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Synthesis

Fluorine flow chemistry yields flucytosine

Streamlined synthesis offers better access to an essential drug for treating HIV/AIDS-related fungal infections

by Stephen K. Ritter
January 23, 2017 | APPEARED IN VOLUME 95, ISSUE 4

In Africa, about one-third of the roughly 2 million HIV/AIDS-related deaths each year stem from the fungal infection cryptococcal meningitis. The first-line treatment for this disease and other HIV/AIDS-related fungal infections is a combination of flucytosine and amphotericin B. Although these two drugs are on the World Health Organization’s List of Essential Medicines, uneven global pricing and distribution has left flucytosine largely unavailable to Africans who need it—flucytosine is relatively expensive to make and there’s little generic competition to reduce cost. Answering a call from the infectious diseases community, a team led by Graham Sandford of Durham University, working in collaboration with scientists at Sanofi Aventis and the nonprofit group MEPI within the EU’s Innovative Medicines Initiative Chem21 network, has developed a streamlined method for making flucytosine that could improve its global availability (Org. Process Res. Dev. 2017, DOI: 10.1021/acs.oprd.6b00420). Flucytosine is currently manufactured in a four-step process starting from uracil, which includes fluorination, chlorination, amination, and hydrolysis steps. Taking advantage of the Durham group’s expertise in selective fluorinations using flow reactors, the team developed a pilot-scale continuous-flow process to convert cytosine directly into flucytosine at a rate of 60 g per hour. Besides improving access to flucytosine to combat fungal infections, the researchers believe the new process could benefit flucytosine’s use as an intermediate in the synthesis of anticancer and HIV drugs.

Direct fluorination of cytosine could ease the availability of flucytosine, an essential antifungal drug for people with HIV/AIDS.
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