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Method for preparing protected meropenem

A technology for meropenem and a compound, which is applied in the field of synthesizers in the field of medical technology, can solve the problems of low yield of meropenem, difficult to obtain raw material c, unfavorable sustainable development, etc., and achieves high molar yield, low cost, and high production efficiency. Easy-to-use effects

Active Publication Date: 2011-01-26
江西如益科技发展有限公司
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0010] The above-mentioned Sumitomo Pharma Leaticds Co., Ltd's route raw material is simple and easy to get, but compound (d) has considerable weight of optical isomers to be separated, and multiple intermediates need to be separated, thus affecting the yield, the route step of Lederle Ltd Correspondingly simple, but the raw material c is not easy to obtain and the cost is high
[0011] On the basis of the above two preparation methods, Chinese patent application 200610083362.7 once developed a three-step "one-pot cooking" method to prepare meropenem, which simplifies the operation and reduces the separation of intermediates, but the preparation of the above compound (IV) requires column purification , while preparing above-mentioned compound (III), need a large amount of 10% sodium dihydrogen phosphate to adjust pH value, need to use toxic solvent acetonitrile when preparing above-mentioned compound (II), and anhydrous mono-p-nitrobenzyl malonate magnesium salt It is difficult to prepare, and the yield of preparation protection meropenem is not high, and the content is not high, which leads to impurities being carried to the finished product during the preparation of meropenem. Therefore, in large-scale production, the preparation cost is still high, which is not conducive to sustainable development

Method used

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  • Method for preparing protected meropenem
  • Method for preparing protected meropenem
  • Method for preparing protected meropenem

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0033] Example 1, compound (II) is also (3S, 4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4[(1R)-1-methyl-3- Synthesis of PNB oxycarbonyl-2-ketopropyl]-azetidin-2-one:

[0034] 50g (3S, 4R-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-[(1R)-1-methyl-1-carboxyethyl]-azacycline Butan-2-one, that is, compound (I), was added to 750ml of dichloromethane, and 34g of carbonyldiimidazole was added under stirring, and stirred at room temperature for 30min, and then 16.0g of anhydrous magnesium chloride, 34.0g of triethylamine, p-nitrogen 70g of benzyl alcohol malonate monoester, after the feeding is completed, the temperature is raised to 40-43°C, and the reaction is refluxed for 6.0h. After the reaction is completed by HPLC tracking, compound (II) is generated. After the reaction is completed, cool to 15-20°C, and add dropwise 1200g of 5% hydrochloric acid, temperature control 15-20°C, stirring and static layering after the dropwise addition, the organic phase is washed with salt water ...

Embodiment 2

[0035] Example 2, compound (III) is (3S,4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-[(1R)-1-methyl-3 - Synthesis of diazo-3-PNBoxycarbonyl-2-ketopropyl]-azetidin-2-one.

[0036] Add 200ml of water to the flask, add 15.0g of sodium azide, stir to dissolve, add dropwise 25.0g of methanesulfonyl chloride at 15-20°C for about 30 minutes, add 200ml of acetone to make it, and control the temperature for 15-20°C Stir and react at 20°C for 2.0h, then cool down to 0-5°C and add compound (II) acetone solution of Example 1, stir and react at 0-5°C for 8.0h, after the reaction is complete, add 250ml of water dropwise within 30 minutes. After the addition, keep stirring at about 5°C for 1 hour; centrifuge and dry to obtain about 102 g of compound (III) as a light yellow to orange solid, which is directly fed downward.

Embodiment 3

[0037] Example 3, compound (IV) is (3S, 4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3-diazo-3-PNB Synthesis of oxycarbonyl-2-ketopropylbuta]-azetidin-2-one.

[0038] The compound (III) obtained in Example 2 was dissolved in methanol, and then 21.0 g of methanesulfonic acid was added dropwise, the temperature was controlled at 20-25° C., and the reaction was carried out under stirring for 8.0 h. After the completion of the reaction was followed by HPLC, compound (VI) was generated. After recovering methanol under reduced pressure, add 600ml of ethyl acetate and stir to dissolve, wash the organic phase with water, then wash with saturated brine, then wash with 100ml of 1.5% sodium bicarbonate by mass percentage, combine the organic phases, add activated carbon and anhydrous magnesium sulfate for decolorization , dry, filter, and then reclaim the extraction solvent under reduced pressure to dryness, add 120ml of ethyl acetate to dissolve, stir and dissolve at 15-20°C, add 1g of se...

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Abstract

The invention provides protected meropenem synthesized under simple conditions. In the invention, a compound (I) is reacted with mono-4-nitrobenzyl malonic acid ester and magnesium chloride to form a compound (II) product; the compound (II) is diazotized to form a compound (III) product; the compound (III) is dehydrated by methanesulfonic acid to obtain a compound (IV) product; the compound (IV) is cyclized to form a compound (V) product, and 4-dimethylaminopyridine, diphenyl chlorophosphate and N,N-diisopropylethylamine are added in turn to participate in reactions to form a product (VI) product; and N,N-diisopropylethylamine and (2S,4S)-2-dimethylaminocarbonyl-4-thio-1-(p-nitrobenzyloxycarbonyl)pyrrolidine are added to participate in a reaction to obtain a compound (VII) product. The method has the advantages that: the cost as well as 'waste gas, liquid and solid' are reduced, the operation is convenient, and the post-treatment is simple; and the total molar yield of the six-step reactions is more than or equal to 74 percent, so the method is easy to industrialize.

Description

technical field [0001] The invention relates to a synthesis method in the technical field of medicine, in particular to a preparation method of protected meropenem. Background technique [0002] Carbon represented by meropenem (molecular formula A) (Sumitomo Pharma Leaticds Co., Ltd), imipenem (molecular formula B) (Nurch & Co Inc) and biapenem (molecular formula C) (Lederle Ltd) Because of its broad-spectrum antibacterial activity, penem antibiotics have received extremely wide attention since they were discovered. Finding efficient preparation methods has always been one of the research priorities and hotspots in the academic and industrial circles. [0003] [0004] After years of hard work, various methods have been developed for the preparation of the β-methylcarbapenem antibiotic core. Among them, the representative synthetic routes mainly include the following two: [0005] One is the disclosed reaction scheme of Sumitomo Pharma Leaticds Co., Ltd disclosed in US49...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06
Inventor 刘雨林宋志刚周强唐松青陶义
Owner 江西如益科技发展有限公司
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