1357289-29-2

Upstream product

• 1335210-23-5 1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid 
• 72235-52-0 2,4-Difluoro-benzylamine 
• 1616340-68-1 methyl 5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dirnethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 

Relevant academic research and scientific papers

Synthesis of two diastereomeric impurities of a fluorinated antiretroviral drug dolutegravir

The study of drug impurities constitutes an important area of process research and development. In the current study the synthesis of two diastereomeric impurities namely R,R- and S,S-isomer of recently approved antiretroviral drug dolutegravir was explored. Accordingly, a simple and scalable process has been developed for the first time for the synthesis of said impurities starting from a common intermediate, e.g. ethyl 5-((2,4-difluorobenzyl)carbamoyl)-3-ethoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate. The methodology involved individual treatment of this common ester with (S)- and (R)-3-amino-1-butanol separately to afford the corresponding target compound in good yield. The IR, 1H, 13C and 19F NMR and Mass spectral data as well as HPLC and HRMS analysis were used to characterize the synthesized impurities. Both the impurities were prepared in gram scale suggesting scale-up potential of the methodology developed. Besides being economical as well as free from the use of expensive catalyst, the methodology involved the use of mild reaction conditions and workup procedure. Additionally, the reaction conditions adopted in the current approach are suitable for the laboratory as well as industrial applications. The current study would be of considerable interest to researchers engaged in the process development for accessing chemically pure dolutegravir.

Method for synthesizing diastereomer impurity in dolutegravir raw material

The invention provides a method for synthesizing a diastereomer impurity in a dolutegravir raw material, which comprises the following steps: 1, carrying out condensation reaction on SM1 serving as araw material and 2,4-difluorobenzylamine to generate a compound I; 2, reacting the compound I with an alkali in a reaction solvent to generate a compound II; 3, hydrolyzing the compound II under an acidic condition to generate a compound III; 4, carrying out acid catalytic reaction on the compound III and R-aminobutanol in a reaction solvent to generate a compound IV; 5, generating a compound V from the compound IV in a reaction solvent under the catalysis of a condensing agent; and 6, demethylating the compound V under the action of an alkali metal salt to generate an impurity VI. The synthetic method of the diastereoisomer impurity in the dolutegravir raw material is simple in process and available in raw material, and the prepared new impurity can provide a reference substance for quality analysis of dolutegravir, so that the quality standard of dolutegravir is improved.