Chaudhari, K., Gohar, A., Claerhout, S., & Ganorkar, R. (2023). ACS omega, 8(11), 10411-10418.
Controlling isomeric impurities in raw materials is crucial for achieving a pure isomer-free active pharmaceutical ingredient (API) in subsequent processes. Clarithromycin 9-(E)-oxime is a key intermediate in the synthesis of the 9a-lactam macrolide, a scaffold for several bioactive macrolides. This process demonstrates a scalable method to prepare substantially pure clarithromycin 9-(E)-oxime with less than 1.2% of the (Z)-isomer.
Procedure:
Hydroxylamine hydrochloride (167.2 kg, 2407 mol, 20 equiv) was dissolved in methanol (450 L, 5 M) at room temperature (20-30°C). Sodium acetate trihydrate (327.5 kg, 2406 mol, 20 equiv) was then added, followed by sodium bicarbonate (5.05 kg, 60.16 mol, 0.5 equiv) and clarithromycin (90 kg, 120.32 mol, 1 equiv). The reaction mixture was heated to 60-70°C and refluxed for 20-24 hours under stirring.
Afterward, the solution was concentrated to a minimum stirrable volume (~1 M) and diluted with a mixture of dichloromethane (900 L, 10 M) and water (540 L, 6 M). The organic phase was separated and treated with a 10% aqueous sodium bicarbonate solution (10 M relative to clarithromycin) to adjust the pH to approximately 8. The biphasic mixture was filtered, and the clear filtrate was separated. The organic layer was washed with brine and concentrated under vacuum.
Dichloromethane (~3-4 M) was added to the concentrated residue, and the mixture was stirred at room temperature for 30 minutes before filtration. The filtrate was concentrated to about 0.5 to 1 residual volume. Isopropyl alcohol (360 L, 4 M) was added to the concentrated organic layer at 40-50°C, and the mixture was further concentrated to a minimum stirrable volume (~1-2 M). The mixture was then heated to 80-85°C for 0-2 hours, cooled gradually to 0-10°C under stirring, and the resulting solid was filtered and washed with isopropyl alcohol.
The wet solid was dried to yield clarithromycin 9-(E)-oxime (59.4 kg, 64.7% yield) with an HPLC purity of 97.49% and clarithromycin 9-(Z)-oxime with a purity of 0.97%.
Qin, Yinhui, et al. Bioorganic Chemistry 127 (2022): 106020.
Bacterial infections remain a significant threat to human health, and the global spread of bacterial drug resistance continues to be a major concern. Consequently, the development of new antibacterial drugs is crucial. In this study, we present a novel approach to the design and synthesis of 14-membered macrolide antibiotics, focusing on the creation of clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4″- and 11-OH positions. A total of 35 clarithromycin derivatives were synthesized through chemical processes.
Synthesis of Clarithromycin Derivatives Incorporating the 1,2,3-Triazole Moiety at the 4″-OH Position (Series A)
The synthesis of compounds 8a-8w (Series A) follows the route outlined in Scheme 1. The process begins with the dehydration of the starting material, clarithromycin (1), followed by the acylation of (10E)-10,11-ene-11-deoxy-clarithromycin (2) with acetic anhydride (Ac2O), yielding 2'-O-acetyl-(10E)-10,11-ene-11-deoxy-clarithromycin (3). This intermediate reacts with N,N'-carbonyldiimidazole (CDI) to form 2'-O-acetyl-4″-O-(1H-imidazol-1-yl)carbonyl-(10E)-10,11-ene-11-deoxy-clarithromycin (4). Treatment of 4 with hydrazine hydrate results in the formation of 2'-O-acetyl-4″-O-hydrazinoyl-(10E)-10,11-ene-11-deoxy-clarithromycin (5). Subsequently, condensation of 5 with various acids (6a-6w), in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), and diisopropylethylamine (DIPEA), produces intermediates 7a-7w. Finally, the acetyl groups in 7a-7w are removed to yield the target compounds 8a-8w.
