LU508276B1

LU508276B1 - Preparation method for synthesizing polysubstituted 2-quinolinone compound through base catalysis

Info

Publication number: LU508276B1
Application number: LU508276A
Authority: LU
Inventors: Liangzhu Huang
Original assignee: Univ Yanan
Priority date: 2023-09-18
Filing date: 2024-09-15
Publication date: 2025-03-17
Also published as: CN117229206B; CN117229206A

Abstract

The invention provides an efficient preparation method for preparing polysubstituted 2-quinolinone from 2- amino benzophenone compounds and ethyl malonyl chloride under the action of alkali, which mainly comprises the following steps: adding the 2-amino benzophenone compounds and imidazole into a corresponding solvent, stirring at low temperature, and reacting at high temperature to obtain the polysubstituted 2-quinolinone. The preparation method comprises the following steps: slowly dropwise adding ethyl malonyl chloride into a reaction system, heating to react for several hours, adding water to quench the reaction, extracting with ethyl acetate, separating liquid, drying, filtering, concentrating, and separating by column chromatography to obtain the product. The preparation and synthesis method is simple and effective in operation, mild in reaction condition, free of inert gas protection, high in yield and easy for large-scale production, can well solve the technical problem of complicated preparation route of the polysubstituted 2-quinolinone compound at present, and can provide an efficient synthesis method for preparation of natural products or drugs containing 2-quinolinone skeletons.

Description

PREPARATION METHOD FOR SYNTHESIZING POLYSUBSTITUTED 2-QUINOLINONE COMPOUND L/508276

THROUGH BASE CATALYSIS

TECHNICAL FIELD

The invention belongs to the field of medicinal chemistry and active heterocyclic compounds, and specifically relates to a preparation method for imidazole-promoted one-pot synthesis of multi-substituted 2- quinolinone compounds.

BACKGROUND

2-Quinolinones are an important class of nitrogen-containing heterocyclic compounds that are widely used in the synthesis of drug molecules and various functional materials because of their unique maternal structure. This type of nitrogen-containing heterocyclic compounds usually has good pharmaceutical activities, such as anti-cancer, antibacterial, anti-malarial, and treatment of Alzheimer's disease and schizophrenia. In addition, 2-quinolinone compounds are also important organic synthesis intermediates for the synthesis of fused heterocyclic compounds.

At present, the reported synthesis methods of 2-quinolinone compounds mainly include the tandem cyclization reaction of aniline and alkyne (scheme la), intramolecular Houben-Hoesch reaction (scheme 1b), Pd-catalyzed carbonyl insertion (scheme lc), and the other methods are multi-step combined reactions, such as step-step amidation condensation and strong base-promoted intramolecular addition cyclization reaction (scheme 1d).

Although the above methods have enriched the synthesis pathways of 2-quinolinone compounds, there are still shortcomings such as harsh reaction conditions, expensive catalysts or substrates, and cumbersome steps. Therefore, ıtis of great significance to develop a method with simple operation, mild conditions, high yield and compatibility to prepare 2-quinolinone compounds.

In response to the above problems, the patent of the present invention intends to design a one-pot efficient synthesis of 2-quinolinone starting from 2-aminobenzophenone and monoethyl malonate chloride under the promotion of alkali without the need for inert gas protection. Similar compounds, further improve and optimize the efficiency and method of constructing the diversity of 2-quinolinone skeleton structures (existing synthesis methods la-1d and the proposed route le of the present invention are shown in the figure below).

SE fd Faire me a ES Kl (ess Re +8 WN TRAM CE a FT ae 8 a. PA es Ba pen FR Brststeg 7 second step 7 5 [ MS weston NSS

Schemel Synthesis method of substituted 2-quinolone compounds

The base-promoted ‘one-pot’ reaction of condensation, addition and cyclization of 2-aminobenzophenone and malonate monoethyl chloride under mild conditions is a theoretically feasible and efficient synthesis method with obvious steps. Economical and in line with the concept of green chemistry. After optimization and screening, the present invention finally uses an appropriate amount of alkali, which has both alkaline and intramolecular aldol condensation catalyst functions. It can promote amidation reaction and intramolecular addition cyclization reaction under mild conditions, and finally realizes the high efficiency of imidazole promotion by the technical route for preparing multi-substituted 2-quinolinone compounds in ‘one-pot ‘reaction. LU508276

SUMMARY OF THE INVENTION

In view of the shortcomings and drawbacks existing in the prior art, the present invention found through experiments and exploration that some bases can promote the condensation and addition of 2-aminobenzophenone and malonate monoethyl chloride under mild conditions. Poly-substituted 2-quinolinone compounds can be successfully prepared through the ‘one-pot’ reaction with cyclization. This provides an efficient synthesis method for base-promoted multi-substituted 2-quinolinone compounds, thus developing A more efficient and convenient synthetic technical route, and this method has the characteristics of good substrate adaptability, cheap and easily available base, simple operation, mild reaction conditions, and easy amplification for large-scale production.

