GSK1349572

Base Information

• Chemical Name: GSK1349572
• CAS No.: 1051375-16-6
• Molecular Formula: C20H19F2N3O5
• Molecular Weight: 419.13
• Mol file: 1051375-16-6.mol

Synonyms:2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS)-;2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS)-;

Chemical Property of GSK1349572

Chemical Property:

• Appearance/Colour: White to Pale Yellow Solid
• Melting Point: 188-192°C
• Boiling Point: 668.958 °C at 760 mmHg
• PKA: 4.50±1.00(Predicted)
• Flash Point: 358.373 °C
• PSA: 100.87000
• Density: 1.532 g/cm³
• LogP: 1.68160
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly, Heated, Sonicated), Methanol (Slightly, Heated, Sonicated)

Purity/Quality:

98%, ^*data from raw suppliers

Dolutegravir ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Uses: Dolutegravir (GSK1349572) is a HIV integrase inhibitor with an IC50 of 2.7 nM and is moderately effective against the significant mutants Y143R, Q148K, N155H, and G140S/Q148H against Raltegravir. Dolutegravir is a second generation HIV-1 integrase strand transfer inhibitor. Dolutegravir is currently in Phase III clinical trials for the treatment of HIV infection. Dolutegravir has been shown to potently inhibit HIV replication in cells such as peripheral blood mononuclear cells (PBMCs), MT-4 cells and CIP4 cells infected with a self-inactivating PHIV lentiviral vector. Dolutegravir is a second generation HIV-1 integrase strand transfer inhibitor. Dolutegravir is currently in Phase III clinical trials for the treatment of HIV infection. Dolutegravir has been shown to potently inhibit HIV replication in cells such as peripheral blood mononuclear cells (PBMCs), MT-4 cells and CIP4 cells infected with a self-inactivating PHIV lentiviral vector.
• Description: In August 2013, the US FDA approved dolutegravir (also referred to as S/GSK1349572) for the treatment of HIV-1 infection in adults and children ages 12 years and older in combination with other antiretroviral drugs. Dolutegravir was approved in Canada in November 2013. HIV/AIDS remains a global epidemic with 35 million people infected, including 2.3 million new infections as of 2012. Dolutegravir joins raltegravir and elvitegravir (this chapter of ARMC) as the latest of three FDA-approved HIV integrase strand transfer inhibitors (INSTIs). Dolutegravir was discovered by rational design from a literature diketo acid HIV integrase inhibitor utilizing X-ray coordinates to predict ideal bond angles between the diketone and distal benzyl group. In dolutegravir, the monocyclic component of the reported inhibitor was replaced with the tricyclic carbamoyl pyridone moiety. The researchers postulated that the appropriate arrangement of three oxygens would permit chelation with two magnesium ions in the binding site thus affording improved potency. Ultimately, this arrangement along with further modifications afforded dolutegravir, a potent inhibitor of HIV integrase (IC50=1.7 nM).
• Clinical Use: Integrase inhibitor:Treatment of HIV
• Drug interactions: Potentially hazardous interactions with other drugsAntidepressants: concentration reduced by St John’s wort.Antiepileptics: concentration reduced by carbamazepine and possibly fosphenytoin, oxcarbazepine, phenobarbital, phenytoin and primidone.Antivirals: concentration reduced by efavirenz, tipranavir, etravirine and fosamprenavir; possibly reduced by nevirapine.

Technology Process of GSK1349572

There total 114 articles about GSK1349572 which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 92.0%

(4R,12aS)-N-(2,4-difluorobenzyl)-7-methyloxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido [1',2',:4,5]pyrazino[2,1-b] [1,3]oxazine-9-carboxamide (1335210-35-9) → dolutegravir (1051375-16-6,1309560-49-3)

Guidance literature:

With lithium bromide; In tetrahydrofuran; methanol; isopropyl alcohol; at 60 ℃; for 6h; Solvent; Large scale;

Reference yield: 92.0%

(4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-pyrazino[2,1-b][1,3]oxazine-9-carboxamide (1206102-11-5) → dolutegravir (1051375-16-6,1309560-49-3)

Guidance literature:

With hydrogen; palladium 10% on activated carbon; In tetrahydrofuran; methanol; for 2.5h; Product distribution / selectivity;

Reference yield: 90.0%

(4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-pyrazino[2,1-b][1,3]oxazine-9-carboxamide (1206102-11-5) → dolutegravir (1051375-16-6,1309560-49-3) + (4R,12aS)-N-(5-benzyl-2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

Guidance literature:

With trifluoroacetic acid; In dichloromethane; at 35 ℃; Reagent/catalyst; Solvent; Temperature; regioselective reaction;

DOI:10.1021/acs.oprd.6b00156

upstream raw materials:

(4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-pyrazino[2,1-b][1,3]oxazine-9-carboxamide

C₁₅H₂₀ClNO₇

C₁₃H₁₄ClNO₆

C₁₅H₁₇ClN₂O₅

Downstream raw materials:

(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino-[2,1-b][1,3]oxazine-9-carboxamide sodium salt

Refernces

• 1、 Aoyama, Yasunori,Hakogi, Toshikazu,Fukui, Yuki,Yamada, Daisuke,Ooyama, Takao,Nishino, Yutaka,Shinomoto, Shoji,Nagai, Masahiko,Miyake, Naoki,Taoda, Yoshiyuki,Yoshida, Hiroshi,Yasukata, Tatsuro. "Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis". . p. 558 - 564. Retrieved 2019.
• 2、 Dietz, Jule-Philipp,Lucas, Tobias,Gro?, Jonathan,Seitel, Sebastian,Brauer, Jan,Ferenc, Dorota,Gupton, B. Frank,Opatz, Till. "Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium". . p. 1898 - 1910. Retrieved 2021.
• 3、 -. "NOVEL PYRROLE AND PYRIDONE DERIVATIVES AND USES THEREOF". . . Retrieved 2020/05/21.