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Simple and convenient preparation method of avibatan intermediate

An intermediate and simple technology, which is applied in the field of simple preparation of avibactam intermediates, can solve the problems of unfavorable environmental protection and industrial production, low activity of octane-2-carboxylate, cumbersome operation process, etc., and achieve the reaction The effect of classic type, high reaction atom economy and simple process

Active Publication Date: 2019-04-26
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate obtained after cyclic ureaification has low activity and cannot be used directly Ammonia methanol solution amidation requires hydrolysis of ester group to carboxyl group and reactivation of carboxyl group to acid anhydride, after which effective amidation can be achieved. The operation process is cumbersome and the atom economy is poor, which is not conducive to environmental protection and industrial production.

Method used

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  • Simple and convenient preparation method of avibatan intermediate
  • Simple and convenient preparation method of avibatan intermediate
  • Simple and convenient preparation method of avibatan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: Preparation of 5R-benzyloxyaminopiperidine-2S-formic acid (Ⅳ)

[0055] Add 150 grams of dichloromethane in the 500 milliliter four-neck flasks that are equipped with stirring, thermometer, 150 grams of mass concentration are 10% sodium hydroxide aqueous solution, 43.0 grams (0.1 mole) 5R-benzyloxyaminopiperidine-2S-formic acid Benzyl ester oxalate (Ⅲ), stirred and reacted at 20-30°C for 3 hours. Acidify the system with 30% aqueous hydrochloric acid to pH 2.5-3.0, and stir at room temperature for 1-2 hours; separate layers, and extract the aqueous layer three times with dichloromethane, 50 grams each time. Combine the organic phases to obtain an organic phase mixed solution; wash once with 20 grams of saturated sodium chloride solution, and recover the solvent from the gained organic phase to obtain 24.5 grams of 5R-benzyloxyaminopiperidine-2S-formic acid, with a liquid phase purity of 99.9%. The yield was 98.0%.

[0056] Gained product NMR data are as fo...

Embodiment 2

[0057] Embodiment 2: Preparation of 5R-benzyloxyaminopiperidine-2S-formic acid (Ⅳ)

[0058] Add 150 grams of 1,2-dichloroethane, 80 grams of 10% lithium hydroxide aqueous solution, 43.0 grams (0.1 mole) of 5R-benzyloxyaminopiperene in a 500 milliliter four-necked flask equipped with a stirring and thermometer. Benzyl pyridine-2S-carboxylate oxalate (Ⅲ), stirred at 20-25°C for 4 hours. Acidify the system with 30% aqueous hydrochloric acid to pH 2.5-3.0, stir at room temperature for 1-2 hours; separate layers, and extract the aqueous layer three times with 1,2-dichloroethane, 50 grams each time. Combine the organic phases to obtain an organic phase mixture; wash once with 20 grams of saturated sodium chloride solution, and recover the solvent from the resulting organic phase to obtain 24.6 grams of 5R-benzyloxyaminopiperidine-2S-formic acid, with a liquid phase purity of 99.9% , The yield was 98.5%.

Embodiment 3

[0059] Embodiment 3: Preparation of 5R-benzyloxyaminopiperidine-2S-formic acid (Ⅳ)

[0060] Add 150 grams of dichloromethane in the 500 milliliter four-necked flask that is equipped with stirring, thermometer, 120 grams of mass concentration are 10% sodium hydroxide aqueous solution, 37.0 grams (0.1 mole) 5R-benzyloxyaminopiperidine-2S-formic acid Ethyl oxalate (Ⅲ), stirred and reacted at 20-25°C for 4 hours. Acidify the system with 30% aqueous hydrochloric acid to pH 2.5-3.0, and stir at room temperature for 1-2 hours; separate layers, and extract the aqueous layer three times with dichloromethane, 50 grams each time. Combine the organic phases to obtain an organic phase mixture; wash once with 20 grams of saturated sodium chloride solution, and recover the solvent from the resulting organic phase to obtain 24.1 grams of 5R-benzyloxyaminopiperidine-2S-formic acid, with a liquid phase purity of 99.9% , and the yield was 96.4%.

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Abstract

The invention discloses a simple and convenient preparation method of an avibatan intermediate. The simple and convenient preparation method of the avibatan intermediate includes the steps that a typeIII compound is taken as a raw material, hydrolyzed under the alkaline condition, and then acidized to prepared a type IV compound, the obtained type IV compound and striphosgene or diphosgene are subjected to cyclic urea and acylating chlorination reactions simultaneously in the presence of an organic base and a catalyst, a type V compound is obtained, and a final product (II) is then obtained after amidation. According to the simple and convenient preparation method of the avibatan intermediate, the cyclic urea, acylating chlorination and amidation reactions are completed by a 'one pot method', and intermediate products do not need to be separated and purified; and raw materials are cheap and easy to get, the process is simple, operability is high, no special protective agent and carbonylation reagent are required, the reaction atom economical efficiency is high, the cost is low, the production process is environment friendly, the purity of the obtained product (II) is high, the yield is high, and cost reduction and environment-friendly production of an avibatan (I) is facilitated.

Description

technical field [0001] The present invention relates to a convenient preparation method of an avibactam intermediate, in particular to a (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1 The invention discloses a simple preparation method of octane-2-carboxamide, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Avibactam belongs to the non-β-lactam inhibitors of diazabicyclooctone compounds. Avibactam can inhibit type A (including ESBL and KPC) and type C β-lactamases. Avibactam When used in combination with various cephalosporins and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases, Escherichia coli containing excessive AmpC enzymes And the activity of Escherichia coli containing both AmpC and extended-spectrum β-lactamases is remarkable. The CAS number of Avibactam (I) is 1192491-61-4, and its chemical...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07D211/60
CPCC07D211/60C07D471/08Y02A50/30Y02P20/55A61P31/04A61K31/437C07B57/00
Inventor 戚聿新李新发王保林徐欣赵银龙腾玉奇
Owner XINFA PHARMA