Clarithromycin-adenine and related conjugates

Macrolide-nucleoside and macrolide-nucleobase conjugates (chimeras) have been synthesised by linking erythromycin A oxime derivatives and clarithromycin C11,C12-oxazolidinone derivatives with 3′-amino-3′-deoxythymidine or adenine through different spacers; clarithromycin-adenine conjugate 16a is the most active species against Micrococcus luteus.     

A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotic levofloxacin

A series of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 8a-g were synthesized via- a copper-catalyzed intramolecular N-aryl amination reaction on substituted 2-(2-bromophenylthio)-ethanamines which were synthesized by the nucleophilic substitution reaction of 2-bromobenzenethiol with Boc-protected amino alcohol derivatives. This strategy provides a short and an efficient entry to (S)-3-methyl-1,4-benzoxazine 12, an advanced synthetic intermediate for the synthesis of levofloxacin.     

Synthesis of 1,2-dihydro-4H-3,1-benzoxazine derivatives via ZnCl2 catalyzed cyclocondensation reaction

A short and facile synthesis of a series of 1,2-dihydro-4H-3,1-benzoxazine derivatives was accomplished in moderate to good yields via the novel cyclocondensation of substituted o-aminobenzonitrile with aldehydes or ketones catalyzed by ZnCl₂.     

Oxidative behaviour of 3-aryl-2H-1,4-benzoxazines

Autoxidation of 3 - phenyl - 2H - 1,4-benzoxazine 8 gives 2 - hydroxy -3 - phenyl - 2H - 1,4-benzoxazine 13, 3 - phenyl - 2H - 1,4-benzoxazin - 2 - one 11, and 2 - phenylbenzoxazole 10 according to the conditions. Oxidation of 8 with DDQ in the presence of air gave mainly the bisacetal 17 but in the absence of air the major product was trans-Δ^2,2′-bi-(3-phenyl-2H-1,4-benzoxazine) 21a. Corresponding dimers were obtained from the 3-p-bromophenylbenzoxazine 9. The trans-isomers 21a and 22a are photochromic and change into their cis-isomers on exposure in solution to direct sunlight.     

Efficient stereoselective synthesis of benzoxazines via copper-catalyzed three-component coupling reactions

A convenient one-pot synthesis of 1,4-benzoxazines via three-component coupling and subsequent O-cyclization is reported. The present reaction provides an efficient protocol to functionalized 1,4-benzoxazine derivatives in good to high yields from aldehydes, amines and alkynes. Furthermore, the O-annulation process is completely regio- and stereoselective, only the six-membered rings and its Z-isomers were obtained.     

Synthesis and study of copper(II), nickel(II), and cobalt(II) complex compounds with dihydrobenzoxazine derivatives

Complex compounds ML₂ of copper(II), nickel(II), and cobalt(II) with 2-(2-hydroxy-5-nitrophenyl)-4,4-diphenyl-1,4-dihydro-2H-3,1-benzoxazine and 2-(2-hydroxyphenyl)-4,4-diphenyl-1,4-dihydro-2H-3,1-benzoxazine (HL) were prepared by electrochemical and chemical syntheses. The complex formation involves the azomethine form of the ligand and gives a six-membered chelate cycle comprising deprotonated phenol and azomethine groups. The coordination entity has a planar structure with trans arrangement of the nitrogen and oxygen atoms.     

Syntheses of methylpyridine and methylpyridine N-oxide decorated benzoxazine and naphthoxazine platforms

Simple, aqueous-based syntheses of methylpyridine and methylpyridine N-oxide decorated 3,4-dihydro-2H-naphthoxazine and 2,3-dihydro-1H-naphthoxazine monomers, as well as thermally promoted syntheses of 3,4-dihydro-2H-benzoxazine monomers and bisoxazine methylpyridine derivatives of substituted 1,5-, 2,6-, and 2,7-dihydroxynaphthalenes are described. The crystal structures of two derivatives are presented.     

A new “one pot” preparation of 2-n,n-dialkylamino-1,3-benzoxazines and naphth[ 1,2-e][ 1,3]oxazines from corresponding ortho hydroxynitriles and phosgeniminium salts

Phosgeniminium salts 2 react easily with ortho hydroxybenzonitriles 1 and 2-hydroxy-1-naphthonitriles 6 to give 1,3-benzoxazine and naphth[1,2-e][1,3]oxazine derivatives respectively with a very good yield.     

Domino aziridine ring opening and Buchwald–Hartwig type coupling-cyclization by palladium catalyst

Highly important trans-3,4-dihydro-2H-1,4-benzoxazine moieties were easily synthesized by domino aziridine ring opening with o-bromophenols and o-chlorophenols followed by the palladium catalyzed coupling-cyclization (intramolecular C_(aryl)–N_(amide) bond formation) with good to excellent yields.     

