Gilla Goverdhan

Identification, characterization and synthesis of impurities of zafirlukast.

Zafirlukast is a drug in the treatment of pulmonary disorders such as asthma. During the process development of zafirlukast, five unknown impurities were detected at levels of below 0.10% (ranging from 0.05 to 0.15%) in reverse phase gradient high performance liquid chromatography (HPLC) method. The molecular weights were determined by LC-MS analysis. These impurities were isolated from crude samples of zafirlukast using gradient reverse phase preparative HPLC and were subsequently synthesized. Based on the spectral data, the structures of these impurities were characterized as 3-methoxy-4-(5-methoxycarbonylamino-1-methyl-1H-indol-3-ylmethyl)-benzoic acid (Impurity 1), {3-[2-methoxy-4-(toluene-2-sulfonylaminocarbonyl)-benzyl]-1-methyl-1H-indol-5-yl}-carbamic acid methyl ester (Impurity 2), {3-[2-methoxy-4-(toluene-3-sulfonylaminocarbonyl)-benzyl]-1-methyl-1H-indol-5-yl}-acetic acid cyclopentyl ester (Impurity 3), {3-[2-methoxy-4-(toluene-4-sulfonylaminocarbonyl)-benzyl]-1-methyl-1H-indol-5-yl}-acetic acid cyclopentyl ester (Impurity 4), and 4-(5-cyclopentyloxy carbonylamino-1-methyl-1H-indol-3-yl methyl)-3-methoxy-benzoic acid methyl ester (Impurity 5). The separation of the impurities by reverse phase HPLC, the confirmation of their structures by IR, MS and NMR spectral data, the mechanism of their formation and their syntheses are discussed in detail.

Application of [3 + 2]-Cycloaddition in the Synthesis of Valdecoxib

Abstract A large scale synthesis of valdecoxib 1 is described. Our work features potential application of [3 + 2]-dipolar cycloaddition involving enamine and in situ–generated nitrile oxide derivatives. GRAPHICAL ABSTRACT

Synthesis of Valganciclovir Hydrochloride Congeners

Abstract Valganciclovir hydrochloride (1) is used for the treatment of cytomegalovirus (CMV) retinitis in patients with weakened immune systems. Valganciclovir hydrochloride is a hydrochloride salt of L-valyl ester of ganciclovir (2) that exists as a mixture of two diastereomers. According to the U.S. Food and Drug Administration specifications, the diastereomeric ratio of valganciclovir hydrochloride 1 should be maintained in the range 55:45 to 45:55. According to the U.S. Food and Drug Administration specifications, the diastereomeric ratio of valganciclovir hydrochloride 1 should be maintained in the range 55:45 to 45:55. During the process development of valganciclovir hydrochloride, six related substances (impurities) were observed along with the final active pharmaceutical ingredient. Among these six impurities, ganciclovir (2) and guanine (3) are the key starting materials and degraded impurities of ganciclovir, respectively. The remaining four impurities were identified as isovalganciclovir hydrochloride (4), methoxymethylguanine (5), O-acetoxy ganciclovir (6), and isovalarylganciclovir (7). The present work describes the synthesis and characterization of these four impurities. GRAPHICAL ABSTRACT

Concise and Alternative Synthesis of Zafirlukast, an Anti-Asthma Drug

Abstract Concise and alternative synthesis of zafirlukast (1) is described. The synthesis features fewer steps, convergent synthesis, and novel intermediates. GRAPHICAL ABSTRACT