Chemical synthesis method for azithromycin intermediate

A technology for azithromycin and intermediates, applied in the field of chemical synthesis of azithromycin intermediates, can solve problems such as side reactions, expensive electrolysis equipment, potential safety hazards and the like

Active Publication Date: 2020-01-14
QINGDAO AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method (1) has expensive catalyst and high pressure conditions, high cost and potential safety hazards, so it is not suitable for industrial production; and method (2) uses expensive electrolysis equipment, high cost and is not suitable for large-scale production; patent US4328334 discloses with NaBH 4 A method for the reduction of erythromycin 6,9-imine ether in methanol solution at 4°C, which requires a large excess of NaBH 4 , and the reduction product exists in the form of boric acid complex, which needs to be further hydrolyzed with inorganic acids such as hydrochloric acid, which induces side reactions and produces a large amount of impurities, which is not suitable for industrial production
Patent CN1625560A has announced the use of a small amount of NaBH 4 The method of reducing erythromycin 6,9-imine ether and citric acid acidic solution to process the reaction mixture can obtain 9-deoxy-9a-aza-9a-homoerythromycin A (actual There are two functions of citric acid: on the one hand, it is acidic to hydrolyze the reduction product in the form of boric acid complex; Oxygen-9a-aza-9a-homoerythromycin A complexes with boric acid again under alkaline conditions), but it is very difficult to recover citric acid in the reaction mixture, so there is no industrial prospect

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0007] Add erythromycin 6,9-imine ether (40g, 55mmoL) into a 500mL three-necked flask, add 200mL methanol and stir to dissolve, cool to 0°C, add (8.9g, 165mmol) KBH in batches 4 and (1.99g, 5.5mmoL), the temperature was controlled not higher than 5°C, and the reaction was stirred for 2h. Add 200mL of water to the reaction mixture, adjust the pH of the solution to 3 with 10% hydrochloric acid, stir for 30min, add 100mL of isobutyl acetate and 45g of IRA-743 resin, then adjust the pH to 9.5 with 20% sodium hydroxide solution, and stir for 15min Afterwards, the resin was collected by filtration, the filtrate was allowed to stand for stratification, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 38.2 g of a white foamy solid, with a yield of 93%.

Embodiment 2

[0009] Add erythromycin 6,9-imine ether (80g, 110mmoL) into a 1L three-necked flask, add 400mL of methanol and stir to dissolve, cool to 0°C, add (17.8g, 330mmol) of KBH in batches 4 and (3.98g, 11mmoL), the temperature was controlled not higher than 5°C, and the reaction was stirred for 2h. Add 400mL of water to the reaction mixture, adjust the pH of the solution to 3 with 10% hydrochloric acid, stir for 30min, add 200mL of isopropyl acetate and 90g of ZXC-700 resin, then adjust the pH to 9.5 with 20% sodium hydroxide solution, and stir for 15min Afterwards, the resin was collected by filtration, the filtrate was allowed to stand for stratification, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 76 g of a white foamy solid, with a yield of 92.8%.

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PUM

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Abstract

The invention relates to a chemical synthesis method for an azithromycin intermediate. According to the chemical synthesis method for the azithromycin intermediate,erythromycin 6,9-imino ether is usedas a raw material and reduced by potassium borohydride and zinc trifluoromethanesulfonate, hydrolysis is assisted through IR.A-743 or ZXC-700 resin, and 9-deoxo-9-alpha-aza-9[alpha]-homoerythromycinA is obtained with a high yield.

Description

technical field [0001] The invention relates to a chemical synthesis method for preparing azithromycin intermediate 9-deoxy-9a-aza-9a-homoerythromycin A. Background technique [0002] Azithromycin is a semi-synthetic azamacrolide antibiotic, which can be synthesized through its precursor 9-deoxy-9a-aza-9a-homoerythromycin A, and its method is to 9-deoxy-9a- Aza-9a-homoerythromycin A undergoes nitrogen methylation at position 9a to obtain azithromycin. Therefore, 9-deoxy-9a-aza-9a-homoerythromycin A is a key intermediate in the synthesis of azithromycin and is crucial to the synthesis of azithromycin. [0003] The synthesis of 9-deoxy-9a-aza-9a-homoerythromycin A is obtained by reduction of erythromycin 6,9-imine ether. There are three ways to achieve this reductive transformation: (1) erythromycin 6,9-imine ether with PtO 2 It is obtained by hydrogenation reduction of catalyst under high pressure; (2) obtained by electrochemical reduction in an inert atmosphere; (3) obtai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H17/00
CPCC07H1/00C07H17/00
Inventor 李玉文马翠丽刘艳娣
Owner QINGDAO AGRI UNIV
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