Synthesis of Voriconazole

Like fluconazole, voriconazole (Muijsers et al., 2002) is polar, with moderate aqueous solubility (0.5 mg/mL), resulting in rapid absorption (maximum concentration achieved in less than 2 h) and oral bioavailability (96%). Moderate food effects have been observed. Distribution is wide with a steady-state volume of 4.6L/kg and moderate binding to plasma proteins (58%). 

Owing to its inferior pharmacokinetic profile, voriconazole is dosed twice daily i.v. doses of 6 mg/kg are used on the first day, followed by 200 mg orally or continued i.v. dosing at 4 mg/kg. Voriconazole is recommended for the treatment of adults with invasive aspergillosis and can be used for rare infections caused by Fusarium spp. and Scedosporium apiospermum, where treatment with other agents has failed. Its primary use is in immunocompromised patients with progressive, life-threatening infections. 

Although 2,4-dichloro-6-ethyl-5-fluoropyrimidine (13) contained the correct carbon skeleton for condensation with the acetophenone, only self-condensation products were obtained following metallation with LDA. A reduction in electrophilicity was achieved by removal of the 2-chloro substituent via a three-step sequence involving hydrolysis of the more reactive 4-chloro substituent, followed by hydrogenation of the 2-chlorine and rechlorination with phosphorous oxychloride. The overall yield for the three steps resulting in 4-chloro-6-ethyl-5-fluoropyrimidine (14) was 72%. 

The key condensation of anions derived from the various ethylpyrimidines was the subject of extensive investigation (Table 5.1). Depending on the substitution pattern on 

TABLE 5.1. Variation in Yields of Diastereomeric Products (Ratio of 16 17) from Various Metallated Pyrimidines 

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Scheme 56 Synthesis of Voriconazole (10) using Reformatsky-type reaction...

Mechanism of Action. Voriconazole inhibits sterol biosynthesis in fungal cell membranes.53 That is, this drug acts like fluconazole and similar agents to impair membrane synthesis, which results in membrane integrity loss and death of the fungal cell. 

In a crossover study in 12 healthy volunteers who took meloxicam 15 mg without pretreatment (controls), after pretreatment with voriconazole (an inhibitor of CYP2C9 and CYP3A4), and after pretreatment with itraconazole (an inhibitor of CYP3A4), voriconazole increased the AUCo 72h of meloxicam by 47% and itraconazole reduced it by 37% [53 ]. The lower plasma meloxicam concentrations during the itraconazole phase were associated with a reduced effect of meloxicam, as demonstrated by weaker inhibition of thromboxane B2 synthesis. 

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