Process for the preparation of an aminoquinazolinone derivative
By generating amino-quinazolinone derivatives through reaction under copper salt and alkali catalysis, the problem of difficult synthesis of quinazolinone derivatives in the prior art has been solved, realizing a low-cost and efficient preparation method.
Patent Information
- Application Number
- CN202311137304.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-05
- Publication Date
- 2025-12-16
- Estimated Expiration
- 2043-09-05
AI Technical Summary
Existing methods for synthesizing quinazolinone derivatives suffer from problems such as difficulties in substrate synthesis, the potential for o-aminobenzoic acid to become a toxic substance, and the use of precious metal catalysis, resulting in high production costs and low efficiency.
By using copper salt and alkaline catalysis, cyanamide is reacted with o-halobenzamide to generate an aminoquinazolinone derivative. The copper salt promotes the formation of carbon-nitrogen bonds and their release under alkaline conditions, thereby reducing production costs and increasing yield.
This method enables the preparation of quinazolinone derivatives with readily available raw materials, low cost, and high yield, thereby improving synthesis efficiency and chemical selectivity.
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Figure CN117209437B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an amido quinazolinone derivative. BACKGROUND
[0002] Quinazolinone and its derivatives are the core structure of many natural drugs of the tyrosine kinase inhibitors, and are also the basic structural unit of the traditional Chinese medicine common alkaline, mainly existing in common mountain, large leaf and other traditional Chinese medicines, and having important biological activity. The quinazolinone and its derivatives have inhibitory activity on epidermal growth factor receptor (EGFR) or its tyrosine kinase (EGFR-TK), vascular endothelial growth factor receptor (VEGFR), nerve growth factor receptor (NGFR) and other multiple action targets, and play multiple pharmacological effects such as anticancer and antiviral.
[0003] Due to the excellent pharmacological activity of such drugs, the research on derivatives based on the quinazolinone nucleus has become a hot spot, especially the establishment of a simple and efficient method for synthesizing quinazolinone derivatives through the structural synthesis and modification of 4-quinazolinone derivatives. At present, the reported synthesis methods of quinazolinone compounds mainly include the following:
[0004] An intermediate similar to indigo acid anhydride (compound B) is first synthesized from anthranilic acid (compound A) under the condition of acetic anhydride or triethoxyethyl ether, and then the intermediate is reacted with amine under the condition of acetic acid to synthesize methyl quinazolinone (compound C), and the target product is obtained by modifying the methyl quinazolinone (J MED CHEM, 2016, 59(10): 5011-5021.);
[0005]
[0006] An intermediate similar to indigo acid anhydride (compound B) is first synthesized from anthranilic acid (compound A) under the condition of acetic anhydride or triethoxyethyl ether, and then the intermediate is reacted with amine under the condition of acetic acid to synthesize methyl quinazolinone (compound C), and the target product is obtained by modifying the methyl quinazolinone (J MED CHEM, 2016, 59(10): 5011-5021.);
[0007]
[0008] An intermediate similar to indigo acid anhydride (compound B) is first synthesized from anthranilic acid (compound A) under the condition of acetic anhydride or triethoxyethyl ether, and then the intermediate is reacted with amine under the condition of acetic acid to synthesize methyl quinazolinone (compound C), and the target product is obtained by modifying the methyl quinazolinone (J MED CHEM, 2016, 59(10): 5011-5021.);
[0009]
[0010] Reaction of anthranilic acid amide (compound E) with amine (compound I) to generate quinazolinone (compound K), and then derivative reaction of quinazolinone to obtain the target product (Chemistry Select, 2017, 2(17): 4963-4968.);
[0011]
[0012] Reaction of anthranilic acid amide (compound E) with pyruvic acid (compound J) to generate compound K, and then ring closure of compound K under basic conditions to obtain quinazolinone (Molecules, 2023, 28(10): 4240.);
[0013]
[0014] In addition, there are reactions of anthranilic acid amine (compound E) with carboxylic acid (compound L) (EUR J MED CHEM, 2021, 212: 112996., 2023: 101597.), and with alcohol (compound M) (Organometallics, 2021, 40(6): 725-734.) to construct quinazolinone.
