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Purification method of pyrrolidine carbapenem antibiotics

A purification method and technology of aqueous solution, applied in the fields of organic chemistry, anti-infective drugs, pharmaceutical formulations, etc., can solve the problems of residual by-products, darkening of color, low product purity, etc., and achieve the effect of increasing stability

Active Publication Date: 2010-11-10
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

However, carbapenem compounds have poor stability in aqueous solution, especially at higher concentrations and temperatures, and the stability is worse, and side reactions such as darkening of color, product polymerization, and degradation often occur, so that the final product will be damaged. There are problems such as low purity and residual by-products, which are unfavorable

Method used

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  • Purification method of pyrrolidine carbapenem antibiotics
  • Purification method of pyrrolidine carbapenem antibiotics
  • Purification method of pyrrolidine carbapenem antibiotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of crude product of doripenem

[0037]

[0038] 100 grams of DN-8 (refer to literature organic process research & development 2003, 7, 649-654 method preparation) was dissolved in water (450mL) and THF (800mL), added 100 grams of Pd / C (water content 66%), heated to At 25°C, under the pressure of 20-24kg, react for 2 hours, exotherm during hydrogenation, keep the reaction temperature at 30-40°C, after the reaction is completed, filter with suction, and wash the palladium with 150mL (THF:water=2:1) Carbon, wash the water layer with ethyl acetate (750mL×2), wash the water layer with n-butanol (500mL×2), cool the water layer to 0°C, a light yellow solid precipitates, keep warm at 0-5°C and stir overnight, then filter with suction , dried under reduced pressure at 25° C. for 15 hours, crude doripenem (32 g, yield 65%, water content 6.1%, purity 96.2%).

Embodiment 2

[0039] Embodiment 2: solution stability investigation

[0040]Take 1 gram of crude doripenem, dissolve it in 50ml of pure water, 0.05g / mL L-proline aqueous solution, and 0.1g / mL L-proline aqueous solution, stir and dissolve until a clear transparent liquid is obtained. Take 10ml and place them at room temperature at 25°C, 40°C, and 50°C, respectively take 10min, 20min, and 30min of the solution for HPLC detection, use the peak area at room temperature at 0min as a control, calculate the relative peak area ratio, and calculate the relative content. To examine its solution stability. It can be seen from the table below that the stability of doripenem in solution is significantly improved at higher temperatures (40° C. and 50° C.) after adding proline.

[0041]

Embodiment 3

[0043] Add the crude product of doripenem (1.0g) into 0.05g / mL L-proline solution (20mL), heat with stirring, and dissolve at 50°C, keep the solution at 50-55°C, add activated carbon ( 50 mg) was stirred for 5 minutes to decolorize, filtered, and the filtrate was cooled to 0-5°C and stirred. Solids precipitated within about 1 hour, and aged at 0-5°C for 2 hours. 10 mL of isopropanol was added dropwise, aged at 0-5°C for 2 hours, stirred overnight at -10°C, and the resulting crystals were filtered out. The obtained crystals were washed with 80% isopropanol aqueous solution (5 mL), and dried under reduced pressure at 30° C. with a water pump (20-30 mmHg) for 4 hours to obtain 0.91 g of doripenem (91% yield, 5.93% water content) , Purity: 99.65%.

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Abstract

The invention relates to a purification method of pyrrolidine carbapenem antibiotics, and in particular to a method for purifying Doripenem through crystallization or re-crystallization. In the method, the Doripenem is separated out from aqueous solution containing Doripenem and proline.

Description

technical field [0001] The invention relates to a method for purifying doripenem, in particular to a method for purifying doripenem through crystallization or recrystallization. Background technique [0002] Doripenem (S-4661) is a broad-spectrum carbapenem antibiotic developed by Japan Shioyagi Company. It has a broad antibacterial spectrum, is stable to most β-lactamases, has strong affinity for PBPSs, and has antibacterial activity. High, stable to DHP-1 and so on. Its 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. [0003] [0004] Patent document CN1432016A discloses two stable crystal forms III and IV of doripenem and their preparation methods. During the preparation process, doripenem is dissolved in pure water at a higher temperature (such as 55° C.) to prepare a solution containing 5 to...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/02A61K31/407A61P31/00
Inventor 朱雪焱袁哲东俞雄张爱明江竹莲
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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