Takeda Chemical Industries, Inc.

Yukio Ishibashi

Kenzo Naito

Haruo Shinbo

Shinichi Imamura

Tetsuo Miwa

Tetsuya Tsukamoto

Yoshiharu Maeda

Masahiro Mizuno

Toshihiko Fujitani

Carbapenem compound, their production and use

Crystalline acetoxymethyl and pivaloyloxymethyl esters of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0] hept-2-ene-carboxylic acid can be obtained by adding a poor solvent to a solution of acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0] hept-2-ene-carboxylic acid in a good solvent. The crystalline penem compounds obtained show improved stability and are useful antibacterial agents.

Crystalline esters of (+)-(5R,

Disclosed are an advantageous method of industrial production of tert-butyl 3-oxobutylate, which is a useful intermediate for synthesis, characterized by reacting tert-butyl alcohol with diketene in the presence of 4-(tertiary amino) pyridine, and an industrially advantageous method of producing cephalosporin compounds or pharmaceutically acceptable salts thereof, using tert-butyl 3-oxobutylate as an intermediate.

Method for production of T-butyl 3-oxobutyrates and their use

A method for producing 3-(3-oxobutyryloxymethyl)-3-cepham-4-carboxylic acids which are antibiotics or intermediates for the synthesis of antibiotics, at a low temperature in a very short period of time and in good yield, characterized by reacting a 3-hydroxylmethyl-3-cephem-4-carboxylic acid with diketene in the presence of a 4-(tertiary-amino)pyridine and if necessary, when a 7-acylamino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is obtained, subjecting it to deacylation at the 7-position thereof.

Method for producing cephem compounds

Method for production of t-butyl 3-oxobutyrates and their use

A method for producing a compound of the formula; ##STR1## wherein R stands for a hydrogen atom, an acyl group or a protective group other than acyl groups, Q stands for a hydrogen atom or an ester residue, Y stands for the residue of a nucleophilic compound and the dotted line shows the double bond at 2- or 3- position of the cephem ring or a salt thereof, characterized by allowing a compound of the formula; ##STR2## [R, Q and the dotted line are of the same meaning as above] or a salt thereof to react with a nucleophilic compound or a salt thereof and a compound of the formula; ##STR3## wherein R.sup.1, R.sup.2, R.sup.3 independently stand for a hydrocarbon group having not more than 8 carbon atoms, or R.sup.1 and R.sup.2, R.sup.1 and R.sup.3 or R.sup.2 and R.sup.3 may be combined to form polymethylene group, according to which the end product [I] of high quality can be provided in a high yield by one reaction step by using the compound [III] of relatively low cost, thus the method of this invention is advantageous for mass-producing the compound [I] on an industrial scale from the compound [II] and a nucleophilic compound.

Method for production of cephalosporin compounds

An advantageous method of producing in large amounts on a commercial scale 2-substituted oxyimino-3-oxobutyric acids, which are useful as intermediates in the synthesis of e.g. aminothiazole cephalosporins, is characterized by reacting a tert-butyl 2-substituted oxyimino-3-oxobutyrate with a hydrogen halide in an anhydrous organic solvent.

Method for production of 2-oxyimino-3-oxobutyric acids

A method of producing 3-alkanoyloxymethyl-3-cephem-4-carboxylic acids, which are useful as antibiotics or as intermediates in the synthesis of antibiotics, by reacting a 3-hydroxymethyl-3-cephem-4-carboxylic acid with a saturated fatty acid anhydride in an aqueous medium in the presence of an acid-acceptor base and a 4-(tertiary amino)pyridine.

Method of producing cephem compounds

A method of producing a 4-halo-2-(substituted or unsubstituted)hydroxyimino-3-oxobutyric acid ester or amide, which is a synthetic intermediate of value for the production of cephalosporins containing an aminothiazole group, characterized by reacting a 2-(substituted or unsubstituted)-hydroxyimino-3-oxobutyric acid or an ester or amide thereof with a silylating agent and reacting the resulting novel 2-(substituted)hydroxyimino-3-silyloxy-3-butenoic acid ester or amide with a halogenating agent.

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Osaka, Japan

Yukio Ishibashi