IL40143A - The preparation of cephalosporins from penicillin sulphoxides and new mixed anhydrides of penicillin sulphoxides - Google Patents

Claims (1)

1. Process for the preparation of derivat comprising converting a acid salt thereof an anhydride of a penicillanic acid heating this acid anhydride intermediate at a temperature up to at most in 1 a dry inert organic solvent with an anhydrous acid which is capable of causing ring expansion of the ring to a in the presence of a compound capable of removing water formed during the ring the penam structure fast enough to prevent the water hydrolysis of the acid anhydride moiety present and forming neutral or basic products on the aforesaid acid being stron enough no or not to a substantial extent to oilylated under the reaction conditions and hydrolysing the resulting compound s tu and separating the formed acid as such or as a calcium or amine Process according to claim 1 for the of acid derivatives of from corresponding suiphoxxdes of the general wherein represents a hydrogen atom or a group linked to the nitrogen atom by a carbon or sulphur optionally having not being affected by the represents a hydrogen atom or a lower alkyl or lowe alkyl or and together with the nitrogen atom to which they are attached collectively represent a heterocyclic a succinirnido oxazolidinyl or imidazolidinyl which may carry not being affected by the one or more and the group represents an acid anhydride wherein is a group of the general wherein R and are the same of different each 5 represents a lower alkyl a a radical containing 5 to 8 carbon henyl a alkyl group aining 1 or 2 carbon atoms in the alkyl a lower lower or phenoxy or a 1 or 2 carbon atoms in the alkox a halogen atom or a group or onyloxy or R and together represent the residue of a 4 ring including and represents a or phosphorus or an acid anhydride group wherein is of the general wherein and are the same or different and each 4 5 represents a lower alkyl a cycloalkyl radical containing 5 to 8 carbon a phenylalkyl group containing 1 or 2 carbon atoms in the alkyl a lower alkylthio or phenoxy or a phenylalkoxy group containing 1 or 2 carbon atoms in the alkoxy a halogen atom or aminopenicillanyl group or or and together represent the residue of a ring including or R and together represent an atom or a sulphur atom and 2 represents a or tin or a carbon atom when and together represent an oxygen or sulphur or an acid anhydride group wherein is of the general sents a haloge a radical containing 5 to 8 carbon a a phenylalkyl group cont 1 to 2 carbon atoms in the a lower lower alkylthio or a phenylalkoxy group containing 1 or 2 carbon atoms the alkoxy or a and and are the or different and each represents a halogen a tuted or or Ry and together represent the residue of a ring including or together represent an oxygen or sulphur represents a phosphorus or tungsten or an acid anhydride wherein is of the general wherein lower alkyl a cycloalkyl radical containing 5 to 8 carbon a or a phenylalkyl group containing 1 or 2 carbon in the alkyl a lower lower or a phenylalkoxy group containing 1 or 2 carbon atoms in the alkoxy and represents a sulphur according to 1 or lower groups to 6 carbon Process according to claim the phenyl groups moieties within the definitions of and Rg carry one or more halogen lower lower and groups Process according to claim wherein the group in the compounds of general formulae III and IV is an acid anhydride in which general formula wherein and are as hereinbefore defined and represents a aluminium or boron or is of general formula and are as hereinbefore defined and represents a germanium o tin or and represent an oxygen atom and represents a carbon and is on alkyl Process according to claim when is a is a l radical of the formula and are the same or different and each of them represents a or halogen or lower alkyl phenyl or alkyl grou containing 1 or 2 carbon atoms in the alkyl group containing 5 to carbon atoms or a or the groups and when not representing or being optionally substituted with one or more halogen lower lower alkoxy or di o Process according to claim wherein the radical is preferably a Process according to claim wherein reagents used for the protection of the carboxylic function of starting materials of general formula IV are those of general formulae VII VIII and of which the free bonds linked to the atoms by the symbols have been saturated by an anhydride preferably a halogen Process according to claim wherein the reagent is selected from the group of and Process according to claim wherein the containing compound is a compound of the IX X XI I X XVI 0 XVII or and are as hereinbefore defined excluding the possibility that any of the represents a or and separately each represent a hydrogen or a hydrocarbon group no aliphatic containing 1 to 8 carbon or and together with the nitrogen to which they are attached a or heterocyclic group which may contain a second he atom selected h the 18 carbon when is an group with a tertiary carbon atom to depicted nitrogen is hydrogen together i the nitrogen to which they are tached and carbonyl group a or group