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Method for preparing ertapenem intermediate

A technology for ertapenem and ertapenem side chains, which is applied in the field of preparing ertapenem intermediates, can solve problems such as unstable nature and difficult preservation, and achieves the effects of good stability, shortened working hours, and reduced costs

Active Publication Date: 2012-09-26
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is because the dimer state is already in an oxidized state, so it is not easy to be oxidized again in the air, and can always maintain stable quality. It overcomes the fact that the single-protected side chain ES' is easy to absorb moisture. Unstable in nature and difficult to preserve, which is beneficial to industrial production

Method used

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  • Method for preparing ertapenem intermediate
  • Method for preparing ertapenem intermediate
  • Method for preparing ertapenem intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Add 5.0g Ertapenem side chain hydrochloride (R 2 for H), 50mL H 2 O, 2.3 g K 2 CO 3 , 0.03g FeCl 2 .4H 2 O. Air was passed into the reaction at room temperature, followed by HPLC. After the reaction was complete, 2.5 g of concentrated hydrochloric acid (37.5%) was added, and solids were precipitated. Filter, and then recrystallize with 25mL of water to obtain 4.6g ertapenem side chain dimer hydrochloride, off-white solid, which is formula (III) ertapenem side chain dimer hydrochloride, HPLC purity greater than 99 %.

[0065] In a 100mL three-necked bottle, N 2 Under protective conditions, add 1.8 g of the above-mentioned ertapenem side chain dimer hydrochloride, 1.5 mL of tri-n-butylphosphine (n-Bu 3 P), 30mL N,N-dimethylformamide (DMF), dissolved and cooled to -30°C, then slowly added 2.4g diisopropylethylamine (DIPEA) and 0.03g 4-N,N- Dimethylaminopyridine (DMAP), then add 3.0g MAP (R 1 For p-nitrobenzyl), the reaction was stopped after 30min, and the reacti...

Embodiment 2

[0067] Add 5.0g Ertapenem side chain hydrochloride (R 2 for H), Na 2 CO 3 1.85g, 0.03g FeCl 2 .4H 2 O, DMF 50mL was passed into air at room temperature for reaction. After the reaction was followed by HPLC, 3.5 g of concentrated hydrochloric acid (37.5%) was added, and then the reaction solution was added to 1000 mL of acetone, and solids were precipitated. After filtration and recrystallization with 50 ml of water, 4.1 g of a light yellow solid was obtained, which was ertapenem side chain dimer hydrochloride of formula (III), and the HPLC purity was greater than 99%.

[0068] In a 100mL three-necked bottle, N 2 Under protective conditions, 1.98 g of the above-mentioned ertapenem side chain dimer hydrochloride, 1.5 mL of tri-n-butylphosphine (n-Bu 3 P), 15mL N, N-dimethylformamide (DMF), 3.0gMAP (R 1 nitrobenzyl), dissolved and cooled to -40°C, then slowly added dropwise 2.1g tetramethylguanidine (TMG), stopped the reaction after 60min, and added the reaction solution d...

Embodiment 3

[0070] Add 5.0g Ertapenem side chain hydrochloride (R 2 for H), Na 2 CO 3 1.85g, 0.03g FeCl 2 .4H 2 O, DMF 50mL was passed into air at 0~5℃ to react. After the reaction was followed by HPLC, 3.0 g of concentrated hydrochloric acid (37.5%) was added after the reaction, and then the reaction solution was added to 1000 mL of acetone, and solids were precipitated. Filter, then recrystallize with 25 mL of water and 1.25 g of acetic acid to obtain 4.3 g of a light yellow solid, which is the side chain dimer hydrochloride of ertapenem of formula (III), and the HPLC purity is greater than 99%.

[0071] In a 100mL three-necked bottle, N 2 Add 4.1 g of the above-mentioned ertapenem side chain dimer hydrochloride, 4.5 mL of tri-n-butylphosphine (n-Bu 3 P), 90mL N, N-dimethylformamide (DMF), then add 9.0g MAP (R 1 For p-nitrobenzyl), dissolve and cool to 0°C, then slowly add 6.3g tetramethylguanidine (TMG) and 0.09g 4-N, N-dimethylaminopyridine (DMAP) dropwise, stop the reaction af...

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Abstract

The invention provides a preparation method of an ertapenem intermediate or pharmaceutically acceptable salts thereof. The method provided by the invention comprises the following steps: carrying out condensation reaction on ertapenem side chain dimer or pharmaceutically acceptable salts thereof and carbapenem mother nuclide in the presence of a compound R3P and alkali to prepare the ertapenem intermediate or pharmaceutically acceptable salts thereof. The preparation method provided by the invention has the advantages of high reaction activity and high speed, can shorten the working hours and lower the cost in industrial production, and avoids using the ertapenem side chain ES', which can easily absorb moisture, can be easily oxidized and can not be easily preserved due to unstable properties, thereby being beneficial to industrial production.

Description

technical field [0001] The invention relates to a method for preparing a carbapenem antibiotic intermediate, in particular to a method for preparing an ertapenem intermediate. Background technique [0002] Ertapenem (ertapenem, shown in Formula 1) is a carbapenem antibiotic with broad-spectrum antibacterial properties, jointly developed by Merck and AstraZeneca, and its chemical name is (4R, 5R, 6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfur-6-[(1R)-1-hydroxyethyl]-4 -Methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, the specific structural formula is as follows: [0003] [0004] Ertapenem sodium (as shown in Formula 2) is the active ingredient of the ertapenem preparation, and its synthesis has received extensive attention. [0005] [0006] The methods for preparing ertapenem sodium disclosed in the literature are carried out according to the following route without exception: [0007] [0008] Specifically, the protected ertap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
CPCY02P20/55
Inventor 任鹏郭靖宁李伟范进伟明守锋陈崇洪
Owner SHENZHEN HAIBIN PHARMA
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