Gist-brocades N.v.

Koninklijke Nederlandsche Gist-en Spiritusfabriek N.v.

Van Veen, Gerardus J.

Verweij, Jan

Kalter, Jan

Henniger, Peter W.

Hirs, Henri G.j.

Grootveld, Herman H.

Peter W Henniger

Johannes K Van Der Drift

Jagdish C Kapur

Antoon Van Harrewijn

Gerard J Van Veen

Jan Verweij

Herman H Grootveld

Herman P Fasel

Henri G Hirs

Robert Heijboer

Jan Kalter

Gerardus J Van Veen

Peter Max Smid

Henri Gj Hirs

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

A process for the preparation of 7.beta.-acylamino-3-substituted-3-cephem-4-carboxylic acid compounds comprising reacting at -70.degree. C. to 0.degree. C. in an inert organic solvent phosphorus pentachloride with a cephalosporin compound in the presence of an olefinic compound having at least one carbon-carbon double bond having not more than three hydrogen atoms attached thereto capable of removing chlorine at least in part by addition to a carbon-carbon double bond.

Cephalosporin deoxygenation process

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

1,2,4-Oxadiazolylacetic acid derivatives. The derivatives include penicillin and cephalosporin amides which have antibiotic properties.

Antibacterial 1,2,4-oxadiazolylacetamido cephalosporins

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

A process for the preparation of acylamido derivatives by reaction of a compound of the formula Z - N = C = O, wherein Z is an optionally substituted alkyl-, aryl- (preferably phenyl or naphthyl) or cycloalkyl or optionally substituted heterocyclic, preferably a penicillanic acid or a cephalosporanic acid nucleus, having carboxyl groups and an optionally present hydroxy group protected, with a carboxylic acid of the formula ##STR1## wherein Z.sup.1 is an optionally substituted hydrocarbon group, in the presence of a catalyst selected from the group consisting of substituted pyridines and their N-oxides, optionally substituted imidazoles or their N-oxides, optionally substituted benzimidazoles or their N-oxides, and optionally substituted imidazo [1,2-.alpha.] pyridines or their N-oxides.

Process for the preparation of heterocyclic compounds

Novel heterocyclic amides of the formula ##STR1## wherein R is selected from the group consisting of lower alkyl and aryl optionally substituted with at least one member of the group consisting of chlorine, fluorine, nitro, amino and lower alkyl and a tertiary alkyl group, R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, carboxyl, lower alkoxycarbonyl, an alkali metal, alkaline earth metal or amine salt of carboxyl, a carbamyl, cyano, an amino and chlorine, R.sub.2 is selected from the group consisting of hydrogen, halogen, cyano, an amino, lower aralkoxycarbonylamino, lower alkyl, carboxyl esterified with lower alkyl, aryl or aralkyl and carbamoyl optionally substituted on the nitrogen atom with lower alkyl or a phenyl and Q is selected from the group consisting of ##STR2## X is selected from the group consisting of hydrogen, hydroxy and lower alkanoyloxy and U is selected from the group consisting of amido forming groups or a group OY, wherein Y is selected from the group consising of hydrogen, salt forming groups, and ester forming groups, or COOY and CH.sub.2 X together form a lactone or lactam, having antibacterial properties, their preparation and novel intermediates thereof.

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Leiden, Netherlands

Peter W Henniger