Gist-brocades N.v.

Johannes K Van Der Drift

Peter W Henniger

Cornelis A Bruynes

Jagdish C Kapur

Gerard J Van Veen

Everardus J Leenderts

Herman H Grootveld

Herman P Fasel

Herwarth Heitman

A process for the preparation of at least one compound of a formula selected from the group consisting of ##STR1## and their salts and esters wherein X is selected from the group consisting of hydrogen and a substituent such as halogen and acetoxy comprising diazotizing a compound of the formula ##STR2## and salts and esters thereof wherein X has the above definition and brominating the resulting diazotized compound with at least an equimolar amount of a nitrosating agent in the presence of 1 to 5 equivalents of a strong acid in solution or suspension in a mixture of water and an at least partially water-miscible organic solvent with the amount of water being 1 to 20% by volume containing at least equimolar amounts of hydrogen bromide and bromine which bromo compounds are useful intermediates for the preparation of penicillanic acid-1,1-dioxide and its derivatives and novel 6-diazo-intermediates.

6-diazo-penicillanic acid 1,1-dioxide derivatives

Preparation of 6-.alpha.-bromo- and/or 6,6-dibromo-penicillanic

A process for the preparation of penicillanic acid-1,1-dioxides of the formula ##STR1## wherein X is selected from the group consisting of hydrogen and substituent such as halogen or acetoxy and R is selected from the group consisting of hydrogen, a pharmaceutically acceptable metal ion and/or ester radical comprising debrominating a 6-.alpha.-bromo- and/or 6,6-dibromo-penicillanic 1,1-dioxide selected from the group consisting of the formula ##STR2## wherein X and R have the above definition in an aqueous containing medium with zinc in association with an acid having a pK.sub.a -value measured in water less than 3.5 and optionally if R is H converting the acid into a pharmaceutically acceptable salt or ester.

Process for the preparation of penicillanic acid 1,1-dioxides

A process for the preparation of [D-.alpha.-amino-p-hydroxyphenylacetamido]-penicillanic acid or cephalosporanic acid compounds comprising reacting a compound having a formula selected from the group consisting of ##STR1## wherein X is selected from the group consisting of hydrogen, acetoxy and five-membered heterocyclic group containing at least one hetero atom of the group consisting of oxygen, sulfur and nitrogen and optionally substituted with e.g. lower alkyl, this residue being attached to the 3-CH.sub.2 group via sulfur atom and wherein a NH radical if present has optionally been silylated with at least one mole equivalent of a silylating agent producing ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are individually selected from the group consisting of lower alkyl, benzyl, cycloalkyl and phenyl in an inert anhydrous, organic solvent, preferably a water-inmiscible organic main-solvent, to form a compound having a formula selected from the group consisting of ##STR3## adjusting the pH to a scale value of 5.5 to 7.5 and reacting the resulting compounds in a pre-cooled solution with an at least equimolar amount of a compound of the formula wherein R.sub.4 is lower alkyl, R.sub.5 is selected from the group consisting of hydrogen and lower alkyl and R.sub.6 and R.sub.7 are lower alkoxy.

Process for preparing cephalosporanic acid compounds

The solvate of sodium amoxicillin and N-methyl-2-pyrrolidone and its preparation which is a stable antibiotic from which injectable solutions may be prepared.

Sodium amoxicillin solvate

A process for the preparation of 6-(D-.alpha.-amino-p-hydroxyphenylacetamido)-penicillanic acid or amoxicillin by reacting 6-aminopenicillanic acid with at least two equivalents of a silylating agent producing trimethylsilyl groups in an anhydrous, inert, water-insoluble organic solvent and reacting the resulting product at a temperature below -25.degree. C with an at least equimolar amount of a compound of the formula ##STR1## wherein R.sub.1 and R.sub.7 are lower alkoxy, R.sub.2 is lower alkyl and R.sub.3 is selected from the group consisting of lower alkyl and hydrogen previously prepared from the corresponding Dane salt and an acid chloride under anhydrous conditions in the presence of a tertiary amine in an inert, water-insoluble organic solvent.

6-(D-.alpha.-Amino-p-hydroxyphenylacetamido)-penicillanic acid

Penicillanic acid derivatives of the formula ##STR1## wherein E is selected from the group consisting of hydrogen, a salt forming cation, and an ester forming residue which is known to improve the absorption characteristics of penicillanic compounds after oral administration to humans or animals, and Y is a group of the formula ##STR2## wherein Z.sub.1 and Z.sub.2 are individually selected from the group consisting of lower alkoxy, optionally substituted phenoxy, optionally substituted benzyl and benzyloxy group, optionally substituted lower alkyl, optionally substituted phenyl, hydroxy and -OM wherein M represents a salt forming cation, and hydrates of the said salts having antibacterial properties and their preparation and novel intermediates.

Novel penicillanic acid

Novel therapeutically useful and disinfecting penicillanic and cephalosporanic acid derivatives of the formula: ##SPC1## Wherein W represents a penicillanic or cephalosporanic acid residue or derivatives thereof and wherein Y represents a carbonamido group N-substituted by a phosphorous or sulfur containing residue or Y represents a phosphorous or sulfur containing substituent, and pharmaceutical and disinfecting compositions containing them and their use and process for the preparation of the said compounds.

Growing community of inventors

Delft, Netherlands

Johannes K Van Der Drift