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Synthesis process and process system of the mother nucleus map of penem antibiotics

A synthesis process and antibiotic technology, which is applied in the field of new synthesis process and process system of penem antibiotic parent core MAP, can solve the problems of limited capacity amplification ratio, low MAP content and high material destruction rate, and achieve the improvement of reaction temperature and transmission rate. The effect of large thermal area and simple equipment structure

Active Publication Date: 2020-12-01
ZHEJIANG HISOAR CHUANNAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of synthesizing MAP with this technology, more by-products are formed during the process of cyclization reaction of raw materials at high temperature to obtain intermediates, which eventually leads to low content of MAP obtained; and the above-mentioned industrial synthesis reaction is usually carried out in a reactor , the reaction effect is greatly affected by stirring and mixing; in addition, the synthesis process has a significant amplification effect, and the destruction rate of the material after amplification is high, resulting in a further decrease in product yield; and limited by the limitations of reaction equipment and cooling system, the production capacity is enlarged than limited

Method used

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  • Synthesis process and process system of the mother nucleus map of penem antibiotics
  • Synthesis process and process system of the mother nucleus map of penem antibiotics
  • Synthesis process and process system of the mother nucleus map of penem antibiotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] A new process for MAP synthesis, which involves the use of pipeline continuous cyclization and continuous esterification. Including the following steps:

[0086] Add 1 part (mass) (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3- Diazo-3-p-nitrobenzyloxyformyl-2-ketone-propyl]-2-azetidinone (structural formula such as formula (I)), 5 parts (quality) methyl tert-butyl ketone and 0.001 The rhodium octanoate dimer of part (mass) is stirred and dissolved, and the temperature is controlled between 20-30°C; Mixture I is obtained.

[0087] Add 0.7 parts (mass) of diphenyl chlorophosphate and 0.36 parts (mass) of N,N-diisopropylethylamine into the second batching kettle under nitrogen protection, and mix well to obtain the mixture II, which is set aside.

[0088]The volume of the first-stage pipeline reactor is 100L, and 80°C hot water is introduced into the jacket as the heat medium, and tap water is introduced into the jacket of the pre-cooling heat exchanger for cooling. ...

Embodiment 2

[0095] A new process for MAP synthesis, which involves the process of adopting pipeline continuous ring closure and continuous esterification reaction. Including the following steps:

[0096] Add 1 part (mass) (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3- Diazo-3-p-nitrobenzyloxyformyl-2-ketone-propyl]-2-azetidinone (structural formula such as formula (I)), 10 parts (mass) methyl tert-butyl ketone and 0.001 The rhodium octanoate dimer of part (mass) is stirred and dissolved, and the temperature is controlled between 20-30°C; Mixture I is obtained.

[0097] Add 0.7 parts (mass) of diphenyl chlorophosphate and 0.36 parts (mass) of N,N-diisopropylethylamine into the second batching kettle under nitrogen protection, and mix well to obtain the mixture II, which is set aside.

[0098] The first-stage pipeline reactor has a volume of 100L, and 90°C hot water is introduced into the jacket as a heat medium, and tap water is passed into the jacket of the pre-cooling heat exchange...

Embodiment 3

[0105] A new process for MAP synthesis, which involves the process of adopting pipeline continuous ring closure and continuous esterification reaction. Including the following steps:

[0106] Add 1 part (mass) (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3- Diazo-3-p-nitrobenzyloxyformyl-2-ketone-propyl]-2-azetidinone (structural formula such as formula (I)), 10 parts (mass) methyl tert-butyl ketone and 0.001 The rhodium octanoate dimer of part (mass) is stirred and dissolved, and the temperature is controlled between 20-30°C; Mixture I is obtained.

[0107] Add 0.7 parts (mass) of diphenyl chlorophosphate and 0.36 parts (mass) of N,N-diisopropylethylamine into the second batching kettle under the protection of nitrogen, and mix well to obtain the mixture II, which is set aside.

[0108] The volume of the first-stage pipeline reactor is 100L, and 100°C hot water is passed into the jacket as the heat medium, and tap water is passed into the jacket of the pre-cooling heat e...

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Abstract

The invention provides a synthesizing process and process system of penem antibiotic parent nucleus MAP. The synthesizing process comprises the following steps: stirring and dissolving (3S,4R)-3-[(R)-1-ethoxyl]-4-[(1R)-1-methyl-3-diazo-3-p-nitrobenzyloxy formyl-2-tone-propyl]-2-azetidinone and methyl tert-butyl ketone and rhodium octanoate dimer in a first preparation kettle to obtain a mixture I;uniformly mixing diphenyl chlorophosphate and N,N-ethyldiisopropylamine in a second preparation kettle to obtain a mixture II; continuously inputting the mixture I in a primary pipeline reactor, reacting to prepare intermediate, and cooling the reactant in a pre-cooling heat exchanger; respectively continuously inputting the cooled reaction product and the mixture II in a secondary pipeline reactor, and reacting to prepre the penem antibiotic parent nucleus MAP. The synthesizing process is simple in equipment structure since continuous reaction is carried out by utilizing pipeline reactors, has high product yield, and can be used for industrial large production.

Description

technical field [0001] The invention relates to a new synthesis process and process system of penem antibiotic mother nucleus MAP. Background technique [0002] Carbapenems (penems) antibiotics belong to β-lactam antibiotics, which are also known as "the last line of defense against infection for humans". They have the characteristics of broad antibacterial spectrum and strong antibacterial activity. One of the drugs of choice for multi-drug resistant bacterial infections. Among them, meropenem, biapenem, imipenem, ertapenem, etc. have been put into commercial production. (4R,5S,6S)-3-Diphenylphosphoryloxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]heptyl- 2-ene-2-carboxylic acid p-nitrobenzyl ester (MAP) is the mother nucleus of 1β-methyl carbapenem antibiotics and the key intermediate for the synthesis of penem antibiotics. [0003] At present, the industrial synthesis route of MAP is mainly as follows: [0004] [0005] Wherein -PNB is p-nitrobenzyl. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65611
Inventor 徐旋毛海舫李洪明赵国标邱翔徐建忠王朝阳张仁徐龙叶杰陈健
Owner ZHEJIANG HISOAR CHUANNAN PHARMA