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Method for preparing key intermediate of beta-methylcarbapenem antibiotic

A technology of methyl carbapenem and antibiotics, applied in the field of organic synthesis and preparative chemistry, which can solve the problems of long synthetic route, low yield, and limited industrial application

Inactive Publication Date: 2013-04-03
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this route is that The synthetic route is too long, the condensation reaction will produce sulfide impurities and cause low yield, and the isomerization reaction of methyl group in the raw material synthesis and post-treatment process limits its industrial application

Method used

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  • Method for preparing key intermediate of beta-methylcarbapenem antibiotic
  • Method for preparing key intermediate of beta-methylcarbapenem antibiotic
  • Method for preparing key intermediate of beta-methylcarbapenem antibiotic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: a kind of method for preparing the key intermediate of β-methyl carbapenem antibiotics is characterized in that the specific preparation steps are as follows:

[0027] (1) Condensation reaction: Add 50.0kg β-methyl-ADC-8 and 500.0 L acetonitrile to a 2000 L reactor, cool the system down to -15~-10°C, and add 37.6kg N to the system at this temperature , N'-dicyclohexylcarbodiimide, after the addition, the system was stirred at -15~-10°C for 60 minutes, slowly added 20.1kg of thiophenol to the system, and the temperature was returned to 15~25°C after dropping , and kept stirring at 15-25°C until β-methyl-ADC-8 completely disappeared, filtered with suction, concentrated, washed, concentrated the washed organic phase, and crystallized with 500L n-heptane to obtain 58.8kg of compound , purity 99.3%, yield 90.2%;

[0028] (2) Alkylation reaction: Add 58.8kg of compound into a 2000L reactor , 45.0kg compound , and 588.0L tetrahydrofuran, lower the temperatu...

Embodiment 2

[0030] Embodiment 2: a kind of method for preparing the key intermediate of β-methyl carbapenem antibiotics is characterized in that the specific preparation steps are as follows:

[0031] (1) Condensation reaction: 20.0kg of β-methyl-ADC-8, 100.0 L of methanol, lower the temperature of the system to -10~-5°C, and add 13.6kg of N,N'-bicyclic to the system at this temperature Hexylcarbodiimide, after the addition, the system was stirred at -10~-5°C for 30 minutes, and 7.3kg of thiophenol was slowly added dropwise to the system. Keep stirring at ℃ until β-methyl-ADC-8 disappears completely, filter with suction, concentrate, wash, concentrate the washed organic phase, and crystallize with 100L n-heptane to obtain 22.7kg of compound , purity 90.5%, yield 87.0%;

[0032] (2) Alkylation reaction: Add 22.7kg of compound into a 1000L reactor , 16.4kg compound , and 227L of 1,4-dioxane, lower the temperature to -35~-40°C, add 1.5 kg of NaH into the system at this temperature, and...

Embodiment 3

[0034] Embodiment 3: a kind of method for preparing the key intermediate of β-methyl carbapenem antibiotics is characterized in that the specific preparation steps are as follows:

[0035] (1) Condensation reaction: Add 40.0kg β-methyl-ADC-8 and 600.0 L ethanol to a 2000 L reactor, cool the system down to -20~-15°C, and add 41.0kg N to the system at this temperature , N'-dicyclohexylcarbodiimide, after the addition, the system was stirred at -20~-15°C for 60 minutes, and 21.9kg of thiophenol was slowly added dropwise to the system, and the temperature was returned to 15~25°C after the addition , and kept stirring at 15-25°C until β-methyl-ADC-8 completely disappeared, filtered with suction, concentrated, washed, concentrated the washed organic phase, and crystallized with 600L n-heptane to obtain 44.3kg of compound , purity 92.3%, yield 85.0%;

[0036] (2) Alkylation reaction: Add 44.3kg of compound into a 3000L reactor , 46.2kg compound , and 1107.5L of 1,4-dioxane, low...

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Abstract

The invention provides a method for preparing a key intermediate of a beta-methylcarbapenem antibiotic. The method comprises the steps that a Dieckmann concentration route is used, beta-methyl-ADC-8 is taken as a starting raw material, so that the synthesis of the key intermediate is firstly solved, and the reaction only requires two steps to form the intermediate. N, N'-dicyclohexylcarbodiimide is taken as a condensating agent for a condensation reaction, and cheap NaH (sodium hydride) is taken as alkali for an alkylation reaction; similarly, the NaH is taken as a catalyst to perform a Dieckmann concentration reaction so that ring-shaped beta-keto ester can be formed with a high yield, and a trapping agent is utilized to remove benzenethiol generated in a system, so as to prevent sulfur ether impurities from being generated in a final product; and a one-pot reaction is adopted to directly perform esterification so that the final product of the key intermediate of the beta-methylcarbapenem antibiotic is formed. The method is mild in reaction condition, simple in operation, stable in processing, high in purity and yield and provides a choice for large-scale production.

Description

(1) Technical field: [0001] The invention relates to the field of organic synthesis and preparative chemistry, in particular to a method for preparing key intermediates of β-methyl carbapenem antibiotics. (2) Background technology: [0002] So far, there have been a large number of natural or synthetic β-lactamase inhibitors reported, which can be divided into oxypenicillane, penem, carbapenem, monocyclic β-lactam oxypenicillin from the chemical structure Alkanes, including carbapenems, especially β-methyl carbapenems, have good antibacterial effects on many drug-resistant bacteria, especially have a strong inhibitory effect on β-type enzymes. [0003] Several β-methyl carbapenem antibiotics on the market so far, such as meropenem, doripenem, ertapenem, etc., mostly use intermediates with mother nuclei in the synthesis process , where R is H or TBS. Therefore the compound The synthesis of has been a research hotspot in the field of medicinal chemistry and organic synthe...

Claims

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Application Information

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IPC IPC(8): C07F9/12
Inventor 洪浩詹姆斯·盖吉李九远
Owner ASYMCHEM LAB TIANJIN
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