US 12,486,232 B2
Method for preparing meta-functionalized pyridine compound
Xiaochen Wang, Tianjin (CN); Zhong Liu, Tianjin (CN); Jiahao He, Tianjin (CN); Junjie Tian, Tianjin (CN); and Xinyue Zhou, Tianjin (CN)
Assigned to NANKAI UNIVERSITY, Tianjin (CN)
Appl. No. 18/038,029
Filed by NANKAI UNIVERSITY, Tianjin (CN)
PCT Filed Oct. 15, 2021, PCT No. PCT/CN2021/124108
§ 371(c)(1), (2) Date May 23, 2023,
PCT Pub. No. WO2023/039975, PCT Pub. Date Mar. 23, 2023.
Claims priority of application No. 202111093323.6 (CN), filed on Sep. 17, 2021.
Prior Publication US 2025/0179021 A1, Jun. 5, 2025
Int. Cl. C07D 213/56 (2006.01); C07D 211/82 (2006.01); C07D 213/26 (2006.01); C07D 213/55 (2006.01); C07D 213/61 (2006.01)
CPC C07D 213/56 (2013.01) [C07D 211/82 (2013.01); C07D 213/26 (2013.01); C07D 213/55 (2013.01); C07D 213/61 (2013.01)] 16 Claims
 
1. A method for preparing a meta-functionalized pyridine compound, the method comprising the following steps:
S1, preparation of 1,4-dihydropyridine, involving:
in a glove box filled with nitrogen, adding a catalyst, a solvent, pinacolborane and pyridine to a reaction flask in order and stirring the mixture for a sufficient reaction to obtain 1,4-dihydropyridine, with the reaction formula as follows:

OG Complex Work Unit Chemistry
wherein:
the catalyst is triarylborane, the molar ratio of the triarylborane to the pyridine is (10-15): 100, and the structural formula of the triarylborane is B(R1)3, wherein R1 is phenyl, pentafluorophenyl, 3,5-bis(trifluoromethyl)-substituted phenyl, or 2,4,6-trifluoro-substituted phenyl;
the equivalent ratio of the pinacolborane to the pyridine is 1.5:1;
the solvent is tetrahydrofuran, 1,2-dichloroethane or an aromatic solvent; and
the reaction temperature is 40-110° C., and the reaction time is 5-12 hours; and
S2, catalyzed functionalization of pyridine at the meta-position, involving:
adding an imine, an aldehyde, a ketone or a halogenation reagent to the above reaction flask, and stirring the mixture in a nitrogen atmosphere until the reaction is completed; and performing distillation under reduced pressure to remove the solvent and column chromatography separation to obtain a pyridine compound substituted with aminomethyl, hydroxymethyl, benzyl, chlorine or bromine at the meta-position, with the reaction formula as follows:

OG Complex Work Unit Chemistry
wherein the reaction temperature is 40-110° C., and the reaction time is 5-24 hours; and
in the structural formula of the above pyridine, 1,4-dihydropyridine, and pyridine compound substituted with aminomethyl, hydroxymethyl, benzyl, chlorine or bromine at the meta-position, R2 is an alkenyl, aryl, alkyl, halogen, ester or heteroaryl substituent, R3 is alkyl, R4 is tert-butoxycarbonyl or benzyloxycarbonyl, R5 is an aryl, alkyl or heteroaryl substituent, R6 is aryl, R7 is an ester group, R8 is an ester group or trifluoromethyl, and R9 is chlorine or bromine.