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Process for the preparation of sodium faropenem

A technology of faropenem sodium and its synthesis method, which is applied in the field of drug synthesis, can solve problems such as heavy metal residues, high price, and limited application, and achieve the effects of improved multi-step synthesis process, simple operation, and shortened reaction time

Inactive Publication Date: 2006-12-27
ZHEJIANG JINHUA CONBA BIO PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route avoids the unstable epoxybutyric acid, and the synthetic route is stereospecific; but the key steps of ring formation, ring opening and ring formation will use 2 equivalents of expensive lithium hexamethyldisilazide (LiHMDS); the Reagents are afraid of water and oxygen, require strict anhydrous operation, and carry out in an inert gas atmosphere, which is expensive
This method also uses heavy metal lead salt as an oxidant, which brings the problem of heavy metal residue that is difficult to solve
Moreover, most of the synthesized intermediates are viscous liquids, which must be purified by column chromatography, and the process is cumbersome, which limits the industrial application of this method

Method used

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  • Process for the preparation of sodium faropenem
  • Process for the preparation of sodium faropenem
  • Process for the preparation of sodium faropenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: (2S,3R)-2-bromo-3-hydroxybutyric acid

[0040] In a 2000 mL three-neck flask, add L-threonine (100 g, 0.84 mol), potassium bromide (300 g, 2.52 mol), and 2M sulfuric acid solution (1200 mL) in sequence, and cool to 0°C. An aqueous solution of sodium nitrite (90 g, 1.3 mol) dissolved in water (250 mL) was added dropwise, the internal temperature was controlled at 0-5° C., and the dropwise addition was completed. Stir at room temperature for 2 hours. It was extracted with ethyl acetate (300 mL×5), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 139 g of the title compound in the form of light yellow viscous. The yield of crude product is 90.4%. The product was directly used in the next reaction without purification.

Embodiment 2

[0041] Example 2: (2S, 3R)-2-bromo-3-hydroxyl-N-(4'-methoxyphenyl)butanamide

[0042] In a 1000mL three-necked flask, (2S, 3R)-2-bromo-3-hydroxybutyric acid (70 grams, 0.38mol), tetrahydrofuran (500mL), and isopropyl chloroformate (47.5 grams, 0.38mol). After cooling to -5°C, triethylamine (38.5 g, 0.38 mol) was added dropwise first, and then a solution of p-methoxyaniline (47 g, 0.38 mol) dissolved in tetrahydrofuran (200 mL) was added dropwise. After the dropwise addition was complete, stirring was continued for 30 minutes. Filter and concentrate. Ethyl acetate (500 mL) was added, followed by washing with 0.5 molar aqueous hydrochloric acid solution (50 mL×3), saturated aqueous sodium chloride solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL), and saturated aqueous sodium chloride solution (100 mL). Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain 98 g of the title compound as a dark yellow solid, and the yi...

Embodiment 3

[0043] Embodiment 3: (2R, 3R)-N-(4'-methoxyphenyl)-2,3-epoxybutanamide

[0044] In a 1000mL three-necked flask, add (2S, 3R)-2-bromo-3-hydroxyl-N-(4-methoxyphenyl)butanamide (98 grams, 0.34mol) prepared in Example 2, and Sodium (20 g, 0.5 mol), tetrahydrofuran (500 mL). Stir vigorously at room temperature for 3 hours and concentrate. Ethyl acetate (500 mL) was added, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL×3) successively. Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, add 100 mL of isopropyl ether, cool, and solidify to obtain 62 g of the title compound as a yellow solid, with a crude yield of 88%. The product was directly used in the next reaction without purification.

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Abstract

The invention provides a method for preparing penicillenic antibiotics faropenem sodium Iwhich takes natural L-threonine as raw material, and method for preparing important intermediate II. The invention is characterized by high productivity, low cost, simple operation, easy post treatment and suitability for industrialization.

Description

Technical field: [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of faropenem sodium. Background technique: [0002] Faropenem sodium is a new oral antibacterial drug. It acts not only on bacteria that are in the reproductive stage, but also on established bacteria. The remarkable advantage of this drug is that it also has a bactericidal effect on bacteria in a static state. Compared with cephalosporin and penicillin, it has a wider antibacterial spectrum, and it has a broad-spectrum antibacterial effect on aerobic and anaerobic Gram-positive bacteria and most Gram-negative bacteria except Pseudomonas aeruginosa; especially for Staphylococcus aureus bacteria, Gram-positive bacteria such as Enterococcus faecalis (E. Existing oral cephalosporins such as cefaclor. The antibacterial activity against staphylococcus, streptococcus, influenza bacillus, Neisseria gonorrhoeae, catarrhal bacillus and many other Gram-posi...

Claims

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Application Information

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IPC IPC(8): C07D499/06
Inventor 宓爱巧程丽曾彪王元桦余斌金庆平
Owner ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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