The technical solutions provided by the present invention are as follows:

A preparation method for base-catalyzed synthesis of multi-substituted 2-quinolinone compounds, which is characterized in that it includes the following steps: 1) Add 2-aminobenzophenones and alkali to the corresponding solvent methylene chloride at a molar ratio of 1:1.5, so that the solute concentration of the 2-aminobenzophenones reaches 0.5mol/L ; 2) Under stirring conditions, slowly drop malonate monoethyl acyl chloride into the above solution under low- temperature cooling. The dosage of the malonate monoethyl acyl chloride is 2-aminodiphenyl according to the acid chloride equivalent it can provide. 110% of the molar dosage of methanone compounds is used; 3) After the dripping of the malonate monoethyl chloride is completed, heat the reaction system to 20-60°C, stir the reaction for 2-24 hours, and then add water to quench the reaction; 4) Extract with ethyl acetate, separate the liquids, dry, filter, concentrate, and then purify to obtain the product;

The above reaction formula for preparing multi-substituted 2-quinolinone compounds is:

O Q SR: qe A ea Q Ÿ comen 1

RL HL Ra + cp “OEt Rl SO

À, SENSO

Rj where R;-R; the number of substituents may be 0-4.

Preferably, the R1-R3 The type of substituent can be selected from F, Br, CI, I, CN, CO-Ft, CO,Me, Ac, ArCO,

CFs, NO», C1-8 alkyl, C1-8 alkoxy, Et, n-Pr, 1-Pr, Bu, CH,=CH, OMe, OEt, OPr, Ph, Ar; further, the R;-

R;Substituents can be selected from F, Br, Cl, I, CN, CO,Et, CO;Me, Ac, ArCO, CF; NO; one or more; further, the

Rı-R; The substituent can be selected from Me, Et, n-Pr, 1-Pr, Bu, CH,=CH, OMe, OEt, OPr, Ph, Ar.

Preferably, the base in step 1) can be selected from KOH, NaOH, K;COs;, Na;COs;, Cs:CO;, DBU, triethylamine, imidazole, N-methylimidazole, further, the base may preferably be imidazole.

Preferably, the stirring rate in step 2) is 200-500r/min, and further, the stirring rate in step 2) is 300r/min.

Preferably, the low-temperature cooling condition in step 2) can be an ice bath.

Preferably, the heating temperature in step 3) is 40-60°C. Further, the heating temperature in step 3) can be selected from 50°C or 60°C.

The preparation method of the ‘one-pot’ base-catalyzed synthesis of multi-substituted 2-quinolinone compounds proposed by the present mvention has the following beneficial effects: 1. Efficiently construct the multi-substituted 2-quinolinone matrix skeleton using the ‘one-pot method’, which greatly simplifies the operation, shortens the synthesis technical route, and overcomes shortcomings such as the need for precious metal catalysis, harsh reaction conditions, and cumbersome multi-step synthesis. LU508276 2. Use an equivalent amount of imidazole as a base catalyst, and the raw materials are cheap and easy to obtain.

Imidazole can not only act as a catalyst to catalyze intramolecular aldol condensation, but also serve as an acid binding agent for amidation, ultimately achieving a convenient one-pot synthesis of 2-quinolinone compounds. 3. This method has good substrate applicability, mild reaction conditions, and does not require inert gas protection. The reactions involved in synthesizing the target substance have simple synthesis steps, few side reactions, good product yield, short time consumption, simple operation, and easy amplification. Features such as good safety and reliability.

DESCRIPTION OF DRAWINGS

Figure 1 is the hydrogen nuclear magnetic spectrum of product 3a in Example 1 "H-NMR (400MHz in de-

DMSO)

Figure 2 is the NMR carbon spectrum of product 3a in Example 1 C-NMR (400MHz in ds-DMSO )

Figure 3 it is the hydrogen nuclear magnetic spectrum of product 3b in Example 2 "H-NMR (400MHz in de-

DMSO)

Figure 4 is the NMR carbon spectrum of product 3b in Example 2 C-NMR (400MHz in ds-DMSO )

Figure 5 it is the hydrogen nuclear magnetic spectrum of product 3c in Example 3. "H-NMR (400MHz in de-

DMSO)

Figure 6 it is the NMR carbon spectrum of product 3c in Example 3. '*C-NMR (400MHz in de-DMSO)

Figure 7 it is the hydrogen nuclear magnetic spectrum of product 3d in Example 4. "H-NMR (400MHz in de-

DMSO)

Figure 8 it is the NMR carbon spectrum of product 3d in Example 4. 3C-NMR (400MHz in ds-DMSO)

Figure 9 it is the hydrogen nuclear magnetic spectrum of product 3e in Example 5. "H-NMR (400MHz in de-

DMSO)

Figure 10 it is the NMR carbon spectrum of product 3e in Example 5. '*C-NMR (400MHz in ds-DMSO )

Figure 11 it is the hydrogen nuclear magnetic spectrum of product 3f in Example 6 "H-NMR (400MHz in de-

DMSO)

Figure 12 it is the NMR carbon spectrum of product 3f in Example 6 3C-NMR (400MHz in ds-DMSO)

Figure 13 it is the hydrogen nuclear magnetic spectrum of 3g of the product of Example 1 "H-NMR (400MHz in d-DMSO )

Figure 14 it is the NMR carbon spectrum of 3g of the product of Example 1 *C-NMR (400MHz in ds-DMSO )

