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Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA

A technology of carbapenems and synthetic methods, which is applied in the field of key intermediates of penems and carbapenem antibiotics, can solve the problems of harsh reaction conditions, low total yield, serious pollution, etc., and achieve easy industrial production , high liquid phase purity and advanced technology

Inactive Publication Date: 2012-12-19
CHINA THREE GORGES UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The first is to use chiral 3-hydroxybutyric acid as the starting material, which is characterized by low total yield and high cost;
[0004] The second is to use chiral 1,3-butanediol as the starting material, which is a better industrialization route. Japanese companies mainly adopt this route, but there is no domestic production of this raw material, and it is not suitable for domestic industrialized large-scale production. ;
[0005] The third method uses 6-APA as the starting material to synthesize 4AA. The raw material cost of this route is too high, the reaction conditions are relatively harsh, and the pollution is serious, so it is not suitable for industrial production.
[0006] Using L-threonine as the starting raw material, although the raw material of this route is convenient and easy to obtain, the reaction conditions are relatively easy, and it is suitable for industrial production, but there is no report on the total synthesis

Method used

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  • Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA
  • Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA
  • Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA

Examples

Experimental program
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Effect test

Embodiment 1

[0080] A method for synthesizing 4AA, a key intermediate of penicillene and carbapenem antibiotics, which consists of the following steps:

[0081] (1) Synthesis of Intermediate I:

[0082] In a 50L reactor, add 10.2kg of industrial hydrochloric acid with a mass concentration of 31% and 5.0L of water. When the internal temperature drops to 0°C, add 3.0kg of L-threonine and 5.0kg of sodium nitrite at -5°C. (The diazotization temperature in step (1)) react for 1 hour. Raise the temperature to 20-25°C and keep it for 1 hour. Turn on the vacuum pump to remove residual NO 2 gas. Cool the inner temperature to 10°C and slowly add 6.5kg of sodium hydroxide and 9.13kg of water to increase the temperature to 25°C and keep it warm for 15 hours. After the heat preservation is completed, cool to -2°C, add concentrated hydrochloric acid dropwise to adjust PH=2.0. Put the material into a 100L extraction kettle, add 50g of tetrabutylammonium bromide and 30.0L of ethyl acetate, stir for 30 minu...

Embodiment 2

[0101] (1) Synthesis of Intermediate I:

[0102] In a 50L reactor, add 10.2kg of industrial hydrochloric acid with a mass concentration of 31% and 5.0L of water. When the internal temperature drops to 0°C, add 3.0kg of L-threonine and 5.0kg of sodium nitrite at 0°C ( The diazotization temperature of step (1) was reacted for 1 hour, and the others were the same as in Example 1. The yield of intermediate I was 65.3%.

[0103] (2) Synthesis of Intermediate II:

[0104] Same as Example 1

[0105] (3) Synthesis of Intermediate III:

[0106] In a 50L reactor, add 1.90kg of Intermediate I, start stirring and pass nitrogen protection, cool the internal temperature to -10°C, start to add 2.2kg of N-methylmorpholine dropwise, control the temperature at -10°C, about 20- After 30 minutes of dripping, slowly add 2.35kg ethyl chloroformate, control the internal temperature at -5°C, and keep it warm for 1 hour. Then add 3.5 kg of Intermediate II, control the internal temperature of -10°C (reaction ...

Embodiment 3

[0118] (1) Synthesis of Intermediate I:

[0119] In a 50L reactor, add 10.2kg of industrial hydrochloric acid with a mass concentration of 31% and 5.0L of water. When the internal temperature drops to 0°C, add 3.0kg of L-threonine and 5.0kg of sodium nitrite at -10°C. (The diazotization temperature in step (1)) was reacted for 1 hour, and the others were the same as in Example 1. The yield of intermediate I was 71.6%.

[0120] (2) Synthesis of Intermediate II:

[0121] The same as in Example 1.

[0122] (3) Synthesis of Intermediate III:

[0123] In a 50L reactor, add 1.90kg of Intermediate I, start stirring and pass nitrogen protection, cool the inner temperature to -10°C, start to add 2.2kg of N-methylmorpholine dropwise, control the temperature at -20°C, about 20- After 30 minutes of dripping, slowly add 2.35kg ethyl chloroformate, control the internal temperature at -5°C, and keep it warm for 1 hour. Then add 3.5 kg of Intermediate II, control the internal temperature of -20°C (r...

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Abstract

The invention relates to a synthetic method for a penem and carbapenem antibiotic type key intermediate 4AA, belonging to the technical field of medicine. The method comprises the following steps of: reacting L-threonine with sodium nitrite-hydrochloric acid to generate a diazo compound; performing an internal nucleophilic substitution reaction on the diazo compound under the action of sodium hydroxide; acidifying to obtain epoxy sodium butanoate; acidifying to obtain epoxy butyrate; reacting the epoxy butyrate with p-methoxyanilinoethyl acetate to obtain a condensation product; generating a quaternary ring compound from the condensation product under the actions of hexamethyldisilazane and lithium amide; and performing hydroxy protection, hydrolysis, oxidative decarboxylation and ozonization deprotection on the ring compound to obtain 4AA. The process has the advantages of readily-available raw material, mild reaction conditions, short reaction time, low pollution, high yield and the like, and is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of penicillene and carbapenem antibiotic drug intermediates, and specifically relates to a key intermediate (3R, 4R)-3-[(1R)-tert Synthesis method of butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (abbreviation: 4AA). technical background [0002] Penicillene and carbapenem antibiotics such as imipenem, panipenem, meropenem, faropenem, ertapenem, biapenem, and donipenem are new atypical β-lactams Antibiotics have antibacterial effects on gram-negative and positive bacteria, aerobic bacteria, and anaerobic bacteria. Now they have become the first choice for the treatment of severe infections and multiple infections and are one of the hot spots in the development of antibacterial drugs. (3R,4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (abbreviation: 4AA) is a synthetic penicillene And the key intermediate of carbapenem antibiotics. At present, the main synthetic routes of 4AA can be summarized i...

Claims

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Application Information

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IPC IPC(8): C07F7/18
Inventor 李德江李永双龚大春
Owner CHINA THREE GORGES UNIV
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