A method for synthesizing quinazolinone compounds

Abstract

The application relates to the field of organic chemical synthesis, in particular to a synthesis method of quinazolinone compounds. The method takes o-amino aryl formamide and 2,4-pentanedione as raw materials, and reacts in a hexafluoroisopropanol solvent, so that the quinazolinone compounds can be obtained at a high yield. The method does not need to add an additional catalyst, is environment-friendly, conforms to the green chemical concept, is simple in experimental operation, simple in post-treatment and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and more particularly to a method for synthesizing quinazolinone compounds. Background Technology

[0002] Quinazolinones are important organic heterocyclic skeletons widely found in bioactive natural products, therapeutic drugs, pesticides, and functional materials. They possess properties such as anti-allergy, anticancer, antitumor, anti-inflammatory, antihypertensive, antimicrobial and antifungal, antimalarial, and insecticidal / sterilizing effects. Furthermore, quinazolinone derivatives exhibit cytotoxic, cardiovascular, and diuretic activities. Examples include methaqualone, a drug with sedative-hypnotic effects; benzylquinone, a drug with anticonvulsant and antispasmodic effects; and chloroquine, an antitussive. Due to their broad application prospects in both medicine and industrial production, the synthesis of quinazolinone compounds has attracted increasing attention from researchers.

[0003] Currently, existing synthetic methods for quinazolinones are quite demanding, with most requiring strong acids or transition metal catalysis in the presence of oxidants and strong bases, making industrial-scale production impossible. Therefore, there is a strong need to find more environmentally friendly and efficient synthetic methods to obtain valuable quinazolinone derivatives. Summary of the Invention

[0004] This invention uses o-aminoarcarboxamide and 2,4-pentanedione as raw materials and hexafluoroisopropanol (HFIP) as a reaction solvent to explore an efficient and green method for synthesizing quinazolinone compounds.

[0005] This invention relates to a method for synthesizing quinazolinone compounds, wherein the reaction of the method is as follows:

[0006]

[0007] Wherein: R1 is selected from bromine or methyl; R2 is selected from any one of methyl, ethyl, methoxy, chlorine, and bromine; HFIP is hexafluoroisopropanol; the reaction temperature is 90–110℃;

[0008] In Formula I, the reactants are o-aminoarcarboxamide and 2,4-pentanedione, the solvent system is hexafluoroisopropanol, and the product is a quinazolinone compound.

[0009] Preferably, the molar ratio of o-aminoarcarboxamide and 2,4-pentanedione is 1:2 to 1:3.

[0010] Furthermore, the molar ratio of the o-aminoarcarboxamide and 2,4-pentanedione is 1:2.5.

[0011] Furthermore, the concentration of the o-aminoarcarboxamide is 0.3–0.5 mol / L.

[0012] Preferably, the reaction temperature is 100°C.

[0013] Preferably, the reaction is carried out by stirring at a rate of 800-1000 rpm for a reaction time of not less than 5 hours.

[0014] Furthermore, the reaction time is 7 hours.

[0015] Preferably, the purification method of the quinazolinone compound is as follows: the obtained reaction mixture is cooled to room temperature, evaporated and concentrated, and the obtained concentrate is subjected to silica gel column chromatography with a mesh size of 200-300 to remove the solvent and obtain the target product quinazolinone compound.

[0016] Furthermore, the eluent in the silica gel column chromatography is petroleum ether and ethyl acetate.

[0017] Furthermore, the volume ratio of petroleum ether to ethyl acetate is 20:1.

[0018] The beneficial effects of this invention are:

[0019] (1) In the synthesis of quinazolinone compounds, hexafluoroisopropanol has strong solubility and good thermal stability, and at the same time has a strong hydrogen bond-donating ability, so the reaction can be promoted without the need for additional catalysts.

[0020] (2) The reaction does not require strong acid or strong base conditions, nor does it require additional reducing or oxidizing agents. It does not require transition metal catalysis, is economical and practical, and the reaction conditions are relatively mild.

[0021] (3) The present invention selects hexafluoroisopropanol as solvent, which has a low boiling point, is recyclable, is environmentally friendly, conforms to the concept of green chemistry, and is easy to operate and simple to process, making it suitable for large-scale industrial production. Attached Figure Description

[0022] Figure 1 As in Example 1 1 H NMR spectrum;

[0023] Figure 2 As in Example 1 13 C NMR spectrum. Detailed Implementation

[0024] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0025] Example 1

[0026] Preparation of 2-methyl-3-phenylquinazoline-4(3H)-one

[0027]

[0028] 2-Amino-N-phenylbenzamide (0.4 mmol, 89.0 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 2-methyl-3-phenylquinazoline-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 91%.

[0029] 1 H NMR (400MHz, CDCl3) δ8.28 (td, J=6.8, 1.6Hz, 1H), 7.69 (d, J=7.2Hz, 1H), 7.59-7.45 (m, 4H), 7.29-7.26 (m, 2H), 2.25 (s, 3H). 13 C NMR (100MHz, CDCl3) δ162.48,154.43,147.64,137.93,134.81,130.22,129.51,128.21,127.27,126.95,126.86,120.97,24.60.