Figure 15 it is the hydrogen nuclear magnetic spectrum of the product in Example 2 at 3h. "H-NMR (400MHz in d-DMSO )

Figure 16 it is the NMR carbon spectrum of product 3h in Example 2 C-NMR (400MHz in ds-DMSO )

Figure 17 it is the hydrogen nuclear magnetic spectrum of product 3i in Example 3. 'H-NMR (400MHz in de-

DMSO )

Figure 18 it is the NMR carbon spectrum of product 3i in Example 3. C-NMR (400MHz in ds-DMSO)

Figure 19 it is the hydrogen nuclear magnetic spectrum of product 3j in Example 4 "H-NMR (400MHz in de-

DMSO)

Figure 20 it is the NMR carbon spectrum of product 3j in Example 4 *C-NMR (400MHz in ds-DMSO)

Figure 21 it is the hydrogen nuclear magnetic spectrum of the product 3k in Example 5. "H-NMR (400MHz in ds-DMSO )

Figure 22 it is the NMR carbon spectrum of product 3k in Example 5 *C-NMR (400MHz in ds-DMSO )

Figure 23 it is the hydrogen nuclear magnetic spectrum of product 31 of Example 6 "H-NMR (400MHz in 5508276

DMSO)

Figure 24 it is the NMR carbon spectrum of product 31 of Example 6 3C-NMR (400MHz in ds-DMSO)

DETAILED DESCRIPTION OF THE INVENTION

The selection of reaction parameter conditions for Examples 1-12 and amplified reactions 1-1 to 1-9 grven by the present invention 1s based on the reactant raw materials of Example 1, by setting different alkali types, solvent conditions, heating temperature and The reaction substrate concentration, obtained through exploration and comparison, is shown in Table 1. The isolation yields of Examples 1-12 and the amplified reaction are all higher than 70%, indicating that the condensation and addition of the imidazole-promoted 2-aminobenzophenone and malonate monoethyl chloride obtained in the present invention under mild conditions .The synthesis method for preparing multi-substituted 2-quinolinone compounds by reacting with the cyclization ‘one-pot method’ is very efficient and has very good transformation and application value.

Example 1

The specific preparation method of compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3a) is as follows:

CRT Add 2-aminobenzophenone (1.0mmol) and imidazole (1.5mmol) to the corresponding ge” 7 solvent dichloromethane (2.0mol/L), stir and slowly add monoethyl malonate under low-

REG “Co: temperature cooling conditions. Ester acid chloride (1.1 eq.) was added to the reaction oo > system. After the acid chloride is added dropwise, without inert gas protection, heat and

Lo j maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add 10 mL of water to quench the reaction, extract with ethyl acetate (10 mL*3), and separate, the liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column — chromatography to obtain pure product 3a, the separation yield is 99%, white solid, mp 204-205°C. The structural formula and characterization data are as follows: '"H NMR (400 MHz, DMSO-de) & 12.28 (s, 1H), 7.58 (ddd, J = 8.4, 6.8, 1.7 Hz, 1H), 7.52 (dd, J = 5.1, 1.9 Hz, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.34 — 7.31 (m, 2H), 7.18 — 7.13 (m, 1H), 7.11 (dd, J = 8.1, 1.6 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 1;

BC NMR (100 MHz, DMSO-ds) & 165.1, 158.6, 148.5, 138.7, 134.1, 131.6, 129.0, 128.6, 128.5, 127.1, 126.7, 122.5, 118.3, 115.8, 60.6, 13.6 ppm, as shown in Figure 2; HRMS (ESI) m/z calcd for C,sH;sNOs;Na [M+Na]*:316.0950, Found: 316.0942.

Example 1-1 (amplification reaction)

Amplification reaction of compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3a), the specific preparation method is as follows:

Add 2-aminobenzophenone (10mmol) and imidazole (15mmol) to the corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low temperature, slowly add malonate monoethyl chloride ( 1.1 equivalent) into the reaction system. After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL water to quench the reaction, extract with ethyl acetate (100mL*3), and separate, the solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3a (2.78 g, isolation yield 95%).

Example 2

The specific preparation method of compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3b) is as follows:

TTY Add 2-amino-5-chlorobenzophenone (1.0mmol) and imidazole (1.5mmol) to 4508276

PA | corresponding solvent dichloromethane (2.0mol/L), stir and cool at low temperature, and ol Aa À, © one slowly add propylene glycol dropwise. Acid monoethyl chloride (1.1 equivalent) was added to the reaction system. After the acid chloride is added dropwise, there is no need to inert, 4 a 5 | and the structural characterization data are as follows: 'H NMR (400 MHz, DMSO-ds) ô nnd 12 44 (s, 1H), 7.63 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (dd, J = 5.0, 1.7 Hz, 3H), 7.42 (d, J= 8.8

Hz, 1H), 7.34 (dd, J = 6.6, 3.0 Hz, 2H), 7.00 (d, J = 2.3 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 0.84 (t, J = 7.1 Hz, 3H) ppm like figure 3 shown; *C NMR (100 MHz, DMSO-de) & 164.7, 158.4, 147.4, 137.5, 133.4, 131.5, 129.3, 128.7, 128.6, 127.7, 126.4, 125.8, 119.6, 117.9, 60.8, 13.5 ppm, such as Figure 4 Shown:HRMS (ESI) m/z calcd for

C:sH,4CINO;Na [M+Na]": 350.0560, Found: 350.0561.

