METHOD Russian patent published in 2025 - IPC C07D401/04 

FIELD: chemistry.

SUBSTANCE: invention relates to a method for in situ formation of a compound having formula (V) from pipecolic acid, wherein the method is carried out in situ in the presence of a solvent, and the solvent is an organic solvent with a boiling point of 50 °C up to 160 °C, water or a mixture of said solvents, wherein the method comprises: (a) reacting pipecolinic acid with an acid chloride of formula (Ia) in the presence of a base or reacting pipecolinic acid with an acid anhydride of formula (Ib), optionally in the presence of a base, leading to the formation of a compound having formula (II)

(b) reacting a compound having formula (II), with a compound of formula (III), leading to formation of a compound of formula (IV)

(c) reacting a compound of formula (IV), with an ammonium ion source, resulting in formation of a compound having formula (V)

where R₁ is selected from hydrogen and methyl, and/or R₂ is selected from hydrogen, C₁-C₂ alkyl and C₂-C₃ alkenyl, and R₃ is selected from C₁-C₃ alkyl, C₂-C₅ alkenyl containing one or two double bonds, C₁-C₃-alkoxy group, C₁-C₄ alkyl-C(O)-, C₁-C₄ alkyl-S-, C₁-C₄ alkyl-SCH₂-, C₁-C₄ alkenyl-S-, C₁-C₄ alkyl-S(O)-, C₁-C₄ alkyl-S(O)₂-, C₁-C₄ alkenyl-S(O)-, C₁-C₄ alkenyl-S(O)₂-, -SH, CF₃S-, cyclopropyl, cyclobutyl, furyl, optionally substituted with methyl, and C₁-C₆ fluoroalkyl; phenyl group of compounds of formulas (III), (IV) and (V), has n substitutes R₄, where n is zero, one, two, three, four or five; each R₄ is independently selected from a linear C₁-C₆ alkyl optionally including up to 5 F atoms; B⁺ is a cation provided by the base, and X is chlorine, bromine or iodine; wherein the base is a metal phosphate, a metal hydroxide, a metal carbonate, a metal bicarbonate or a combination thereof.

EFFECT: obtaining a novel method for in situ production of a compound of formula (V) from pipecolinic acid, which reduces the number of purification and extraction steps; use same solvent throughout method; at the end of the reaction, the solvent can be recycled; chiral hydrocarbon group formed by radicals R₁, R₂ and R₃, remains unchanged during entire reaction; acyl chloride and compounds of formula (III) can be obtained in a laboratory on-site for synthesis and can be used crudely and in a solution, which reduces the effect of lachrymation reagents on the environment; occurrence of such a secondary reaction as hydrolysis of acid chloride, to a lesser extent; milder reaction conditions; reduce amount or number of required reagents; reduce the amount of the ammonium ion source required for the third reaction step; obtain acceptable output; obtaining acceptable selectivity.

13 cl, 2 tbl, 4 ex