Method for synthesizing Arbekacin and intermediate dibekacin thereof

Abstract

The invention relates to an organic synthesis method, in particular to a method for synthesizing an Arbekacin and an intermediate dibekacin thereof. The method comprises the following steps of: takinga kanamycin B as initial raw material, carrying out the following processes of aldol condensation, sulfonylation, sodium iodide replacement and elimination to form double bond, de-protection under acidic condition, amino-electron reduction and final hydrogenation, thus obtaining the dibekacin; taking 3',4'-dideoxy -3',4'-didehydro-kanamycin B as raw material, using a di-tert-butyl dicarbonate toselectively protect the amidogen of 3, 2', 6', 3'' sites; subsequently using the synthesized active ester to protect the 1-site amidogen; subsequently using tri-fluoroacetic acid to remove BOC; and carrying out hydrazinolysis and catalysis and hydrogenation of platinum oxide, thus obtaining the Arbekacin. The synthesis method has the advantages of simple operation, high outcome yield, reducing thecost of raw material, optimizing the reaction route, lowering the requirements to the reaction conditions and being beneficial to industrial production.

Description

technical field [0001] The invention relates to an organic synthesis method, in particular to a synthesis method of arbekacin and its intermediate dibekacin. Background technique [0002] Aminoglycoside antibiotics have a wide antibacterial spectrum and strong antibacterial activity, and are widely used in clinical practice. However, these antibiotics have ear and kidney toxicity to varying degrees, and are easy to be inactivated by inactivating enzymes. Bacteria develop resistance to them nature, which limits its application. [0003] The structure of aminoglycoside antibiotics contains multiple hydroxyl groups and amino groups, which are the targets of many inactivating enzymes. Therefore, deleting the hydroxyl group that has nothing to do with antibacterial activity or protecting individual amino groups can avoid the attack of these inactivating enzymes, thereby enhancing the antibacterial activity against drug-resistant bacteria. Based on this, Umezawa et al. in Japan ...

AI Technical Summary

Problems solved by technology

[0018] 1) The reaction steps of synthesizing dibekacin with this method are too long, both in terms of economic benefits and large-scale production.

[0019] 2) Impurities are easily produced in reaction F. Although the final product can be obtained through chemical conversion, many steps will be added, which will not only increase the reaction cost, but also make the operation more complicated

[0020] 3) The biggest bottleneck hindering the amplified production of this synthetic route is that the last step of removing amino and hydroxyl protection (see reaction H) yield is too low, only 26%, although the yield of the first few steps can reach 90%, but The total yield is only 15%

[0029] 1) in reaction C ', the consumption of sodium iodide and zinc powder is too large, and the add-on of zinc powder is 5~10 times of product 2, and the add-on of sodium iodide is 10 times of product 2, causes serious iodine easily Pollution and zinc pollution; when using chloroform for extraction, due to the addition of too much zinc powder, chloroform is easily emulsified, making post-processing difficult

[0030] 2) In the reaction F', water is used as the solvent, the hydrogenation reaction is not easy to carry out, and the reaction can only be carried out by pressurization

[0036] 1) Protecting different amino groups with three different amino protecting groups in reactions a', b' and c' will produce many impurities, which will bring a lot of inconvenience to the separation work of the reaction, and will also affect the Yield

[0037] 2) Dimethyl sulfoxide is used as a solvent in both reactions a' and b', which is difficult to post-process, and the use of diethyl ether is also dangerous, and it is not suitable for use in production

Images