Method for preparing meta-functionalized pyridine compound

Patent metadata

Field	Value
Publication number	US-12486232-B2
Application number	US-202118038029-A
Country	US
Kind code	B2
Filing date	Oct 15, 2021
Priority date	Sep 17, 2021
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

A method for preparing a meta-functionalized pyridine compound is provided. The method has a first step, S1, for 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 at 40-110° C. for a reaction for 5-12 hours to obtain 1,4-dihydropyridine. In a second step, S2, catalyzed functionalization of pyridine at the meta-position is provided by 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 meta-functionalized pyridine, wherein the reaction temperature is 40-110° C., and the reaction time is 5-24 hours.

First claim

What is claimed is:

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:

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(R 1 ) 3 , wherein R 1 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:

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, R 2 is an alkenyl, aryl, alkyl, halogen, ester or heteroaryl substituent, R 3 is alkyl, R 4 is tert-butoxycarbonyl or benzyloxycarbonyl, R 5 is an aryl, alkyl or heteroaryl substituent, R 6 is aryl, R 7 is an ester group, R 8 is an ester group or trifluoromethyl, and R 9 is chlorine or bromine.

2 . The method according to claim 1 , wherein a 4 Å molecular sieve is further added to the reactants of step S1, and the feeding ratio of the 4 Å molecular sieve to the pyridine is 50 mg/0.2 mmol.

3 . The method according to claim 1 , wherein in step S2, the imine is

the aldehyde is

the ketone is

and the halogenation reagent is

4 . The method according to claim 1 , wherein when R 2 is a halogen, the halogen is fluorine, chlorine or iodine.

5 . The method according to claim 1 , wherein when R 2 is heteroaryl, the heteroaryl is furyl, thienyl or pyridyl.

6 . The method according to claim 1 , wherein R 3 is methyl.

7 . The method according to claim 1 , wherein when R 5 is heteroaryl, the heteroaryl is furyl, thienyl or pyridyl.

8 . The method according to claim 1 , wherein R 6 is m-nitro- or m-trifluoromethyl-substituted phenyl.

9 . The method according to claim 1 , wherein R 7 is a methyl ester group or an ethyl ester group.

10 . The method according to claim 1 , wherein when R 8 is an ester group, the ester group is a methyl ester group or an ethyl ester group.

11 . The method according to claim 2 , wherein in step S2, the imine is

the aldehyde is

the ketone is

and the halogenation reagent is

12 . The method according to claim 2 , wherein R 3 is methyl.

13 . The method according to claim 2 , wherein when R 5 is heteroaryl, the heteroaryl is furyl, thienyl or pyridyl.

14 . The method according to claim 2 , wherein R 6 is m-nitro- or m-trifluoromethyl-substituted phenyl.

15 . The method according to claim 2 , wherein R 7 is a methyl ester group or an ethyl ester group.

16 . The method according to claim 2 , wherein when R 8 is an ester group, the ester group is a methyl ester group or an ethyl ester group.

Assignees

• Univ Nankai

Inventors

• Wang Xiaochen
• Liu Zhong
• He Jiahao
• Tian Junjie
• Zhou Xinyue

Classifications

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• C07D213/55

  Acids; Esters · CPC title

• C07D213/26

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D211/82 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D213/56 Primary

  Amides · CPC title