Dihydropyridinone derivatives and selective synthesis method thereof

Abstract

The application discloses a dihydropyridinone derivative and a selective synthesis method thereof. Under the synergistic promotion of triethylamine Et3N and chromium trichloride CrCl3, ammonium acetate (NH4OAc) is used as an N source to perform multi-component form [1+2+1+2] cascade cyclization of ketone, aldehyde and Meldrum's acid to synthesize the dihydropyridinone derivative with high selectivity. The application only uses Et3N and CrCl3 as promoters, and avoids using complex ligands and sensitive organic metal reagents. Meanwhile, the formal [1+2+1+2] cyclization reaction is applicable to various substrates, has good tolerance to various substituents, and can provide easily obtained dihydropyridinone with a good yield. In addition, the reaction has the characteristics of low additive price, mild reaction condition and easily obtained starting material. The multi-component cascade cyclization protocol is realized by using easily commercially available starting materials under mild conditions, and the dihydropyridinone compound with high regioselectivity is constructed.

Description

[Technical Field]

[0001] This invention belongs to the field of catalytic organic synthesis and relates to a dihydropyridinone derivative and its highly selective synthesis method. [Background Technology]

[0002] Amide bonds play a crucial role in synthetic chemistry and materials science, and their structural units are ubiquitous in many natural products and bioactive peak molecules, thus attracting considerable attention in medicinal chemistry. Dihydropyridones, as a special type of amide-containing structure, are commonly used scaffolds in drug synthesis, pesticides, and electronic materials. For example, pirfenidone, a novel antifibrotic drug, was approved by the FDA in 2008 for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF). Furthermore, Rho kinase (ROCK1) inhibitors can effectively and selectively inhibit spontaneous hypertension and related diseases. It is worth noting that carboxylamide derivatives exhibit selective α-... 1a Adrenaline receptor antagonism can be used to treat patients with benign prostatic hyperplasia.

[0003] Although heterocyclic structures containing dihydropyridone molecules have wide applications in the pharmaceutical field, efficient methods for synthesizing dihydropyridones remain scarce due to the unique bonding characteristics of the amide bond structure. Currently known examples include the [3+3] cyclization reaction of α,β-unsaturated esters with amides under NHC organic catalysis (Angew. Chem., Int. Ed. 2013, 52, 8592-859), the [3+3] cyclization reaction of 2-bromoenal with enamines catalyzed by NHC (Adv. Synth. Catal. 2013, 355, 1089-1097), and the method of constructing dihydropyridones by the co-catalysis of chiral isothioureas and Brønsted acids (Org. Lett. 2020, 22, 2261-2265). Despite these encouraging advances, we still hope to develop a practical, efficient, and easy-to-operate method that can directly utilize commercially available starting materials, thereby avoiding the challenges of limited substitution categories, low functional group compatibility, and multi-step synthesis of starting materials. Therefore, we have developed a method for the formation of a multi-component [1+2+1+2] cascade cyclization reaction using commercially available aldehydes, ketones, Michaelis-Menten acid, and ammonium acetate (NH4OAc) under the synergistic promotion of Et3N and CrCl3. This method does not use additional ligands, has simple and easy-to-operate conditions, good substrate adaptability, high yield, and the starting materials are commercially available. Currently, there are no published documents or patent applications reporting the formation of a multi-component [1+2+1+2] cascade cyclization reaction to obtain dihydropyridinones, either domestically or internationally. [Summary of the Invention]

[0004] This invention develops a highly efficient transformation method for the synthesis of dihydropyridones and their derivatives using Et3N and CrCl3 synergistic promotion. The reaction utilizes readily available ketones, aldehydes, NH4OAc, and Meldrum's acid via a multi-component [1+2+1+2] cascade cyclization approach to obtain functional group-tolerant dihydropyridone compounds in high yield. This interesting method features simple operation, readily available starting materials, mild reaction conditions, good functional group tolerance, and high atom economy. Furthermore, this strategy can provide an excellent synthetic route for highly functionalized or complex dihydropyridones.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows:

[0006] A selective synthesis method for a class of dihydropyridinone derivatives includes the following steps: under a nitrogen atmosphere, using Et3N and CrCl3 as promoters, ammonium acetate as the N source, and methanol as an ultra-dry solvent, ketones, aldehydes, and cycloisopropyl malonate (Missell's acid) are stirred at 30℃-100℃ for 24-36 hours to obtain a product containing dihydropyridinone.

[0007] Further improvements involved diluting the product containing dihydropyridone derivatives with ethyl acetate, adding water, and extracting three times with ethyl acetate. The organic phases were collected and combined, and then anhydrous Na2SO4 was added to dehydrate the combined organic phases. The mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was then separated by column chromatography on silica gel to obtain purified dihydropyridone derivatives.

