A process for the preparation of pyridine derivatives

Abstract

The application discloses a method for preparing a pyridine derivative, comprising the following steps: S1, reacting a ure compound with a pyridine compound in the presence of an electrophilic activation reagent to prepare a pyridine guanidine; S2, reacting the pyridine guanidine with a nucleophile or a radical precursor to prepare a dihydropyridine intermediate; and S3, hydrolyzing the dihydropyridine intermediate with an oxidizing agent to prepare the pyridine derivative and the ure compound. The pyridine compound is cheap and easy to obtain, and is reacted with the activated ure to form a pyridine salt, so that various complex pyridine derivatives with high added value are obtained with high selectivity. The ure is used as a large steric group to selectively synthesize the complex pyridine derivative, the ure compound is low in price and very stable to water and air, the prepared pyridine guanidine has good C-4 functional group region selectivity, and is compatible with ionic precursors and radical precursors.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing pyridine derivatives. Background Technology

[0002] Pyridine is recognized as one of the most common aromatic heterocycles in pharmaceuticals, ligands, catalysts, and materials. Given the wide application of pyridine compounds, efficient and regioselective functionalization of pyridine from readily available compounds is the most direct route to obtaining complex pyridine derivatives. However, due to the inertness of pyridine, selective functionalization of pyridine compounds has always been a challenging problem. Compared to the well-developed C-2 and C-3 functionalization of pyridine, C-4 functionalization has only been developed in recent decades. Currently, achieving C-4 selective functionalization of pyridine mainly involves introducing sterically hindered groups that interact with the nitrogen atom to shield the competitive reaction at the C-2 position. These sterically hindered groups mainly include fumarate esters, triazine salts, triarylboranes, azacarbene nickel-aluminum compounds, and silane cations. Each of the aforementioned sterically hindered groups can typically only yield a specific type of pyridine compound through one mechanism (ionic addition or radical addition). These sterically hindered groups are mostly highly sensitive to water and air, resulting in extremely poor practicality, and the types of precursors for addition are limited. Therefore, there is an urgent need to develop a new, inexpensive sterically hindered group that can exist in air for the preparation of pyridine derivatives, and through which a diverse range of precursor ions and radicals can be used for the addition of pyridine. Summary of the Invention

[0003] In order to overcome the problems existing in the prior art, the purpose of this invention is to provide a method for preparing pyridine derivatives.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] This invention provides a method for preparing pyridine derivatives, comprising the following steps:

[0006] S1. In the presence of an electrophilic activating agent, urea compounds react with pyridine compounds to prepare pyridineguanidine;

[0007] S2. The pyridine guanidine is reacted with a nucleophile or a free radical precursor to prepare a dihydropyridine intermediate.

[0008] S3. The dihydropyridine intermediate is hydrolyzed with an oxidant to obtain pyridine derivatives and urea compounds;

[0009] The structural formulas of the urea compounds and pyridine guanidine are shown in formulas a and b, respectively:

[0010]

[0011] Among them, R 1 and R 3 Each is independently selected from substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl groups having 2 to 10 carbon atoms, and substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms; R 2 and R 4 Each group is independently selected from substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl groups having 2 to 10 carbon atoms, and substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms, and adjacent groups may form cyclizations with each other;

[0012] Generally, the term "substituted" means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, for example, a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position are either the same or different.

[0013] Among them, R 5 Selected from hydrogen, alkyl, aryl, ester, or halogen;

[0014] The pyridine derivative is shown in formula c:

[0015]

[0016] Wherein, Nu represents a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl group in the nucleophile; R represents a substituted or unsubstituted alkyl, or substituted or unsubstituted aryl group in the free radical; R 5 It is selected from hydrogen, alkyl, aryl, ester or halogen.

[0017] Preferably, the substituents in the substituted alkyl, substituted alkenyl, and substituted alkynyl groups are each independently selected from one or more of halogens (fluorine, chlorine, bromine, iodine), hydroxyl, carboxyl, acetal, amino, primary amino, secondary amino, ester, carbonyl, amide, and cyano.

