{"id":67,"date":"2026-06-17T23:39:13","date_gmt":"2026-06-17T23:39:13","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=67"},"modified":"2026-06-17T23:39:13","modified_gmt":"2026-06-17T23:39:13","slug":"synthesis-of-lenacapavir","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-lenacapavir\/","title":{"rendered":"Synthesis of Lenacapavir"},"content":{"rendered":"\n

Lenacapavir (YEZTUGO (PrEP) and SUNLENCA (HIV-1 treatment)) \u2014 Drug Intelligence Dossier<\/h1>\n\n\n\n

Compiled:<\/strong> 2026-06-17 \u00b7 Trigger event:<\/strong> FDA approval, 2025-06-18 Innovator:<\/strong> Gilead Sciences, Inc. (development code GS-6207) Status:<\/strong> Approved NME<\/p>\n\n\n\n

INN:<\/strong> lenacapavirBrand (US):<\/strong> YEZTUGO (PrEP) and SUNLENCA (HIV-1 treatment)CAS:<\/strong> 2189684-44-2ChEMBL:<\/strong> \u2014MW:<\/strong> 968.3 g\/molNDA #:<\/strong> NDA 220020 \/ 220018 (YEZTUGO, PrEP); original NME NDA 215974 \/ 215973 (SUNLENCA, treatment, 2022-12-22)Approval:<\/strong> 2025-06-18<\/p>\n\n\n\n

Lenacapavir (Sunlenca \/ for PrEP, Yeztugo) is a first-in-class HIV-1 capsid inhibitor<\/strong> \u2014 a multi-stage inhibitor that targets the viral capsid protein (CA) rather than an enzyme.<\/p>\n\n\n\n

Synthesis Route of the Originator<\/h2>\n\n\n\n

Lenacapavir is among the most synthetically complex small molecules ever approved (MW 968 free acid; 10 fluorines; 3 stereocentres; indazole + pyridine + cyclopropane-fused pyrazole + alkynyl sulfone). Gilead’s commercial route (Org. Process Res. Dev. 2024, DOI 10.1021\/acs.oprd.4c00242) converges three major fragments onto a bis-bromopyridine core that already carries the pre-set (1S)-1-amino-2-(3,5-difluorophenyl)ethyl group. The four end-game operations are: (1) Sonogashira-type alkynylation at pyridine C6 with 3-methyl-3-(methylsulfonyl)but-1-yne; (2) amide coupling of the C2 amine with the chiral (3bS,4aR) difluoro-trifluoromethyl cyclopropa-cyclopenta-pyrazole acetic acid; (3) Suzuki\u2013Miyaura coupling at C3 with the 3-amino-4-chloro-1-(2,2,2-trifluoroethyl)indazol-7-yl boronic ester; (4) telescoped bis-methanesulfonylation of the indazole 3-amino group followed by hydrolysis to the mono-methanesulfonamide, giving the API; conversion to the sodium salt gives the drug substance. The major fragments are made in dedicated multistep asymmetric sequences: the pyrazole fragment in a 10-step route (OPRD 2024, DOI 10.1021\/acs.oprd.4c00235) via (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one from (R)-epichlorohydrin (OPRD 2024, DOI 10.1021\/acs.oprd.4c00527); the enantiopure benzylic-amine fragment via a new asymmetric route (JOC 2024, DOI 10.1021\/acs.joc.4c02380); a concise one-pot Heck\/Suzuki variant of the assembly is also reported (OPRD 2025, DOI 10.1021\/acs.oprd.5c00443). All five end-game intermediate SMILES were validated in RDKit (final free acid == target). Transformation names and the four-step order are verbatim from the OPRD 2024 abstract; per-step reagents\/temperatures are representative unless quoted \u2014 verify against the primary OPRD\/JOC papers before scale-up.<\/p>\n\n\n\n

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a<\/sup>Reagents and conditions: (1) 3-methyl-3-(methylsulfonyl)but-1-yne (alkynyl sulfone), Pd\/Cu catalysis, amine base \u2014 selective at the C6-bromide, leaving the C3-bromide for the later Suzuki step (per OPRD 2024 final-assembly sequence; exact catalyst\/solvent in the primary paper \u2014 representative here). The (1S) benzylic stereocentre is set upstream in the amine-fragment synthesis (JOC 2025, DOI 10.1021\/acs.joc.4c02380; discovery uses an Ellman (S)-sulfinamide, the process uses a dynamic kinetic resolution).; (2) (2-{(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl}acetic acid) + a standard amide-coupling activator (e.g. T3P\/HATU + amine base) \u2014 representative; the C3-bromide is retained for the next step. The pyrazole fragment is built in a 10-step asymmetric route (OPRD 2024, DOI 10.1021\/acs.oprd.4c00235) via the (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one intermediate from (R)-epichlorohydrin CAS 51594-55-9 (OPRD 2025, DOI 10.1021\/acs.oprd.4c00527). Fragment C acid = CAS 1620056-83-8; alkynyl sulfone = CAS 2109226-54-0.; (3) Indazol-7-yl pinacol boronic ester (3-amino, 4-chloro, N1-CH\u2082CF\u2083), Pd catalyst, base, aqueous co-solvent \u2014 forms the pyridine\u2013indazole biaryl bond (per OPRD 2024). A concise one-pot sequential Heck\/Suzuki variant is also reported (OPRD 2025, DOI 10.1021\/acs.oprd.5c00443). The indazole 3-amino group is carried free at this stage.; (4) Methanesulfonyl chloride (excess) bis-mesylates the indazole 3-NH\u2082 to N(SO\u2082CH\u2083)\u2082; controlled hydrolysis removes one mesyl to give the mono-methanesulfonamide (the API motif). Telescoped per OPRD 2024 final assembly.; (5) Treat the free acid (acidic methanesulfonamide N\u2013H) with a sodium base; crystallise \u2192 lenacapavir sodium (C\u2083\u2089H\u2083\u2081ClF\u2081\u2080N\u2087NaO\u2085S\u2082, MW 990.3), the drug substance in SUNLENCA and YEZTUGO..<\/p>\n\n\n\n

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Crystal Forms, Salts, and Solid-State Profile<\/h2>\n\n\n\n