[0008] Further improvements were made, with the molar ratio of ammonium acetate, CrCl3, ketone, aldehyde, triethylamine, and Michaelis acid being 0.75:0.09:0.30:0.42:0.9:0.75.

[0009] Further improvements include the following ketones: acetophenone, 3'-methylacetophenone, 4'-ethylacetophenone, 4'-isopropylacetophenone, 4'-n-pentylacetophenone, 3'-methoxyacetophenone, 4'-methoxyacetophenone, 4'-ethoxyacetophenone, 2'-fluoroacetophenone, 3'-fluoroacetophenone, 4'-fluoroacetophenone, 2'-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, 2'-bromoacetophenone, and 3'-bromoacetophenone. One of the following: 4'-bromoacetophenone, 4'-iodoacetophenone, 2'-nitroacetophenone, 4'-nitroacetophenone, 3'-trifluoromethylacetophenone, 4'-cyanoacetophenone, 4'-methylthioacetophenone, 4'-sulfonylacetophenone, 4'-phenylacetophenone, 3',4'-dichloroacetophenone, 3',4'5'-trifluoroacetophenone, pinacolone, acetylcyclohexane, diphenylacetophenone, cycloheptanone, cyclooctanone, cyclododecanone, and acetophenone.

[0010] In a further improvement, the aldehyde is one of benzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-tert-butylbenzaldehyde, 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 2-bromobenzaldehyde, 4-bromobenzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, hexanal, and cyclopentylbenzaldehyde.

[0011] A class of dihydropyridone derivatives, the chemical formula of which is as follows:

[0012]

[0013] Among them, R 1 R 2 R 3 All are substituted groups, selected from H, Me, Et, i Pr, n Pentyl, OMe, OEt, F, Cl, Br, I, NO2, CF3, CN, SMe, SO2Me or Ph.

[0014] The resulting compounds will have different functions depending on the substituent groups, as shown below:

[0015]

[0016] Rho kinase (ROCK1) inhibitors (I) can effectively and selectively inhibit spontaneous hypertension and related diseases. Carboxylamide derivatives (II) have been shown to have selective α-reactive protein (ARP) activity. 1aAdrenaline receptor antagonism can be used to treat patients with benign prostatic hyperplasia. References: 1. a) Goodman, KB; Cui, H.; Dowdell, SE; Gaitanopoulos, DE; Ivy, RL; Sehon, CA; Stavenger, RA; Wang, GZ; Viet, A; Q.; Xu, W.; Ye, G.; Semus, SF; Evans, C.; Fries, HE; ​​Jolivette, LJ; Kirkpatrick, RB; Dul, E. ; Khandekar, SS; Yi, T.; Jung, DK; Wright, L..L.; Smith, GK; Behm, DJ; Bentley, R.; Doe, CP; Hu, E.; Lee, D JMed.Chem.2007,50,6-9;b)Homan,KT;Larimore,KM;Elkins,JM;Szklarz,M.;Knapp,S.;Tesmer,JJGACS Chem. Biol. 2015, 10, 310-319; c) Feng, Y.; LoGrasso, PV; Defert, O.; Li, RJ Med. Chem. 2016, 59, 2269-2300.

[0017] 2. Nantermet, PG; Barrow, JC; Selnick, HG; Homnick, CF; Freidinger, RM; Chang, RSL; O'Malley, SS; Reiss, DR; Broten, TP; Ransom, RW; Pettibone, DJ; Olah, T.;

[0018] The advantages of this invention are as follows:

[0019] This invention presents a novel method for the highly selective synthesis of dihydropyridinone derivatives via a multi-component [1+2+1+2] cascade cyclization of ketones, aldehydes, and Meldrum's acids, using ammonium acetate (NH4OAc) as the nitrogen source and synergistically promoted by triethylamine (Et3N) and chromium trichloride (CrCl3). This method uses only Et3N and CrCl3 as promoters, avoiding the use of complex ligands and sensitive organometallic reagents. Furthermore, this formal [1+2+1+2] cyclization reaction is applicable to a variety of substrates, exhibits good tolerance to various substituents, and provides readily available dihydropyridinones in good yields. In addition, the reaction features inexpensive additives, mild reaction conditions, and readily available starting materials. It achieves a multi-component cascade cyclization protocol using readily available starting materials under mild conditions, constructing highly regioselective dihydropyridinone compounds. [Attached Image Description]

[0020] Figure 1 This is a schematic diagram of the reaction formula of the present invention.