Example 2-1 (amplification reaction)

Amplification reaction of compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3b), the specific preparation method is as follows:

Add 2-amino-5-chlorobenzophenone (10mmol) and imidazole (15mmol) to the corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low temperature, malonic acid monomer is slowly added dropwise. Ethyl ester acid chloride (1.1 eq.) was added to the reaction system. After the acid chloride 1s added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL water to quench the reaction, extract with ethyl acetate (100mL*3), and separate,

The solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3b (2.95 g, isolation yield 90%).

Example 3

The specific preparation method of compound 6-chloro-4-(2'-fluorophenyl)-2-quinolinone-3-carboxylic acid cthyl ester (3c) is as follows:

ETT Add 2-amino-5-chloro-2'-fluorobenzophenone (1.0mmol) and imidazole (1.5mmol) to

NF 25 | the corresponding solvent dichloromethane (2.0mol/L), stir and cool at low temperature, a EN “cooët Slowly add malonate monoethyl chloride (1.1 equivalent) dropwise to the reaction system.

F. 1 After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50° 1 7 C in the air for 12 hours. After TLC check until the reaction is complete, add 10 mL of water to eee Éd quench the reaction, extract with ethyl acetate (10 mL*3), and divide , the liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3c, the separation yield is 95%, white solid, mp 224-225°C. The structural formula and characterization data are as follows: '"H NMR (400 MHz, DMSO-ds) 8 7.67 (dd, J = 8.8, 2.3 Hz, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.47 — 7.36 (m, 4H), 6.95 — 6.90 (m, 1H), 3.97 (dd, J = 7.1, 5.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H) ppm, such as Figure 5 shown; °C NMR (101 MHz, DMSO-d6) 6164.7, 159.1 (d, J = 247.5 Hz), 158.6, 142.7, 137.8, 132.6 (d, J = 8.0 Hz), 132.4, 131.2 (d, J = 2.0 Hz), 129.4, 127.2, 125.6, 125.5(d, J = 3.0 Hz), 121.3 (d, J = 17.2 Hz), 119.6, 118.5, 116.4 (d, J = 20.2 Hz), 61.4, 14.0 ppm, such as Figure 6 Shown; HRMS (ESI) m/z calcd for

CisH13CIFNO3Na [M+Na] "368.0466, Found: 368.0461.

Example 3-1 (amplification reaction)

Amplification reaction of compound 6-chloro-4-(2'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3c), the specific preparation method is as follows: 2-amino-5-chloro- 2'-Fluorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low temperature, malonate monoethyl chloride (1.1 equivalent) into the reaction system. After the acid chloride 1s added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL water to quench the reaction, extract with ethyl acetate (100mL*3),

and separate, the solution was dried, filtered, and concentrated to obtain a crude product that was separated nif 908276 purified by column chromatography to obtain pure product 3c (2.87 g, isolation yield 83%).

Example 4

The specific preparation method of compound 4-(4'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3d) is as follows:

CTT Add 2-amino-4'-fluorobenzophenone (1.0mmol) and imidazole (1.5mmol) to the me” NO | corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low à A, #*<cooë temperature, slowly add propylene dropwise. Diacid monoethyl chloride (1.1 equivalent)

À. | was added to the reaction system. After the acid chloride is added dropwise, without inert

I > 10 | gas protection, heat and maintain 50°C in the air for 12 hours. After TLC checks until the 1 | reaction is complete, add 10 mL of water to quench the reaction.Extract with ethyl acetate pm (10mL * 3), separate the solution, dry, filter, and concentrate to obtain the crude product.

Purify the product by column chromatography to obtain pure product 3d with a separation yield of 99%. It is a white solid at mp 209-210°C. The structural formula and characterization data are as follows: 'H NMR (400 MHz, … DMSO-d6) 6 12.30 (s, 1H), 7.61 — 7.56 (m, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.39 (s, 2H), 7.37 (d, J = 2.5 Hz, 2H), 7.16 (t,J = 8.1 Hz, 1H), 7.11 (dd, J = 8.2, 1.5 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 0.89 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 7; °C NMR (101 MHz, DMSO-d6) 6 165.5, 8 162.9 (d, J = 246.0 Hz), 159.0, 148.1, 139.2, 132.2, 131.5 (d, J = 8.4 Hz), 130.9 (d, J = 3.1 Hz), 127.5, 127.5, 123.1, 118.8, 116.2 (d, J = 14.9 Hz), 116.0, 61.2, 14.1 ppm, as shown in Figure 8; HRMS (ESI) m/z calcd for C;sH,4FNO3Na [M+Na]+:334.0855, Found: 334.0852.

Example 4-1 (amplification reaction)

Amplification reaction of compound 4-(4'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3d), the specific preparation method is as follows: 2-amino-4'-fluorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent dichloromethane (2.0mol/L), and after stirring and cooling at low temperature, malonate monoethyl chloride (1.1 equivalent) was slowly added dropwise to the reaction system.

After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50° C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3d (2.80 g, isolation yield 90%).