an or X in the and each a h no ic unsaturation containing 1 to 8 carbon represents a hydrogen atom or a hydrocarbon group with no aliphatic unsaturation containing 1 to 8 carbon atoms or a group represents an group containing 1 to 8 carbon Y represents an alkylene group containing 3 to 18 carbon atom at least 3 and not more than 5 carbon atoms between the nitrogen atom and the carbonyl group to which Y is attachedj and n is X or Process according to claim wherein the silicon compound of the general formulae IX to XVII is selected from the group of acetarnide trifluoroacetaxnide trimethylsilyi acetarnide ure trimethylsilyi Process according to claim wherein the silicon compound of the general formulae and XIX are selected from the group of i and e Process according to claim wherein the containing compound is or 1 Process according to claim wherein the amount of compound used is at least one and a half molecular equivalent per mole of penicillanic or at least one molecular equivalent per mole of penicillanic acid anhydride Process according to claim wherein the amount of compound used is at least 2 to 4 molecular equivalent per mole of penicillin Process according to claim wherein the anhydrous acid is an acid which is not or not to a substantial extent by the compound added to the reaction under the reaction conditions Process according to claim wherein the acid hydrogen hydrogen and concentrated sulphuric hydrogen perchloric periodic nitric chloric iodic selenic substituted acetic acids such as bromoacetic trichloroacetic or trifiuoroacetic substituted sulphonic acids such as acid and trifluoromethylsulphonic naphthalcnesulphonic oxalic picric and OH acids such as pentacyanocyclopentadien and and and in containing nitro carbonyl Process according to claim wherein the acid is hydrogen Process according to claim the acid is orated as such in the reaction or is combined with a base forming an acid addition salt Process according to claim wherein the base is selected from the group of cycloaliphatic or heterocyclic hexamethylonetotramine pyridine and and pyridine or substituted for one or more lower or or lowe mino groups such the 2 2 2 and and also or Process according to claim wherein the base is a substituted a substituted or a substituted Process accessing to claim wherein an excess of the base is employed in relation Process according to claim wherein the complex is formed in in the reaction mixture by initially protecting a penicillanic acid sulphoxide starting material in solution in the dry inert organic solvent by reaction with an acid Process according to claim wherein bases being soluble in the employed and having a p a between 4 and are Process according to claim wherein the of substances reaction in relation to each of acid sulphoxide employed to 4 moles of acid about to 1 to equivalents of protecting reagent to 1 at least 2 equivalents of compound 3 to 7 when an acid complex is to 10 moles of complex to about 4 to 2 equivalents of carboxylic protecting to 1 at least 2 of compound 3 to 7 additional quantity of the base itself for from 1 to 10 the quantity of additional base erably increasing in direct relationship with the amount of complex Process according to claim wherein the inert organic solvent used is dimethylacetamide dioxan glycol diethyl tetraethyleneglycol diethyl benzylcyanide butyl isoamylacetat diethyloxalate carbon methyl ethyl methyl or isobutyl or a such as 1 hylenechlorid and Process according to claim the dry organic inert solvent is Process according to claim wherein the ture employed during ring enlargement is between 50 and Process according to claim wherein the ture employed during ring enlargement is between 60 and 130 preferably between 70 and 110 Process according to claim wherein for each mole of penicillanic acid sulphoxide bcn ylpenicillin there is employed 1 to 4 moles of preferably hydrogen bromide or hydrogen to 15 moles of preferably the amount of base always exceeding that of and 2 to 4 moles of rimethylsilyl and the is carried out at a temperature of to in a dry inert organic preferably Process according to claim wherein for of peneillanic acid employed to 1 of acetyl bromide or phosphorus to 15 moles of the amount of exceeding that of the developing to 3 moles of derivatives whenever prepared by the process according to one of the preceding aminopenicillanic acid anhydrides Wherein the symbols R to R are the same or different and each represents a halogen or R and together represent an oxygen or sulphur represents a halogen atom or a lower lower haloalkyl or aryl is a aluminium or phosphorus is ium or tin and is a phosphorus or tungsten represents a group or a group or wherein X represents a chlorine or bromine 34 The mixed anhydride of phenoxymethylpenicillin sulphoxide and acetic 35 e mixed anhydride of benzylpeniciULn sulphoxide and acetic 36 The mixed anhydride of benzylpenicillin sulphoxide and propionic 37 The mixed anhydride of benzylprnicillin sulphoxide and benzoic 38 The mixed anhydride of phenoxymethylpenicillin sulphoxide and benzoic 39 The mixed anhydride phenoxymethylpenicillin sulphoxide insufficientOCRQuality