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Ertapenem monosodium salt crystal and preparation method thereof

A technology of ertapenem and monosodium salt, which is applied in the field of organic chemistry, can solve the problems of poor stability of amorphous ertapenem monosodium salt and whether the unreported crystal form retains stability, etc., achieving good stability, The effect of low residual solvent amount and low production cost

Active Publication Date: 2012-02-29
SHANGHAI ACEBRIGHT PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The four reported crystalline forms A, B, C and D of ertapenem monosodium salt all contain residual organic solvents, and the crystalline forms A, B and C can be dried by nitrogen flow to reduce the residual solvents to meet the requirements of pharmaceuticals. Standards are used, but whether the crystalline form is retained and the resulting stability issues are not reported
The monosodium salt of amorphous ertapenem has poor stability

Method used

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  • Ertapenem monosodium salt crystal and preparation method thereof
  • Ertapenem monosodium salt crystal and preparation method thereof
  • Ertapenem monosodium salt crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1.86g NaHCO 3 Dissolve in 60ml of distilled water; cool to 0-5°C, add ertapenem monosodium salt raw material 10.0g, dissolve; adjust pH=5.5 with 3mol / L acetic acid-methanol solution at 0-5°C; add 2g of activated carbon Decolorize for 20 minutes, filter out activated carbon under the protection of argon and ice-water bath; add 100ml of methanol, cool to -20~-15℃, add 50ml of n-propanol dropwise, stir at a slow speed for 40min, a large amount of solids are precipitated, then add the remaining 100ml of n-propanol, stirred and crystallized for 40min after dropping; filtered, washed the filter cake with a small amount of acetone, and drained the solvent with an oil pump to obtain 7.4g of white solid; finally passed a flow of aqueous argon with a dew point of 4-6°C for 24h to obtain the Ertapenem monosodium salt crystal 7.2g.

Embodiment 2

[0058] Dissolve 0.88g NaOH in 120ml distilled water; cool to 0-5°C, add ertapenem monosodium salt raw material 10.0g, dissolve; adjust pH=5.5 with 3mol / L acetic acid-methanol solution at 0-5°C Add 2g of activated carbon for decolorization for 20 minutes, filter the activated carbon under argon protection and ice-water bath; add 100ml of methanol, cool to -20~-15°C, add 0.1g of seed crystals, and dropwise add 150ml of n-propanol, stir and analyze crystallize for 40 min; filter, wash the filter cake with a small amount of acetone, and drain the solvent with an oil pump to obtain 7.2 g of white solid; finally pass a flow of aqueous argon with a dew point of 0-4°C for 24 h to obtain the ertapenem monosodium salt crystal 7.0 g (recorded as batch 1).

[0059] The above steps were repeated two more times to obtain 7.4 g (referred to as batch 2) and 7.1 g (referred to as batch 3) of ertapenem monosodium salt crystals, respectively.

[0060] Table 1 shows the solvent residues of the 3...

Embodiment 3

[0069] 4.4g Na 2 CO 3 Dissolve in 60ml of distilled water to prepare sodium-containing inorganic alkali aqueous solution; cool to 0-5°C, add 10.0g of ertapenem monosodium salt raw material, dissolve; use 3mol / L formic acid-methanol solution at 0-5°C Adjust the pH to 5.6; add 2g of activated carbon for decolorization for 20 minutes, filter out the activated carbon under argon protection and ice-water bath; add 180ml of methanol, cool to -10~-5°C, add 0.1g of seed crystals, add dropwise 180ml of n-propanol, drop After that, stir and crystallize at a slow speed for 40 minutes; filter, wash the filter cake with a small amount of ethanol, and drain the solvent with an oil pump to obtain 6.9 g of white solid; finally, pass it through an aqueous argon flow with a dew point of 10-14°C for 6 hours to obtain the Ertapene Nandan sodium salt crystal 6.8g (recorded as batch 4).

[0070] The above steps were repeated two more times to obtain 7.0 g (referred to as batch 5) and 7.1 g (refer...

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Abstract

The invention discloses an ertapenem monosodium salt crystal and a preparation method thereof. The ertapenem monosodium salt crystal has a powder X-ray diffraction spectrum shown by a figure 1. The preparation method of the crystal comprises: dissolving an ertapenem monosodium salt serving as a raw material and a sodium-containing inorganic salt in water at 0 to 5 DEG C; cooling to -2 to 10 DEG C, regulating the pH value to 5 to 6 by using an acidic solution, adding active carbon for decolorization, and filtering; adding methanol and cooling to 0 to -40 DEG C; dripping normal propyl alcohol, stirring and crystallizing; and filtering, washing a filter cake by using an organic solvent, and pumping the solvent completely by using an oil pump. The ertapenem monosodium salt provided by the invention has the advantages of low residual solvent content, high stability and the like. The preparation method disclosed by the invention has the advantages of simple process, low preparation cost, suitability for industrial production and the like and has an industrial application value.

Description

technical field [0001] The invention relates to a crystal of ertapenem monosodium salt and a preparation method thereof, belonging to the technical field of organic chemistry. Background technique [0002] Ertapenem monosodium salt (Ertapenem Sodium) was invented by British AstraZeneca, and later transferred to Merck for further research and development. It is a new broad-spectrum long-acting carbocyanine for injection with a 4-position (R) methyl group. Mycelene antibiotics, which were first listed in the United States in 2002, have a broad antibacterial spectrum, are stable against renal dehydropeptidase-1 (DHP-1), have excellent pharmacokinetic parameters, good clinical therapeutic effect, good tolerance, and no adverse reactions. It is clinically used to treat infections caused by moderately to severely sensitive bacteria in adults, and can obtain satisfactory curative effect on community-acquired mixed infections. The structural formula of ertapenem monosodium salt is ...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/20C07D477/02
Inventor 安晓霞吕锋胡猛刘军毕光庆
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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