Synthesis of raltegravir

Inventors

Gurjar, Mukund Keshav • Sonawane, Swapnil Panditrao • Maikap, Golakchandra Sudarshan • Patil, Gulabrao Dagadu • Shinde, Shivnath Bhaupatil • Shalikrao, Pankaj • Mehta, Samit Satish

Assignees

Emcure Pharmaceuticals Ltd

Abstract

The present invention relates to a novel synthetic route for the preparation of raltegravir and pharmaceutically acceptable salts, starting from 2-amino-2-methylpropanenitrile and oxadiazole carbonyl chloride, through the formation of a pyrimidinone intermediate of formula (V).

Core Innovation

The patent describes a process for preparation of raltegravir of formula (I) through a sequence of defined intermediates. It includes reacting 2-amino-2-methylpropanenitrile with oxadiazole carbonyl chloride in the presence of a base to give N-(2-cyanopropan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide of formula (II), then converting the resulting oxadiazole carboxamide intermediate to compounds of formulas (IV) and (V) through treatment with hydroxyl amine derivatives and reaction with dialkyl acetylene dicarboxylate.

The process further couples the intermediate of formula (V) with p-fluorobenzyl amine to obtain either raltegravir of formula (I) directly or a coupled intermediate of formula (VIa). When compound of formula (VIa) is isolated, it is subsequently methylated with a methylating agent to yield raltegravir. The patent specifies that R′ is methyl and relates the sequence of these transformations to formation of the final raltegravir structure.

In the described embodiments, the inventors argue that the synthetic route is cost-effective and reduces prior-art impurities, in particular O-methylated derivatives, while avoiding steps needed to manage E/Z isomer mixtures. The patent also reports regioselective N-methylation with high comparative selectivity versus O-methylation, along with reported yields and high purity, including regioselectivity >99% and overall purity >99.5%. The provided examples include preparation of intermediates such as compounds II, IVa, Va, VI, and the final raltegravir (I), with representative analytical data.

Claims Coverage

The supplied claim set includes one full multi-step independent process claim and five independent claims that respectively cover preparation of intermediate (II), preparation of intermediates (IVa/IVb), preparation of intermediate (Va), preparation of intermediate (VIa), and methylation of intermediate (VIa) to raltegravir. Across the independent claims, the inventive coverage centers on converting a defined oxadiazole carboxamide through hydroxyl amine derivative chemistry, dialkyl acetylene dicarboxylate cyclization to a pyrimidinone intermediate, coupling with p-fluorobenzyl amine, and a methylation step for raltegravir formation.

Overall, the independent claims cover preparation of key intermediates (II, IVa/IVb, Va, VIa) and the final sequence that converts intermediate (VIa) to raltegravir by methylation, with the broadest independent claim tying these transformations together into a complete process for preparation of raltegravir.

Stated Advantages

Documented Applications

No documented applications found