Example 5

The specific preparation method of compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3e) 1s as follows:

CRT Add 2-amino-5-bromobenzophenone (1.0mmol) and imidazole (1.5mmol) to the

Rs NO corresponding solvent dichloromethane (2.0mol/L), stir and cool at low temperature, and

Ë A A slowly add propylene glycol dropwise. Acid monoethyl chloride (1.1 equiv) was added to

BE hl CORE the reaction system. After the acid chloride is added dropwise, without inert gas

A, protection, heat and maintain 50°C in the air for 12 hours. After TLC checks until the

P reaction is complete, add 10 mL of water to quench the reaction. Extract with ethyl acetate re (10mL * 3), separate the liquid, dry, filter, and concentrate to obtain the crude product.

Purify the pure product 3e by column chromatography, with a separation yield of 70%. It is a white solid at mp 233-234°C. The structural formula and characterization data are as follows: 'H NMR (400 MHz, DMSO-ds) ô 12.43 (s, 1H), 7.75 (dd, J = 8.8, 2.2 Hz, 1H), 7.55 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 2.2 Hz, 2H), 7.38 — 7.33 (m, 3H), 7.14 (d, J = 2.2 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 9:1"°C NMR (100 MHz, DMSO-ds) 6 164.7, 158.3, 147.3, 137.8, 134.2, 133.4, 129.3, 128.8, 128.7, 128.6, 127.7, 120.1, 118.1, 114.2, 60.8, 13.5 ppm, as shown in Figure 10; HRMS (ESI) m/z caled for C:3H:4BrNO3Na [M+Na]":394.0055,

Found: 394.0047. LU508276

Example 5-1 (amplification reaction)

Amplification reaction of 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3e), the specific preparation method is as follows: 2-amino-5-bromobenzophenone (10mmol) and Imidazole (15 mmol) was added to the corresponding solvent dichloromethane (2.0 mol/L), and after stirring and cooling at low temperature, malonate monoethyl chloride (1.1 equivalent) was slowly added dropwise to the reaction system. After the acid chloride 1s added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3e (2.83 g, isolation yield 76%).

Example 6

The specific preparation method of compound 5,7-dibromo-2-quinolimone-3-carboxylic acid ethyl ester (3f) is as follows:

TTT Add 2-amino-4,6-dibromobenzaldehyde (1.0mmol) and imidazole (1.5mmol) to

Br. ~~ N ,0 15 | the corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low 3 { [ | temperature, slowly add propylene dropwise. Diacid monoethyl chloride (1.1 equivalent) eg 057 COOËt was added to the reaction system. After the acid chloride 1s added dropwise, without inert

Br | gas protection, heat and maintain 50°C in the air for 12 hours. After TLC checks until the

Sree? reaction is complete, add 10 mL of water to quench the reaction. Extract with ethyl acetate (10mL * 3), separate the liquid, dry, filter, and concentrate to obtain the crude product. Purify the pure product 3f by column chromatography with a separation yield of 95%. It is a light yellow solid and stored at mp 233-234°C.

The structural formula and characterization data are as follows: 'H NMR (400 MHz, DMSO-d) 6 11.05 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 11; BC NMR (100 MHz, DMSO-de) 8163.3, 157.9, 142.0, 137.0, 131.0, 128.1, 124.9, 120.2, 116.2, 113.5, 60.8, 13.7 ppm, as shown in Figure 12; HRMS (ESI) m/z calcd for Ci2HoBr2NO3Na [M+Na]*:395.8847, Found: 395.8841.

Example 6-1 (amplification reaction)

A scale-up reaction of compound 5,7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3f), the specific preparation method is as follows: 2-amino-4,6-dibromobenzaldehyde (10mmol) and Imidazole (15 mmol) was added to the corresponding solvent dichloromethane (2.0 mol/L), and after stirring and cooling at low temperature, malonate monoethyl chloride (1.1 equivalent) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50° C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL of water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3f (3.30 g, isolation yield 88%).

Example 7

The specific preparation method of compound 4-(4'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3g) is as follows: 1. H © | Add 2-amino-4'-chlorobenzophenone (1.0mmol) and imidazole (1.5mmol) to the if Li T 40 | corresponding solvent dichloromethane (2.0mol/L). After stirring and cooling at low

A hd “COL temperature, slowly add propylene dropwise. Diacid monoethyl chloride (1.1 equivalent)

GE | was added to the reaction system. After the acid chloride is added dropwise, without mert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC checks until the —— reaction is complete, add 10 mL of water to quench the reaction, and use ethyl alcohol to quench the reaction Extract with ethyl acetate (10mL * 3), separate the solution, dry, filter, and concentrated 208276 obtain the crude product. Purify the product by column chromatography to obtain 3g of pure product with a separation yield of 76%. It is a white solid and stored at mp 218-219°C. The structural formula and characterization data are as follows: "TH NMR (400 MHz, DMSO-ds) 6 11.05 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 4.29 (q,