[0018] Preferably, R 1 and R 3 Each is independently selected from unsubstituted alkyl groups having 1 to 10 carbon atoms, unsubstituted alkenyl groups having 2 to 10 carbon atoms, and unsubstituted alkynes having 2 to 10 carbon atoms.

[0019] Preferably, the urea compound is a symmetrical urea compound.

[0020] More preferably, the R 1 and R 3 Both are unsubstituted alkyl groups having 1 to 6 carbon atoms.

[0021] Preferably, the reaction formula for the method of preparing the pyridine derivative is as follows:

[0022] Step 1:

[0023]

[0024] Step 2:

[0025]

[0026] Step 3:

[0027]

[0028] Actual reaction:

[0029]

[0030] Preferably, the structural formulas of the urea compound and pyridine guanidine are shown as formula d and formula e, respectively:

[0031]

[0032] Among them, R 1 R 3 and R 5 As mentioned above; n is 1 or 2.

[0033] Preferably, the pyridine derivative has any one of the following structural formulas:

[0034]

[0035] Preferably, the electrophilic activating agent is trifluoromethanesulfonic anhydride.

[0036] Preferably, in step S1, the reaction temperature is 0-40°C.

[0037] Preferably, in step S1, the reaction time is 4h-48h.

[0038] Preferably, in step S1, the molar ratio of the urea compound to the pyridine compound is (1-1.5):1.

[0039] Preferably, in step S1, the molar ratio of the electrophilic activating agent to the urea compound is (0.9-3):1.

[0040] Preferably, in step S2, the reaction temperature is -78 to 50°C.

[0041] Preferably, in step S2, the reaction time is 5 min to 24 h.

[0042] Preferably, in step S2, the molar ratio of pyridine guanidine to the nucleophile or free radical precursor is 1:(1.2-4).

[0043] Preferably, in step S3, the reaction temperature is from room temperature to 70°C.

[0044] Preferably, in step S3, the reaction time is 2h-48h.

[0045] Preferably, in step S3, the molar ratio of the dihydropyridine intermediate to the oxidant is 1:(1.5-5).

[0046] Preferably, the nucleophile is selected from one or more of Grignard reagents, lithium reagents, cyano nucleophiles, and enol nucleophiles.

[0047] More preferably, the Grignard reagent is selected from cycloalkyl magnesium halides or alkyl magnesium halides.

[0048] Preferably, the free radical precursor is selected from carboxylic acid compounds, boric acid compounds, or alkanes.

[0049] Preferably, the oxidant is selected from one or more of nitrous acid, potassium ferricyanide, iodobenzene acetate, manganese acetate, and silver nitrate.

[0050] The beneficial effects of this invention are:

[0051] This invention provides a method for preparing pyridine derivatives. By reacting inexpensive and readily available pyridine compounds with activated urea to form pyridine salts, a variety of complex pyridine derivatives with high added value can be obtained with high selectivity. This method involves a one-pot reaction, continuously subjecting pyridine to urea protection, addition, and oxidation. Starting from pyridine raw materials, only one column chromatography separation is required to obtain high-value-added pyridine derivatives. This invention utilizes urea as a sterically hindered group for the selective synthesis of complex pyridine derivatives. Urea compounds are inexpensive and highly stable to water and air. The resulting pyridineguanidine exhibits excellent regioselectivity for C-4 functionalization and is compatible with both ionic and radical precursors. Attached Figure Description

[0052] Figure 1 The product's 1H NMR spectrum;

[0053] Figure 2 The product is shown in the carbon NMR spectrum. Detailed Implementation

[0054] Example 1

[0055] 4-n-pentylpyridine was prepared according to the following reaction formula:

[0056] Step 1:

[0057]

[0058] Step 2:

[0059]

[0060] Step 3:

[0061]

[0062]

[0063] Based on the above chemical reaction formula, the preparation process includes the following steps:

