Processes for preparing a diazabicyclooctane compound
Inventors
Abe, Takao • Furuuchi, Takeshi • Sakamaki, Yoshiaki • Inamura, Seiichi • Morinaka, Akihiro
Assignees
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Publication Number
US-11117896-B2
Publication Date
2021-09-14
Expiration Date
Abstract
A process for preparing a diazabicyclooctane compound represented by the following formula (I): wherein A represents RcO—; B represents NH or NC1-6 alkyl; C represents a benzyl group; Rc represents a C1-6 alkyl group; A is substituted with one substituent Fn1, wherein Fn1 represents an azetidine group; the process including: (a) silylating the compound represented by the following formula (IV-c): wherein in the formula (IV-c), OBn represents benzyloxy, and (b) carrying out an intramolecular urea formation reaction.
Core Innovation
The invention provides a process for preparing (2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide represented by formula (III-059). The process removes the benzyl of the benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) under a hydrogen atmosphere in the presence of palladium-carbon to obtain formula (IIb-Boc-059).
The process sulfates the hydroxyl group at the 6-position of formula (IIb-Boc-059) using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine to prepare formula (III-Boc-059). In formula (III-Boc-059), Boc represents tert-butoxycarbonyl and M represents H, pyridinium, sodium or tetrabutylammonium.
Finally, the process deprotects the tert-butoxycarbonyl group in formula (III-Boc-059) with an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboric acid to obtain the target compound. The sequence combines hydrogenolytic removal of the 6-position benzyloxy benzyl group, sulfation of the resulting 6-position hydroxyl, and acid deprotection of Boc.
Claims Coverage
The claim coverage centers on one independent process claim, with dependent refinements that specify the sulfation base and the allowed values of M. Three main inventive features are present: hydrogenolytic benzyl removal, sulfation with a sulfur trioxide-pyridine complex, and Boc deprotection with an enumerated acid set.
Hydrogenolytic removal of benzyloxy at the 6-position
Removing the benzyl of the benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) under a hydrogen atmosphere in the presence of palladium-carbon to prepare formula (IIb-Boc-059).
Sulfation of the 6-position hydroxyl with sulfur trioxide-pyridine complex
Sulfating the hydroxyl group at the 6-position of formula (IIb-Boc-059) with a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine to prepare formula (III-Boc-059), wherein M represents H, pyridinium, sodium or tetrabutylammonium.
Acid deprotection of tert-butoxycarbonyl
Deprotecting the tert-butoxycarbonyl group with an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboric acid.
Specified sulfation base
The sulfation step is performed in the presence of 2-picoline or 2,6-lutidine.
Defined counterion parameter M
In formula (III-Boc-059), M is selected as H, pyridinium, sodium or tetrabutylammonium.
The inventive coverage is a sequential process of hydrogenolytic benzyl removal at the 6-position, sulfation of the 6-position hydroxyl with a sulfur trioxide-pyridine complex, and Boc deprotection with an enumerated acid set. Dependent claims further narrow the sulfation base and the permitted values of M.
Stated Advantages
Not explicitly described in patent.
Documented Applications
β-lactamase inhibitory use (class A/C/D β-lactamases including KPC-2, CTX-M-15, ESBL, AmpC, and IMP) is indicated in the provided description content.
Biological assay examples for preparing β-lactamases (AmpC, TEM-1, KPC-2, OXA-2) and measuring β-lactamase inhibitory activity using nitrocefin with IC50 classification.
Evaluation of synergistic potentiation with β-lactam antibiotics by MIC determinations across bacterial strains/enzymes, with synergistic effect classification using synergy tables (Tables 5-9).
Treatment of bacterial infection using β-lactamase inhibitors, including combination with β-lactam antibiotics.
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