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Novel acylide derivative and preparing method thereof

A technology of acyl lactones and derivatives, which is applied in the fields of chemical synthesis and pharmaceuticals, and can solve problems such as unsatisfactory anti-drug-resistant bacteria activity

Inactive Publication Date: 2015-10-07
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compared with the corresponding ketolides, the anti-drug-resistant bacteria activity of the disclosed acyl lactones is not ideal yet.

Method used

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  • Novel acylide derivative and preparing method thereof
  • Novel acylide derivative and preparing method thereof
  • Novel acylide derivative and preparing method thereof

Examples

Experimental program
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preparation example Construction

[0101] The present invention also provides a preparation method of novel acyl lactone derivatives, the specific steps comprising:

[0102] Step 1. Dissolve the compound of general formula (1) in acetonitrile, add aryl bromide, cuprous iodide, bis(triphenylphosphine)palladium dichloride and triethylamine to react at 80°C for 4h, Obtain as the compound of general formula (2);

[0103] Step 2. Dissolve the compound of general formula (2) in dichloromethane, add 2-pyridineacetic acid hydrochloride, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and pyridine and react at 0°C for 1h After that, continue to react at 15-25°C for 4-24h;

[0104] Step 3, dissolving the reaction product of step 2 in methanol, and refluxing at 65° C. for 3 h to obtain a compound having general formula (3);

[0105]

[0106] In the embodiment of the present invention, preferably, in the general formula (2) and the general formula (3),

[0107] The groups represented by R in the general formula (2)...

example 1

[0156] First preparation: 2'-O-acetyl-3-O-descladinose-3-hydroxy-6-O-methylerythromycin A9-O-[3-(3'-(6'-nitro )pyridyl)-2-propynyl]oxime-11,12-cyclocarbonate (2a)

[0157] Dissolve 1.00 g (1.41 mmol) of compound 1 in acetonitrile (10 mL), add bis(triphenylphosphine) palladium dichloride (51 mg, 0.073 mmol), cuprous iodide (27 mg, 0.014 mmol), triethylamine (0.30 mL, 2.11 mmol), 2-nitro-5-bromopyridine (865 mg, 4.26 mmol). The reaction system was replaced with argon gas 8 times, and stirred in an oil bath at 80° C. for 4 h under the protection of argon gas. After the reaction was completed, distilled water (10 mL) was added to terminate the reaction, extracted twice with ethyl acetate (20 mL), the upper organic phase was washed with saturated brine (10 mL), and distilled under reduced pressure to obtain a dry solid. Compound 2a (248 mg, 0.30 mmol, 21.3%) was obtained by column chromatography (100-200 mesh silica gel, mobile phase V (dichloromethane): V (ethanol): V (ammonia) ...

example 2

[0166] First preparation: 2'-O-acetyl-3-O-descladinose-3-hydroxy-6-O-methylerythromycin A9-O-[3-(2'-(6'-amino) Pyridyl)-2-propynyl]oxime-11,12-cyclocarbonate (2b)

[0167] Dissolve 1.00 g (1.41 mmol) of compound 1 in acetonitrile (10 mL), add bis(triphenylphosphine) palladium dichloride (51 mg, 0.073 mmol), cuprous iodide (27 mg, 0.014 mmol), triethylamine (0.30 mL, 2.11 mmol), 2-amino-6-bromopyridine (731 mg, 4.22 mmol). The reaction system was replaced with argon gas 8 times, and stirred in an oil bath at 80° C. for 4 h under the protection of argon gas. After the reaction was completed, distilled water (10 mL) was added to terminate the reaction, extracted twice with ethyl acetate (20 mL), the upper organic phase was washed with saturated brine (10 mL), and distilled under reduced pressure to obtain a dry solid. Compound 2b (291 mg, 0.36 mmol, 25.5%) was obtained by column chromatography (100-200 mesh silica gel, mobile phase V (dichloromethane): V (ethanol): V (ammonia) ...

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Abstract

The invention provides a novel acylide derivative which has a general formula I or a general formula II or which is an acceptable salt or ester composed of a compound having the general formula I or the general formula II and an inorganic acid or organic acid. The novel acylide derivative according to the embodiment has a novel structure and has excellent antibacterial activity on clinically common sensitive bacteria and drug resistant bacteria, and part of compounds of the novel acylide derivative are as good as or better than telithromycin in inhibitory and bactericidal activity. The existing knowledge about the structure-activity relation of acylides is broken through, the novel acylide derivative having bactericidal activity is provided and is as good as the telithromycin in the market in activity, and the novel acylide derivative is easy to industrially produce. Researches show that targets of the acylides acting on bacterial ribosomes are different from those of ketolides. In total, compared with the prior ketolides having defects, the novel acylide derivative has better market prospect in resisting drug resistant bacteria.

Description

technical field [0001] The invention relates to the fields of chemical synthesis and pharmacy, in particular to a novel acyl lactone derivative and a preparation method of the novel acyl lactone derivative. Background technique [0002] Fourteen-membered macrolide antibiotics-erythromycin (erythromycin) is a very important drug for the treatment of respiratory tract infections. It has provided humans with an efficient and safe way to use drugs for half a century. play an irreplaceable role. At present, more and more strains of respiratory pathogens isolated clinically show drug resistance, such as Streptococcus pneumoniae (S.pneumoniae), Staphylococcus aureus (S.aureus) and Streptococcus pyogenes (S.pyogenes). Although the second-generation erythromycin-clarithromycin and azithromycin, which appeared in the 1980s, have good pharmacokinetic properties, they have no antibacterial activity against erythromycin-resistant bacteria. Pneumonia caused by drug-resistant bacteria is...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00A61P31/04
Inventor 梁建华韩煦郭斯阳
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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