Processes for producing diazabicyclooctane compounds
Inventors
Abe, Takao • Furuuchi, Takeshi • Sakamaki, Yoshiaki • MITSUHASHI, Nakako • SAITO, Yumiko
Assignees
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Publication Number
US-10131665-B2
Publication Date
2018-11-20
Expiration Date
Abstract
A crystalline form of a diazabicyclooctane derivative represented by the following Formula (VII), and processes for producing the same:
Core Innovation
The patent relates to processes for producing compounds represented by Formula (IV), Formula (IV-1), Formula (VI), Formula (VI-1), Formula (VII), and Formula (VII-1). The processes include reacting a compound represented by Formula (III) with R3ONH2 or tert-butyl 2-(aminooxy)ethylcarbamate in the presence of a base, followed by treating the compound with a palladium carbon catalyst under a hydrogen atmosphere, performing sulfation using a sulfur trioxide-trimethylamine complex in the presence of a catalytic amount of base in a hydrous solvent, and treating with tetrabutylammonium hydrogensulfate.
The invention also includes removing a tert-butoxycarbonyl group or other protecting group with an acid, precipitating a crude product by adding a poor solvent, and obtaining a crude compound represented by Formula (VII-CR) or Formula (VII-1-CR). The final compound is produced by alternately adding the crude compound and an ice-cold buffer, including an ice-cold phosphate buffer in the Formula (VII-1) process, to obtain a solution having a pH of 4 to 5.5, with optional desalting using a synthetic adsorbent to produce Formula (VII) or Formula (VII-1).
The compounds are described with benzyloxy (OBn) and defined substitution variables including R1, R3, R4, R5, and R6, with R3 being a C1-6 alkyl or a heterocyclyl optionally substituted with 1 to 5 R4 groups and with ring-closure relationships among R3, R5, and R6. The patent also describes crystal polymorph behavior for Formula (VII) and analytical characterization such as DSC and powder X-ray diffraction.
Claims Coverage
The independent claims cover connected process steps for forming aminooxy-linked intermediates from Formula (III), hydrogenating with a palladium carbon catalyst under hydrogen, sulfating with a sulfur trioxide-trimethylamine complex in a hydrous solvent with catalytic base, converting with tetrabutylammonium hydrogensulfate, and obtaining final products by alternately adding crude material with an ice-cold buffer to achieve pH 4 to 5.5 with optional desalting using a synthetic adsorbent. The claims also define alternative branches to Formula (IV-1), Formula (VI-1), Formula (VII), and Formula (VII-1) and include enumerated R1 and R3/R4/R5/R6 constraints.
R3ONH2 coupling to form Formula (IV) from Formula (III)
Reacting a compound represented by Formula (III) with a compound R3ONH2 to obtain a compound represented by Formula (IV), with OBn defined as benzyloxy and with R1 and R3 defined by the specified structural constraints.
Hydrogenation with palladium carbon catalyst under hydrogen
Treating a compound of Formula (IV) with a palladium carbon catalyst under a hydrogen atmosphere, simultaneously or consecutively subjecting the resultant compound to sulfation using a sulfur trioxide-trimethylamine complex in a hydrous solvent with a catalytic amount of base.
Tetrabutylammonium hydrogensulfate conversion to Formula (VI)
Treating the resultant compound after sulfation with tetrabutylammonium hydrogensulfate to obtain a compound represented by Formula (VI).
Alternately adding crude Formula (VII-CR) and ice-cold buffer to achieve pH 4 to 5.5
Alternately adding a crude compound represented by Formula (VII-CR) and an ice-cold buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce Formula (VII).
Aminooxy-carbamate formation from Formula (III) with tert-butyl 2-(aminooxy)ethylcarbamate
Reacting a compound represented by Formula (III) with tert-butyl 2-(aminooxy)ethylcarbamate in the presence of a base to obtain a compound represented by Formula (IV-1).
Integrated route to Formula (VII-1) including phosphate buffer pH adjustment
After obtaining a crude compound represented by Formula (VII-1-CR), alternately adding the crude compound and an ice-cold phosphate buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce Formula (VII-1).
Overall claim coverage centers on processes that form intermediates from Formula (III), hydrogenate with a palladium carbon catalyst under hydrogen, sulfate with a sulfur trioxide-trimethylamine complex in a hydrous solvent with catalytic base, convert with tetrabutylammonium hydrogensulfate, and obtain Formula (VII) or Formula (VII-1) by alternately adding a crude compound with an ice-cold buffer to reach pH 4 to 5.5, optionally followed by desalting with a synthetic adsorbent.
Stated Advantages
Controlled decomposition.
High yield/purity.
Stable polymorphs over storage.
Reduced related substances.
Obtain a stable crystalline API instead of an amorphous or lyophilized API form.
Reduce yield loss and instability associated with isolating and pH-adjusting crude acid-containing intermediates and with concentration/solvent evaporation.
Reduce contamination and byproduct formation associated with overreaction during sulfation.
Documented Applications
Pharmaceutical compositions comprising a β-lactam antibiotic and a β-lactamase inhibitor, where the compounds of the invention act as a β-lactamase inhibitor.
Production of diazabicyclooctane derivatives represented by Formula (VII) and Formula (VII-1) as stable crystalline APIs rather than amorphous or lyophilized forms.
Combination pharmaceutical use with β-lactam antimicrobial agents/β-lactam antibiotics including penicillins, cephems, carbapenems, and other β-lactams.
Pharmaceutical compositions for oral administration and multiple parenteral routes, including powdered IV formulations.
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