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Simple and convenient preparation method of relebactam

A technology of relebactam and compounds, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of low atom economy, cumbersome operation, and unfavorable industrialization

Active Publication Date: 2020-04-28
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] EDC hydrochloride and 1-hydroxybenzotriazole are used as condensation agent in above-mentioned reaction route 3, and atom economy is low; Used trimethyl sulfoxide iodide and metal iridium catalyst are expensive, greatly increased product cost
This route is cumbersome to operate and high in cost, which is not conducive to the realization of industrialization

Method used

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  • Simple and convenient preparation method of relebactam
  • Simple and convenient preparation method of relebactam
  • Simple and convenient preparation method of relebactam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: the preparation of L-diethyl glutamate hydrochloride (preparation of formula II compound intermediate)

[0090] Add 2.4 L of absolute ethanol to a 5 L reaction flask equipped with a spherical condenser, drying tube, tail gas absorption device and constant pressure dropping funnel, and add 294.0 g (2.0 moles) of L-glutamic acid under stirring. 593.5 grams (2.0 moles) of triphosgene were dissolved in 1.5 L of dichloromethane. At 0°C, add triphosgene in dichloromethane dropwise into the reaction system containing L-glutamic acid, keeping the temperature below 25°C. After the dropwise addition, the temperature was raised to 50° C. and the reaction was refluxed until the solid was completely dissolved. The reaction was stopped, the temperature of the reaction system was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain a transparent light yellow oil. Add 800ml methyl tert-butyl ether to make a slurry. Suction filtrat...

Embodiment 2

[0091] Embodiment 2: the preparation of N-methoxycarbonylmethyl-N-benzyl-L-glutamic acid diethyl ester (preparation of formula II compound intermediate)

[0092] Add 4.0 L of acetonitrile to a 5 L reaction flask equipped with a spherical condenser, a drying tube, a thermometer and a constant pressure dropping funnel. Add 480.0 g (2.0 moles) of L-glutamic acid diethyl ester hydrochloride prepared according to the method in Example 1 to the system, stir and dissolve at room temperature. Add 829.2 g (6.0 moles) of anhydrous potassium carbonate to the system and stir at room temperature. 219.85 g (2.02 mol) of methyl chloroacetate and 33.85 g (0.2 mol) of potassium iodide were successively added to the system. The system was heated to 80°C for reaction. After the reaction was detected by GC, 258.56 grams (2.04 moles) of benzyl chloride were added to the system, and the temperature was kept at 80°C. After the reaction was detected by GC, the reaction was stopped and cooled to room...

Embodiment 3

[0093] Embodiment 3: Preparation of (S)-N-benzyl-5-oxo-2-piperidinecarboxylic acid (II)

[0094] Under the protection of nitrogen, add 500 mL of pretreated toluene and 32.16 g (0.47 moles) of sodium ethoxide solid to a 1 L reaction flask equipped with a mechanical stirrer, a condenser tube, a drying tube, a thermometer and a constant pressure dropping funnel, stir, and heat for 110 °C to reflux. 132.85 g (0.36 mol) of N-methoxycarbonylmethyl-N-benzyl-L-glutamic acid diethyl ester prepared in Example 2 was dissolved in 100 mL of toluene and transferred to a constant pressure dropping funnel. Under the condition of reflux, start to drop the toluene solution of the raw material, and continue the reflux reaction after the dropwise addition is completed. After the completion of the reaction detected by GC, the reaction was stopped, and the temperature was lowered to room temperature. The reaction system was slowly added dropwise to 400 mL of saturated ammonium chloride solution, a...

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Abstract

The invention discloses a simple and convenient preparation method of relebactam. According to the method, a key intermediate (2S,5R)-5-benzyloxyamino piperidine-2-formic acid is prepared by using (S)-N-protective group-5-oxo-2-piperidinecarboxylic acid or a salt form thereof as an initial raw material; the (2S,5R)-5-benzyloxyamino piperidine-2-formic acid and phosgene, solid phosgene or diphosgene are subjected to acylating chlorination, cyclic ureation, and reaction with 1-protective group-4-aminopiperidine to obtain (2S,5R)-6-benzyloxy-N-(1-protective group-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-formamide; and debenzylation, sulfonyl oxidation, ammonium salt formation and deprotection are performed to prepare relebactam. According to the invention, the raw materials are cheap, easyto obtain and low in cost, the technological process is safe, simple and convenient to operate, small in wastewater and waste salt yield and environmentally friendly, the reaction atom economy is high, the reaction selectivity of each step is high, the purity and the yield are high, and industrial production is facilitated.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of relebactam, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Relebactam (Relebactam, I) is a novel diazabicyclooctone compound non-β-lactam β-lactamase inhibitor developed by Merck, and its structure is similar to that of avibactam. The pivotal phase III study of relebactam and imipenem-cilastatin combination therapy has achieved positive trial data. Compared with the imipenem-cilastatin regimen, relebactam and imipenem The combination of nan-cilastatin is effective in treating imipridine-sensitive bacterial infections with less nephrotoxicity. Therefore, it is of great significance to study the synthesis and function of relebactam. The CAS number of relebactam (I) is 1174018-99-5, and its chemical name is [(1R,2S,5R)-2-(N-(4-piperidinyl)aminocarbonyl)-7-oxo- 1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid, the structural formula is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08Y02P20/55
Inventor 王保林戚聿新徐欣腾玉奇李新发
Owner XINFA PHARMA
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