METHOD OF PRODUCING A TRICYCLIC SULFUR-CONTAINING DERIVATIVE OF 1,2-DIHYDROQUINOLINE FOR INHIBITING REPLICATION OF BETA-CORONAVIRUSES, INCLUDING SARS-CoV-2 Russian patent published in 2024 - IPC C07D495/04 A61K31/4365 A61P31/14 

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a method of producing a tricyclic sulfur-containing derivative of 1,2-dihydroquinoline of general formula I, having the property of inhibiting replication of beta-coronaviruses, including SARS-CoV-2, consisting in modification of tricyclic sulfur-containing derivative of 1,2-dihydroquinoline by preliminary alkylation with methyl iodide with subsequent substitution of sulfur under the action of arylamines and/or alkylation or acylation at the nitrogen atom, as follows: synthesis of imines of 4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones is carried out through formation of methylthiodithiol salt by reaction of 4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione with methyl iodide with subsequent substitution of sulfur as a result of reaction with primary amines in presence of 1.8–2.2 equimole of triethylamine, while boiling in absolute butanol, followed by extraction of the desired reaction product and its recrystallisation from isopropyl alcohol; synthesis of compounds I with X=S is carried out by N-acylation with carboxylic acid chlorides in a mixture of absolute toluene and pyridine, taken in volume ratio of 10 parts of absolute toluene: 0.8–1.2 parts of pyridine, followed by removal of the pyridinium salt and extraction of the reaction product by crystallisation from the filtrate, or with carboxylic acid anhydrides of starting 4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones in absolute dioxane, followed by extraction of the reaction product and its recrystallisation from toluene. In general formula (I), R1 is a substitute selected from methyl-, ethyl-, methoxy-, ethoxy groups; R2 is a substitute, selected from methyl-, ethyl-, methoxy-, ethoxy groups; R3 is a substitute selected from methyl-, ethyl-, methoxy-, ethoxy groups; R4 is a substitute, selected from methyl-, benzyl-, 3-phenylacryloyl-, 3-(4-methoxyphenyl)acryloyl-, 3-phenylpropanoyl-, phenylethyl, 2-(4-fluorophenoxy)acetyl-, 4-chlorophenoxyacetyl-, 2-(2,4-dichlorophenoxy)acetyl-, 4-nitrobenzoyl-, 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl-) group; 3,4-dichlorophenylcarbamoyl-, furan-2-carbonyl-, ethylcarbamoyl-, 2-naphthyloxyacetyl-, 2-(1,3-dioxoisoindolin-2-yl)acetyl-, 2-(1,3-dioxohexahydro-1H-isoindol-2(3H)-yl)acetyl-, 2-morpholinoacetyl-, piperidin-1-ylacetyl-, 2-(4-carbamoylpiperidin-1-yl)acetyl-, 2-(2,5-dioxopyrrolidin-1-yl)acetyl-, 2-phenoxyacetyl-, 2-1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl)acetyl-, 2-benzo[d]oxazol-2-ylthio)acetyl-, 2-(benzo[d]thiazol-2-yloxy)acetyl-, benzoxazol-2-ylmercaptoacetyl-, furanoyl-, 2-naphlinylyoxymethylcarbonyl, 3,4-dichlorophenylcarbamoyl; X is a substitute selected from sulfur, unsubstituted or substituted at positions 2,3,4,5,6 of arylimine, selected from group comprising 4-(4-chlorobenzyloxy)phenylimino-, 4-(6-methylbenzo[d]thiazol-2-yl)phenylimino-, 4-(N-benzoylsulfamoyl)phenylimino-, 4-ethoxyphenylimino-, 4-ethoxycarbonylphenylimino-, phenylimino-, 4-chlorophenylimino-, 3-chlorophenylimino-, 4-sulfamoylphenylimino-, 4-(N-acetylsulfamoyl)phenylimino-, 4-(N-(thiazol-2-yl)sulfamoyl)phenylimino-, 2-nicotinoylhydrazon-, 4-((4-chlorobenzyl)oxy)phenylimino-, 2-methoxyphenylimino-, 4-(N-(pyrimidin-2-yl)sulfamoyl)phenylimino-, 4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylimino-.

EFFECT: use of the invention enables to reduce the synthesis time to 2–3 hours and significantly expand the range of used amines.

4 cl, 1 dwg, 1 tbl, 20 ex

(I)