J=171Hz 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 11; 3C NMR (100 MHz, DMSO-de) 6163.3, 157.9, 142.0, 137.0, 131.0, 128.1, 124.9, 120.2, 116.2, 113.5, 60.8, 13.7 ppm, as shown in Figure 12; HRMS (ESI) m/z calcd for C12HoBroNO;Na [M+Na]*:395.8847, Found: 395.8841. 'H NMR (400 MHz, DMSO-de) 6 12.33 (s, 1H), 7.63 — 7.56 (m, 3H), 7.41 (d, J = 8.2 Hz, 1H), 7.38 — 7.34 (m, 2H), 7.18 — 7.13 (m, 1H), 7.10 (dd, J = 8.2, 1.4

Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 0.90 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 13; !*C NMR (101 MHz,

DMSO-de) 6 165.0, 158.4, 147.4, 138.7, 133.9, 132.9, 131.8, 130.6, 128.7, 127.037, 126.8, 122.7, 118.1, 115.9, 60.819, 13.6 ppm, as shown in Figure 14; HRMS (ESI) m/z caled for C:gH,4CINO;Na [M+Na]":350.0560, Found: 350.0561.

Example 7-1 (amplification reaction)

Amplification reaction of compound 4-(4'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3g), the specific preparation method is as follows: 2-amino-4'-chlorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent dichloromethane (2.0mol/L), and after stirring and cooling at low temperature, malonate monoethyl chloride (1.1 equivalent) was slowly added dropwise to the reaction system.

After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50° C in the air for 12 hours. After TLC check until the reaction is complete, add 100mL of water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the liquid was dried, filtered and concentrated to obtain a crude product which was separated and purified by column chromatography to obtain 3g of pure product (2.30g, isolation yield 70%).

Example 8

The specific preparation method of compound 6-chloro-(2'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3h) is as follows:

CH Add 2-amino-3,2'-dichlorobenzophenone (1.0mmol) and imidazole (1.5mmol) to

Ry AO the corresponding solvent dichloromethane (2.0mol/L), stir and cool at low temperature,

BUR J © on slowly Add dropwise malonate monoethyl chloride (1.1 equivalent) to the reaction ol À | system. After the acid chloride is added dropwise, without inert gas protection, heat and

I | 30 maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add en i 10 mL of water to quench the reaction, extract with ethyl acetate (10 mL*3), and separate

The liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography for 3h. The isolation yield was 71%, a white solid, mp 218- 219°C. The structural formula and characterization data are as follows: 'H NMR (400 MHz, DMSO-ds) 6 12.55 (s, 1H), 7.66 (ddd, J = 8.8, 4.1, 1.7 Hz, 2H), 7.57 (td, J = 7.8, 1.7 Hz, 1H), 7.51 (td, J = 7.5, 1.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.5, 1.6 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 3.99 — 3.89 (m, 2H), 0.82 (t, J = 7.1 Hz, 3H) ppm, as shown in Figure 15; 3C NMR (101 MHz, DMSO-de) & 164.6, 158.8, 145.7, 137.8, 132.6, 132.5, 132.3, 131.8, 131.3, 130.1, 128.6, 128.1, 127.2, 125.6, 119.4, 118.5, 61.3, 14.0 ppm, as shown in Figure 16; HRMS (ESI) m/z caled for C:gH13CI:NO;Na [M+Na]:384.0170, Found: 384.0164.

Example 8-1 (amplification reaction)

Amplification reaction of compound 6-chloro-(2'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3h), the specific preparation method is as follows: 2-amino-5,2"-di Chlorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent methylene chloride (2.0mol/L). After stirring and cooling at low temperature, slowly add monoethyl malonate chloride (1.1 equivalent) dropwise to in this reaction system. After the acid chloride 1s added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours 208276

After TLC check until the reaction is complete, add 100mL of water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain a pure product for 3h (2.72 g, isolation yield 75%).

Example 9

The specific preparation method of N-methyl-6-chloro--phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3i) 1s as follows:

TTY Add N-methyl-2-amino-5-chlorobenzophenone (1.0mmol) and imidazole

AN AQ | (1.5mmol) to the corresponding solvent dichloromethane (2.0mol/L), stir and cool at 1 ] 10 | low temperature, Slowly add malonate monoethyl chloride (1.1 equivalent) dropwise

Cl a T TCOE to the reaction system. After the acid chloride is added dropwise, without inert gas : LE | protection, heat and maintain 50°C in the air for 12 hours. After TLC check until the

N | ; reaction 1s complete, add 10 mL of water to quench the reaction, extract with ethyl

Nd acetate (10 mL*3), and divide , the liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3i. The separation yield is 75%, white solid, mp 197-199°C. The structural formula and characterization data are as follows:

IH NMR (400 MHz, Chloroform-d) 8 7.54 (ddd, J = 9.0, 4.9, 2.4 Hz, 1H), 7.50 — 7.45 (m, 3H), 7.39 — 7.30 (m, 3H), 7,25 (s, 1H), 4.11 — 4.04 (m, 2H), 3.77 (d, J = 4.9 Hz, 3H), 0.95 (td, J = 7.1, 5.0 Hz, 3H) ppm, as shown in Figure 17; BC NMR (101 MHz, Chloroform-d) 5 165.4, 158.8, 147.0, 138.5, 133.8, 131.7, 129.3, 128.9, 128.7, 128.2, 127.9, 127.8, 121.6, 116.0, 61.6, 30.0, 13.8 ppm, as shown in Figure 18; HRMS (ESI) m/z calcd for

CoH sCINOsNa [M+Na]*:364.0716, Found: 364.0711.