Detailed Implementation Methods

[0021] The reaction formula of this invention is as follows:

[0022]

[0023] Example 1:

[0024] NH4OAc (0.75 mmol, 2.5 equivalents), CrCl3 (0.09 mmol, 0.3 equivalents), and Michaelis-Menten acid (0.75 mmol, 2.5 equivalents) were added to a 10 mL Schlenk tube equipped with a magnetic stirrer. The tube was evacuated with a pump and then filled with nitrogen three times. Then, acetophenone (0.30 mmol), benzaldehyde (0.42 mmol, 1.4 equivalents), triethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) were added under a N2 atmosphere. The mixture was stirred at 50 °C for 24 hours (using a constant-temperature oil bath). After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and then extracted three times with ethyl acetate. The organic phase was collected, and the combined organic layers were dehydrated with an appropriate amount of anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified to dihydropyridinone by column chromatography on silica gel.

[0025] The product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give 4,6-diphenyl-3,4-dihydropyridine-2(1H)-one as a white solid. Yield: 55 mg, 74%. 1H NMR (400MHz, CDCl3) δ8.14(s,1H),7.55-7.50(m,2H),7.46-7.28(m,8H),5.59(dd,J=4.1,1.6Hz,1H ), 3.98(ddd,J=10.6,7.0,4.0Hz,1H), 2.90(dd,J=16.2,6.9Hz,1H), 2.74(dd,J=16.2,10.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ171.2,143.1,137.3,134.8,129.0,129.0,128.9,127.2,127.1,125.2,106.8,39.0,38.7.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 NO + 250.1226; found 250.1217.

[0026] Example 2:

[0027] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 3'-methylacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0028] Example 3:

[0029] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 4'-ethylacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0030] Example 4:

[0031] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add 0.30 mmol of 4'-isopropylacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0032] Example 5:

[0033] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 4'-n-pentylacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0034] Example 6:

[0035] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 3'-methoxyacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0036] Example 7:

[0037] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 4'-methoxyacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0038] Example 8:

[0039] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuating with a pump, fill with nitrogen three times. Then, add 0.30 mmol of 4'-ethoxyacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0040] Example 9:

[0041] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 2'-fluoroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0042] Example 10:

[0043] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add 0.30 mmol of 3'-fluoroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0044] Example 11:

[0045] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add 0.30 mmol of 4'-fluoroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0046] Example 12:

[0047] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 2'-chloroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0048] Example 13:

[0049] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 3'-chloroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0050] Example 14:

[0051] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add 0.30 mmol of 4'-chloroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 2 hours (using a constant-temperature oil bath). After cooling to room temperature, add the remaining ingredients under a N2 atmosphere and stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified dihydropyridinone.

[0052] Example 15:

[0053] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 2'-bromoacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0054] Example 16:

[0055] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 3'-bromoacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0056] Example 17:

[0057] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 4'-bromoacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0058] Example 18:

[0059] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 4'-iodoacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0060] Example 19:

[0061] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 2'-nitroacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0062] Example 20:

[0063] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.30 mmol of 4'-nitroacetophenone, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0064] Example 21:

[0065] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of 3'-trifluoromethylacetophenone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0066] Example 22:

[0067] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.30 mmol of 4'-cyanoacetophenone, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0068] Example 23:

[0069] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.30 mmol of 4'-methylthioacetophenone, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0070] Example 24:

[0071] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.30 mmol of 4'-sulfone acetophenone, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0072] Example 25:

[0073] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 4'-phenylacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0074] Example 26:

[0075] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 3',4'-dichloroacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0076] Example 27:

[0077] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of 3',4',5'-trifluoroacetophenone, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0078] Example 28:

[0079] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add pinacolone (0.30 mmol), benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0080] Example 29:

[0081] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetylcyclohexane, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0082] Example 30:

[0083] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.30 mmol of diphenyl ethyl ketone, and 0.75 mmol of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a nitrogen atmosphere, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0084] Example 31:

[0085] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of cycloheptanone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0086] Example 32:

[0087] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of cyclooctanone, 0.42 mmol (1.4 equivalents) of benzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0088] Example 33:

[0089] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, 0.75 mmol (2.5 equivalents) of Michaelis-Menten, and 0.30 mmol of cyclododecone to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, add benzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0090] Example 34:

[0091] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a nitrogen atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 2-methylbenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0092] Example 35:

[0093] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.09 mmol (0.3 equivalents) of CrCl3, and 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 3-methylbenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0094] Example 36:

[0095] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 4-methylbenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0096] Example 37:

[0097] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 4-ethylbenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0098] Example 38:

[0099] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, under a N2 atmosphere, add acetophenone (0.30 mmol), 4-tert-butylbenzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0100] Example 39:

[0101] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 3-methoxybenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0102] Example 40:

[0103] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, add acetophenone (0.30 mmol), 4-methoxybenzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0104] Example 41:

[0105] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, add acetophenone (0.30 mmol), 4-fluorobenzaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0106] Example 42:

[0107] NH4OAc (0.75 mmol, 2.5 equivalents), Michaelis acid (0.75 mmol, 2.5 equivalents), and CrCl3 (0.09 mmol, 0.3 equivalents) were added to a 10 mL Schlenk tube equipped with a magnetic stirrer. The tube was evacuated with a pump and then filled with nitrogen three times. Then, acetophenone (0.30 mmol), 4-chlorobenzaldehyde (0.42 mmol, 1.4 equivalents), triethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) were added under a N2 atmosphere. The mixture was stirred at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and water was added. The mixture was then extracted three times with ethyl acetate. The organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layers. The mixture was concentrated under reduced pressure. The crude product was purified to dihydropyridinone by column chromatography on silica gel.

[0108] Example 43:

[0109] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 2-bromobenzaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0110] Example 44:

[0111] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, 0.42 mmol (1.4 equivalents) of 4-bromobenzaldehyde, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, add acetophenone (0.30 mmol), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0112] Example 45:

[0113] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of 1-naphthaldehyde, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0114] Example 46:

[0115] Add 0.75 mmol (2.5 equivalents), 0.42 mmol (1.4 equivalents), 0.75 mmol (2.5 equivalents), and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, add 0.30 mmol of acetophenone, 0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0116] Example 47:

[0117] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 0.30 mmol of acetophenone, 0.42 mmol (1.4 equivalents) of hexanal, 0.9 mmol (3 equivalents) of triethylamine, and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0118] Example 48:

[0119] Add 0.75 mmol (2.5 equivalents) of NH4OAc, 0.75 mmol (2.5 equivalents) of Michaelis-Menten acid, and 0.09 mmol (0.3 equivalents) of CrCl3 to a 10 mL Schlenk tube equipped with a magnetic stirrer. After evacuation by pumping, fill with nitrogen three times. Then, add acetophenone (0.30 mmol), cyclopentylformaldehyde (0.42 mmol (1.4 equivalents), triethylamine (0.9 mmol (3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH) under a N2 atmosphere. Stir the mixture at 50 °C for 24 hours (using a constant-temperature oil bath). After cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three more times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. Separate the crude product by column chromatography on silica gel to obtain purified dihydropyridinone.

[0120] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for the selective synthesis of a class of dihydropyridinone derivatives, characterized in that, The process includes the following steps: Under a nitrogen atmosphere, using Et3N and CrCl3 as promoters, ammonium acetate as the nitrogen source, and methanol as an ultra-dry solvent, ketone I, aldehyde II, and Michaelis-Menten acid are stirred at 30℃-100℃ for 24-48 hours to obtain a product containing dihydropyridinone III; the product containing dihydropyridinone derivatives is diluted with ethyl acetate, water is added, and the mixture is extracted three times with ethyl acetate. The organic phases are collected and combined, and then anhydrous Na2SO4 is added to dehydrate the combined organic phases. The mixture is then concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography on silica gel to obtain the dihydropyridinone derivatives; the molar ratio of ammonium acetate, CrCl3, ketone, aldehyde, triethylamine, and Michaelis-Menten acid is 0.75:0.09:0.30:0.42:0.9:0.

75. The reaction formula is as follows: ； Wherein, the ketone is acetophenone, 3'-methylacetophenone, 4'-ethylacetophenone, 4'-isopropylacetophenone, 4'-n-pentylacetophenone, 3'-methoxyacetophenone, 4'-methoxyacetophenone, 4'-ethoxyacetophenone, 2'-fluoroacetophenone, 3'-fluoroacetophenone, 4'-fluoroacetophenone, 2'-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, 2'-bromoacetophenone, 3'-bromoacetophenone, 4 One of the following: '-bromoacetophenone, 4'-iodoacetophenone, 2'-nitroacetophenone, 4'-nitroacetophenone, 3'-trifluoromethylacetophenone, 4'-cyanoacetophenone, 4'-methylthioacetophenone, 4'-sulfonylacetophenone, 4'-phenylacetophenone, 3',4'-dichloroacetophenone, 3',4'5'-trifluoroacetophenone, pinacolone, acetylcyclohexane, diphenylacetophenone, cycloheptanone, cyclooctanone, cyclododecanone, and acetophenone; The aldehyde is one of benzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-tert-butylbenzaldehyde, 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 2-bromobenzaldehyde, 4-bromobenzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, hexanal, and cyclopentylbenzaldehyde.

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