Patent Watch

January 10, 2011

Prepare desired forms of atazanavir hydrogen sulfate. The hydrogen sulfate salt of atazanavir (4) is available as Reyataz for treating HIV. S. Kim and co-inventors describe a process to prepare crystalline forms of H2SO4, including a novel, highly crystalline triethanolate solvate of the salt designated as form E3.

A detailed report on the synthesis of 4 and various intermediates has been published (Xu, Z. et al. Org. Process Res. Dev. 2002, 6, 323–328). This patent focuses on the synthesis of 4 and its hydrogen sulfate and the methods used to prepare the polymorphs and solvate.

The figure shows the route used to prepare 4 from the tert-butoxycarbonyl–protected diamine 1. In the first step, the Boc groups are removed, and the HCl salt of 2 is recovered as an aqueous solution. This is treated with 2 mol of active ester 3 in the presence of K2HPO4 to form 4 in CH2Cl2 solution. A solvent-exchange step produces a solution of 4 in N-methylpyrrolidone and acetone.

Treating this solution with concd H2SO4 produces the hydrogen sulfate salt. This procedure is carried out by adding the acid at an increasing rate in five stages over 5 h. The amounts added and the time between additions are defined by a cubic equation that is part of the claims of the patent.

The crystals obtained are designated as form A hydrogen sulfate. They can be converted to what is called pattern C material, the preferred crystalline form. The conversion is carried out by suspending form A crystals in water and stirring to produce a gel. The gel is dried and ground to give pattern C that is characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The form E3 solvate is obtained from free base 4 by slurrying it in EtOH, adding H2SO4, and crystallizing. The yield of form E3 is 74.3 %; other yields are not reported.

The inventors prepared 3 from reactants 5 and 6 in the presence of an approximately equimolar amount of carbodiimide 7. The reaction takes place at room temperature in CH2Cl2 and is followed by HPLC separation. The reaction time is not reported, nor is the yield of 3, which is recovered in solution and used to prepare 4.

The patent includes XRD, TGA, DSC, and 1H NMR data and details of formulations made from pattern C crystals. (Bristol-Myers Squibb [Princeton, NJ]. US Patent 7,838,678, Nov. 23, 2010; Keith Turner)

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