Bictegravir

Bictegravir is a pivotal active pharmaceutical ingredient (API) in the treatment of HIV-1 infection, serving as the integrase strand transfer inhibitor component of the single-tablet regimen Biktarvy®. As a potent and selective inhibitor of HIV-1 integrase, Bictegravir demonstrates an IC₅₀ of 7.5 nM for strand transfer activity and exhibits potent antiviral effects in primary CD4⁺ T lymphocytes with an EC₅₀ of 1.5 ± 0.3 nM. Bictegravir maintains efficacy against clinical isolates of HIV-1 with EC₅₀ values ranging from 0.04 to 1.7 nM in human peripheral blood mononuclear cells. The compound's long dissociative half-life from the integrase-DNA complex contributes to its high resistance barrier—Bictegravir shows only a 2.1-fold EC₅₀ increase against the G140S+Q148H mutant compared to 4.3-fold for dolutegravir and over 100-fold for raltegravir and elvitegravir. Beyond its therapeutic application, Bictegravir serves as a reference standard for analytical method development, impurity profiling, and quality control testing in the manufacture of HIV antiretroviral therapies.

 

 Product Parameters

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Parameter	Specification
Product Name	Bictegravir
CAS Number	1611493-60-7
Molecular Formula	C₂₁H₁₈F₃N₃O₅
Molecular Weight	449.38 g/mol
Physical Form	Solid powder
Appearance	White to off-white solid
Melting Point	>130 °C (dec.)
Boiling Point	682.5 ± 55.0 °C (Predicted)
Density	1.62 ± 0.1 g/cm³ (Predicted)
Storage Condition	Sealed in dry,Store in freezer, under -20°C

Application

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Bicetilavir (BIC) is a second-generation integrase chain transfer inhibitor (INSTI) approved for use in fixed-dose regimens with emtricitabine and tenofovir alafenamide in HIV treatment, demonstrating potent antiviral activity against both wild-type viruses and first-generation drug-resistant strains in vitro.

 

Synthetic Route

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Step 1: Treat 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridin-3-carboxylic acid (1-A, 3.15 g, 10.0 mmol), suspended in acetonitrile (36 mL) and acetic acid (4 mL), with methanesulfonic acid (0.195 mL). Heat the mixture to 75 °C. After 7 hours, cool the crude mixture and store it at –10 °C for three days. Reheat the crude mixture to 75 °C for 2 hours, then cool it before use in the next step without purification.

 

Step 2: Mix crude 1-(2,2-dihydroxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridin-3-carboxylic acid (16.8 mL from the crude mixture of Step 1, approximately 4 mmol) with (1S,3R)-3-amino cyclopentanol (0.809 g, 8 mmol), dilute with acetonitrile (16.8 mL), and treat with potassium carbonate (0.553 g, 4 mmol). Heat the reaction mixture to 85 °C, stir for 15 minutes, cool to room temperature, and continue stirring for 16 hours. Add HCl (50 mL, 0.2 M) and extract the clear yellow solution three times with dichloromethane. Dry the combined organic layers with sodium sulfate, filter, and concentrate to obtain a yellow solid. Precipitate the crude product from dichloromethane/hexane to yield the desired intermediate 15-B as a light beige powder.

Step 3: Dissolve compound 15-B (38 mg, 0.12 mmol) in 1 mL of acetonitrile, add 2,4,6-trifluorobenzylamine (34 mg, 0.21 mmol), HATU (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (DIPEA) (23 mg, 0.18 mmol), and stir at room temperature for 2 hours. LC-MS analysis subsequently confirmed complete consumption of compound 15-B and formation of intermediate 45-A. Proceed to the next step with the reaction mixture.

 

Step 4: Add MgBr₂ (55 mg, 0.30 mmol) to the crude reaction mixture obtained from the previous step. Stir the reaction mixture at 50 °C for 1 hour, acidify it with a 10% HCl aqueous solution, separate the phases into an aqueous phase and a dichloromethane phase, and extract the aqueous phase with dichloromethane. The combined organic phases are dried with MgSO₄, filtered, concentrated, and purified by HPLC using ACN/H₂O containing 0.1% TFA as the mobile phase, yielding compound 45, brigetiravir.

 

Pharmacological Action

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Bicetilavir is primarily eliminated from the liver via oxidation by cytochrome P450 3A4 (CYP3A4) and glucuronidation by UDP-glucuronyltransferase 1A1 (UGT1A1). Consequently, due to significantly reduced serum exposure of bicetilavir, potent inducers of UGT1A1 and CYP3A4 (e.g., rifamycin/anticonvulsants) should be avoided. Chelation with multivalent cations may reduce absorption; otherwise, drug-drug interactions are rare.

 

New Anti-AIDS Drugs

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Bictegravir (BIC) is a novel integrase inhibitor and one of the components of Gilead Sciences' innovative drug Biktarvy. Biktarvy was approved in the United States on February 7, 2018, and in the European Union on June 20,2018, with its efficacy and safety demonstrated in Phase III clinical trials. Today, international HIV treatment has fully entered the era of "integrase inhibitors."

 

On August 9, 2020, the three-in-one compound tablet formulation Biktarvy (Bicentel), developed and manufactured by Gilead Sciences, comprising the human immunodeficiency virus type 1 (HIV-1) integrase chain transfer inhibitor (INSTI) bicitavir, along with two HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs)—emtricitabine (FTC) and tenofovir alafenamide (TAF)—received marketing approval from the National Medical Products Administration.

 

Bicagenevir tablets can be used as initial therapy for adult HIV-1-infected individuals or as a replacement regimen in previously treated patients who have achieved virological suppression (HIV RNA <50 copies/mL) for more than three months without treatment failure history and without resistance mutations associated with the components of BIC/FTC/TAF. Bicagenevir tablets represent an ideal choice for HIV-infected individuals due to their ability to initiate rapid treatment, provide potent viral suppression, offer higher resistance barriers, demonstrate superior long-term safety, exhibit minimal drug interactions, and are convenient for administration.

 

Bicentel tablets received FDA approval in February 2018 and became the first to be launched in the United States. Just 18 months later, Gilead Sciences brought Bicentel tablets to Chemicalbook China, bringing China's HIV treatment comprehensively in line with the world's most advanced therapeutic regimens, benefiting Chinese HIV-infected individuals and providing another powerful tool for China's AIDS prevention and control efforts!

 

Contact Us

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Need Bictegravir for your HIV antiretroviral manufacturing campaign, analytical method development, or regulatory filing? Cosperpharm is your trusted partner for high-purity API and reference standards. Reach out today—our team is ready to support your project from R&D through commercial production.