[0015]
[0016] However, there are still problems such as that anthranilic acid is the first type of easily-made-toxic chemical, difficulty in synthesis of substrates, and need for noble metal catalysis in synthesis. SUMMARY
[0017] The purpose of the embodiments of the present application is to provide a preparation method of an amido quinazolinone derivative, aiming to solve the problems raised in the above background art.
[0018] The embodiments of the present application are implemented as follows: a preparation method of an amido quinazolinone derivative, comprising the following steps: under the catalysis of a copper salt and a base, reacting cyanamide and o-halobenzamide to obtain an amido quinazolinone derivative, and the reaction formula is as follows:
[0019]
[0020] Preferably, the cyanamide is one of calcium cyanamide (lime nitrogen), lithium cyanamide, sodium cyanamide, potassium cyanamide, monomethylamine, and dicyanamide.
[0021] Preferably, the cyanamide is calcium cyanamide or monomethylamine.
[0022] Preferably, the L group in the o-halobenzamide is one of fluorine, chlorine, bromine, iodine, and amino, and the X group is oxygen or sulfur.
[0023] Preferably, the L group is chlorine, bromine or iodine.
[0024] Preferably, each of R1, R2, R3, R4 and R5 in the o-halobenzamide and amine-based quinazolinone derivative is independently selected from one of hydrogen, halogen, substituted or unsubstituted C 1～10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1～10 alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, azido.
[0025] Preferably, the molar ratio of cyanamide to o-halobenzamide is 1:0.9-3.0, the molar ratio of copper salt to o-halobenzamide is 1:0.05-0.5, and the molar ratio of base to o-halobenzamide is 1:0.5-3.5.
[0026] Preferably, the molar ratio of cyanamide to o-halobenzamide is 1:1.0-20, the molar ratio of copper salt to o-halobenzamide is 1:0.05-0.5, and the molar ratio of base to o-halobenzamide is 1:1.5-3.0.
[0027] Preferably, the reaction is carried out in the presence of a solvent, which is one or more of water, methanol, ethanol, acetonitrile, benzene, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, ethylene glycol, polyethylene glycol (PEG-200-600);
[0028] The copper salt includes but is not limited to one or more of cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper bromide, copper iodide, basic copper carbonate, copper carbonate, copper acetate, copper formate, copper benzoate, copper triflate, cuprous triflate;
[0029] The base includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium formate, potassium formate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, DBU.
[0030] Preferably, the reaction temperature is 60-140°C, and the reaction time is 1-24h.
[0031] Preferably, the reaction temperature is 80-130°C, and the reaction time is 4-12h.
[0032] Preferably, the reaction is carried out under air or an inert atmosphere, which is a nitrogen atmosphere or an argon atmosphere.
[0033] Preferably, the cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide and potassium cyanamide, water is added as a catalyst, and the molar ratio of water to o-halobenzamide is 1:0.5-3.
[0034] Preferably, after the reaction, the reaction solution is extracted with ethyl acetate, the organic phase is washed with water for several times and dried with anhydrous magnesium sulfate, and finally the organic phase is concentrated to obtain the amido quinazolinone derivative.
[0035] Preferably, the concentration is one of normal pressure distillation, reduced pressure distillation and rotary evaporation.
[0036] Preferably, the post-treatment can also be purified by column chromatography, and the column chromatography uses 200-300 mesh silica gel as a separation resin, and at least one of petroleum ether, n-hexane, dichloromethane, water, acetonitrile, methanol, ethyl acetate is selected as an eluent.
[0037] Preferably, the quinazolinone derivative has the following structure:
[0038]
[0039] The preparation method of the amido quinazolinone derivative provided by the embodiment of the present application can promote the formation of carbon-nitrogen bond by introducing copper salt catalyst into o-halobenzamide by coordination, and can obtain quinazolinone derivative by removing under the action of base, so that raw materials and catalysts are more easily obtained, production cost can be effectively reduced, yield and chemical selectivity can be improved, and the method can be conveniently applied to the preparation of various quinazolinone derivatives. BRIEF DESCRIPTION OF DRAWINGS
[0040] Figure 1 The nuclear magnetic 1H NMR spectrum of compound 5a provided for the embodiment 1 of the present application is shown in the following figure:
[0041] Figure 2 The nuclear magnetic 13C NMR carbon spectrum of compound 5a prepared in the embodiment 1 of the present application is shown in the following figure. DETAILED DESCRIPTION
[0042] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application is further described in detail below in combination with the drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application, and are not used to limit the present application.
