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Doripenem side-chain compound and preparation method and application thereof

A chain compound and compound technology, applied in the field of doripenem side chain compound and its preparation, can solve the problems of increasing side chain manufacturing costs, troubles, hidden dangers of final product purification, etc.

Active Publication Date: 2013-11-27
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Although compound (VI) is a crystalline solid powder, after it is connected to the carbapenem core (II), it must be removed at a lower temperature with anhydrous aluminum trichloride / anisole. Protecting group (BOC), the application of anhydrous aluminum trichloride has brought hidden trouble to the purification of final product undoubtedly; In addition, because the protecting group of side chain and parent nucleus can not be removed with the same method step, this has also increased final product Manufacturing costs
Although the protective group of the side chain (VII) is consistent with the mother nucleus, the compound is a foamy solid, and it is difficult to obtain a product with high purity and content, which brings certain troubles to the subsequent reaction.
[0013] CN101531623 prepared the side chain (VI) of doripenem by the following method, which also has the problems brought by the compound (VI). In addition, the dimer compound (VIII) is first oxidized, and finally reduced to the side chain (VI ) process also increases the manufacturing cost of the side chain

Method used

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  • Doripenem side-chain compound and preparation method and application thereof
  • Doripenem side-chain compound and preparation method and application thereof
  • Doripenem side-chain compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] The synthesis of embodiment 1 compound (XII)

[0089] At room temperature, 16.54g (0.06mol) of the compound of formula (X) was dissolved in 125ml of tetrahydrofuran, and 20.8g (0.08mol) of triphenylphosphine and 0.08mol of the compound of formula (XI) were added. Add 16 g (0.08 mol) of diisopropyl azodicarboxylate (DIAD), and control the rate of addition so that the reaction temperature is not higher than 0°C. After the addition is complete, warm up to room temperature and continue stirring. HPLC monitors that the reaction is complete, and the solvent is evaporated under reduced pressure, 100ml of toluene is added, cooled to 0°C, stirred for 4 hours, filtered, and the filter cake is washed several times with 50ml of toluene cooled to 0°C, and the filtrate is evaporated under reduced pressure to obtain the formula ( XIII) Crude compound. The obtained crude product was directly put into the next step reaction without further purification.

[0090] (2S,4S)-1-tert-butox...

Embodiment 2

[0093] The synthesis of embodiment 2 compound (XII)

[0094] At room temperature, 16.54g (0.06mol) of the compound of formula (X) was dissolved in 125ml of toluene, and 20.8g (0.08mol) of triphenylphosphine and 0.08mol of the compound of formula (XI) were added. Add 16 g (0.08 mol) of diisopropyl azodicarboxylate (DIAD), and control the rate of addition so that the reaction temperature is not higher than 0°C. After the addition is complete, warm up to room temperature and continue stirring. The completion of the reaction was monitored by HPLC, the temperature was lowered to 0° C., stirred for 4 hours, filtered, and the filter cake was washed several times with 50 ml of toluene cooled to 0° C., and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude compound of formula (XII). The obtained crude product was directly put into the next reaction without further purification.

[0095] (2S,4S)-1-tert-butoxycarbonyl-4-acetylthio-2-(N-tert-buty...

Embodiment 3

[0098] The synthesis of embodiment 3 compound (XIII)

[0099] Under nitrogen protection, stir and dissolve 3g (0.072mol) of sodium hydroxide in 80ml of water and 12ml of methanol mixed solvent, cool to 0°C, dropwise add the crude product of formula (XII) compound (containing 0.024mol of formula (XII) compound) After adding 12ml of dichloromethane solution and a few drops of tributylphosphine, continue to stir for 2 hours, HPLC monitors the completion of the reaction, add dichloromethane to the reaction solution under nitrogen protection, extract 2 times, 40ml each time, collect the water phase and cool To -5 ~ 0 ° C, under the protection of nitrogen, add 2M hydrochloric acid to the pH of the solution to 4 ~ 6, control the drop rate of hydrochloric acid, so that the solution temperature does not exceed 0 ° C, add dichloromethane to extract 3 times, 50ml each time, combine the organic phase , added anhydrous sodium sulfate to dry for 2 hours, filtered, and distilled off the so...

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Abstract

The invention provides a Doripenem side-chain compound shown by the formula (IX), wherein R represents hydrogen, p-nitrobenzyloxycarbonyl or p-methoxyl carbobenzoxy. The compound does not contain a protective group or only contains one protective group, and can be directly connected with a mother nucleus compound to prepare Doripenem, so that the utilization efficiency of a mother nucleus is improved, the operation is simplified, the hydrogenation reaction efficiency is improved, the manufacture cost of a product is reduced, in addition, the side-chain compound is a crystal so as to have better material attributes including stability, separability or purity, the crystal is reacted with the mother nucleus compound to obtain the Doripenem with high quality, and the advantages of convenience in purification, low cost and convenience in direct use are provided. In addition, the invention provides a preparation method of the Doripenem side-chain compound, which has the advantages of simpleness in operation, and the like, and is suitable to be applied in factories in a large scale. The invention also provides application of the Doripenem side-chain compound in the preparation of Doripenem.

Description

technical field [0001] The invention relates to a doripenem side chain compound and a preparation method thereof. Background technique [0002] Doripenem, the structure is shown in (I), chemical name: (+)-(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl- 7-oxo-3-[[(3S,5S)-5-[(aminosulfonylamino)-methyl]-3-pyrrolidinyl]sulfur]-1-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid is a new type of broad-spectrum carbapenem antibiotic developed by Shionogi Corporation of Japan, which was first launched in Japan in December 2005. It is usually prepared by condensation reaction of carbapenem core (II) and side chain compound (III) to obtain compound (IV), and then catalytic hydrogenation to remove the protective group, as shown below: [0003] [0004] (PNB=p-O 2 NC 6 h 4 CH 2 ) [0005] In recent years, various doripenem side chain structures and preparation methods thereof have been developed. Japan Shionogi Company (Organic Process Research & Development, 2003, volume 7, pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/12C07D477/20C07D477/06
CPCY02P20/55
Inventor 卢兆强龙利松李广成吕志立丁诚吴聪泉付立珍梁婷
Owner SHENZHEN HAIBIN PHARMA
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