1. Field of the Invention
The present invention relates to a process for preparing (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 (I) ##STR3## or a pharmacologically acceptable salt thereof.
2. Description of the Prior Art
Since the discovery of an antibiotic substance "thienamycin" from the nature [U.S. Pat. No. 3,950,357; J. Am. Chem. Soc., 100, 313 (1987)], many researches have been carried out to develop carbapenem antibiotics. As a result of the extensive study, there has been developed imipenem (INN) which is a practically available antibacterial agent for clinical use.
Recently, Kumagai et al. proposed (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 of formula (I) above as carbapenem antibiotic. See U.S. Pat. Nos. 4,866,171; 4,925,836; and 4,925,935 (the entire specifications of these patents are incorporated herein by reference). This compound is carba-2-penem-3-carboxylic acid compound in which a .beta.-methyl group is introduced at 1-position and 6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl thio group which is represented by the following ##STR4## is introduced at 2-position of the carbapenem skelton. Owing to the presence of these specific substitutions, the compound of formula (I) has superior antibacterial activity with excellent chemical and physicochemical stabilities in living bodies, and is extremely stable against dehydropeptidase (DHP) known as a kidney enzyme.
The only synthesis for 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-methylcarbapenem-3-carboxylate of formula (I) heretofore known in Kumagai et al. is from an imino intermediate. That is, according to Kumagai et al., the comound of formula (I) can be prepared by reacting a compound represented by formula (II): ##STR5## wherein R.sup.1 is a carboxyl protecting group, and R.sup.a is an acyl group,
with a mercapto reagent represented by formula (VII): ##STR6## wherein R.sup.b is an amino protecting group, to give a compound represented by formula (VIII): ##STR7## wherein R.sup.1 and R.sup.b have the same meanings as above, and subjecting the compound of the formula (VIII) to removal of the protecting groups R.sup.1 and R.sup.b to give the carbapenem compound of the formula (IX) ##STR8## and then, reacting the resulting compound of formula (IX) with formimidic acid ester to give the carbapenem compound of formula (I).
One presumed course of reaction in the formation of the compound of formula (I) by the reaction of the compound of formula (IX) with the formimidic acid ester derivative is that by the reaction of the compound (IX) with the formimidic acid ester derivative, (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(1,2-di-iminomethyl)-4-pyraz olidinyl]thiocarbapenem-3-carboxylic acid of the following formula ##STR9## is formed as an intermediate, and this imino intermediate is transitory compound and undergoes cyclization reaction to form the compound of formula (I).
Finding a method for preparing the 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-methylcarbape nem-3-carboxylate of formula (I) through a method other than from the imino intermediate has been an objective of the research of the present inventors and their assignee since the discovery of the useful therapeutic indications of the 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. Despite the efforts of the researches of the assignee to find a way to make (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethylethyl]-1-methyl-c arbapenem-3-carboxylate without going through the transitory intermediate, efforts heretofore have been unsuccessful. One apparent method for making (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2 -a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapenem- 3-carboxylate is disclosed in Merck European Patent Application 168,707 (1986), that is discussed in detail in Kumagai et al. U.S. Pat. No. 4,866,171 at column 1, lines 22-49. There is a picture representation of the compound 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a]-[1,2,4-triazolium halide which is a key compound for the synthesis in the European application. Nowhere in the European application is there any disclosure of the synthesis of a 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium halide nor is any method for the synthesis of a 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a]-[1,2,4]triazolium halide available within the skill of the art.