[0043] The specific implementation of the present application is described in detail below in combination with specific embodiments.
[0044] Embodiment 1
[0045] A preparation method of an amido quinazolinone derivative (compound 5a) is provided, and the structure and preparation method are as follows: A preparation method of an amido quinazolinone derivative (compound 5a) is provided, and the structure and preparation method are as follows:
[0046] Method 1:
[0047]
[0048] The specific steps are: weigh cyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzamide (1 mmol, 275 mg), and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug the rubber plug, replace three times with high-purity nitrogen, then add DMSO (2 mL) to the flask under nitrogen protection, move it into a 110°C oil bath and stir overnight, track the reaction with TLC, after the reaction is completed, cool the flask to room temperature, add 10 mL of saturated brine to the system and stir, extract with ethyl acetate (10 mL x 3), combine the organic phases, remove the solvent with a rotary evaporator, and obtain the crude product; the crude product is loaded on silica gel, eluent is petroleum ether: ethyl acetate = 1:1 by volume, and column chromatography purification is performed to obtain pure 2-amino-3-phenylquinazolin-4(3H)-one, white solid, separation yield 83.2%.
[0049] Method 2:
[0050]
[0051] The specific steps are: weigh cyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzamide (1 mmol, 275 mg), and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug the rubber plug, replace three times with high-purity nitrogen, then add DMSO (2 mL) to the flask under nitrogen protection, move it into a 110°C oil bath and stir overnight, track the reaction with TLC, after the reaction is completed, cool the flask to room temperature, add 10 mL of saturated brine to the system and stir, extract with ethyl acetate (10 mL x 3), combine the organic phases, remove the solvent with a rotary evaporator, and obtain the crude product; the crude product is loaded on silica gel, eluent is petroleum ether: ethyl acetate = 1:1 by volume, and column chromatography purification is performed to obtain pure 2-amino-3-phenylquinazolin-4(3H)-one, white solid, separation yield 83.2%.
[0052] Structure identification of compound 5a:
[0053] Nuclear magnetic resonance data:
[0054] 1H NMR (400 MHz, DMSO-d6) δ 7.937 (dd, J = 7.9, 1.6 Hz, 1H), 7.668 - 7.485 (m, 4H), 7.397 (d, J = 7.2, 2H), 7.304 (d, J = 8.2 Hz, 1H), 7.197 - 7.051 (m, 1H), 6.468 (s, 1H).
[0055] 13 C NMR (100 MHz, DMSO-d6) δ 162.34, 152.21, 150.48, 135.94, 134.87, 130.45, 129.66, 129.34, 127.02, 124.38, 122.04, 117.30.
[0056] Preparation of compound 5a 1 H NMR, 13 C NMR as Figure 1 , as Figure 2 indicated, the analysis results show that the target product obtained is correct.
[0057] Example 2
[0058] A preparation method of an amino quinazolinone derivative (compound 5b), its structure and preparation method are as follows:
[0059]
[0060] The specific steps are as follows: weigh monocyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzoyl-p-methoxyaniline (1 mmol, 305 mg), and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug with a rubber plug, replace with high-purity nitrogen for three times, then add DMSO (2 mL) into the flask under nitrogen protection, move it into an oil bath pot at 110°C and stir, and react overnight. The reaction is tracked by TLC detection, after the reaction is completed, the flask is cooled to room temperature, 10 mL of saturated brine is added into the system and stirred, extracted with ethyl acetate (10 mL x 3), the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product; the crude product is subjected to silica gel loading, eluent is petroleum ether: ethyl acetate = 1:1 by volume, and column chromatography purification is carried out to obtain pure 2-amino-3-p-methoxyphenylquinazolin-4(3H)-one, white solid, separation yield 88.4%.