[0030] Example 2

[0031] Preparation of 7-bromo-2-methyl-3-phenylquinazoline-4(3H)-one

[0032]

[0033] 2-Amino-4-bromo-N-phenylbenzamide (0.4 mmol, 116.4 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and the product was separated by 200-mesh column chromatography to obtain 7-bromo-2-methyl-3-phenylquinazoline-4(3H)-one (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 93%.

[0034] 1H NMR (400MHz, CDCl3) δ8.15(d,J=8.8Hz,1H),7.90(d,J=2.0Hz,2H),7.62-7.56(m,4H),7.31-7.28(m,2H),2.73(s,3H). 13 C NMR (100MHz, CDCl3) δ162.02,155.84,148.66,137.61,130.31,130.23,129.81,129.69,129.49,128.75,128.09,119.81,24.67.LC-MS m / z:calcd for C10H19NNaS2[M+Na]+240.0857,found:240.01.

[0035] Example 3

[0036] Preparation of 2,5-dimethyl-3-phenylquinazoline-4(3H)-one

[0037]

[0038] 2-Amino-6-methyl-N-phenylbenzamide (0.4 mmol, 90.5 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and the product was separated by 200-mesh column chromatography to obtain 2,5-dimethyl-3-phenylquinazoline-4(3H)-one (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 91%.

[0039] 1 H NMR (400MHz, CDCl3) δ7.62-7.48(m,5H),7.28-7.21(m,3H),2.82(s,3H),2.21(s,3H). 13 C NMR (100MHz, CDCl3) δ163.09,154.11,149.19,141.77,138.17,133.98,120.23,129.57,129.37,128.31,125.11,119.38,24.41,23.24.

[0040] Example 4

[0041] Preparation of 3-(3-methoxyphenyl)-2-methylquinazolin-4(3H)-one

[0042]

[0043] 2-Amino-N-(3-methoxyphenyl)benzamide (0.4 mmol, 96.9 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 3-(3-methoxyphenyl)-2-methylquinazoline-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 85%.

[0044] 1 H NMR (400MHz, CDCl3) δ8.27(dd,J=8.0,1.6Hz,1H),7.77(td,J=7.2,1.6Hz,1H),7.68(d,J=8.0Hz,1H),7.49-7.44( m,2H),7.05(dd,J=8.4,2.4Hz,1H),6.85(dd,J=7.6,3.2Hz,1H),6.79(t,J=2.4Hz,1H),3.84(s,3H),1.72(s,3H). 13 C NMR (100MHz, CDCl3) δ162.43,161.03,154.54,147.56,138.89,134.90,130. 97,127.29,126.94,126.86,120.92,120.28,115.30,113.89,55.71,24.33.

[0045] Example 5

[0046] Preparation of 3-(3-chlorophenyl)-2-methylquinazolin-4(3H)-one

[0047]

[0048] 2-Amino-N-(3-chlorophenyl)benzamide (0.4 mmol, 98.6 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and reacted at 100°C and 1000 rpm for 7 hours. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and the product was separated by 200-mesh column chromatography to obtain 3-(3-chlorophenyl)-2-methylquinazoline-4(3H)-one (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 92%.

[0049] 1H NMR (400MHz, CDCl3) δ8.26 (dd, J=8.0, 1.6Hz, 1H), 7.78 (td, J=7.2, 1.6Hz, 1H), 7.68 (d, J=7.6Hz, 1H),7.51-7.46(m,3H),7.31-7.30(m,1H),7.20-7.17(m,1H),6.79(t,J=2.4Hz,1H),2.87(s,3H). 13 C NMR (100MHz, CDCl3) δ162.31,153.77,147.54,138.98,135.84,135.05,131.18,129.95,128.76,127.27,127.10,127.08,126.69,120.79,24.56.

[0050] Example 6

[0051] Preparation of 3-(3-bromophenyl)-2-methylquinazolin-4(3H)-one

[0052]

[0053] 2-Amino-N-(3-chlorophenyl)benzamide (0.4 mmol, 116.4 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 3-(3-bromophenyl)-2-methylquinazoline-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 90%.

[0054] 1 H NMR (400MHz, CDCl3) δ8.26 (d, J=8.0Hz, 1H), 7.78 (td, J=7.2, 1.6Hz, 1H), 7.67 (t,J=8.0Hz,2H),7.50-7.44(m,3H),7.23(dd,J=8.4,1.2Hz,1H),2.26(s,3H). 13 C NMR (100MHz, CDCl3) δ162.30,153.75,147.54,139.10,135.04,132.84,131.57,131.42,127.27,127.16,127.09,123.55,120.78,24.59.

