阅读说明：本技术 一种阿奇霉素中间体的化学合成方法 (Chemical synthesis method of azithromycin intermediate ) 是由 李玉文 马翠丽 刘艳娣 于 2018-07-05 设计创作，主要内容包括：本发明涉及一种阿奇霉素中间体的化学合成方法,具体以红霉素6,9-亚胺醚为起始原料通过硼氢化钾和三氟甲磺酸锌还原,经IR.A-743或ZXC-700树脂辅助水解,高收率得到9-脱氧-9-α-氮杂-9α-同型红霉素A。(The invention relates to a chemical synthesis method of an azithromycin intermediate, which specifically comprises the steps of reducing erythromycin 6, 9-imino ether serving as a starting raw material by potassium borohydride and zinc trifluoromethanesulfonate, carrying out assisted hydrolysis by IR.A-743 or ZXC-700 resin, and obtaining 9-deoxy-9-alpha-aza-9 alpha-homoerythromycin A with high yield.)

1. The synthesis of an azithromycin intermediate, namely 9-deoxy-9-a-aza-9 a-homoerythromycin A, comprises the following steps:

(1) using 2-3 molar equivalents of KBH at 0-5 deg.C₄And 0.1 molar equivalent of zinc trifluoromethanesulfonate is used for reducing erythromycin 6, 9-imino ether dissolved in methanol, the reaction is carried out for 2 hours, 12 percent of boric acid complex reduction product generated by hydrochloric acid hydrolysis is added into the solution after the reaction, then boron complex resin is added, then alkali liquor is used for neutralization to reach the pH =9-10, the resin is collected by filtration, the filtrate is extracted by organic solvent, 9-deoxo-9 a-aza-9 a-homoerythromycin A can be obtained with high yield, the resin obtained by filtration and complexed with boric acid can be treated by acid to obtain boric acid and free resin, the resin can be recycled after regeneration, and the boric acid can be recycled as a by-productThe reduction method is economical, environment-friendly and suitable for industrial production.

2. The boron complex resin of claim 1, wherein said boron complex resin is Amberlite IRA743 or ZXC-700 in KBH₄3-5 times of the dosage (mass).

3. The method according to claim 1, wherein the organic solvent is selected from isopropyl acetate and isobutyl acetate.

Technical Field

The invention relates to a chemical synthesis method for preparing an azithromycin intermediate 9-deoxidation-9 a-aza-9 a-homoerythromycin A.

Background

Azithromycin is semi-synthetic azamacrolide antibiotic, can be synthesized from a precursor 9-deoxo-9 a-aza-9 a-homoerythromycin A, and is obtained by performing nitrogen methylation reaction on 9-deoxo-9 a-aza-9 a-homoerythromycin A at the 9a position. Therefore, the 9-deoxidation-9 a-aza-9 a-homoerythromycin A is a key intermediate for synthesizing the azithromycin and is very important for the synthesis of the azithromycin.

The synthesis of 9-deoxo-9 a-aza-9 a-homoerythromycin A is carried out by reducing erythromycin 6, 9-imino ether. There are three ways in which this reductive transformation can be achieved: (1) reacting erythromycin 6, 9-imino ether with PtO₂Is obtained by high-pressure hydrogenation reduction of a catalyst; (2) electrochemically reducing in inert atmosphere to obtain the final product; (3) reducing with sodium borohydride in methanol solvent. The method (1) has expensive catalyst and high pressure condition, and has high cost and potential safety hazard, so the method is not suitable for industrial production; the electrolysis equipment used in the method (2) is expensive, has high cost and is not suitable for large-scale production; patent US4328334 discloses the use of NaBH₄Method for reducing erythromycin 6, 9-imino ether in methanol solution at 4 DEG CMethod which requires a large excess of NaBH₄And the reduction product exists in the form of boric acid complex, further hydrolysis is needed by using inorganic acid such as hydrochloric acid, side reaction is induced by hydrolysis, a large amount of impurities are generated, and the method is not suitable for industrial production. Patent CN1625560A discloses the use of small amounts of NaBH₄The method for treating the reaction mixture by reducing the erythromycin 6, 9-imino ether and citric acid acidic solution can obtain 9-deoxo-9 a-aza-9 a-homoerythromycin A (actually, citric acid has the action of two, namely, the acid hydrolyzes the reduction product existing in the form of boric acid complex on one hand, and the citric acid is used as a chelating agent to chelate boric acid in the process of neutralizing the reaction solution with alkali to avoid the hydrolyzed free 9-deoxo-9 a-aza-9 a-homoerythromycin A from complexing the boric acid again under the alkali condition), but the citric acid is very difficult to recover from the reaction mixed solution, so that the method has no industrial prospect.

Aiming at the defects existing in the reduction process, the optimization of the reduction process condition is the key for synthesizing 9-deoxidation-9 a-aza-9 a-homoerythromycin A.

Disclosure of Invention

The invention aims to provide a high-efficiency, environment-friendly and economic preparation method for synthesizing an azithromycin intermediate 9-deoxo-9 a-aza-9 a-homoerythromycin A. The method comprises the following specific steps: (1) using 2-3 molar equivalents of KBH at 0-5 deg.C₄And 0.1 molar equivalent of zinc trifluoromethanesulfonate, reducing erythromycin 6, 9-imino ether dissolved in methanol, reacting for 2 hours, adding 10% of hydrochloric acid into the solution after the reaction to hydrolyze the generated boric acid complex reduction product, then adding Amberlite III RA743 or ZXC-700 resin, then neutralizing the solution with alkali liquor to pH =9-10, filtering and collecting the resin, extracting the filtrate with isopropyl acetate or isobutyl acetate to obtain 9-deoxo-9 a-aza-9 a-homoerythromycin A with high yield, performing acidic treatment on the boric acid-complexed resin obtained by filtering to obtain boric acid and free resin, wherein the free resin can be recycled after regeneration, and the boric acid can be recycled as a byproduct.

Detailed Description