[0061] Structure identification of compound 5b:
[0062] Nuclear magnetic resonance data:
[0063] 1H NMR (500 MHz, DMSO-d6) δ 7.903 (dd, J = 7.9, 1.6 Hz, 1H), 7.618 - 7.584 (m, 1H), 7.292 - 7.249 (m, 3H), 7.132 - 7.090 (m, 3H), 6.333 (s, 2H), 3.832 (s, 3H).
[0064] 13 C NMR (125 MHz, DMSO-d6) δ 162.02, 159.50, 152.09, 150.07, 134.28, 129.91, 127.85, 126.51, 123.87, 121.39, 116.80, 115.16, 55.37.
[0065] The structure of compound 5b is as follows: 1 H NMR, 13 The C NMR data analysis results show that the target product obtained is correct.
[0066] Example 3
[0067] A preparation method of an amino quinazolinone derivative (compound 5c) is provided, the structure and preparation method of which are as follows:
[0068]
[0069] Specific steps are as follows: weigh monocyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzoyl-p-methyl aniline (1 mmol, 299 mg), and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug the rubber plug, replace three times with high-purity nitrogen, and then add DMSO (2 mL) to the flask under nitrogen protection, move the flask into an oil bath at 110°C and stir, and react overnight. Track the reaction by TLC detection, after the reaction is completed, cool the flask to room temperature, add 10 mL of saturated brine to the system, and stir; extract with ethyl acetate (10 mL x 3), combine the organic phases, and remove the solvent by a rotary evaporator to obtain a crude product; after the crude product is loaded on silica gel, column chromatography purification is performed with a eluent of petroleum ether: ethyl acetate = 1:1 by volume to obtain pure 2-amino-3-p-methylphenyl quinazolin-4(3H)-one, a white solid, with a separation yield of 87.3%.
[0070] Structure identification of compound 5c:
[0071] Nuclear magnetic resonance data:
[0072] 1H NMR (400 MHz, DMSO-d6) δ 7.903 (dd, J = 7.9, 1.6 Hz, 1H), 7.633 - 7.590 (m, 1H), 7.377 (d, J = 8.2 Hz, 2H), 7.280 - 7.222 (m, 2H), 7.144 - 7.105 (m, 1H), 6.373 (s, 2H), 2.403 (s, 3H).
[0073] 13 C NMR (125 MHz, DMSO-d6) δ 162.32, 152.30, 150.33, 139.05, 134.84, 133.25, 130.97, 129.00, 127.00, 124.26, 121.99, 117.26, 21.32.
[0074] The preparation method of compound 5c is as follows: 1 H NMR, 13 The C NMR data analysis result shows that the obtained target product is correct.
[0075] Example 4
[0076] A preparation method of an amino quinazolinone derivative (compound 5k) is provided, and the structure and preparation method are as follows:
[0077]
[0078] The specific steps are as follows: weigh monocyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzoyl-p-trifluoromethoxyphenylamine (1 mmol, 416 mg) and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug with a rubber plug, replace three times with high-purity nitrogen, and then add DMSO (2 mL) to the flask under nitrogen protection, move the flask into an oil bath at 110°C and stir overnight. The reaction is tracked by TLC detection, and after the reaction is completed, the flask is cooled to room temperature, 10 mL of saturated brine is added to the system, and stirred; extracted with ethyl acetate (10 mL x 3), combined the organic phase, and removed the solvent by rotary evaporation instrument to obtain the crude product; the crude product is loaded on silica gel, eluent is petroleum ether: ethyl acetate = 1:1 by volume, and then column chromatography purification is performed to obtain pure product 2-amino-3-p-trifluoromethoxyphenyl quinazolin-4(3H)-one, white solid, separation yield 76.2%.
[0079] Structure identification of compound 5k:
[0080] Nuclear magnetic resonance data:
[0081] 1H NMR (400 MHz, CDC13) δ 8.129 (d, J = 7.9 Hz, 1H), 7.695-7.601 (m, 1H), 7.524-7.371 (m, 4H), 7.319 (d, J = 8.3 Hz, 1H), 7.234 (t, J = 7.6 Hz, 1H), 5.085 (s, 2H).
[0082] 13 C NMR (100 MHz, CDC13) δ 162.12, 150.42, 150.08, 148.30, 135.20, 133.10, 130.42, 127.51, 123.89, 123.52, 122.83, 121.63, 119.06, 117.38.
