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PROCESS FOR THE PREPARATION OF BIAPENEM

IP.com Disclosure Number: IPCOM000239695D
Publication Date: 2014-Nov-25
Document File: 3 page(s) / 66K

Publishing Venue

The IP.com Prior Art Database

Abstract

Disclosed herein is a process for the preparation of biapenem.

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PROCESS FOR THE PREPARATION OF BIAPENEM 

Abstract

Disclosed herein is a process for the preparation of biapenem.

Biapenem is chemically known as 6-[[2(4R,5S,6S)-carboxy-6-[(1R)-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4] triazol-4-ium inner salt and is represented by Formula I.  It is indicated for the treatment of bacterial infection and sepsis.

Formula I

Reported herein is a process for the preparation of biapenem, wherein the process comprises treating p-nitrobenzyl (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo-[1,2-a][1,2,4]
triazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride (hereinafter, “PNB-biapenem chloride”) (formula IV) with hydrogen gas in the presence of an N-methylmorpholine-acetic acid buffer solution.

Also reported herein is a process for the preparation of “PNB-biapenem chloride of formula IV, wherein the process comprises a step of reacting p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (Formula II) with 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (Formula III) to provide a wet cake or solution ofPNB-biapenem chloride, which is further converted into biapenem.

 

Formula IV

            

Formula II                                         Formula III

The starting materials, p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (Formula II) and 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (formula III), can be obtained using known methods, similar or identical to the processes described in U.S. Patent Nos. 4,866,171 and 5,241,073 respectively.

EXAMPLES

Example 1: Preparation of p-nitrobenzyl (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo-[1,2-a][1,2,4]triazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride (Formula IV, PNB-Biapenem chloride) from p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (Formula II, β-methylenol phosphate)

p-Nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (Formula II, 50 g) was added to dimethylformamide (100 mL) and stirred for 10 minutes to obtain a clear solution.  The solution was cooled to about...