

A series of novel 3-O-(3-aryl-E-2-propenyl)clarithromycin derivatives 8 and 3-O-(3-aryl-2-propargyl)clarithromycin derivatives 11 were designed, synthesized, and evaluated for their in vitro antibacterial activities. Compared with 8c and 11c (Ar was 5-pyrimidyl), 3-O-(3-(5'-pyrimidyl)-Z-1-propenyl) counterpart 6c displayed 4- to 64-fold more potent activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae. Moreover, the activities of 6c, 8c, and 11c against erythromycin-resistant S. aureus and S. pneumoniae were in general 4-fold higher than those of the reference compound, clarithromycin and azithromycin.

Design, synthesis and antibacterial activity of a novel alkylide: 3-O-(3-aryl-propenyl)clarithromycin derivatives.

A series of novel 3-O-(3-aryl-propenyl)clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Regioselective allylation at 3-OH was efficiently achieved in the presence of 9-oxime ether, compared with 9-keto. Most of the side chains were identified as the 3-O-(3-aryl-Z-prop-1-enyl) group, not the expected 3-O-(3-aryl-E-prop-2-enyl) group. Some derivatives of this series showed improved activities against erythromycin-resistant Staphylococcus aureus and Staphylococcus pneumoniae compared with the reference compound, clarithromycin, but weaker activities against susceptible strains.

[Novel synthesis and spectral characterization of nelfinavir].

An efficient and environmentally friendly procedure for the one-pot synthesis of (3S,4aS,8aS)-2-((2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyl)- N-tert -butyl-decahydroisoquinoline-3-carboxamide(VII), the intermediate of nelfinavir, was described, and activating ester was applied to getting nelfinavir(IX). Under the catalysis of potassium hydroxide, benzyl (R)-1-((S)-oxiran-yl)-2-(phenylthio) ethyl carbamate was obtained(IV) in methanol. Then IV and (3S,4aS,8aS)- N-tert -butyl-decahydroisoquinoline-3-carboxamide(V) were refluxed in methanol until the reaction was finished. Potassium hydroxide(w(KOH) = 40%) in water was added to remove benzyloxycarbonyl group in water bath with a yield of 89.0%. 3-acetoxy-2-methylbenzoic acid-succinimide ester(II) reacted with VII and acetyl group was removed by dense aqueous ammonia, giving nelfinavir(IX). The vibrations of functional groups of thiIIs compound corresponding to the main infrared absorption peaks were discussed. The molecular ion and quasi molecular ion peaks were obtained via MALDI-TOF MS, and 1H NMR and 13CNMR shifts of this compound were assigned by means of DEPT(distortionless enhancement by polarization transfer spectrum), HMBC(1H detected heteronuclearmultiple bond correlation spectrum), HSQC(1H detected heteronuclear single-quantum coherence spectrum) and DQF-COSY(double-quantum filtered-correlated spectroscopy). The results provided useful information for structure characterization and quality control of nelfinavir.

Investigation of beta-CD-derivatized erythromycin as chiral selector in CE.

A novel water-soluble beta-CD-derivatized erythromycin (EM) was synthesized and used as an effective chiral selector for the resolution of chiral compounds in CZE. The purpose of substitution at the primary hydroxyl site of beta-CD with 1-oxygen-2,3-epoxypropane is to produce a compound having functions of both beta-CD and EM. beta-CD-derivatized EM exhibited excellent enantioselectivities compared with single beta-CD and EM for chiral separation in CE. We also investigated the influence of pH and concentration of BGE, concentration of chiral selector, applied potential, and organic modifier on chiral compounds' separation.

[Effect of high performance liquid chromatographic instrument system on the analysis of erythromycin A oxime].

A HPLC chromatography for the determination of erythromycin A oxime and relative compounds was studied, and the effect of chromatography systems including a HITACHI L-7100, a Shimadzu LC-6A, a Waters 474 and relative columns was analyzed. It was revealed that different HPLC apparatus and columns have obvious impact on the peak separation and retention time under the general chromatographic condition. The suitable chromatographic conditions for several different chromatography systems were summarized with good linear relationship, which is very significant to the quality control of erythromycin A oxime and relative compounds.

[Analysis of the key intermediates for the regioselectivity control in the methylation of the manufacture of clarithromycin by reversed-phase high performance liquid chromatography].

2',4''-O-Bis(trimethylsilyl)erythromycin A-9-O-(1-isopropoxycyclohexyl)oxime (2',4''-TMS-EMIPCH) and 2',4''-O-bis(trimethylsilyl)-6-O-methylerythromycin A-9-O-(1-isopropoxycyclohexyl)oxime (2',4"-TMS-IPCH) are the key intermediates for manufacturing clarithromycin. A qualitative and quantitative method for baseline separation of E- and Z-isomers and related process substances has been established. A DIKMA-Inertsil ODS-3 column (150 mm x 4.6 mm i.d., 5 microm) was used. The column temperature was maintained at 40 degrees C. The mobile phase was CH3CN-H2O (95:5, v/v). The flow rate was 1.5 mL/min and the detection wavelength was UV 205 nm. Good linearities for E-2',4''-TMS-EMIPCH and E-2',4''-TMS-IPCH were obtained in the ranges of 6-60 microg (r = 0.9994) and 6-72 microg (r = 0.9998), respectively. The method described has also been demonstrated to work equally well on other 2',4''-O-bis(trimethylsilyl)erythromycin 9-oxime hydroxyl derivatives, which provided the criterion for optimizing the protective groups at 9-oxime hydroxyl position and the study of regioselectivity of methylation at the 6-OH position.