PROCESS FOR THE PREPARATION OF (6R,7S,7AS)-6-((R)-1-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)ETHOXY)-7-(4-FLUOROPHENYL)HEXAHYDRO-3H-PYRROLISIN-3-ONE Russian patent published in 2023 - IPC C07D487/04 

FIELD: chemistry.

SUBSTANCE: invention relates to a method for producing (6R,7S,7aS)-6-((R)-1-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-7-(4-fluorophenyl)hexahydro-3H-pyrrolysin-3 -one (compound I). The method is carried out according to the sequence of stages: 1) condensation of 4-nitrobutyric acid methyl ester and 4-fluorobenzaldehyde by boiling in an organic solvent in the presence of a primary amine as a catalyst to form methyl (E)-5-(4-fluorophenyl)-4-nitropent- 4-enoate (nitroalkene II); solvent to form cyclic 4-(4-fluorophenyl)-3-(3-methoxy-3-oxopropyl)-6-((2-phenylcyclohexyl)oxy)-5-(acyloxy)-5,6-dihydro-4H-1,2-oxazine-2-oxide (cyclic nitronate IV); 3) hydrolysis of the ester group in the obtained cyclic nitronate IV under basic conditions with the formation of cyclic 4-(4-fluorophenyl)-5-hydroxy-3-(3-methoxy-3-oxopropyl)-6-((2-phenylcyclohexyl)oxy)-5,6-dihydro-4H-1,2-oxazine-2-oxide (cyclic nitronate V); 4) reductive recycling of the resulting cyclic nitronate V during hydrogenation at elevated temperature and hydrogen pressure in the presence of a platinum catalyst in a protic solvent medium to form 7-(4-fluorophenyl)-6-hydrohexahydro-3H-pyrrolisin-3-one (pyrrolizidinone VI); 5) alkylation of the resulting pyrrolizidinone VI with 1-(3,5-bis(trifluoromethyl)phenyl)ethyl 2,2,2-trichloroacetimidate (imidate VII) at a reduced temperature in an aprotic solvent in the presence of a strong protic acid, followed by isolation of the target product.

EFFECT: improvement of the method for obtaining compound I, which is an antagonist of the human NK1 receptor, by reducing the number of stages and increasing the overall yield of the product.

6 cl, 2 ex