Processes for preparing a diazabicyclooctane compound
Inventors
Abe, Takao • Furuuchi, Takeshi • Sakamaki, Yoshiaki
Assignees
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Publication Number
US-12103928-B2
Publication Date
2024-10-01
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 relates to 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 uses protected intermediates represented by formulae (IV-a2), (IV-a3) and (IV-a4), and coupling with tert-butyl 2-(aminooxy)ethylcarbamate or benzyl 2-(aminooxy)ethylcarbamate in the presence of an active ester, an active amide or a dehydration condensing agent to prepare compounds represented by formulae (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059).
The process further includes sequential deprotection of trifluoroacetyl, tert-butoxycarbonyl, or 2-trimethylsilylethoxycarbonyl groups by base treatment, acid treatment, or fluoride, followed by silylating and an intramolecular urea formation reaction to prepare compounds represented by formulae (IIa-Boc-059) or (IIa-Cbz-059). The route then removes the benzyl of the benzyloxy at the 6-position under a hydrogen atmosphere in the presence of a hydrogenolysis catalyst, and in some embodiments in the presence of palladium-carbon, with simultaneous tert-butoxycarbonylation in the presence of di-tert-butoxydicarbonate to prepare formula (IIb-Boc-059).
The hydroxyl group at the 6-position of formula (IIb-Boc-059) is sulfated to prepare formula (III-Boc-059), wherein M represents H, pyridinium, sodium or tetrabutylammonium. Sulfation is carried out using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine, and the tert-butoxycarbonyl group is finally deprotected by acid treatment, including hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid or tetrafluoroboric acid.
Claims Coverage
The document includes two independent process claims. Across the independent claims, the inventive features cover protected intermediate coupling, sequential deprotection, silylating and intramolecular urea formation, 6-position benzyl removal with concurrent tert-butoxycarbonylation, 6-position sulfation with defined counterion M, and final tert-butoxycarbonyl deprotection.
Protected intermediate coupling with aminooxy carbamate
Coupling a compound represented by formula (IV-a2) or (IV-a4) with tert-butyl 2-(aminooxy)ethylcarbamate, or coupling a compound represented by formula (IV-a3) with benzyl 2-(aminooxy)ethylcarbamate, in the presence of an active ester, an active amide or a dehydration condensing agent to prepare formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059).
Sequential deprotection and intramolecular urea formation
Deprotecting trifluoroacetyl by base, removing tert-butoxycarbonyl by acid treatment, or removing 2-trimethylsilylethoxycarbonyl by fluoride, then after silylating carrying out an intramolecular urea formation reaction to prepare formula (IIa-Boc-059) or (IIa-Cbz-059).
6-position benzyl removal with simultaneous tert-butoxycarbonylation
Removing the benzyl of the benzyloxy at the 6-position under a hydrogen atmosphere in the presence of a hydrogenolysis catalyst, including palladium-carbon in one claim, and simultaneously carrying out tert-butoxycarbonylation in the presence of di-tert-butoxydicarbonate to prepare formula (IIb-Boc-059).
6-position sulfation to the sulfooxy product
Sulfating the hydroxyl group at the 6-position of formula (IIb-Boc-059) to prepare formula (III-Boc-059), wherein M represents H, pyridinium, sodium or tetrabutylammonium; one claim specifies a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine.
Final tert-butoxycarbonyl deprotection
Deprotecting the tert-butoxycarbonyl group by acid treatment; one claim specifies hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid or tetrafluoroboric acid.
Across the independent claims, the coverage is a multi-step process to the sulfooxy diazabicyclooctane carboxamide target, combining protected intermediate coupling, staged deprotection, intramolecular urea formation, 6-position benzyl removal with concurrent tert-butoxycarbonylation, 6-position sulfation, and final Boc deprotection.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Administration of a compound of formula (I/II/III) (and salts/hydrates/solvates) in combination with β-lactam antibiotics, including penicillins, cephems, and carbapenems, in the context of antimicrobial resistance classes including class A/C β-lactamases, ESBL, and KPC2.
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