One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine

Abstract

In Africa around 625 000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment for CM is a combination of amphotericin B and flucytosine, both now WHO Essential Medicines. However, flucytosine is not even registered for use in any African nation due, in part, to its relatively high cost of manufacture and lack of generic manufacturers. Currently, flucytosine is manufactured by an expensive four-step manufacturing process.Here we report a one-step continuous flow process involving the reaction of inexpensive cytosine with fluorine gas using stainless steel tubular laboratory and pilot-scale silicon carbide reactor devices which is readily scaleable to a manufacturing process with a low initial capital expenditure.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

“…Efforts by international agencies to make flucytosine available are gaining momentum. 7,15,28,29 In conclusion, in our trial, 1 week of amphotericin B plus flucytosine was the most effective option for induction therapy for patients with HIVassociated cryptococcal meningitis in resourcelimited settings. Our results also suggest that in the absence of availability of amphotericin B or in conditions in which amphotericin B cannot be administered safely, the oral combination of fluconazole plus flucytosine provides an effective and sustainable alternative.…”

“…6 Flucytosine is currently unavailable, although the molecule is used widely as a constituent of emtricitabine, and generic manufacture is possible at low cost. 7 Most countries therefore rely on generic or donated fluconazole induction monotherapy; however, the rate of fungal clearance with fluconazole is slower than that with amphotericin B, even at an elevated dosage, and mortality associated with this treatment is 50 to 60% at 10 weeks and is higher than 70% at 1 year even in study cohorts. 8,9 Phase 2 studies have defined several promising treatment strategies that are associated with fungal clearance similar to that with 2-week amphotericin B regimens and that have more favorable safety profiles.…”

Multifunctional 2‐ and 3‐Fluoropyrroles

“…Furthermore, we used Pd catalyzed cross coupling chemistry to diversify the range of fluoropyrrole products obtainable by this general strategy. Suzuki-type cross coupling conditions adapted from those reported by Ghosez [54] allowed us to synthesize a range of aryl-substituted products (17)(18)(19)(20) with the conditions tolerating substituted arylboronic acids bearing both electron-donating and electron-withdrawing substituents as well as heteroaromatic boronic acids in good to excellent yields (Scheme 4). The structures of 16 and 19 were confirmed by X-ray crystallography (Figure 1).…”

“…[7][8][9] In particular, fluorinated six-membered heterocycles are structural units found within a number of commercially important life science products. Fluoro-pyridine or -pyrimidine motifs have well-established synthetic protocols at both discovery and industrial scales [10][11][12][13][14][15][16][17] and, as a result, life science products containing six-membered fluoroheteroaromatic units such as Voriconazole (antifungal, Pfizer), Capecitabine (anticancer, Roche) and Diclosulam (herbicide, Dow) have now reached the commercial market [18][19][20] with many others such as Abemaciclib (anticancer, Eli Lilly), Riociguat (heart failure, Bayer) and Verubecestat (Alzheimers, Merck) in clinical trials. [21] In contrast, while functionalized five-membered heterocycles such as pyrroles, thiophenes and furans are prevalent structural units within life science products and many biologically active compounds, [22] corresponding occurrences of fluorinated five-membered heteroaromatic substrates in life science products are very rare.…”

Synthesis of 5‐Fluorocytosine Using 2‐Cyano‐2‐fluoroethenolate as a Key Intermediate

“…A synthetic challenge of this deceivingly simple target molecule lies in the introduction of the fluorine atom. There are only a few 5‐FC syntheses available and most of them use an electrophilic fluorination with highly expensive and aggressive gaseous F 2 , . Handling of fluorine gas on an industrial scale poses additional problems.…”