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New crystal form of ertapenem sodium and preparation method thereof

A technology of ertapenem sodium and crystal form, which is applied in the field of organic synthesis, can solve the problems of low purity and yield, and achieve the effects of improving purity, easy production, and high yield

Active Publication Date: 2021-12-17
ASYMCHEM LAB TIANJIN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The main purpose of the present invention is to provide a new crystal form of ertapenem sodium and its preparation method to solve the problem of low purity and yield of ertapenem sodium crystal form products in the prior art

Method used

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  • New crystal form of ertapenem sodium and preparation method thereof
  • New crystal form of ertapenem sodium and preparation method thereof
  • New crystal form of ertapenem sodium and preparation method thereof

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preparation example Construction

[0037] The present invention also provides a method for preparing the above-mentioned new crystal form of ertapenem sodium, the preparation method comprising the following steps: adding crude ertapenem sodium to an aqueous alkali solution containing sodium ions to form a first system; Add methanol and n-propanol to the first system to form the second system; after cooling the second system to -10~15°C, add the mixed solution of acid, methanol and n-propanol to the second system in 3~10 times, The third system is formed; the volume of the mixed solution is 30~50% of the volume of the second system; after the temperature of the third system is lowered to -30~-15°C, the temperature of the third system is raised to -10~15°C to form the third system Four systems; the fourth system is sequentially filtered, washed and dried to obtain a new crystal form of ertapenem sodium; wherein, the HPLC purity of the crude ertapenem sodium is 90-98%.

[0038] The present invention can effectivel...

Embodiment 1

[0055] The preparation process is as follows:

[0056] Sodium bicarbonate solution (purified water 1000mL, sodium bicarbonate 25.35g) was prepared, and 100g of crude ertapenem sodium (CAS: 153773-82-1; HPLC purity 93%) was added to it to form the first system. The concentration of crude ertapenem sodium in the first system was 100 mg / mL.

[0057] Methanol (280ml) and n-propanol (350ml) were added to the first system to form a second system.

[0058] At 0~5°C, add the mixed solution of acetic acid, methanol and n-propanol (acetic acid: 18.15g, methanol 250ml, n-propanol 300ml) to the second system in 8 times to form the third system. The amount of each addition is 12.5% ​​of the volume of the mixed solution of acetic acid, methanol and n-propanol; the time interval between two adjacent additions is 30 minutes.

[0059] Methanol (1260ml) and n-propanol (2265ml) were added to the third system.

[0060] The temperature of the third system was lowered to -25°C, and then the temp...

Embodiment 2

[0072] The difference with Example 1 is: sodium bicarbonate consumption is 20.28g; Add acetic acid, the mixed solution of methyl alcohol and n-propanol (acetic acid: 14.52g, methyl alcohol 250ml, n-propanol 300ml) in the second system in 3 times; The temperature of the third system was lowered to -25°C, and then the temperature of the third system was raised to 5°C to obtain the fourth system. The concentration of ertapenem sodium in the first system was 100 mg / mL. The amount of each addition is 33% of the volume of the mixed solution of acid, methanol and n-propanol; the time interval between two adjacent additions is 30min. The cooling rate is 0.12°C / min, the heating rate is 0.12°C / min, and the heating and cooling cycle is only performed once.

[0073] For X-ray powder diffraction (XRPD) of the above products see Figure 4 . Its crystal form has 27 main characteristic peaks ( ) at 4.4°, 5.1°, 7.1°, 8.2°, 10.8°, 12.1°, 12.8°, 14.0°, 14.8°, 15.7°, 16.4°, 17.7°, 18.6°, 19....

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Abstract

The invention provides a new crystal form of ertapenem sodium and a preparation method thereof. The new crystal form of ertapenem sodium has 27 main characteristic peaks in the powder X-ray diffraction pattern. The above-mentioned ertapenem sodium of the present invention has a rod-like crystal habit with a large particle size, is not easy to aggregate, and is easier to perform drying treatment, and a product with high crystallinity and purity can be obtained by simple drying treatment. At the same time, the above-mentioned new crystal form of the present invention has better stability, and the crystal form can be kept unchanged to the greatest extent during the subsequent washing and drying process, thereby further improving the purity of the product. Moreover, based on the larger particle size and better stability of the new crystalline form of ertapenem sodium in the present invention, it is easier to produce on a large scale in factories, so that high-purity, high-yield ertapenem sodium products can be obtained.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a new crystal form of ertapenem sodium and a preparation method thereof. Background technique [0002] The structure of ertapenem sodium is: (4R,5S,6S)-3-[[[[(3S,5S)-5-[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl] Monosodium Thio]-6-[(1R)-1-Hydroxyethyl]-4-methyl-7-oxocarbonyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Salt, ertapenem sodium was first discovered by Merck & Co. (U.S.) and Astrazeneca, it has broader activity than most other β-lactam antibiotics and is more resistant to β-lactamase, which It is also a major mechanism of resistance in many bacteria. In clinical trials, the antibiotic showed better pharmacokinetic properties than other carbapenems, allowing monotherapy and once-daily dosing. [0003] Crystal form is a key characteristic of any given crystalline product. Different crystal forms often lead to different properties, such as stability, solubility...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/02C07D477/20C07B2200/13
Inventor 詹姆斯·盖吉马克·麦克劳斯章文春陈朝勇井丁丁张保杰蒋勇
Owner ASYMCHEM LAB TIANJIN
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