[0083] The preparation method of compound 5k is as follows: 1 HNMR, 13 The C NMR data analysis result shows that the obtained target product is correct.
[0084] Example 5
[0085] A preparation method of an amino quinazolinone derivative (compound 5u) is as follows:
[0086]
[0087] The specific steps are as follows: weigh monocyanamide (1.5 mmol, 63 mg), potassium tert-butoxide (2 mmol, 224 mg), o-bromobenzoyl-m-dimethyl aniline (1 mmol, 304 mg) and cuprous iodide (0.1 mmol, 19 mg) in a 25 mL round-bottom flask, add a magnetic stirrer, plug the rubber plug, replace three times with high-purity nitrogen, and then add DMSO (2 mL) to the flask under nitrogen protection, move the flask into an oil bath at 110°C and stir overnight. Track the reaction by TLC detection, after the reaction is completed, cool the flask to room temperature, add 10 mL of saturated brine to the system and stir; extract with ethyl acetate (10 mL x 3), combine the organic phases, and remove the solvent by a rotary evaporator to obtain a crude product; after the crude product is loaded on silica gel, column chromatography purification is performed with a eluent of volume ratio of petroleum ether: ethyl acetate = 1:1, and then the pure product 2-amino-3-(3,5-dimethyl) phenyl quinazoline-4(3H)-thione is obtained, which is a white solid with a separation yield of 76.1%.
[0088] Structure identification of compound 5u:
[0089] Nuclear magnetic resonance data:
[0090] 1H NMR (400 MHz, DMSO-d6) δ 7.021 (dd, J = 8.0, 1.6 Hz, 1H), 6.699 - 6.657 (m, 1H), 6.384 (d, J = 8 Hz, 1H), 6.220 - 6.183 (m, 2H), 6.059 (s, 2H), 5.572 (s, 2H), 1.424 (s, 6H).
[0091] 13 C NMR (125 MHz, DMSO-d6) δ 162.28, 152.18, 150.53, 139.67, 135.71, 134.79, 131.09, 126.94, 126.61, 124.40, 121.96, 117.29, 21.26.
[0092] The compound 5u is prepared according to the following reaction scheme: 1 H NMR, 13 The C NMR data analysis results show that the obtained target product is correct.
[0093] The above descriptions are only preferred embodiments of the present application, and are not intended to limit the present application. Any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims
1. A process for the preparation of an aminoquinazolinone derivative, characterized in that, The method comprises the following steps: The reaction is carried out in the presence of a solvent, and the solvent is dimethyl sulfoxide; ； The copper salt is one or more of cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper bromide, copper iodide, basic copper carbonate, copper carbonate, copper acetate, copper formate, copper benzoate, copper triflate, cuprous triflate; The base is potassium tert-butoxide; The temperature of the reaction is 110 DEG C; The cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide, potassium cyanamide, monomethylamine and dicyanamide; The L group is bromine, and the X group is oxygen or sulfur; R2, R3, R4 and R5 are all H; The R1 is: The molar ratio of the cyanamide to the o-halobenzamide is 1:0.9-3.0, the molar ratio of the copper salt to the o-halobenzamide is 1:0.05-0.5, and the molar ratio of the base to the o-halobenzamide is 1:0.5-3.
5. , , , or .
2. The process for the preparation of an amine-based quinazolinone derivative according to claim 1, characterized in that, The reaction time is 1-24 hours.
3. The process for the preparation of an amine-based quinazolinone derivative according to claim 1, characterized in that, The reaction is carried out in the presence of air.
4. The process for the preparation of an amine-based quinazolinone derivative according to claim 1, characterized in that, The cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide and potassium cyanamide, water is added as a catalyst, and the molar ratio of water to the o-halobenzamide is 1:0.5-3.
5. The method for preparing the aminoquinazolinone derivative according to claim 1, characterized in that, After the reaction is completed, the reaction solution is extracted with ethyl acetate, the organic phase is washed with water for multiple times, dried with anhydrous magnesium sulfate, and finally, the organic phase is concentrated to obtain the aminyl quinazolinone derivative.
6. The method for preparing the aminoquinazolinone derivative according to claim 1, characterized in that,