Preparation of clarithromycin. Selective 6-O-methylation of the novel erythromycin A 9-O-(2-pyrimidyl)oxime

A new method for the preparation of clarithromycin is described through the highly regioselective O-methylation at C(6)-OH of the novel derivative 9-pyrimidyloxime erythromycin A. The facile synthesis of 6,11-O-dimethyl- and 6,11,12-O-trimethyl erythromycin A is also reported. These compounds are useful as standards to assess clarithromycin purity in quality control processes.     

Untersuchungen zur Synthese von Thiazolo[2,3-c][1,4]benzoxazinen. 17. Mitteilung über Studien zur Chemie der 1,4-Oxazine

Reaction of C2 unsubstituted benzoxazine derivative2b with -bromo compounds only yields the substitution products4a,b and7, whereas from the 2-benzoxazine carboxylate9b the tricyclic heterocycle12 is obtained.

     

Enantioselective synthesis of a key intermediate of Levofloxacin using microbial resolution

The important key intermediate in the synthesis of Levofloxacin, (S)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine, was prepared enantioselectively by microbial resolution. When lyophilized microorganism selected from soil was treated with the corresponding amide, the (S)-amine was obtained with high enantiomeric purity (99% ee).     

New benzoxazine and benzothiazine dyes

2H-1,4-benzoxazine can be generated in situ from 1-(o-aminophenoxy)-2,2′-dimethoxyethane in trifluoroacetic acid whence further reaction leads to the benzoxazine bye 7. The benzothiazine dye 9 can be derived in similar fashion from 1-(o-aminophenylthio)-2,2-diethoxyethane.     

Acylative kinetic resolution of racemic amines using N-phthaloyl-(S)-amino acyl chlorides

A comparative study of the kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2,3-dihydro-3-methyl-4H-1,4-benzoxazine using N-phthaloyl-(S)-amino acyl chlorides as chiral acylating agents is described. Temperature and solvent effects on the stereochemical features have been examined. It has been found that N-phthaloyl-(S)-phenylalanyl and N-phthaloyl-(S)-2-phenylglycyl chlorides bearing aromatic substituents close to the stereogenic centre are more stereoselective acylating agents than N-phthaloyl-(S)-alanyl chloride. For the preparative kinetic resolution of racemic amines N-phthaloyl-(S)-phenylalanyl chloride proved to be the most appropriate chiral acylating agent.     

A new efficient method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines via iodocyclization

An efficient approach for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives is described by molecular iodine- mediated cyclization. The reaction condition is very simple, offers easy isolation, and affords good to excellent yields of the products.     

Novel rearrangement of 1H-2,3-benzoxazines to cyclic N-acyl hemiaminals: application to the synthesis of 1-arylnaphthalene skeletal congeners

The rearrangement of 1H-2,3-benzoxazine derivatives has been investigated. The reaction affords cyclic hemiaminal derivatives for their conversion to the corresponding 1-arylisobenzofurans, which can be trapped by various dienophiles to afford skeletal congeners of 1-arylnaphthalene lignans.     

A new and efficient one-pot synthesis of 2-hydroxy-1,4-dihydrobenzoxazines via a three-component Petasis reaction

The secondary amines synthesized by the reaction between 2-aminophenols and aromatic aldehydes, via the reduction of the corresponding imines, were employed in the synthesis of new 2-hydroxy-2H-1,4-benzoxazine derivatives through a one-pot Petasis multicomponent reaction in good to excellent yields.     

A direct efficient diastereoselective synthesis of enantiopure 3-substituted-isobenzofuranones

Condensation of (−)-8-benzylaminomenthol with o-phthaldehyde lead to the chiral perhydro-1,3-benzoxazine 2 as single diastereoisomer. That compound reacted with different organometallics leading to 3 in excellent de. Hydrolysis of carbinols, followed by oxidation of the intermediates allowed for the synthesis of enantiopure phthalides.     

Extension of the erythromycin biosynthetic pathway : Isolation and structure of erythromycin E

Erythromycin A is slowly metabolized to a new antibiotic, erythromycin E (5), when incubated with fermentations of certain strains of the producing organism Streptomyces erythreus. Erythromycin E contains a novel ortho ester grouping not previously encountered in macrolide antibiotics. The isolation of erythromycin E extends and further delineates the latter stages of the erythromycin biogenetic pathway.     

Novel erythromycin A 9-tritylhydrazone: selective 6-O-methylation and conformational analysis

The straightforward synthesis of the novel 9-tritylhydrazone erythromycin A and its highly regioselective O-methylation at C(6)-OH are described. Preliminary conformational data based on X-ray diffraction, ¹H NMR and molecular mechanics is also presented with the aim of understanding the observed high regioselectivity. The facile synthesis of 6,12-O-dimethylerythromycin A, a standard to assess clarithromycin purity in quality control processes, is reported as well.