[0055] Example 7

[0056] Preparation of 2-methyl-3-p-tolylquinazolin-4(3H)-one

[0057]

[0058] 2-Amino-N-(3-chlorophenyl)benzamide (0.4 mmol, 90.5 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 2-methyl-3-p-tolylquinazolin-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 95%.

[0059] 1 H NMR (400MHz, CDCl3) δ8.26(dd,J=8.0,1.6Hz,1H),7.75(td,J=7.2,1.6Hz,1H),7.68(dd,J=8.0,1.2Hz,1H),7.45(td,J=7.2,1.2Hz 1H),7.35(d,J=7.6Hz,2H),7.13(d,J=8.4Hz,2H),2.44(s,3H),2.45(s,3H). 13 C NMR (100MHz, CDCl3) δ162.58,154.71,147.64,139.53,135.24,134.72,130.84,127.85,127.27,126.89,126.76,120.96,24.57,21.45.

[0060] Example 8

[0061] Preparation of 3-(4-methoxyphenyl)-2-methylquinazolin-4(3H)-one

[0062]

[0063] 2-Amino-N-(4-methoxyphenyl)benzamide (0.4 mmol, 96.9 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 3-(4-methoxyphenyl)-2-methylquinazoline-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 90%.

[0064] 1 H NMR (400MHz, CDCl3) δ8.26(dd,J=8.0,1.6Hz,1H),7.76(td,J=7.2,1.6Hz,1H),7.67(d,J=8.0Hz,1H),7.46(t,J=7.6Hz 1H),7.18-7.15(m,2H),7.07-7.04(m,2H),3.87(s,3H),2.26(s,3H). 13 C NMR (100MHz, CDCl3) δ162.74,160.13,155.01,147.60,134.76,130.40,129.17,127.29,126.89,126.79,120.95,115.41,55.75,24.62.

[0065] Example 9

[0066] Preparation of 3-(4-bromophenyl)-2-methylquinazolin-4(3H)-one

[0067]

[0068] 2-Amino-N-(4-bromophenyl)benzamide (0.4 mmol, 116.4 mg), 2,4-pentanedione (1.0 mmol, 102.7 μL, 2.5 equiv.), and hexafluoroisopropanol (1.0 mL) were added to a pressure-resistant tube and stirred at 1000 rpm for 7 hours at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator, and 3-(4-bromophenyl)-2-methylquinazoline-4(3H)-one was obtained by 200-mesh column chromatography (eluent: petroleum ether / ethyl acetate: 20 / 1). The yield was 92%.

[0069] 1 H NMR (400MHz, CDCl3) δ8.26 (dd, J=8.0, 1.6Hz, 1H), 7.78 (td, J=8.4, 1.6Hz, 1H), 7.71-7.67 (m, 3H), 7.48 (t, J=8.0Hz 1H),7.15(d,J=8.4Hz,2H),2.25(s,3H). 13 C NMR (100MHz, CDCl3) δ162.34,153.95,147.47,136.86,135.07,133.53,129.98,127.28,127.12,126.97,123.75,120.74,24.53.

Claims

1. A method for synthesizing quinazolinone compounds, characterized in that, The reaction of the method is as follows: Equation I: Formula I Wherein: R1 is selected from bromine or methyl; R2 is selected from any one of methyl, ethyl, methoxy, chlorine, and bromine; HFIP is hexafluoroisopropanol; the reaction temperature is 90~110 ℃; In Formula I, the reactants are o-aminoarcarboxamide and 2,4-pentanedione, with a molar ratio of 1:2 to 1:3; the solvent system is hexafluoroisopropanol; and the product is a quinazolinone compound.

2. The method for synthesizing quinazolinone compounds according to claim 1, characterized in that, The molar ratio of o-aminoarcarboxamide and 2,4-pentanedione is 1:2.

5.

3. The method for synthesizing quinazolinone compounds according to claim 2, characterized in that, The concentration of the o-aminoarcarboxamide is 0.3~0.5 mol / L.

4. The method for synthesizing quinazolinone compounds according to claim 1, characterized in that, The reaction temperature is 100 °C.

5. The method for synthesizing quinazolinone compounds according to claim 1, characterized in that, The reaction is carried out by stirring at a rate of 800-1000 rpm for a period of not less than 5 hours.

6. The method for synthesizing quinazolinone compounds according to claim 5, characterized in that, The reaction time is 7 hours.

7. The method for synthesizing quinazolinone compounds according to any one of claims 1 to 6, characterized in that, The purification method for the quinazolinone compounds is as follows: the obtained reaction mixture is cooled to room temperature, evaporated and concentrated, and the concentrated solution is subjected to silica gel column chromatography with a mesh size of 200-300 to remove the solvent and obtain the target product quinazolinone compounds.

8. The method for synthesizing quinazolinone compounds according to claim 7, characterized in that, The eluents used in the silica gel column chromatography are petroleum ether and ethyl acetate.

9. The method for synthesizing quinazolinone compounds according to claim 8, characterized in that, The volume ratio of petroleum ether to ethyl acetate is 20:1.

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