4 minute read
Aug. 5, 2022

Lenacapavir Synthesis Highlights


In this guest article, Dr. Luíza Cruz breaks down the synthesis of Gilead’s lenacapavir (GS-6207), Drug Hunter’s Small Molecule of the Year – 2020. Lenacapavir is a promising first-in-class, long-acting injectable (LAI) HIV capsid inhibitor. Interesting synthetic steps employed in this route include an unusual sodium chlorite-mediated benzylic oxidation, efficient installation of the gem-difluoro moiety, and a highly selective Sonogashira/Suzuki coupling sequence.

Lenacapavir Synthesis Breakdown

As the first HIV capsid inhibitor, lenacapavir’s design and development included some of these challenges. From an early capsid inhibitor hit, PF-3540074, to GS-CA1, there was an impressive improvement in potency, selectivity, and PK profile, even though GS-CA1 is a much larger molecule and doesn't conform to the classic rules of drug design. There is no published story behind the design of GS-CA1, nor the optimization that led to lenacapavir yet, but the molecule’s long action and clinical properties are already impressive.

Many have expressed curiosity about how this molecule was made. Of course, the manufacturing route is unlikely to be published for commercial reasons (unless the drug is discontinued), and there are many challenges that have likely been further resolved that Gilead’s impressive process team probably has great solutions for that we won’t know about for a while. Here’s a quick rundown of what’s known.

Lenacapavir’s synthetic strategy consisted of breaking down the molecule into four manageable smaller parts that were ultimately combined in 6 high-yielding steps. Only one non-classical protecting group and chromatographic separation were present in these final connections. The four smaller building blocks were amenable to large-scale laboratory synthesis:

  • rac-1 was synthesized in 6 steps starting from 1 mol (96 g) of bicyclo[3.1.0]hexan-3-one; chiral SFC was used to separate isomers.

  • 2 was prepared in one step (55% yield after chromatography).

  • Starting from the correspondent benzonitrile, intermediate 3 was synthesized in 3 steps.

  • Central structure 4 was prepared in 4 steps.

Fast and Clean Installation of the gem-Difluoro group

The importance of fluorine in medicinal chemistry is well-known: modulation of potency, physicochemical, and especially metabolic properties. Particularly, the gem-difluoro group is very attractive to a medicinal chemist, with its capacity to sterically mimic a methylene group while bearing a completely different polarity. Historically, access to gem-difluoro compounds has been hampered by the scarce availability of reagents and harsh reaction conditions.

However, with the discovery of the difluorodesulfurization method in 1976 and its improvement in 1986, these compounds could be readily made starting from ketones or aldehydes and halo fluorides in two steps and under mild conditions. Halogen fluorides can be made in situ with hydrogen fluoride in pyridine and N-halo compounds, such as N-halosuccinimides. The Gilead team used this approach to produce key intermediate 1 in 6 high-yielding steps.

Ketone 5, which was made by the condensation of ethyl hydrazinoacetate and the appropriate ketal lithium salt, followed by an unusual benzylic oxidation using sodium chlorite, was used to prepare dithiolane 6 in 98% yield, followed by installation of the gem-difluoro group using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as the N-halo source, affording rac-1 in 68% yield.

Highly Selective Sonogashira, followed by Suzuki Coupling in 3,6-Dibromopyridin-2-yl Intermediate

Once the four modules were ready, the final synthesis of GS-6207 began. The 3,6-dibromopyridin-2-yl intermediate 4 was subjected to a Sonogashira cross-coupling with sulfonyl-but-1-yne 2.

Selective reaction in the 6-position afforded intermediate 7 in 88% yield, which was then submitted to a Suzuki coupling with dioxaborolane 3, affording 8 in 92% yield after column chromatography. 8 was then doubly mesylated in the amine present in the indazole moiety, followed by Boc removal, amide coupling with 1, and final removal of one of the mesyl groups, affording GS-6207 (lenacapavir).

Synthesis of intermediates

The pyrazole moiety present in 1 was synthesized in two steps, starting from the appropriate ketone via aldol reaction with ethyl trifluoroacetate, followed by treatment of the resultant lithium enolate with ethyl hydrazinoacetate and acid-catalyzed cyclodehydration. Then an unusual but efficient benzylic oxidation using sodium chlorite took place, followed by ester hydrolysis giving 5. From there, installation of the gem-difluoro group to rac-1 in two steps (as discussed above) and final chiral SFC separation gave enantiomerically pure 1.

Fragment 2 was synthesized in a single step from the correspondent alkyne in an intriguing substitution at a tertiary position using copper (I) chloride.

Starting from the appropriately substituted benzonitrile, fragment 3 was synthesized in three steps: condensation with hydrazine gave the 3-aminoindazole intermediate, followed by substitution at position 1 and, lastly, a Miyaura borylation cross-coupling reaction to install the boronic ester.

In the synthesis of fragment 4, the appropriate picolinaldehyde was condensed with (S)-2-methylpropane-2-sulfinamide, forming a chiral imine that was subjected to stereocontrolled nucleophilic attack by (3,5-difluorobenzyl)zinc bromide. The resultant sulfinamide was hydrolyzed and replaced with a Boc group to provide 4.

Final thoughts and list of published syntheses

We hope you found some interesting synthetic transformations in this digest. We also hope the Gilead process group will share more details someday, but for now, you can find the published routes here:

  1. Clinical targeting of HIV capsid protein with a long-acting small molecule

  2. Initial patent disclosure WO 2018/035359 A1

  3. Different formulations and salts: WO 2019/035904 A1; WO 2019/035973 A1

  4. Optimization of synthesis: WO 2019/161280 A1


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