Novel crystal of doripenem, preparation method and use thereof

A doripenem and crystallization technology, which is applied in the field of application and pharmaceutical compositions containing new crystal forms of doripenem, can solve the problems of high preparation cost, discoloration, and complicated preparation process, and achieve the effect of low preparation cost

Active Publication Date: 2008-01-09
CHENGDU DIAO JIUHONG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Chinese patents CN92111069.3 and CN200510021270.1 relate to the manufacture of doripenem, but only involve the preparation of its amorphous powder. The stability of the amorphous powder of doripenem during storage is poor, and it can be used for a long time under normal conditions. During storage, there will be problems of discoloration and decrease in purity
The type IV crystal must be obtained by drying the type III crystal, preferably by heating and drying under reduced pressure. The preparation process is complicated and the preparation cost is high.

Method used

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  • Novel crystal of doripenem, preparation method and use thereof
  • Novel crystal of doripenem, preparation method and use thereof
  • Novel crystal of doripenem, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] [Example 1] Preparation of crude product of doripenem:

[0042]Doripenem can be synthesized by previously known methods. Such as using the method disclosed in CN200510021270.1 to obtain the crude product of doripenem. It can also be prepared by:

[0043] (1), preparation of mercaptopyrrolidine derivatives

[0044] (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-acetylthiopyrrolidine 50 g (81.8 mg mol) was dissolved in 200 milliliters of tetrahydrofuran, and 20 milliliters of aqueous solution of 6 grams of lithium hydroxide was added dropwise under an ice bath. After the addition was completed, stirring was continued for 120 minutes, acidified with 6 equivalents of hydrochloric acid, and a solid viscous substance was precipitated, which was washed with ethyl acetate Add ethanol after dissolving, freeze and precipitate 32 grams of light yellow amorphous solid powder, yield 68.8%.

[0045] (2), preparation of protected pyrrol...

Embodiment 2

[0049] [Example 2] Preparation of new crystals of doripenem of the present invention

[0050] 1. Preparation of seed crystals: Add 10 grams of crude doripenem into 100 ml of distilled water, extract 3 times with 40 ml of ethyl acetate, place the aqueous solution at room temperature (8-13°C) overnight, precipitate crystals, filter, Dry under vacuum at room temperature to obtain seed crystals.

[0051] 2. Preparation of new crystals: add 10 g of crude doripenem to 200 ml of distilled water, heat to dissolve at 50±5°C, add 0.5 g of needles and decolorize with activated carbon for 10 minutes, filter, and cool the filtrate to 0-5°C Finally, 20 mg of V-type crystal seed crystals were added, stirred for 4 hours to precipitate the crystals, and then slowly added dropwise with 100 ml of isopropanol. After the dropwise addition, the temperature was lowered to -10°C to continue crystallization and aging overnight, and then the crystals were filtered out. The obtained crystals were washe...

Embodiment 3

[0066] [Example 3] Repeated preparation of new crystals of doripenem of the present invention:

[0067] In order to confirm the repeatability of the above-mentioned Example 1, the V-type crystal obtained in Example 2 was used as the seed crystal to carry out repeated tests. The powder X-ray diffraction measurement result of the obtained crystal placed for one month is shown in Fig. 2, and there are main peaks at diffraction angles (2θ)=6.471, 15.290, 16.402, 17.508, 20.748, 23.063 and 25.396 (degrees). In addition, there are lower peaks at the diffraction angle (2θ) = 11.275, 12.224, 12.894, 14.506, 18.444, 19.375, 21.739, 23.661, 24.528, 24.890, 25.911, 27.256, 27.981, 29.269, 30.804, 33.929, 39. .

[0068] Moisture content: theoretical value (dihydrate): 7.89%, measured value by thermogravimetric analysis (TGA): 8.003%.

[0069] The melting point measured by differential scanning calorimetry (DSC) is 175.71° C.; the infrared spectrum data and nuclear magnetic resonance dat...

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Abstract

A (1R, 5S, 6S)-6-((1R)-1-ethoxyl)-2-((3S, 5S)-5-sulfonamide-amino-methyl-pentazane-3-base) sulfur-1-methyl-1-carbon-2-penicillic vinyl-3-carboxylic acid or its hydrate, its medicinal composite containing multi-nipenan crystal, its production and use in preparation of anti-infectious medicine are disclosed. In the crystallizing powdery X-ray diagram, it has main peak at diffraction angle (2 theta)=6.46, 15.27, 16.41, 17.49, 20.72, 23.05 and 25.38 deg. minus or plus 0.1. It's simple and cheap, and has excellent thermodynamic stability and dissolubility.

Description

technical field [0001] The present invention relates to a new crystal form of a drug, in particular to doripenem—(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S, 5S)-5 - new crystals of sulfamoylaminomethylpyrrolidin-3-yl]thio-1-methyl-1-carbo-2-penem-3-carboxylic acid or hydrate thereof, and a preparation method thereof; It also relates to the use of the new crystal form of doripenem in the preparation of anti-infective drugs and the pharmaceutical composition containing the new crystal form of doripenem. Background technique [0002] It is represented by the following formula that doripenem is a new 1β-methyl carbapenem antibiotic, and the side chain at the 2-position is a tetrahydropyrrole ring substituted with sulfamoamide. The structure-activity relationship research shows that the acylation or sulfonylation of the side chain amino group of doripenem is conducive to the increase of antibacterial activity, and the inhibitory activity against Gram-positive bacteria is higher...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/407A61P31/04
Inventor 于源周武春徐大勇黄瑜刘忠荣李伯刚周红英张煤段成旺
Owner CHENGDU DIAO JIUHONG PHARMA FACTORY
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