A kind of synthetic method of gamithromycin

Abstract

The invention discloses a method for synthesizing gamithromycin, which uses 9-deoxy-8a-aza-8a-homoerythromycin A as a raw material, and diaces with propionaldehyde in a protic solvent under the catalysis of an organic acid. Alcohol reaction forms propyral 9-deoxy-8a-aza-8a-homoerythromycin A, then reduces through boron reducing agent, removes protecting group under acidic conditions, obtains gamithromycin; preparation process of the present invention The yield of the obtained gamithromycin product can reach more than 92.0% before post-treatment, after recrystallization treatment, its purity can reach more than 99.0%, the overall yield can reach more than 90.0%, and the reaction process is mild, Able to realize industrialized mass production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of gamithromycin. Background technique [0002] Gamithromycin is a semi-synthetic 15-membered azamacrolide antibacterial drug, which is usually used for the prevention and treatment of cattle disease caused by pathogenic bacteria such as Mannella hemolyticus, Pasteurella multocida, and Histophilia somnolus. Respiratory system diseases; Gamithromycin is used for food animals. It has the advantages of broad antibacterial spectrum, strong antibacterial activity, single administration, long half-life, fast absorption, high bioavailability, and low residue, which is in line with the development trend of veterinary drugs in my country. Good clinical application value and broad market prospect. [0003] At present, the synthesis of gamithromycin generally takes deoxyazaerythromycin as the reaction substrate, and adopts different methods to introduce propyl g...

AI Technical Summary

Problems solved by technology

[0004] Heck et al. used tetrakis(triphenylphosphine) palladium as catalyst, triethylamine as acid-binding agent, generated after substitution reaction with allyl acetate and 9-deoxy-8a-aza-8a-homoerythromycin A Gamithromycin (EP0508699A) is finally obtained through palladium-carbon hydrogenation reduction, but an expensive heavy metal catalyst is used in the preparation process, and the yield is low and the product cost is high;

[0005] Studies on the synthesis and antibacterial activity of gamimycin and its intermediates (Jiang Zhiyao) reported that 9-deoxy-8a-aza-8a-homoerythromycin A was used as the reaction substrate and reacted with bromopropane to obtain a content of 63.87 %Gamithromycin, the main problem of this method is that product purity is low, and impurity is many, and purification difficulty is high;

[0006] Z·Mendez uses 9-deoxy-8a-aza-8a-homoerythromycin A as the reaction substrate, and propionaldehyde as the propylation reagent, catalyzed by palladium carbon or platinum carbon, and obtained by reduction under 20 bar hydrogen pressure The content is 88% gamimycin, but the preparation process uses expensive heavy metals from the catalyst, high-pressure reaction, and the purity of gaminomycin is medium;

[0007] Synthesis and process route research of gamimycin (Yu Lijia) reported 9-deoxy-8a-aza-8a-homoerythromycin A and n-propionaldehyde as raw materials, dissolved in alcohol solvents, and cyanoboron Sodium hydride is used as a reducing agent, and acetic acid is used to adjust the pH of the reaction solution to 7 to 8. After the reaction, the pH of the reaction solution needs to be adjusted to acidity, so that the generated boric acid ester impurities are converted into gamimycin, and adjusted to be alkaline to obtain Gamithromycin, yield 38%, but this method product yield is low, impurity is high, and production cost is high;

[0008] CN105646618A reports that 9-deoxy-8a-aza-8a-homoerythromycin A and n-propionaldehyde are used as raw materials, hydrosilane is used as a reducing agent, and organotin or inorganic tin is used as a catalyst to obtain gamithycin with a yield of about 85%. , the disadvantages of this method: the tin reagent is a highly toxic substance, and the treatment after the reaction is complicated, and the waste liquid is highly toxic and difficult to handle;

[0009] CN103554201A has reported that after reacting with 9-deoxy-8a-aza-8a-homoerythromycin A and propionaldehyde, pyridine boronic acid is added dropwise to obtain the crude product of gamithromycin, then the crude product is dissolved in methyl tert-butyl ether, dropwise Add trifluoroacetic acid to form a salt, filter, free the filter cake with dichloromethane and potassium carbonate aqueous solution, separate the water phase, concentrate the organic phase to obtain pure gaminomycin, but the reduction reaction of this method is easy to produce gamimycin boric acid Ester impurities need to be carried out at low temperature (-5 ~ 5°C), and the post-treatment process is complicated, which limits its large-scale production

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