[0064] S1. Weigh 4.2 mmol of N,N-diisobutylpropenylurea (1,3-diisobutyl-3,4,5,6-tetrahydro-2-pyrimidinone) and 4.0 mmol of pyridine as starting materials; weigh 4.08 mmol of trifluoromethanesulfonic anhydride as an electrophilic activating agent; and measure 12.0 mL of dry dichloromethane as a solvent. Place N,N-diisobutylpropenylurea in a reaction tube, evacuate, and purge with nitrogen. Slowly add trifluoromethanesulfonic anhydride to activate the amide bonds of the urea. After activation, add the pyridine starting material. React at 0°C for 4 h to obtain a white solid pyridine guanidine salt. This guanidine salt does not require column purification and will precipitate directly from the solution system with stirring at room temperature. It can be obtained by filtration through a sintered glass funnel and washing with dichloromethane (separation yield: 86%).

[0065] S2. Add 5 mL of tetrahydrofuran to the reaction flask of pyridine guanidine salt to form a suspension. Using pentyl magnesium bromide as a nucleophile, slowly add 0.75 mmol of pentyl magnesium bromide to pyridine guanidine salt at a low temperature of -78℃. During the addition process, the suspension gradually becomes clear. The total reaction time is 10 min. The excess Grignard reagent can be quenched with water to obtain a mixture of dihydropyridine intermediates. This intermediate can be separated or directly oxidized and hydrolyzed by adding an oxidant.

[0066] S3. Add 1 mL of sodium nitrite aqueous solution (0.5 M) and 0.1 mL of glacial acetic acid to the quenched reaction solution, and stir at room temperature for 8 h to obtain fully para-pentyl-substituted pyridine (separation yield: 79%) and the starting material isobutylurea. The 1H and 1C NMR spectra of the obtained para-pentylpyridine product are shown below. Figure 1 , Figure 2 As shown.

[0067] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A process for the preparation of a pyridine derivative, characterized in that, Includes the following steps: S1. In the presence of an electrophilic activating agent, urea compounds react with pyridine compounds to prepare pyridineguanidine; S2. The pyridine guanidine is reacted with a nucleophile to prepare a dihydropyridine intermediate; S3. The dihydropyridine intermediate is hydrolyzed with an oxidant to obtain pyridine derivatives and urea compounds; The structural formulas of the urea compounds, pyridineguanidine, dihydropyridine intermediates, and pyridine compounds are shown in formulas d, e, f, and g, respectively: Formula d; Formula e; Formula f; Formula g; n is 1 or 2; wherein R 1 and R 3 are each independently selected from alkyl having 1 to 10 C atoms, alkenyl having 2 to 10 C atoms, alkynyl having 2 to 10 C atoms; X - is OTf - ; The structural formula of the pyridine derivative is shown in formula c: Formula c has any of the following structural formulas: ； The electrophilic activating agent is trifluoromethanesulfonic anhydride; The nucleophile is selected from Grignard reagents; The oxidant is selected from nitrous acid.

2. The method for preparing pyridine derivatives according to claim 1, characterized in that, Step S1, the reaction conditions for the reaction are selected from one or more of the following: A) The reaction temperature is 0℃-40℃; B) The reaction time is 4 h-48 h; C) The molar ratio of the urea compound to the pyridine compound is (1-1.5):1; D) The molar ratio of the electrophilic activating agent to the urea compound is (0.9-3):

1.

3. The method for preparing pyridine derivatives according to claim 1, characterized in that, Step S2, the reaction conditions for the reaction are selected from one or more of the following: E) The reaction temperature is -78℃ to 50℃; F) The reaction time is 5 min-24 h; G) The molar ratio of pyridine guanidine to the nucleophile is 1:(1.2-4).

4. The method for preparing pyridine derivatives according to claim 1, characterized in that, Step S3, the reaction conditions for the reaction are selected from one or more of the following: H) The reaction temperature is from room temperature to 70°C; I) The reaction time is 2 h-48 h; J) The molar ratio of the dihydropyridine intermediate to the oxidant is 1:(1.5-5).

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