Example 9-1 (amplification reaction)

Amplification reaction of N-methyl-6-chloro--phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3i), the specific preparation method is as follows: N-methyl-2-amino-5- Chlorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent methylene chloride (2.0mol/L). After stirring and cooling at low temperature, slowly add monoethyl malonate chloride (1.1 equivalent) dropwise to in this reaction system. After the acid chloride is added dropwise, without inert gas protection, heat and maintain 50°C in the air for 12 hours.

After TLC check until the reaction is complete, add 100mL of water to quench the reaction, extract with ethyl acetate (100mL*3), and separate , the solution was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3i (3.04 g, isolation yield 89%).

Example 10

The specific preparation method of compound 4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3j) is as follows:

CTH TTT Add 2-aminobenzophenone (1.0mmol) and imidazole (1.5mmol) to the

NO 35 | corresponding solvent dichloromethane (2.0mol/L), stir and cool at low temperature, then

Lh 2, 0 slowly add monomethyl malonate dropwise Acid chloride (1.1 eq.) was added to the 1 à | reaction. After the acid chloride is added dropwise, without inert gas protection, heat and

I~ A | maintain 50°C in the air for 12 hours. After TLC check until the reaction is complete, add ex” 10 mL of water to quench the reaction, extract with ethyl acetate (10 mL*3), and divide, the liquid was dried, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography to obtain pure product 3j. The separation yield is 99%, white solid, mp 220-221°C. The structural formula and characterization data are as follows: 'H NMR (400 MHz, DMSO-ds) & 12.32 (s, 1H), 7.57 (d,J = 1.8

Hz, 1H), 7.53 (dd, J = 5.0, 1.8 Hz, 1H), 7.51 (dd, J = 3.5, 1.3 Hz, 2H), 7.41 (d, J= 8.1 Hz, 1H), 7.33 (d, /=2.9 Hz, 1H), 7.32 — 7.31 (m, 1H), 7.18 — 7.14 (m, 1H), 7.12 (dd, J = 8.2, 1.6 Hz, 1H), 3.47 (s, 3H) ppm, as shown in Figure

19; 13C NMR (101 MHz, DMSO-ds) § 165.9, 158.6, 148.7, 138.76, 134.1, 131.7, 129.1, 128.6, 128.5, 127.2, 12004/508276 122.6, 118.3, 115.9, 52.0 ppm, as shown in Figure 20; HRMS (ESI) m/z caled for C1i6H20NO3S [M+H]*:162.1163,

Found: 162.1164.

Example 11

The specific preparation method of compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3K) is as follows:

WH 2-amino-5-chlorobenzophenone (1.0mmol) and imidazole (1.5 mmol) was added

ASS À wl | to the corresponding solvent dichloromethane (2.0 mol/L), and after stirring and cooling

À A 2 | at low temperature, malonate monomethyl ester chloride (1.1 equivalent) was slowly

Cm he COs) added dropwise to the reaction system. After the acid chloride 1s added dropwise, without a E | inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC inspection

J | until the reaction is complete, add 10 mL of water to quench the reaction, extract with

TTT ethyl acetate (10mL * 3), separate the solution, dry, filter, and concentrate. The crude product is purified by column chromatography to obtain pure product 3k with a separation yield of 99%. It is a white solid at mp 208-209°C. The structural formula and characterization data are as follows: 'H NMR (400 MHz,

DMSO-de) 612.48 (s, 1H), 7.76 (dd, J = 8.8, 2.2 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.9 Hz, 2H), 7.38 — 7.33 (m, 3H), 7.15 (d, J = 2.2 Hz, 1H), 3.48 (s, 3H) ppm, as shown in Figure 21; 3C NMR (101 MHz, DMSO-d) ô 165.4, 158.4, 147.5, 137.8, 134.3, 133.4, 129.4, 128.9, 128.8, 128.5, 127.6, 120.1, 118.2, 114.2, 52.1 ppm, as shown in Figure 22; HRMS (ESI) m/z calcd for C17H,2NO;NaBr [M+Na]*:379.9904, Found: 379.9898.

Example 12

The specific preparation method of compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (31) 1s as follows:

PR à 2-amino-5-bromobenzophenone (1.0mmol) and imidazole (1.5 mmol) was added aN Oo to the corresponding solvent dichloromethane (2.0 mol/L), and after stirring and cooling i a. ) A 25 at low temperature, malonate monomethyl ester chloride (1.1 equivalent) was slowly

Br DE SF "CO,CH; added dropwise to the reaction system. After the acid chloride is added dropwise,

A x, without inert gas protection, heat and maintain 50°C in the air for 12 hours. After TLC

N 2 | mspection until the reaction is complete, add 10 mL of water to quench the reaction,

Ser Sed extract with ethyl acetate (10mL * 3), separate the liquids, dry, filter and concentrate to obtain the crude product, which is separated and purified by column chromatography to obtain 31 of pure product.

