Process for the preparation of 2-acetylquinazolin-4(3H)-ones

Abstract

The application provides a preparation method of 2-acetylquinazolin-4(3H)-one compounds. The application uses FeCl3-TEMPO catalyst to selectively oxidize the benzyl position hydrogen benzyl position to carbonyl, and directly oxidize the 2-position side chain of quinazolinone to carbonyl at a lower temperature, so as to obtain 2-acetylquinazolin-4(3H)-one compounds, which is of great significance. The synthesis method uses simple and low-cost reaction catalyst, does not need harsh reaction conditions, does not need an autoclave, and has short reaction time, and is suitable for industrial production.

Description

[0001] Cross-reference to Related Applications

[0002] This application claims priority to Chinese Patent Application No. 2023115519176, filed on November 20, 2023, entitled "Preparation Method of 2-Acetylquinazolin-4(3H)-one Compound", the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0003] The present application relates to the field of medicinal chemistry, and relates to a 2-substituted quinazolin-4(3H)-one compound, in particular to a preparation method of a 2-acetylquinazolin-4(3H)-one compound. BACKGROUND

[0004] 2-substituted quinazolin-4(3H)-one compounds are a kind of nitrogen-containing heterocyclic compounds with good biological activity, which show excellent activity in antitumor, anti-inflammatory, antihypertensive and antibacterial aspects, such as P13K inhibitor Idelalisib for treating hematological malignancies, diuretic metolazone for preventing and treating hypertension, and antifungal agent Abacumazole, etc. The master's thesis of Guo Rui (Synthesis and biological activity evaluation of quinazolinone derivatives, Northwest A&F University, 2018) also reports that a plurality of 2-substituted quinazolin-4(3H)-one compounds can inhibit fungal hypha growth and inhibit Curvularia lunata spore germination. Because of the wide biological activity of 2-substituted quinazolin-4(3H)-one compounds, their synthesis has attracted the attention of medicinal chemists. SUMMARY

[0005] The present application provides a preparation method of a 2-acetylquinazolin-4(3H)-one compound.

[0006] The present application is achieved in this way:

[0007] A preparation method of a 2-acetylquinazolin-4(3H)-one compound (compound IV), characterized in that: compound III is reacted under an oxygen atmosphere to obtain compound IV, 2-acetylquinazolin-4(3H)-one compound, by catalysis of a catalyst. The catalyst is a Fe(III) combined catalyst.

[0008]

[0009] In the formula, R is each independently hydrogen or halogen; R1 is alkyl, isobutyl or benzyl.

[0010] According to an embodiment of the present application, the Fe(III) combined catalyst comprises FeCl3, TEMPO and I2.

[0011] According to one embodiment of the present application, the compound of formula I and the compound of formula II are reacted in the presence of oxygen and a promoter to obtain the compound of formula III.

[0012]

[0013] wherein R is each independently hydrogen, halogen; R1 is alkyl, isobutyl, benzyl.

[0014] According to one embodiment of the present application, the promoter is imidazole hydrochloride.

[0015] A method for preparing a 2-acetylquinazolin-4(3H)-one compound, characterized in that: a compound of formula I and a compound of formula II are reacted in the presence of oxygen and a promoter to obtain a compound of formula III, and then the compound of formula III is catalytically reacted in the presence of oxygen and a catalyst to obtain a compound of formula IV; the promoter is imidazole hydrochloride; the catalyst is a Fe(III) combined catalyst; and the Fe(III) combined catalyst comprises FeCl3, TEMPO and I2.

[0016]

[0017] In the above synthesis method, the amount of the promoter imidazole hydrochloride used in the reaction is 2-3 equivalents, based on 1 equivalent of the compound of formula I.

[0018] In the above Fe(III) combined catalyst, the amount of FeCl3 used is 0.01-0.1 equivalent, and the amount of TEMPO used is 0.02-2.0 equivalent, based on 1 equivalent of the compound of formula III. Further, in the Fe(III) combined catalyst used in the reaction, the amount of FeCl3 or FeCl2 used is 0.01-0.06 equivalent, and the amount of TEMPO used is 0.30-1.5 equivalent.

[0019] In the synthesis method of the present application, the solvent used for preparing the compound of formula III from the compound of formula I and the compound of formula II in the presence of the promoter is solvent A, which is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylbenzene and benzene; and N,N-dimethylformamide is preferred.

[0020] In the synthesis method of the present application, the reaction temperature for preparing the compound of formula III from the compound of formula I and the compound of formula II in the presence of the promoter is temperature A, and in order to improve the yield and purity of the above synthesis method, the above reaction temperature A is 80-150°C; and 120-150°C is preferred.

