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Preparation method of doripenem

A C1-C6, allyl technology, applied in the preparation field of carbapenem compound doripenem, can solve the problems of complicated operation, fast reaction speed, difficult to remove, etc. The effect of product purity

Active Publication Date: 2012-10-17
SHANGHAI RUNSHI MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this method no longer needs to be carried out under ultra-low temperature conditions, there are still the following disadvantages: firstly, MES buffer is used, and because the raw material doripenem intermediate 2 used in the reaction and the resulting product doripenem are all dissolved in the reaction solution , the reaction speed is fast, there are many degradation products, and the buffer and other impurities must be removed after the reaction, so column chromatography purification is still required, and the operation is cumbersome, which is not conducive to large-scale production
This method simplifies the process steps to a certain extent and improves the product purity, but the post-treatment process still needs to be divided into equal steps, the operation is cumbersome, and corresponding equipment needs to be added in industrial production.
[0015] In addition, in the preparation methods of doripenem recorded in the prior art, the reaction solvents used in the deprotection reaction all contain organic solvents, which have the following disadvantages: ①It is not conducive to environmental protection; ②Because most of the organic solvents are flammable and explosive reagents, and Poor smell, high requirements for the design of the production workshop, and increase the risk of the operation position, which is not easy for the health of the workers; ③ some palladium complexes are dissolved in the solution, and it is not easy to remove, resulting in excessive heavy metals in the product

Method used

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  • Preparation method of doripenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of doripenem

[0042] Add 1.0kg (1.36mol) of doripenem intermediate 2, 10% Pd / CO 0.5Kg, 0.32L (2.75mol) of 2,6-lutidine, 15L of deionized water, and nitrogen into a 50L hydrogenation kettle. Substitute several times, replace with hydrogen several times, add hydrogen to the pressure of 2.0Mpa in the kettle, react at 25°C for 3h, filter the reaction solution, recover and reuse palladium carbon, add 45L isopropanol to the filtrate, stir and analyze at 0-5°C After crystallization for 5 hours, 0.42Kg of doripenem was suction filtered, the molar yield was 73.5%, the HPLC purity was 99.2%, and the heavy metal content was <10ppm.

Embodiment 2

[0043] Embodiment 2: Preparation of doripenem

[0044] Add 1.0kg (1.36mol) of doripenem intermediate 2, 10% Pd / CO 0.5Kg, 0.08L (0.68mol) of 2,6-lutidine, 15L of deionized water, and nitrogen into a 50L hydrogenation kettle. Substitute several times, replace with hydrogen several times, add hydrogen to the pressure of 2.0Mpa in the kettle, react at 40°C for 4h, filter the reaction solution, recover and reuse palladium carbon, add 75L ethanol to the filtrate, stir and crystallize at 0~5°C for 5h , 0.40Kg of doripenem was suction filtered, the molar yield was 70.0%, the HPLC purity was 98.2%, and the heavy metal content was <10ppm.

Embodiment 3

[0045] Embodiment 3: Preparation of doripenem

[0046] Add 1.0Kg (1.09mol) of doripenem intermediate 3, 10% Pd / CO 0.5Kg, 0.32L (5.45mol) of 3,5-lutidine, 15L of deionized water, and nitrogen into a 50L hydrogenation kettle. Substitute several times, replace with hydrogen several times, add hydrogen to the pressure of 1.5Mpa in the kettle, react at -10°C for 5h, filter the reaction solution, recover and reuse palladium carbon, add 45L ethanol to the filtrate, stir and crystallize at 0-5°C After 5 hours, 0.31Kg of doripenem was filtered with suction, the molar yield was 67.7%, the HPLC purity was 98.5%, and the heavy metal content was <10ppm.

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Abstract

The invention relates to a preparation method of doripenem as shown in the formula 1. The method comprises the following steps of: using a doripenem intermediate II as a raw material, using a single solvent--water as a reaction solvent and conducting a hydrogenated deprotection reaction in the presence of alkali and a catalyst. The single solvent water is used as a reaction solvent, thus solving a series of problems caused by the use of an organic solvent in the reaction solvent, reducing product degradation and raising product purity. In addition, the preparation method is economical, safe and environmentally friendly, and is more suitable for industrial operation at large scale.

Description

technical field [0001] The invention belongs to the field of synthesis of carbapenem antibiotics, and in particular relates to a preparation method of a carbapenem compound doripenem. Background technique [0002] Doripenem, Doripenem, the chemical name is (4R, 5S, 6S)-3-[((3S, 5S)-5-[[(sulfamoyl)amino]methyl]-3-pyrrolidinyl)mercapto -6-[(1R)-1-hydroxyethyl]4-methyl-7-oxyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid], the structural formula is as follows 1 shows: [0003] [0004] Doripenem is a new carbapenem antibiotic, the 2-side chain is a tetrahydropyrrole ring substituted with sulfamamide. The structure-activity relationship research shows that the acylation or sulfonylation of the side chain amino group is conducive to the increase of antibacterial activity, and its inhibitory activity against Gram-positive bacteria is higher than that of meropenem, and its inhibitory activity against Gram-negative bacteria is higher than that of meropenem. Imipenem, which i...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06
CPCY02P20/55
Inventor 史颖陈玉洁杨品康宏艳贾铭刘然
Owner SHANGHAI RUNSHI MEDICAL TECH CO LTD
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