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Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains

A technology of ertapenem side chain and ertapenem, applied in the field of antibiotic preparation, can solve the problems of high raw material cost, labor cost, cumbersome operation, and low yield

Active Publication Date: 2014-11-05
HUNAN CHEMAPI BIOLOGICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The operation is cumbersome, the yield is low, and the cost of raw materials and labor are high

Method used

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  • Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains
  • Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains
  • Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Synthesis of (2S,4R)-4-hydroxy-1-(((4-nitrobenzoyl)oxy)carbonyl)pyrrolidine-2-carboxylic acid (5):

[0124] Add 12kg of water and 1kg of sodium hydroxide to a 20L reactor, stir to dissolve, cool down to 25-30°C, add 1.5kg of L-hydroxyproline, stir to dissolve, cool down to 0-5°C, and start to control the temperature at 0-5°C A solution of 2.7 kg of p-nitrobenzyl chloroformate and 3 kg of dichloromethane was added dropwise. The dropwise addition time is about 2 hours. After the dropwise addition is completed, keep stirring at about 0-5°C for 3 hours. The detection response is complete. Separate the dichloromethane phase, wash the water phase with 3 kg of dichloromethane, separate the water phase, control the temperature to no more than 15 degrees, adjust the pH value to 2 with concentrated sulfuric acid, cool down to 0°C, filter, wash with water, and dry to obtain the product (2S, 4R)- 4-Hydroxy-1-(((4-nitrobenzoyl)oxy)carbonyl)pyrrolidine-2-carboxylic acid (5) 31.95kg...

Embodiment 2

[0126] Synthesis of 4-nitro(1S,4S)-3-oxo-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylic anhydride (3):

[0127] Under nitrogen protection, 31.3 g of (2S,4R)-4-hydroxy-1-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidine-2-carboxylic acid (5) was dissolved in 300 mL of dichloromethane, Add 12.1 g of triethylamine, stir to dissolve and cool down to -15°C, add 13.5 g of isopropyl chloroformate dropwise, and stir and react at this temperature for 30 minutes. 16.2 g of triethylamine was added, and 16 g of methanesulfonyl chloride was added dropwise at this temperature, followed by stirring at this temperature for 30 minutes. Add 25.3 g of triethylamine and 100 mL of 10.2 g of sodium sulfide water. React at 5-10°C for 1 hour. After the reaction was completed, wash once with 300 mL of 1N hydrochloric acid, once with 300 mL of saturated brine, and extract once with 200 mL of dichloromethane for combining the aqueous phases. Combined with anhydrous sodium sulfate and dried, filtered, and the...

Embodiment 3

[0129] (2S, 4S)-4-nitrobenzyl-4-mercapto-2-((3-(((4-nitrobenzyl)oxy)carbonyl)phenyl)carbamoyl)pyrrolidine-1- Synthesis of formate (2) (ie: ertapenem side chain III):

[0130] Under nitrogen protection, 20g of 4-nitro(1S,4S)-3-oxo-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylic anhydride (3) was dissolved in dichloro 140mL of methane was added, 19.5g of 3-aminobenzoic acid p-nitrobenzyl ester was added, the reaction was stirred at room temperature for 7 hours, and the solvent was evaporated to obtain (2S, 4S)-4-nitrobenzyl-4-mercapto-2-((3- (((4-nitrobenzyl)oxy)carbonyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (2). mp.148-150°C.

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Abstract

The invention discloses ertapenem and ertapenem side chains, as well as preparation methods of ertapenem and ertapenem side chains. L-hydroxyproline is protected by p-nitrobenzyl ester to obtain (2S,4R)-4-hydroxyl-1-(((4-Nitrobenzformyl)-oxyl)caboyl)pyrrolidine-2-carboxylic acid; then 4-nitro(1S,4S)-3-oxo-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxylic anhydride can be obtained, and reacts with m-aminobenzoic acid p-nitrobenzyl ester to obtain ertapenem side chain III; and the ertapenem can be synthesized through two-step chemical reaction of condensation and deprotection to the ertapenem side chain III and a raw material MAP. An ertapenem side chain I (10), an ertapenem side chain II (13) and the ertapenem side chain III (2) which are prevailing in the market can be synthesized through simple steps, without the need of ultralow temperature, industrialization is easy, and the product purity is high, and the operation is simple and convenient.

Description

technical field [0001] The invention relates to the technical field of antibiotic preparation, in particular to ertapenem, ertapenem side chains and a preparation method thereof. Background technique [0002] In the prior art, the preparation method of ertapenem is as follows: [0003] US2011 / 288289, US2009 / 312539, WO2013 / 121279, US2011 / 288289, Journal of Organic Chemistry; vol.70; nb.19; (2005); p.7479 report synthetic route one: [0004] [0005] Journal of Organic Chemistry; vol.70; nb.19; (2005); p.7479 reports the following synthetic route 2: [0006] [0007] US2009 / 312539 and WO2013 / 121279 report the following synthetic route 3: [0008] [0009] WO2013 / 121279, US2010 / 4463, and EP2388261 report the following synthetic route 4: [0010] [0011] WO2013 / 150550 reports the following synthetic route five: [0012] [0013] US5478820 reports the following synthetic route six: [0014] [0015] EP2388261 reports the following synthetic route seven: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06C07D207/16
CPCC07D207/16C07D477/06C07D477/20
Inventor 范荣李加前
Owner HUNAN CHEMAPI BIOLOGICAL TECH
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