ES423963A1 - Heterocyclic compounds - Google Patents

Abstract

Procedure to prepare derivatives of 6-substituted-aminopenicyllanic and cephalosporanic acids, with the general formulas: **(See formula)** where Q represents the group **(See formula)** where U represents an amido group (eg saccharyl, succinimido or phthalamido) or a group OE' where E' represents hydrogen, a salt-forming cation, a steric residue such as a (lower) alkyl group substituted by choice with a (lower) alkanoyloxy group which can also be substituted, a silyl group, a phenacyl group, a benzyl group, a benzohydryl group, a trichlorethyl group, or tert-butyl group, x represents a hydrogen atom, a hydroxy group , a (lower) alkanoyloxy (preferably acetoxy) group or residue of a nucleophilic agent, such as a halogen atom, an acid group; a cyano group, and carbamoyloxy group, a choice substituted heterocyclic mononuclear group containing a sulfur or nitrogen atom (eg, pyridinyl); an -S-Q' group (where Q' represents a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazol-pyridinyl or puridinyl group), or X represents an amino group where Q represents a group with the formula XX; R1 represents a lower alkyl group (eg methyl, ethyl, propyl, osopropyl, butyl, sec.butyl, isobutyl, t-butyl) optionally substituted in primary or secondary position with 1 fluorine, chlorine atom, a group hydroxy, or lower alkoxy (eg fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl) or a cycloalkyl group optionally substituted with 1 or more lower alkyl groups, hydroxy or lower alkoxy groups or where R1 represents an adamantyl group or a phenyl group substituted by choice with a maximum of 3 of the substituents selected from chlorine, fluorine, hydroxy, lower alkoxy and lower alkyl, or where R1 represents a five-membered mononuclear heterocyclic group, (for example, furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl) substituted by choice with lower alkyl groups, or where represents an aralkyl group (for example, benzyl) substituted by choice in the phenyl nucleus as mentioned above , ou n carboxymethyl group, and represents, together with the definition indicated above for R1, a hydrogen atom, a (lower) alkyl group optionally substituted with a chlorine or fluorine atom, a (lower) alkoxy group, a cycloalkyl group, a phenyl group, which in turn is substituted by choice with a maximum of three of the aforementioned substituents, or Z1'' represents a carboxy group esterified with a residue of (lower) alkyl, phenyl, cycloalkyl or aralkyl, being at choice said phenyl radicals substituted with a maximum of one of the aforementioned substituents, or represents an N-substituted carbamoyl group of choice with one or two lower alkyl groups, a phenyl group, a five-membered mononuclear heterocyclic group, a cycloalkyl group , one or two arylalkyl (lower) or cycloalkylalkyl (lower) groups, with the phenyl and cycloalkyl groups being substituted with a maximum of one of the substituents a Indicated above, o represents a carbamoyl group having its nitrogen atom as a member of a heterocyclic ring (eg morpholino) and where R2 represents a group **(See formula)** where n represents O, 1, 2 or 3, and R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a hydrogen atom, a lower alkyl, a cycloalkyl, phenyl or aralkyl group, or R4 represents a group -COOE, where E represents a hydrogen atom or a salt-forming group (when n &g; 1), or a residue of (lower) alkyl, benzyl or phenyl ester, or R4 represents a carbamoyl group N- optionally substituted with one or two and (lower) alkyl, or alkenyl groups, a phenyl group, a cycloalkyl group, one or two arialkyl (lower) or cycloalkylalkyl (lower) groups, with the phenyl and cycloalkyl groups being substituted with a maximum of one of the aforementioned substituents, or where R3 and R4, together with the carbon atom to which they are attached, represent a substituted cycloalkyl group of choice, and Z4 represents a hydrogen atom or a substituted aryl group of choice comprising react an acid with the s general formulas: **(See formula)** in which (see graph) are as previously defined for R1 and Z1 or represent groups that can easily become those that fall within the definition of R1 and Z''1 and that can be influenced or can also react under reaction conditions employed (eg protected amino, hydroxy and carboxy groups), or **(See formula)** where (see graph) are as defined above for R2 and Z4 or represent groups that can easily become those that fall within the definition of R2 and Z4 and that can be influenced or react under reaction conditions as well, or **(See formula)** where (see graph) are as previously defined for Z2 and Z3 or represent groups that can easily become those that fall within the definition of Z2 and Z3 and that can also be influenced or react under reaction conditions, with an intermediate phosphazo prepared in situ, obtained by the reaction of phosphorous trichloride and an amine salt or a compound according to the formulas: **(See formula)** in the presence of an exactly predetermined excess of amine used, under anhydrous conditions, followed by separation, isolation or both of the obtained compound and the removal of the protecting groups present at choice in order to form the corresponding free penicillanic or cephalosporic acid, and transform at choice these acids in their salts or esters. 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