[0021] In the synthesis method of the present application, the solvent used for preparing the compound of formula IV from the compound of formula III in the presence of oxygen and a catalyst is solvent B, which is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylbenzene and benzene; and N,N-dimethylformamide is preferred.

[0022] The reaction temperature for the preparation of compound IV from compound III by catalysis of the catalyst in the oxygen atmosphere is temperature B. In order to improve the yield and purity of the above-mentioned synthesis method, temperature B is 60-150°C; preferably 80-120°C.

[0023] Specifically, a preparation method of a 2-acetylquinazolin-4(3H)-one compound is characterized in that: compound III is prepared from compound I and compound II in the oxygen atmosphere by the action of a promoter, and then compound IV is prepared from compound III in the oxygen atmosphere by catalysis of a catalyst; the promoter is imidazole hydrochloride, and the amount is 2.2-2.7 equivalents; the catalyst is a Fe(III) combined catalyst; the Fe(III) combined catalyst includes FeCl3 and TEMPO, wherein the amount of FeCl3 is 0.02-0.05 equivalents, and the amount of TEMPO is 0.37-1.11 equivalents; in the process of preparing compound III from compound I and compound II by the action of the promoter, the solvent A used is N,N-dimethylformamide, and the reaction temperature A is 120-150°C; in the process of preparing compound IV from compound III in the oxygen atmosphere by catalysis of the catalyst, the solvent B used is N,N-dimethylformamide, and the reaction temperature B is 80-120°C.

[0024] The above-mentioned Fe(III) combined catalyst further includes iodine, and the amount of iodine is 0.02-2.0 equivalents.

[0025] Further, the compound IV is selected from compounds 2a-2c:

[0026] 2-acetylquinazolin-4(3H)-one (2a);

[0027] 2-isobutyrylquinazolin-4(3H)-one (2b);

[0028] 2-benzoyl-7-chloroquinazolin-4(3H)-one (2c).

[0029] Beneficial effects

[0030] The application provides a preparation method of 2-acetylquinazolin-4(3H)-one compound. In the preparation process of quinazolin-4(3H)-one compound, the conversion of the benzyl carbonylation of quinazolinone is very difficult, and the application provides a method for obtaining the carbonylation product by using FeCl3-TEMPO catalyst oxygen oxidation of the benzyl quinazolinone, which can selectively oxidize the benzyl hydrogen benzyl position to carbonyl, and directly oxidize the 2-position side chain of quinazolinone to carbonyl at a lower temperature to obtain 2-acetylquinazolin-4(3H)-one compound, which is of great significance. The synthesis method provided by the application uses simple and low-cost reaction catalyst, does not need harsh reaction conditions, does not need an autoclave, and has short reaction time, and is suitable for industrial production. DETAILED DESCRIPTION

[0031] In order to make the purpose and technical scheme of the application clearer, the preferred embodiments of the application are described in detail below. It should be explained that: the following embodiments are only used to further illustrate the application, and cannot be understood as a limitation on the protection scope of the application. Some non-essential improvements and adjustments made by those skilled in the art according to the above content of the application all belong to the protection scope of the application. The raw materials and reagents used in the application are all commercially available products.

[0032] Example 1

[0033] A 50 mL round-bottom flask was added with a compound of formula I, imidazole hydrochloride, a compound of formula II, and DMF as a solvent, and stirred at 150 DEG C under reflux for 13 hours. When the reaction was completed, the temperature was reduced to 80 DEG C, the obtained solution was heated, 2 ml of DMF was added to dissolve the reaction mixture, and then a saturated NaCl solution (25 ml) was added. The obtained mixture was extracted with ethyl acetate (25 ml) twice. The combined organic layer was washed with water (50 ml) and then with brine (50 ml), then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography column, recrystallized with petroleum ether and ethyl acetate or with petroleum ether / EA to obtain the target product, a compound of formula III.

[0034] The inventors carried out the nucleophilic addition reaction of anthranilamide with N,N-dimethylpropanamide in the presence of imidazole hydrochloride (2.5 equiv) to synthesize quinazolinone class of compounds of formula III. The results are listed in Table 1. The inventors found that at 80 °C, the nucleophilic addition reaction of anthranilamide with N,N-dimethylpropanamide in the presence of imidazole hydrochloride (2.5 equiv) gave 3a in 24% yield (Table 1, entry 1). When the inventors used FeCl3, Yb(OTf), AlCl3, O2 / FeCl3, TsOH-H2O (p-toluene sulfonic acid monohydrate) as catalysts, the yields of the products were 20-56% (Table 1, entries 2-7), respectively. These results indicated that the temperature was very important for this addition reaction, while the strength of Lewis acid had no effect on the reaction. Inspired by these results, the inventors obtained the best yield at 150 °C under an oxygen atmosphere (Table 1, entry 7). While under an O3 atmosphere, the reaction did not proceed (Table 1, entry 9). When the temperature was increased or decreased, the yield decreased (Table 1, entries 8, 9 and 10). The experiments demonstrated that the temperature had a significant effect on the reaction. Finally, the inventors investigated the effect of solvent on the reaction. The reaction was carried out in HFIP (hexafluoroisopropanol) (Table 1, entry 12), and the addition reaction did not occur. When the reaction was carried out in DMA and mesitylene (mestilene), the yields were 64-71% (Table 1, entries 10 and 11).

