- Method for synthesize Avibactam key intermediate (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester and recrystallization process of Avibactam key intermediate
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The invention discloses a one-step method for synthesize Avibactam key intermediate (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester and a recrystallization process of the Avibactam key intermediate. L-pyroglutamic acid is taken as a raw material to synthesize faint yellow (S)-N-tert-butyloxycarboryl pyroglutamic acid-2-benzyl ester by one step, and recrystallizing is carried out to obtain white (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester, wherein the purity is 99% or above, and the yield is 95% or above. The method is mild in reaction condition and simple in operation and is green and efficient, the product is stable, a next-step reaction is facilitated, and industrial production is facilitated.
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Paragraph 0011-0014
(2019/10/04)
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- RETRACTED ARTICLE: A New Synthetic Route to Avibactam: Lipase Catalytic Resolution and the Simultaneous Debenzylation/Sulfation
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An efficient synthesis of avibactam starting from commercially available ethyl-5-hydroxypicolinate was completed in 10 steps and 23.9% overall yield. The synthesis features a novel lipase-catalyzed resolution, in the preparation of (2S,5S)-5-hydroxypiperidine-2-carboxylate acid, which is a valuable precusor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. An optimized one-pot debenzylation/sulfation reaction, followed by cation exchange, gave the avibactam sodium salt on a 400.0 g scale.
- Wang, Tao,Du, Liang-Dong,Wan, Ding-Jian,Li, Xiang,Chen, Xin-Zhi,Wu, Guo-Feng
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p. 267 - 272
(2018/03/22)
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- AVIBACTAM FREE ACID
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The present invention relates to avibactam free acid, a method for preparing avibactam free acid and a method for preparing avibactam sodium by further reacting avibactam free acid. The invention further refers to a pharmaceutical composition comprising avibactam free acid, one or more alkaline sodium salt(s) and one or more beta-lactam antibiotic(s). The pharmaceutical composition of the present invention can be used as medicament, in particular for treatment and/or prevention of bacterial infections.
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Page/Page column 25; 26; 27; 28
(2018/03/25)
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- Synthetic method for avibactam sodium salt
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The invention discloses a synthetic method for avibactam sodium salt. The method comprises the following steps: taking (2S, 5R)-5-[(benzyl oxyl) amino] piperidine-2-formamide as a starting material; constructing a urea ring by carbonyl diimidazole under the effect of dimethyldichlorosilance to obtain (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide; then carrying out hydrogenation to remove benzyl; carrying out sulfonation reaction on the compound and a sulfonated reagent; synthesizing into a quaternary ammonium salt intermediate by using quaternary ammonium salt; and finally carrying out ion exchange to obtain the avibactam sodium salt. The improved process is low in cost, simple and convenient to operate, good in product quality and suitable for industrial production. In a process of synthesizing the intermediate (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide, dimethyldichlorosilance which is low in price is used, and therefore, the production cost is greatly reduced.
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Paragraph 0036; 0040
(2017/12/29)
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- Method for synthesizing beta-lactamase inhibitor Avibactam
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The invention relates to a method for synthesizing a beta-lactamase inhibitor Avibactam and belongs to the technical field of preparation of beta-lactamase inhibitors. The method disclosed by the invention comprises the following steps: (1) taking a compound 2 as a raw material, and reacting with RNH2 so as to produce a compound 3; (2) enabling the compound 3 and a biocatalyst to produce a compound 4 in an organic solvent in the presence of glucose or sucrose; (3) enabling the compound 4 to react with trifluoroacetic anhydride so as to obtain a compound 5; (4) enabling the compound 5 to react with RONH2 so as to produce a compound 6; (5) hydrolyzing the compound 6 under alkaline conditions so as to produce a compound 7; (6) enabling the compound 7 to react with triphosgene so as to produce a compound 8; (7) enabling the compound 8 to react with ammonium formate in the presence of a catalyst so as to produce a compound 9 in the organic solvent, wherein the catalyst is a Pd/C system; and (8) enabling the compound 9 to react with a sulfonating agent, thereby obtaining the product 1. The method disclosed by the invention is stable in process, high in yield, simple and safe in operation and low in production cost.
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- Development of a Manufacturing Route to Avibactam, a β-Lactamase Inhibitor
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Process development work to provide an efficient, robust, and cost-effective manufacturing route to avibactam, a β-lactamase inhibitor is presented herewith. Aspects of this optimization work include the counterintuitive introduction of a protecting group to effect a difficult urea formation and the use of controlled feed hydrogenation conditions to facilitate an elegant one pot debenzylation and sulfation reaction. Overall, the commercial process delivers avibactam in much improved yield with significant reduction in the environmental footprint.
- Ball, Matthew,Boyd, Alistair,Ensor, Gareth J.,Evans, Matthew,Golden, Michael,Linke, Simon R.,Milne, David,Murphy, Rebecca,Telford, Alex,Kalyan, Yuriy,Lawton, Graham R.,Racha, Saibaba,Ronsheim, Melanie,Zhou, Shao Hong
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p. 1799 - 1805
(2016/10/31)
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- PROCESSES FOR PREPARING HETEROCYCLIC COMPOUNDS INCLUDING TRANS-7-OXO-6-(SULPHOOXY)-1,6-DIAZABICYCLO[3,2,1]OCTANE-2-CARBOXAMIDE AND SALTS THEREOF
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The present invention relates to compounds and processes for preparing compounds of Formula (I), including compounds such as trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof (e.g., NXL-104).
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- Heterocyclic compounds as inhibitors of beta-lactamases
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This invention discloses and claims methods for inhibiting bacterial β-lactamases and treating bacterial infections by inhibiting bacterial β-lactamases in man or an animal comprising administering a therapeutically effective amount to said man or said animal of a compound, or pharmaceutically acceptable salt thereof, of formula (I) either alone or in combination with a β-lactamine antibiotic wherein said combination can be administered separately, together or spaced out over time. Pharmaceutical compositions comprising a compound of formula (I), or a combination of a compound of formula (I) and a therapeutically effective amount of a β-lactamine antibiotic, and a pharmaceutically acceptable carrier are also disclosed and claimed. 1
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