Lederle (Japan), Ltd.

Yunosuke Nagase

Yoshimitsu Nagao

Hiroshi Matsunaga

Yoshisuke Machida

Muneo Hikida

Toshio Kumagai

Satoshi Tamai

Takao Abe

Toshi Kumagai

Novel and improved simple process for preparing carbapenem compound, (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbap enem-3-carboxylate represented by the following formula: ##STR1## This compound may be prepared by using a mercapto reagent, 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium derivative of the following formula: ##STR2## wherein X.sup..crclbar. is an anion charge.

Process for preparing (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo

Novel and improved simple process for preparing carbapenem compound, (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbap enem-3-carboxylate represented by the following formula: ##STR1## This compound may be prepared by using a mercapto reagent, 6,7-dihydro-6-mercapto-5H-pyrazolo-[1,2-a][1,2,4]triazolium derivative of the following formula: ##STR2## wherein X.sup..crclbar. is an anion charge.

(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(1,2-diiminomethyl)-4-pyrazol idinyl-thio-carbapenem-3-carboxylic acid is provided as an intermediate, which is converted into (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl]thio-6 -[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate. This compound is an antibacterial agent, which also may be in the form of the corresponding acid or pharmaceutically acceptable salt, in which case there is included an anionic group balancing the traizolinium positive charge. As such as anionic group may be mentioned, for example, the chloride, acatate or carbonate. As the salt may be mentioned the alkali metal salts, for example, sodium. Also provided is a method for the preparation of (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate, which comprises contacting (1R,5S,6S)-2-[4-pyrazolidinyl]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapene m-3-carboxylic acid with ethyl formimidate hydrohalide under conditions to introduce iminomethyl substitution at each of the free hydrogen positions of the nitrogen atoms of the pyrazolidinyl nucleus and recovering the in situ formed (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate.

(1R,5S,6S)-2-[(6,7-dih

Methods and compositions are provided for controlling or preventing a bacterial infection which are based upon (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate or a pharmaceutically acceptable salt thereof.

Antibacterially effective methods and compositions based upon

(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(1,2-diiminomethyl)-4-pyrazol idinyl]-thio-carbapenem-3-carboxylic acid is provided as an intermediate, which is converted into (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate. This compound is an antibacterial agent, which also may be in the form of the corresponding acid or pharmaceutically acceptable salt, in which case there is included an anionic group balancing the traizolinium positive charge. As such an anionic group may be mentioned, for example, the chloride, acatate or carbonate. As the salt may be mentioned the alkali metal salts, for example, sodium. Also provided is a method for the preparation of (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate, which comprises contacting (1R,5S,6S)-2-[4-pyrazolidinyl]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapene m-3-carboxylic acid with ethyl formimidate hydrohalide under conditions to introduce iminomethyl substitution at each of the free hydrogen positions of the nitrogen atoms of the pyrazolidinyl nucleus and recovering the in situ formed (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2,-a][1,2,4]triazolium-6-yl)]thio -6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate.

Methods for the manufacture of

(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(1,2-diiminomethyl)-4-pyrazol idinyl]-thio-carbapenum-3-carboxylic acid is provided as an intermediate, which is converted into (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenum-3-carboxylate. This compound is an antibacterial agent, which also may be in the form of the corresponding acid or pharmaceutically acceptable salt, in which case there is included an anionic group balancing the traizolinium positive charge. As such an anionic group may be mentioned, for example, the chloride, acatate or carbonate. As the salt may be mentioned the alkali metal salts, for example, sodium. Also provided in a method for the preparation of (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate, which comprises contacting (1R,5S,6S)-2-[4-pyrazolidinyl]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapene m-3-carboxylic acid with ethyl formimidate hydrohalide under conditions to introduce iminomethyl substitution at each of the free hydrogen positions of the nitrogen atoms of the pyrazolidinyl nucleus and recovering the in situ formed (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[R-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate.

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Shiki, Japan

Yunosuke Nagase