[0035] The reaction scheme is:

[0036]

[0037]

[0038] Reaction conditions: Unless otherwise noted, all reactions were carried out with anthranilamide (3.67 mmol, 1 equiv), N,N-dimethylpropanamide (3.67 mmol, 1 equiv), imidazole hydrochloride (9.18 mmol, 2.5 equiv). a All solvents were 2 ml.

[0039] b Isolated yield.

[0040] c No reaction occurred.

[0041] The inventors utilized the synthetic quinazolinone of formula III to produce the compound of formula IV in the presence of a catalyst and explored the reaction catalysts, the results of which are listed in Table 2. First, the experiment started with the reaction of 2-ethylquinazolin-4(3H)-one (compound la) with FeCl3(2 mol%) in the presence of DMF as catalyst. However, when CuBr2was used as catalyst, only 43% yield was obtained (entry 2). Then, the oxidation performance of different Lewis acids was compared. When CF3CO2Ag was used to replace FeCl3, the yields of Zn(OTf)2, AgBr, and AlCl3were low (entries 3-6). The use of HOTf, TsOH-H2O, and BF3-C2H5OC2H5to replace FeCl3did not produce the desired metallated product (entries 8 and 9). Finally, the best solvent for the reaction was DMF, and the reaction did not work in DMA or HFIP (entries 10-11). These results indicated that the conventional solvent had little effect on the reaction. On the basis of the original conditions, the Tempo-iodine catalytic system was introduced, and an oxygen balloon was added to increase the oxygen concentration. It was found that the reaction time could be shortened to 4 h, and the reaction temperature could be shortened to 120 °C, with the best yield (entry 12). The oxidation yield was significantly reduced when Tempo was used (entry 7). Without FeCl3or Tempo-iodine, the reaction did not produce any product (entries 14-17). Next, the oxidation ability of different transition metal catalysts was compared. The doping of TiCl4, CuCl, NiCl2, and FeCl2could be used to obtain the desired product, although the yield was relatively low (entries 18-21). Among the transition metal catalysts, FeCl2could also be used for oxidation, and FeCl3had the best yield (entry 1 and entry 12).

[0042] Table 2

[0043]

[0044]

[0045] Reaction conditions: All reactions were carried out with 2-ethylquinazolinone (0.26 mmol, 1 equiv), FeCl3(0.07 mmol, 0.04 equiv), iodine I2(1.85-5.55, 0.37-1.11 equiv), and TEMPO (1.85-5.55, 0.37-1.11 equiv) unless otherwise noted.

[0046] a All solvents were 2 ml.

[0047] b Isolated yield.

[0048] c No reaction occurred.

[0049] Example 2:

[0050] Method for obtaining carbonyl compounds by selective oxidation (2a-2c)

[0051] To a 50 mL three-necked flask, add a quinazolinone compound (1 equivalent), TEMPO (0.37-1.11 equivalents), FeCl3 (0.04 equivalents), and 2 mL of N,N-dimethylformamide. Replace the air with an oxygen balloon three times to maintain a full oxygen atmosphere. Warm the resulting solution to 120°C and stir at this temperature. Monitor by TLC. When the reaction is complete, cool to room temperature, add ethyl acetate (30 mL), and decolorize with activated carbon. Filter, and wash the organic layer with saturated brine. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify on a silica gel column to obtain the desired product.

[0052]

[0053]

[0054]

[0055] Reaction conditions: 1 equivalent of quinazolinone compound, 0.04 equivalent of FeCl3, 0.37-1.11 equivalent of TEMPO, 0.37-1.11 equivalent of iodine I2, reaction temperature of 120°C, reaction time of 4-12h.

[0056] The inventors studied the universality of the method and found that the reaction time for the oxidation-catalytic synthesis of 2-carbonylquinazolinone compounds using an iron (III) combination catalyst is shorter than that for the catalytic synthesis of 2-carbonylquinazolinone compounds, and the yield is higher (2a); as the 2-side chain grows, the yield decreases (2b); and when a group with larger steric hindrance, such as a benzene ring, is added, the reaction yield still decreases (2c).

