Michael E. Pierce

Kinetics and Mechanism of Hydrolysis of Efavirenz

AbstractPurpose. To determine the kinetics and mechanism of hydrolysis of efavirenz [(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one] in aqueous solutions. Methods. The solution stability was examined at 60°C and an ionic strength of 0.3 M over the pH range of 0.6 to 12.8. The loss of efavirenz and the appearance of degradants were followed with a reverse-phase high-performance liquid chromatography assay. Characterization of the degradants was accomplished with liquid chromatography-mass spectrometry. Results. The degradation of efavirenz followed apparent first-order kinetics over the pH range of 0.6 to 12.8 at 60°C. The catalytic effect of phosphate and borate buffers was negligible while acetate and citrate demonstrated buffer catalysis. The overall rate constant indicated a pH minimum (the pH of maximum stability) of approximately 4. Mass spectra data identified a degradant with a molecular weight consistent with hydrolysis of the cyclic carbamate to the corresponding amino alcohol. The degradation route was confirmed with spiking experiments with an authentic sample of the amino alcohol indicating that the carbamate hydrolysis pathway was the predominant reaction throughout the pH range studied. Subsequent degradation of the amino alcohol proceeded at the extremes of the pH range studied via rearrangement to the quinoline. Conclusions. The pH-rate profile was consistent with a combination of a V-shaped profile in the pH range of 0-9 and a sigmoid-shaped profile in the pH range of 4-13. The plateau that began at pH 10-11 is a result of the ionization of the amine of the carbamate inhibiting the base-catalyzed hydrolysis of efavirenz, given that the ionized form of the carbamate is resonance-stabilized toward hydroxide-catalyzed degradation. Thus, increasing the pH resulted in a parallel decrease in the unionized fraction and increase in hydroxide ion concentration resulting in a constant kobs value.

Synthesis of HIV-1 Reverse Transcriptase Inhibitor DMP 266

Abstract Abstract: DMP 266, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor was prepared in six steps starting from commercially available 4-chlorophenyl isocyanate. The racemic compound was formed very efficiently from N-tert-butoxycarbonyl-4-chloroaniline and resolution was accomplished via the (-)-camphanates. Present address: B. I. Chemical, Inc., P.O. BOX 1658, Petersburg, VA 23805, U.S.A.)

A new and practical synthesis of vinyl dichlorides via a non-Wittig-type approach

Abstract A practical approach for the conversion of aldehydes to vinyl dichlorides has been developed. These are three-step, one-pot reactions involving the formation of trichlorocarbinol by treatment of aldehydes with trichloroacetic acid and sodium trichloroacetate followed by in situ protection and elimination reactions to form the desired vinyl dichlorides in 85 to 95% yields.

The Discovery and Development of Angiotensin II Antagonists

During the development of losartan, various issues arose that could have stopped losartan and hampered the successful development of the angiotensin II antagonists in general. Some of these issues were real problems that had to be solved if losartan was to advance, such as the need for a commercially viable synthesis. Other issues, such as whether EXP3174 would form in humans, were anticipated as potential problems that should be addressed. Because of the combined efforts of discovery and development groups at DuPont, and later at Merck and DuPont Merck, the development of losartan was rapid. While some people were working to answer questions such as the antihypertensive efficacy of losartan in humans as quickly as possible, other people were searching for potential backups to losartan. Without an efficient integration of Discovery and Development efforts, the commercially successful development of any drug would be threatened, and it helped to give losartan a critical 2-year lead on the most advanced competitive Ang II antagonists.

A Large Scale Preparation of the Cognitive Enhancer Linopirdine

Abstract Linopirdine is a pharmacologically potent drug which stimulates central nervous system neurotransmitter release. A facile process used to synthesize linopirdine on a commercial manufacturing scale consisting of seven chemical steps with only a single isolated intermediate is described.

Chemoselective allylic addition of allyltrichlorosilane to α-oxocarboxylic acids: synthesis of tertiary α-hydroxy carboxylic acids

Abstract Allyltrichlorosilane can add to α-oxocarboxylic acids in the presence of DMF and HMPA. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reaction. The reaction presumably proceeds in an intramolecular fashion through a ‘rigid’ bicyclic transition state assembly involving a hypervalent silicate species, which produces the chemoselectivity approaching 100%.

Purification of Nucleoside-5′-diphosphates: A New Ion-Exchange Method

Abstract Inosine- and uridine-5′-diphosphates can be purified by ion-exchange chromatography utilizing a new ion-exchange method where Type 1 ion-exchange resins and the absorbed nucleoside polyphosphates are changed to the basic form by rinsing the column with dilute sodium hydroxide and subsequently eluting with dilute hydrochloric acid and sodium chloride.

OXIDATIVE REMOVAL OF p-METH-OXYBENZYL-AMINO PROTECTING GROUP IN THE PRESENCE OF A PROXIMAL HYDROXY FUNCTION: A SOLUTION TO A PROCESS PROBLEM IN SUSTIVA® (EFAVIRENZ) SYNTHESIS

A practical and scaleable synthetic procedure for the deprotection of a p-methoxy benzyl group from the tertiary carbinol 2 in the commercial synthesis of SUSTIVA® (efavirenz) 1 is described. The methodology involves a two step, one pot operation with an isolated yield of 82.5% with a product purity of > 99.5%.

A PRACTICAL PHOTOCHEMICAL SYNTHESIS OF 6-AZA-1,10-PHENANTHROIC ANHYDRIDE

Abstract A high yield synthesis of 6-aza-1, 10-phenanthroic anhydride has been developed. The key step is a volume-efficient photochemical cyclization of azastilbene 5 to the photochemically stable dihydroazaphenanthrene 9.