Preparation of the Key Dolutegravir Intermediate via MgBr2-Promoted Cyclization.

Jiahui Kong,Renbao He,Hao Chen,Haijian Xia,Yongping Yu

doi:10.3390/molecules26102850

Jiahui Kong, Renbao He + Show 3 more

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https://doi.org/10.3390/molecules26102850

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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.

Highlights

HIV currently affects over 37 million people around the world [1,2,3]
A new generation of synthetic route (Scheme 2ii) has aroused intensive interest, which started from substituted ethyl acetoacetate [11,12,13,14,15,16,17,18]. 4-methoxyacetoacetic acid methyl ester(11) was synthesized by chlorination of diketene and subsequent substitution via
In designing a more efficient and robust synthetic route of intermediate 1, it was initially envisioned that the central pyridinone ring could be derived from P5, which in turn could be obtained by reacting a vinylogous amide P4 with methyl bromoacetate [21,22,23]

Summary

Introduction

HIV currently affects over 37 million people around the world [1,2,3]. In recent years, a number of innovative medicines have made HIV a manageable disease [4,5,6]. Most of the synthetic routes for dolutegravir involve three key intermediates: pyridinone moiety (intermediate 1), (R)-3-aminobutan-1-ol (intermediate 2) and (2,4-difluorophenyl)methanamine (intermediate 3) (Scheme 1). Carboxylated catalyzed by Pd(PPh3 ) , pyridinone intermediate 10 (similar structure with intermediate 1) was synthesized in a low yield. This route required numerous synthetic steps along with tedious chromatographic purification processes, leading to a low total yield (5∼10%). A new generation of synthetic route (Scheme 2ii) has aroused intensive interest, which started from substituted ethyl acetoacetate [11,12,13,14,15,16,17,18]. A new generation of synthetic route (Scheme 2ii) has aroused intensive interest, which started from substituted ethyl acetoacetate [11,12,13,14,15,16,17,18]. 4-methoxyacetoacetic acid methyl ester(11) was synthesized by chlorination of diketene and subsequent substitution via

Methods

Results

Conclusion