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Prepn of carbapenum type antibiotic Faropenum sodium

A technology of faropenem sodium and compounds, which is applied in the field of preparation of carbapenem antibiotic faropenem sodium, and can solve the problems of complex preparation, low yield, harm to human body and environment, etc.

Active Publication Date: 2007-01-03
SHANGHAI NEW ASIA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But above-mentioned method reaction yield is lower, and total yield is only 12.5%.
At the same time, the side chain 3 is a mercapto compound, which has a very smelly smell and is complicated to prepare. It needs to be continuously injected with toxic gas hydrogen sulfide to obtain it, which is harmful to the human body and the environment.
In addition, during the reaction process, triphenylphosphine is used for intramolecular Witting cyclization, and the main and by-products of penem are difficult to separate and the yield is low, which is not conducive to industrial production.

Method used

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  • Prepn of carbapenum type antibiotic Faropenum sodium
  • Prepn of carbapenum type antibiotic Faropenum sodium
  • Prepn of carbapenum type antibiotic Faropenum sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1. Preparation of (3S, 4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-tritylthio-azetidin-2-one (III )

[0089]

[0090] Dissolve 7.65g of sodium hydrogen in 164ml of DMF, add dropwise to 52.77g of triphenylmercaptan (294.35) / 287ml of DMF solution at 0°C, add dropwise within 0.5 hours, stir the mixture for 10 minutes, then add within 15 minutes 50g 4AA / 164ml DMF solution, kept at 0°C, continued to stir for 45 minutes, poured the reaction mixture into 900g of saturated ammonium chloride ice solution, extracted with 1000ml of ether (three times), washed the ether layer twice with water, and washed with saturated brine Twice, dried over anhydrous sodium sulfate, evaporated to dryness, and the solid residue was washed twice with 300ml ether, sucked dry, dried, and weighed to obtain 72g of solid, with a yield of 82.2%. Melting point: 94-96°C

[0091] TLC: petroleum ether: ethyl acetate = 4: 1 Rf = 0.3

Embodiment 2

[0092] Example 2. Preparation of (3S, 4R)-1-(allyloxyoxalyl)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4tritylthio-nitrogen Heterobutan-2-one (IV)

[0093]

[0094]

[0095] In a 1000ml three-neck flask, add 50g "III" and 50ml dichloromethane to dissolve, cool to -10°C in an ice-salt bath, add dropwise a solution of 25g allyl oxalyl chloride in dichloromethane (40ml), and then drop Add a solution of 18g of triethylamine in dichloromethane (40ml), keep the dropwise addition temperature not exceeding -5°C, react the mixture at -5°C--10°C for 1.5 hours, add water (150ml) to dilute, and dichloromethane (100ml) Extracted, combined organic phases, washed with water, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 58 g of a light yellow solid with a yield of 95%.

[0096] TLC: petroleum ether: ethyl acetate = 4: 1 Rf = 0.4

Embodiment 3

[0097] Example 3. Preparation of (3S, 4R)-1-(allyloxyoxalyl)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-thiosilver-aza Cyclobutan-2-one (V)

[0098]

[0099] The above product "IV" was dissolved in 1000ml of methanol, and 2ml (25mmol) of pyridine and a solution of silver nitrate (100g) in methanol (500ml) were added. The mixture was stirred at below 10°C in the dark for 3 hours, concentrated and extracted with dichloromethane (1000ml). The organic layer was washed with water (800ml), dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain the silver salt. It was directly used in the next reaction without purification.

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Abstract

The present invention provides Faropenum sodium preparing process, and the preparation process has short reaction path, no use of strong stimulating substance sulfhydryl compound and chlorosulfoxide, mild reaction condition, no need of purifying intermediate product and simple operation and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry. Specifically relates to a preparation method of carbapenem antibiotic faropenem sodium. Background technique [0002] Carbapenems are a new group of β-lactam antibiotics. Their structures are different from traditional β-lactam products such as penicillins and penems. Their mother nucleus is different from other penicillins and penems. On the 5-membered ring, sulfur is replaced by carbon, and there is a C=C double bond between the 2 and 3 positions. In addition, its 6-hydroxyethyl side chain is in trans conformation. Studies have shown that it is this group with a special configuration that makes this type of compound highly stable to β-lactamase. Significantly different from the usual cis conformation of penems. This class of antibiotics has the characteristics of a broad antibacterial spectrum, and is effective against G + and G - Bacteria, aerobic bacteria, and anaerobic bact...

Claims

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Application Information

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IPC IPC(8): C07D499/86C07D499/06
Inventor 柯慧商鼎刘红管海蓉
Owner SHANGHAI NEW ASIA PHARMA
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