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Preparation method of faropenem

A technology of faropenem and tert-butyldimethylsiloxyethyl, which is applied in the field of pharmaceutical synthesis, can solve the problems of unfavorable large-scale industrial production, excessive heavy metal residues and high cost, and achieves shortened production cycle, high reaction yield and cost. low effect

Active Publication Date: 2013-04-24
SUZHOU ERYE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Need to use a large amount of tetrabutylammonium fluoride and [tetrakis (triphenylphosphine)] palladium and triphenylphosphine when removing above-mentioned protecting group, these reagents cost height, toxicity is big, is unfavorable for large-scale industrial production, and will The introduction of heavy metal palladium makes the heavy metal residues in faropenem exceed the standard, which is not suitable for the production of raw materials
Moreover, when the above method is used to remove the protecting group, the yield of each step can only reach 60%-75%, which further increases the production cost

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0027] Preparation of tert-butoxyoxalyl chloride

[0028] Mix tert-butanol (89g, 1.2mol) and an appropriate amount of triethylamine (139g, 1.25mol) and dissolve in 300mL of dichloromethane, slowly add dropwise to oxalyl chloride diluted with 200mL of dichloromethane at -10°C ( 152g, 1.2mol), the dropwise addition temperature was controlled within the range of -10~0°C, and the dropwise addition was completed within 2 hours. Maintain the reaction at -10~0°C for 1 hour, stop the reaction, and let the temperature rise to room temperature naturally. The reaction solution was distilled under reduced pressure to obtain 164 g of tert-butoxyoxalyl chloride, which was detected by gas chromatography with a purity of 95%.

Embodiment 2

[0030] (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-tetrahydrofuran-2-formylthio]azetidin-2- Preparation of Ketone (Intermediate 1)

[0031] Dissolve R-(+)-thiotetrahydrofuran-2-carboxylic acid (158g, 1.2mol) in 100mL of dichloromethane, dilute triethylamine (139g, 1.25mol) with 50mL of dichloromethane and add dropwise to In the above solution, the pH value was 9 after dropping, and the stirring was continued for 0.5 hour, and it was set aside.

[0032] (3R, 4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-acetoxy]azetidin-2-one (287g, 1mol) was dissolved in 500mL of dichloromethane, zinc chloride (142g, 1.045mol) was added at room temperature, after stirring for 15 minutes, triethylamine of R-(+)-thiotetrahydrofuran-2-carboxylic acid prepared above was added For salt, the temperature during the dropwise addition should not be higher than 30°C. After dropping, react at room temperature for 8 hours. Stop the reaction, pour the reaction solution into 1000mL 3% so...

Embodiment 3

[0034] (3R,4R)-1-tert-butoxyoxalyl-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-tetrahydrofuran-2-formyl Preparation of Thio]azetidin-2-one (Intermediate 2)

[0035] Intermediate 1 (323g, 0.9mol) was dissolved in 500mL of dichloromethane, cooled to -10°C, tert-butoxyoxalyl chloride (164g, 0.95mol) prepared in Example 1 was added dropwise, and the dropwise was completed. Triethylamine (145mL, 1.04mol) was diluted with 200mL of dichloromethane and added dropwise to the above reaction solution, the rate of addition was controlled so that the internal temperature was not higher than -5°C. After dropping, keep the reaction for 1.5 hours, stop the reaction, wash with water, 5% sodium bicarbonate solution, and saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a light yellow oil, which is recrystallized from dichloromethane / petroleum ether , to obtain 414.5 g of pale yellow needle-like crystals. 1 H-NMR (CDCl3, 500MHz) δ: 0.41 (s, 6H), 1.01 (s, 9H), 1.3...

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Abstract

The invention relates to a preparation method of faropenem. The invention discloses a method for preparing faropenem by removing hydroxy and carboxyl protecting groups by one step, which comprises the following steps: (1) condensing (3R,4R)-3-[(R)-1-tert-butyl-dimethylsiloxyethyl]-4-[(R)-acetoxy]azacyclobutyl-2-one and R-(+)-thiotetrahydrofuryl-2-formic acid by using zinc halide as a catalyst to obtain an intermediate 1; (2) carrying out acylation reaction on the intermediate 1 and tert-butoxyoxalyl chloride by using alkali as a catalyst to obtain an intermediate 2; (3) cyclizing the intermediate 2 under the action of triethyl-phosphite to obtain an intermediate 3; and (4) simultaneously removing hydroxy and carboxyl protecting groups from the intermediate 3 under the action of trifluoroacetic acid, and neutralizing with alkali to obtain the faropenem. The preparation method disclosed by the invention can remove the protecting groups on hydroxy and carboxyl groups by one step, shortens the production cycle, has the advantages of low cost and low toxicity of deprotection reagents, can not generate heavy metal residues, has higher reaction yield, and is very suitable for industrial production of active pharmaceutical ingredients.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of faropenem. [0002] Background technique [0003] Faropenem, the chemical name is (5R, 6S )-6-[(1R)-hydroxyethyl]-2-[(2R)-tetrahydrofuran] penem-3-carboxylic acid monosodium salt, produced by Japan Suntory was first developed and marketed in 1997. The drug is an atypical β-lactam penem antibiotic with strong antibacterial activity, especially against Gram-positive bacteria such as Staphylococcus aureus, penicillin-resistant pneumococcus, streptococcus faecalis and Bacteroides fragilis, etc. The antibacterial activity of anaerobic bacteria is obviously higher than that of existing cephalosporins, and the activity against Gram-negative bacteria is similar to that of oral cephalosporins, and it is stable to various β-lactamases. Various clinical studies have shown that the drug has the advantages of good clinical effect, high safety, and little neph...

Claims

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Application Information

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IPC IPC(8): C07D499/893C07D499/16
CPCY02P20/55
Inventor 朱炜陈学文刘志陆文娟陆夕明
Owner SUZHOU ERYE PHARMA CO LTD
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