Synthesis of Clarithromycin Derivatives Incorporating the 1,2,3-Triazole Moiety at the 11-OH Position (Series B)
The structures and preparation of the target compounds 19a-19l (Series B) are outlined in Scheme 1. In brief, clarithromycin (1) was first treated with diluted HCl to produce 3-O-descladinosyl-clarithromycin (12). The 2'-OH group of 12 was then acylated with acetic anhydride (Ac2O) to form 2'-O-acetyl-3-O-decladinosyl-clarithromycin (13). Next, the 11,12-OH groups of 13 underwent cyclization with triphosgene in the presence of pyridine to yield 2'-O-acetyl-3-O-decladinosyl-clarithromycin 11,12-cyclic carbonate (14). This compound was oxidized using pyridinium chlorochromate to obtain 2'-O-acetyl-3-oxo-clarithromycin 11,12-cyclic carbonate (15).
The preparation of 2'-O-acetyl-3-oxo-11-O-(4-hydroxybutylamino)carbonyl-clarithromycin (16) was achieved by reacting 15 with 4-amino-1-butanol in the presence of pyridine hydrochloride. The hydroxyl group of 16 was then selectively esterified with methanesulfonyl chloride in dichloromethane (DCM) to yield 2'-O-acetyl-3-oxo-11-O-(4-methylsulfonyloxybutylamino)carbonyl-clarithromycin (17). Azidation of 17 with sodium azide (NaN3) in a mixture of water (H2O) and dimethylformamide (DMF) produced 2'-O-acetyl-3-oxo-11-O-(4-azidobutylamino)carbonyl-clarithromycin (18).
Finally, the azide group of 18 underwent a click reaction with various substituted phenylacetylenes, followed by deprotection with methanol (CH3OH), resulting in the formation of the target compounds 19a-19l.
Adil, Hadeel, et al. Materials Science for Energy Technologies 7 (2024): 73-84.
Various polylactic acid (PLA) thin films incorporating clarithromycin and metal oxide nanoparticles (magnesium, titanium, zinc, and nickel oxides) were fabricated. Among the metal oxides, nickel oxide nanoparticles were found to provide the most significant enhancement to the stability of PLA. These metal oxides are known for their highly alkaline properties. On the other hand, the heteroatom and aromatic structure of clarithromycin allow it to absorb harmful radiation and act as an ultraviolet absorber. Consequently, the incorporation of both metal oxide nanoparticles and clarithromycin significantly improved the PLA's resistance to photodegradation.
Fabrication of PLA Films:
PLA films were prepared using a solvent casting method. A mixture containing 100 mL of chloroform (CHCl3), 20 mg of clarithromycin, 40 mg each of magnesium, titanium, zinc, and nickel oxide nanoparticles, and 4 g of PLA was stirred for 1 hour. The solution was sonicated for 30 minutes to remove any air bubbles. It was then poured onto a glass tray, and the solvent was allowed to evaporate for 24 hours at room temperature. The resulting films were carefully removed from the tray and stored overnight in a vacuum oven at room temperature.
What is the CAS number for Clarithromycin?
The CAS number for Clarithromycin is 81103-11-9.
What are some synonyms for Clarithromycin?
Some synonyms for Clarithromycin are Erythromycin and 6-O-methyl-.
What is the molecular weight of Clarithromycin?
The molecular weight of Clarithromycin is 747.95.
What is the molecular formula of Clarithromycin?
The molecular formula of Clarithromycin is C38H69NO13.
What is the boiling point of Clarithromycin?
The boiling point of Clarithromycin is 86°C.
What is the melting point of Clarithromycin?
The melting point of Clarithromycin is 217-220°C.
What is the flash point of Clarithromycin?
The flash point of Clarithromycin is >110°C (230°F).
What is the percentage of actives in Clarithromycin?
The percentage of actives in Clarithromycin is 95%.
In what physical state is Clarithromycin typically found?
Clarithromycin is typically found in a solid physical state.
What are some typical applications of Clarithromycin?
Some typical applications of Clarithromycin include use as an antimicrobial agent and antibacterial agent.
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