The isolation yield is 99%, white solid, mp 233-234°C. Its structural formula and structural characterization data are as follows: 'H NMR (400 MHz, DMSO-de) 6 12.48 (s, 1H), 7.66 (dd, J = 8.8, 2.4 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 2.0 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.37 — 7.33 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 3.48 (s, 3H) ppm, such as Figure 23 shown; *C NMR (101 MHz, DMSO-de) 6 165.5, 158.4, 147.5, 137.5, 133.4, 131.7, 129.4, 128.8, 128.5, 127.6, 126.4, 125.9, 119.6, 118.0, 52.1 ppm, such as Figure 24 Shown; HRMS (ESI) m/z calcd for

C,7H,:NO;NaCl [M+Na]*:336.0402, Found: 336.0403.

Optimization screening test of reaction conditions

Taking Example 1 as the basic test object, adjust the test parameters according to the test parameters described in Table 1 below to explore the comparative data of isolation yield under different alkali conditions, solvent conditions, heating temperature conditions and reaction concentration conditions, and test results. as follows:

Table 1 Comparison of isolation yields of 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3a) under different test parameters

Q Py LU508276 a Ph 9 condilions TR AL het

LA AcOEt eee] N “HH, Lo Sa CR USE 1a 2a Ja H

Serial The

Number base amount of temperature | concentration 3a yield talyst solvent | alkah is (°C) MD %) catalys used 0 (eq.)

CHCL Um | 15 | w% | 061%

CH,Cl, (2mL)

CHCl, (2mL)

CH2Cl (mL)

CH:Ch (2mL)

N-

CH.Cl, (2mL) 1.5 40 0.5 75 methylimidazole

Tran [+ date [or Om mtu | cites nt ea Om) > so Om

CH: Om)

CH: an

CH: aml

CH: an)

CH2CR QmL

CH2CR (2mL) | 15 | 60 | 05 | 86

CHCl (4mL

CH,CL (ImL 22 (Example imidazole | CH2Cl,(0.5mL) 1.5 50 2.0 1)

Judging from the comparison results of the above experiments, dichloromethane 1s selected as the solvent, imidazole is selected as the base, 50°C is selected as the temperature, and the reaction concentration is 2.0 mol/L.

The product formation rate of this type of reaction is optimal under this reaction condition. This experimental data proves that the parameter setting in the synthesis method of the present invention does not require selecting conventional base types, conventional solvents, or setting conventional temperature conditions to achieve the invention intention of the present invention.

It should be understood that although this specification is described in terms of implementations, thi{808276 description is only for the sake of clarity.

Those skilled in the art should take the description as a whole to form other implementations that can be understood by those skilled in the art, which should also belong to protection scope of the present invention.

Claims

CLAIMS LU508276

1. A preparation method for base-catalyzed synthesis of multi-substituted 2-quinolinone compounds, Its characteristics are: Includes the following steps: 1) Add 2-aminobenzophenones and alkali to the corresponding solvent methylene chloride at a molar ratio of 1:1.5, so that the solute concentration of the 2-aminobenzophenones reaches 0.5mol/L ; 2) Under stirring conditions, slowly add malonate monoethyl acyl chloride dropwise to the solution in step 1) under low-temperature cooling, the dosage of the malonate monoethyl acyl chloride is 2-amino based on the acid chloride equivalent it can provide, use 110% of the molar dosage of benzophenones; 3) After the dripping of the malonate monoethyl chloride is completed, heat the reaction system to 20-60°C, stir the reaction for 2-24 hours, and then add water to quench the reaction; 4) Extract with ethyl acetate, separate the liquids, dry, filter, concentrate, and then purify to obtain the product; the above reaction formula for preparing multi-substituted 2-quinolinone compounds is: A SA o © Ÿ. BE A Sr Ra + ei AA ot RN Lau Ry SFR Ry the number of R1-R3 substituents may be 0-4.

2. The preparation method according to claim 1, its characteristics are: the types of the R1-R3 substituents can be selected from F ‚Br ‚C1 ,I ‚CN ,COEt, CO,Me, Ac, ArCO, CFs, NO,, C1-8 alkyl, C1-8 alkoxy, Et, n-Pr, 1-Pr, Bu, Bn, CH,=CH, one or more of OMe, OFEt, OPr.

3. The preparation method according to claim 2, its characteristics are: the R1-R3 substituents may be selected from F, Br, CI, I, CN, CO-Ft, CO:Me, Ac, ArCO, CF;, NO; , one or several.

4. The preparation method according to claims 1-3, its characteristics are: the base in step 1) can be selected from KOH, NaOH, K,CO;, Na:CO;, Cs:CO;, DBU, triethylamine, one of imidazole and N-methylimidazole.

5. The preparation method according to claim 4, its characteristics are: the base in step 1) may preferably be imidazole.

6. The preparation method according to claims 1-5, its characteristics are: the stirring rate of step 2) is 200-300r/min.

7. The preparation method according to claim 6, its characteristics are: the stirring rate of step 2) is 300r/min.

8.The preparation method according to claims 1-7, its characteristics are: the low-temperature cooling condition in step 2) can be an ice bath.

9.The preparation method according to claims 1-8, its characteristics are: the heating temperature in step 3) may preferably be 40-60°C.

10. The preparation method according to claim 9, its characteristics are: the heating temperature in step 3) can be selected from 50°C or 60°C.