[0057] NMR data of the target product

[0058] 2-Acetylquinazolin-4(3H)one (2a, 89.5 mg, 87%), white solid 1 H NMR(600MHz,DMSO-d6)δ12.00(s,1H),8.10(d,J=7.7Hz,1H),7.77(ddd,J=8.5,7 .2,1.6Hz,1H),7.60(d,J=7.9Hz,1H),7.48–7.44(m,1H),1.27(t,J=7.5Hz,3H). 13C NMR (151 MHz, DMSO-d6) δ 162.50 (d, J = 56.1 Hz), 158.88, 134.61, 127.11, 126.20 (d, J = 26.8 Hz), 121.29, 51.02, 28.34, 22.56, 11.60.

[0059] 2-isobutyrylquinazolin-4(3H)-one (2b, 40.7 mg, 65%), white solid 1 H NMR (600 MHz, CDCl3) δ 10.19 - 10.05 (m, 1H), 8.37 (dd, J = 8.0, 1.5 Hz, 1H), 7.88 (dd, J = 8.1, 1.3 Hz, 1H), 7.85 (dd, J = 7.0, 1.5 Hz, 1H), 7.64 - 7.61 (m, 1H), 4.09 (p, J = 6.9 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 171.09, 139.76, 129.08, 123.42, 119.56, 46.10, 32.00, 29.90, 26.04, 22.75

[0060] 2-benzoyl-7-chloroquinazolin-4(3H)-one (2c, 37.6 mg, 47%), white solid 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.23 - 8.14 (m, 3H), 7.86 (d, J = 2.3 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.70 - 7.65 (m, 1H), 7.60 (t, J = 7.8 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 187.40, 160.98, 150.93, 139.79, 134.92, 134.35, 131.33, 129.11, 129.06, 128.53, 127.88, 122.20.

Claims

1. A method for preparing 2-acetylquinazoline-4(3H)one compound IV, characterized in that: Compound III is reacted with a catalyst in an oxygen atmosphere to prepare 2-acetylquinazoline-4(3H)one compound IV; the catalyst is an Fe(III) combined catalyst; ； Wherein, R is independently hydrogen or halogen; R1 is alkyl or benzyl; the Fe(III) combination catalyst includes FeCl3, TEMPO and iodine; the solvent used in the reaction is solvent B, which is selected from N,N-dimethylformamide.

2. The method according to claim 1, wherein: Compound I and compound II are reacted with a accelerator in an oxygen atmosphere to obtain compound III; Wherein, R is independently hydrogen or halogen; R1 is alkyl or benzyl; the accelerator is imidazole hydrochloride; The solvent used in the reaction is solvent A, which is selected from N,N-dimethylformamide or N,N-dimethylacetamide.

3. The method according to claim 1, wherein: In the Fe(III) combined catalyst, the amount of FeCl3 used is 0.01-0.1 equivalent, the amount of TEMPO used is 0.02-2.0 equivalent; and the amount of iodine used is 0.02-2.0 equivalent.

4. The method according to claim 2, wherein: The amount of imidazole hydrochloride used as the promoter in the reaction is 2-3 equivalents. In the Fe(III) combined catalyst used in the reaction, the amount of FeCl3 used is 0.01-0.06 equivalents, the amount of TEMPO used is 0.30-1.5 equivalents; and the amount of iodine used is 0.02-2.0 equivalents.

5. The method according to claim 4, wherein: The reaction temperature for preparing compound III by reacting compound I with compound II under the action of a promoter is temperature A, which is 80-150°C; the reaction temperature for preparing compound IV by catalyzing compound III under an oxygen atmosphere with a catalyst is temperature B, which is 60-150°C.

6. The method according to claim 5, wherein: Compound III is prepared by reacting a compound of formula I with a compound of formula II under an oxygen atmosphere via a promoter, and then compound III is catalyzed by a catalyst under an oxygen atmosphere to prepare compound IV; the promoter is imidazole hydrochloride, and the amount used is 2.2-2.7 equivalents; the catalyst is an Fe(III) combination catalyst; the Fe(III) combination catalyst includes FeCl3 and TEMPO, wherein the amount of FeCl3 is 0.02-0.05 equivalents, the amount of TEMPO is 0.37-1.11 equivalents, and the amount of iodine is 0.02-2.0 equivalents; solvent A is N,N-dimethylformamide, and the reaction temperature A is 120-150°C; solvent B is N,N-dimethylformamide, and the reaction temperature B is 80-120°C.

7. The method according to any one of claims 1 to 6, wherein: The compound IV is selected from compounds 2a-2c: 2-Acetylquinazolin-4(3H)one (2a); 2-Isobutyrylquinazolin-4(3H)one (2b); 2-Benzoyl-7-chloroquinazolin-4(3H)-one (2c).

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