Dolutegravir

Dolutegravir is a pivotal active pharmaceutical ingredient (API) in the treatment of human immunodeficiency virus type 1 (HIV-1) infection, approved by the U.S. Food and Drug Administration on August 12, 2013. As a highly potent integrase strand transfer inhibitor, Dolutegravir works by inhibiting the action of the HIV integrase enzyme, which is necessary for the integration of viral DNA into the host genome, thereby preventing viral replication and reducing HIV viral load. Dolutegravir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients aged 12 years and older weighing at least 40 kg. Due to its high barrier to resistance, favorable safety profile, and convenient once-daily dosing, Dolutegravir has become a preferred integrase inhibitor in first-line and salvage antiretroviral regimens worldwide. In quality control contexts, Dolutegravir is associated with numerous process-related and degradation-related impurities, including Dolutegravir Impurity 31, the RR isomer (Impurity B), and N-nitroso Dolutegravir, which serve as critical reference standards for analytical method development, method validation, and ANDA submissions. The compound is supplied as a white to off-white powder with a melting point of 187–193 °C, and is stored at −20 °C for long-term stability.

Product Parameters

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Parameter	Specification
Product Name	Dolutegravir
CAS Number	1051375-16-6
Molecular Formula	C₂₀H₁₉F₂N₃O₅
Molecular Weight	419.38 g/mol
Appearance	White to off-white to pale beige powde
Melting Point	187–193 °C
Boiling Point	669.0 ± 55.0 °C (predicted)
Density	1.53 g/cm³ (predicted)
pKa	4.50 ± 1.00 (predicted)
Storage Condition	−20 °C; refrigerator

Synthetic Route

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At 25°C under nitrogen protection, lithium bromide (10.60 g, 122.06 mmol) was added to a solution of the drulterene precursor amide (23.0 g) in acetonitrile (460 mL, 20 volumes). The resulting reaction mixture was heated to 85°C and allowed to react for approximately 3 hours. Reaction progress was monitored using TLC. Upon completion, the mixture was cooled to room temperature. Then, 0.5 M hydrochloric acid (460 mL) was added; the mixture was stirred at 20–25°C for another 3 hours. The solids were filtered and washed with a mixture of acetonitrile and water (1:1, 100 mL) for 30 minutes. The wet solids were dissolved in acetonitrile (230 mL), followed by gradual addition of 230 mL water at 20–25°C while stirring for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The resulting solid was vacuum-dried at 40–45°C for 6 hours to yield the target product.

 

 

Application

Dolutegravir (DTG), marketed under the brand name TIVICAY, was approved by the U.S. Food and Drug Administration on August 12,2013. It is an integrase chain transfer inhibitor (INSTI) of human immunodeficiency virus type 1 (HIV-1) and is indicated for use in combination with other antiretroviral agents to treat HIV-1 infection in adults, children aged 12 years or older, and children weighing at least 40 kg.

 

Bioactivity

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Dolutegravir (GSK1349572, S/GSK1349572) is a two-metal-binding HIV integrase inhibitor with an IC50 of 2.7 nM in cell-free assays, exhibiting moderate activity against the raltegravir-resistant mutant strains Y143R, Q148K, N155H, and G140S/Q148H.

 

 

Contact Us

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