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Tenofovir For The Developing World

ACS Meeting News: Process chemists rework synthesis of anti-HIV drug to lower its cost

by Bethany Halford
September 27, 2010 | A version of this story appeared in Volume 88, Issue 39

When pharmaceutical companies develop new drugs, their use in the developing world isn’t often a major consideration. That’s where David S. Teager comes in. As a process chemist with the Clinton Health Access Initiative (CHAI), Teager explores the chemistry that goes into making drugs to fight the diseases that are ravaging the developing world—AIDS, tuberculosis, and malaria, to name a few—with the goal of improving those syntheses in ways that bring down the cost of lifesaving compounds.

At last month’s American Chemical Society meeting in Boston, Teager spoke about CHAI’s recent work on the anti-HIV drug tenofovir during a symposium cosponsored by the Divisions of Organic Chemistry and Medicinal Chemistry. Teager and his CHAI collaborators have been working on ways to tweak the synthesis to boost yields and use cheaper reagents.

“Anything that we find we basically give away to our partner companies,” Teager said. “What we hope is that by distributing the information and getting people to make these drugs more inexpensively, we’ll get a leapfrog effect in the market that will help a new generics manufacturer come on-line in producing one of these drugs.”

Any cost-cutting changes they make will push prices down, Teager explained. “That means that a company that’s already producing the drug has to figure out ways to reduce the cost in order to stay competitive in the market, whether it’s by using our technology or by pushing things through on their own,” he said.

When the first generic supplier of tenofovir entered the market about four years ago, a year’s course of the drug cost about $210 per patient, a price that Teager said is largely out of reach for patients in still-developing nations. But because tenofovir is now becoming a first-line treatment against HIV/AIDS in many of those countries, CHAI recognized the importance of figuring out a way to make the drug less expensively.

From the route published in the patent literature, tenofovir poses significant challenges for a generic drug producer, Teager pointed out. For a three-step process, the overall yield is an abysmal 13%.

“Generics companies have to evaluate what their product portfolio is going to be, and on the basis of the chemistry alone, tenofovir doesn’t seem like an appealing target,” Teager said. Companies are likely to question whether they will make any profit from such a drug. Because of the CHAI team’s process chemistry improvements, he noted, companies now have a better approach to tenofovir.

“By helping new generics suppliers get into the market and get the best prices on the raw materials and also by giving them access to the process improvements that we developed through our support of research, the price of tenofovir in 2010 per patient per year is $87,” Teager noted.

Because tenofovir itself has insufficient bioavailability due to its poor solubility, the compound is administered as a prodrug, tenofovir disoproxil fumarate, or TDF, which is metabolized in the body to give tenofovir. Gilead, which first brought tenofovir onto the market in 2001, made TDF in three stages, with four reactions.

The CHAI team decided not to reinvent the wheel when it came to preparing TDF, Teager said. Rather, they used their knowledge of process chemistry to improve the existing synthesis. They recently published their improvements in a paper in Organic Process Research & Development (DOI: 10.1021/op1001337).

The first stage of the synthesis is a base-promoted alkylation of adenine with R-propylene carbonate. This stage in the reaction didn’t need much optimization, Teager said, but the CHAI team was able to boost the purity of the desired product by selectively crystallizing it from the reaction solution with a mixture of methanol and isopropyl alcohol.

The second stage of the synthetic scheme left more room for improvement. Here, two reactions are done in a so-called telescoped process—an alkylation with a tosylate followed by hydrolysis.

The team’s first thought was to explore the type of base that was used in the alkylation. They verified that one reported base, magnesium tert-butoxide, was the best choice. Getting a reliable supply of quality magnesium tert-butoxide, however, was a problem.

“Low cost doesn’t do any good if the reaction doesn’t work very well,” Teager said. So CHAI sought a reliable local source of the base for the generics manufacturer in India. Getting that pinned down, he added, has “been a big help in tenofovir manufacture.”

The next reaction, hydrolysis of the diester intermediate to tenofovir, uses Lewis acid-promoted nucleophilic dealkylation. The patent reports using six equivalents of trimethylsilyl bromide for this step. But this reagent is expensive, and its quality is known to be variable. It also requires special handling. CHAI-supported researchers discovered that the use of trimethylsilyl chloride in combination with sodium bromide worked just as well but cost less and didn’t need any special handling (Tetrahedron 2010, 41, 8137).

The third stage of the sequence, conversion of tenofovir to the disoproxilated prodrug, was the area that Teager thought needed the most improvement. “If you follow the procedure out of Gilead’s patent, the yield is only about 35%,” he said.

“It’s a classic problem with prodrugs,” Teager explained. “The same thing that helps it fall apart in the body to deliver the drug can also make it fall apart in your reactor.”

Tenofovir is isolated as a hydrate, and Teager’s group first recognized that removing the water of hydration was critical to the success of making the prodrug. In addition, they found that adding a tetrabutylammonium bromide phase-transfer agent boosted the yield, cut reaction time, and allowed the reaction to take place at a lower temperature. Ultimately, the phase-transfer agent made it possible to get 75% conversion of the tenofovir starting material in less than six hours, compared with only 60% conversion in 10 hours without the phase-transfer material.

With a modified workup, the CHAI team bumped the yield up to over 62% for this step, bringing the overall yield of the TDF prodrug to 24%, up from the 13% that was originally reported.

“This work illustrates the importance of lowering production costs through insightful process chemistry improvements,” commented Robert Singer, a process chemist with Pfizer who was one of the symposium’s coorganizers. “These process improvements are particularly important for bringing this medicine to the Third World at an affordable cost.”

“While tenofovir disoproxil fu­ma­rate has been produced commercially for some time with an optimized synthesis, these scientists were still able not only to improve the process significantly, but also to increase the yield by 87% while cutting the cost of production,” added Ahmed Abdel-Magid, chief scientific officer of Therachem Research Medilab and another coorganizer of the symposium. “This is a good example that shows how process chemists utilize scientific knowledge to make medicine affordable and improve the quality of people’s lives.”


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