Preparation of the Key Dolutegravir Intermediate via MgBr2-Promoted Cyclization

Abstract

A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr2-promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-(N,N-dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr2 to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.

Synthesis of Dolutegravir Exploiting Continuous Flow Chemistry

“…Recently, Kong and co-workers stated in their batch study toward a dolutegravir intermediate that LiOH presented satisfactory results; however, the reaction time was very long (24 h). They attempted the use of KOH; however, their results revealed a very low selectivity with a high percentage of unwanted diacid byproducts …”

“…They attempted the use of KOH; however, their results revealed a very low selectivity with a high percentage of unwanted diacid byproducts. 22 …”

Synthetic Approaches to a Key Pyridone-carboxylic Acid Precursor Common to the HIV-1 Integrase Strand Transfer Inhibitors Dolutegravir, Bictegravir, and Cabotegravir

“…Yu and co-workers developed a new hectogram-scale synthetic route to the acid 6 via MgBr 2 -promoted intramolecular cyclization. 21 The synthesis reacts commercially available methyl oxalyl chloride ( 19 ) with ethyl 3-( N , N -dimethylamino)acrylate ( 20 ) using pyridine as a base in DCM at −5 °C to afford the vinylogous amide 21 ( Scheme 5 ). The authors standardized these conditions by varying the base and reaction temperature.…”

The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones

“…The chemistry of these heterocycles is actively developed not only for the design of biologically important compounds [ 7 , 8 , 9 ], but also for effective preparation in the industry [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 , 15 ]. At the same time, there is a need to search for new multifarious pyridone building blocks [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and convenient synthetic tools for the construction of polycyclic pyridones [ 1 , 2 , 3 , 15 ], including CH functionalization [ 26 ].…”