Patent Watch

February 18, 2013

Choose the right starting materials for a chiral drug synthesis. Co-inventors W. R. Epa, S. M. Maruccio, and J. J. Deadman disclose a process for preparing and resolving 1,3-oxathiolanes that are substituted at the 2- and 4-positions. The compounds are useful for treating HIV and are believed to have less-cytotoxic side effects than other drugs.

Only one diastereomer of each two–chiral-center compound is active, making a stereoselective synthesis highly desirable. The inventors state that this is made possible by choosing the substituents on the starting materials correctly. Figure 1 outlines the first stage of the synthesis, in which enantiomers cis- and trans-1 are produced by the copper-catalyzed coupling of oxathiolane oxide 2 and cytosine 3.

Compound 2 is first silylated with Me3SiI in the presence of Et3N, after which CuCl2 and compound 3 are added. The product is isolated as a viscous brown oil in 89% yield and then purified by recrystallization from refluxing MeOH. The cis/trans ratio of product 1 is 2.45:1.

The inventors describe two mixed-solvent recrystallization procedures that they call entrainment. One process uses seed crystals, and the other does not. With seeding, the yield of cis-1 (the desired enantiomer) is 44%, and its optical purity is 99.3%. Without seeding, the yield of cis-1 is 42% with 98.1% optical purity. The patent contains several examples in which the effects of stirring, time, seeding, and mixed solvents on recrystallization are determined.

NH3 and MeOH are used to remove the protecting benzyl groups in cis-1 to form the cis-amino alcohol, recovered in 94% yield. Alternatively, deprotection with NaOMe–MeOH gives the cis-amino alcohol in 88% yield.

The inventors prepared oxathiolane oxide 2 by oxidizing oxathiolane 4 with H2O2, as shown in Figure 2. The product is isolated as an oil that solidifies; it is used without further purification.

The inventors also describe the preparation of compound 5, a fluoro derivative of cis-1, by the reaction of 2 with fluorocytosine 6 (Figure 2). Numerous derivatives of cis-1 and 5 that contain alternative protecting groups are also covered in the patent. (Avexa Ltd. [Richmond, Australia]. US Patent 8,318,934, November 27, 2012; Keith Turner)

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