Method for synthesizing quinazolinone compound by catalyzing and cyclizing titanocene dichloride

Abstract

According to the method, a 2-aminobenzamide compound and orthoester are used as reaction substrates, titanocene dichloride is used as a catalyst, methanol or ethanol is used as a solvent, and the quinazolinone compound is synthesized through cyclization under the catalysis of titanocene dichloride. According to the method, titanocene dichloride generates Lewis acid (Cp2Ti (OCH3) Cl or Cp2Ti (OEt) Cl) and # imgabs0 # acid (HCl) with high catalytic activity in situ under the action of a 2-aminobenzamide compound and methanol or ethanol, and the quinazolinone compound is efficiently and catalytically synthesized under the combined action of the two acids. The method has the advantages that the reaction system is cheap and easy to obtain, the substrate range is wide, the reaction condition is mild, the yield of the target product is high, and the method has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of quinazolinone compound synthesis, and particularly relates to a method for efficiently catalyzing and synthesizing quinazolinone compounds with dichlorotitanocene. Background Art

[0002] Quinazolinone compounds are an important class of six-membered nitrogen heterocyclic compounds. Due to their multiple biological activities, they are widely used in the research of anti-cancer, anti-malarial, anti-inflammatory and anti-tuberculosis drugs.

[0003] The synthesis of quinazolinone compounds can usually be achieved by the following four methods: (1) strong acid ( Acid) catalysis; (2) high temperature synthesis; (3) high temperature oxidation synthesis; (4) photocatalytic synthesis. In the synthesis method of quinazolinone compounds, the reaction of strong acid synthesis usually uses an equivalent catalyst (TFA) to complete the reaction, which cannot realize the industrial preparation of quinazolinone compounds. Some research groups have realized the method of preparing quinazolinone compounds at high temperature without catalyst. At high temperature of 90-120℃, the universality of the substrate is not good. Although 19 quinazolinone compounds were synthesized under high temperature oxidation conditions with CuBr2 as catalyst for 24h, which expanded the universality of the substrate, it was not able to achieve mild and efficient synthesis of such compounds. Another research group proposed to use 4CzIPN as photocatalyst under blue light irradiation and react in oxygen atmosphere for 12h to achieve a more gentle way to synthesize quinazolinone compounds, but it cannot avoid the problems of expensive photocatalysts used in photocatalysis and complex reaction systems. In order to solve the problems of limited substrate types, harsh reaction conditions, complex catalytic systems, and expensive catalysts in quinazolinone compounds, it is very necessary to develop a more gentle and efficient catalytic system. Summary of the invention

[0004] The purpose of the present invention is to overcome the problems of limited substrate types, harsh reaction conditions, complex catalytic systems, expensive catalysts, etc. in existing methods for synthesizing quinazolinone compounds, and to provide a method for synthesizing quinazolinone compounds by catalyzing cyclization of dichlorotitacenes.

[0005] In order to achieve the above-mentioned purpose, the technical solution adopted by the present invention is: adding a 2-aminobenzamide compound shown in formula I, an orthoester shown in formula II, and dichlorotantalum (Cp2TiCl2) to an organic solvent, stirring the reaction at room temperature, and separating and purifying after the reaction is completed to obtain a quinazolinone compound shown in formula III.

[0006]

[0007] In the formula, R 1 represents any one of H, C1-C4 alkyl, halogen, and nitro; R 2represents any one of H, C1-C4 alkyl, and phenyl; R 3 It represents any one of H, cyclopropyl, propargyl, phenyl, C1-C4 alkyl-substituted phenyl, and halogenated phenyl.

[0008] Furthermore, preferably R 1 represents any one of H, methyl, F, Cl, and Br; R 2 represents any one of H, methyl, ethyl, and phenyl; R 3 represents any one of H, cyclopropyl and propargyl.

[0009] In the above-mentioned synthesis method, the reaction is preferably carried out at room temperature for 2 to 6 hours.

[0010] In the above synthesis method, the addition amount of the dichlorotitanocene is preferably 2.5% to 5.0% of the molar amount of the 2-aminobenzamide compound.

[0011] In the above synthesis method, the molar ratio of the 2-aminobenzamide compound to the orthoester is preferably 1:1.2 to 1.6.

[0012] In the above synthesis method, preferably the organic solvent is methanol or ethanol.

[0013] The beneficial effects of the present invention are as follows:

[0014] The invention uses 2-aminobenzamide compounds and orthoesters as raw materials, methanol or ethanol as solvent, and cheap and easily available dichlorotitanocene as catalyst. Under the action of 2-aminobenzamide compounds and methanol or ethanol, dichlorotitanocene in situ generates high catalytic activity bis-acid Lewis acid (Cp2Ti(OCH3)Cl or Cp2Ti(OEt)Cl) and The acid (HCl) catalyst and the double acid catalyst work together to catalyze the reaction of 2-aminobenzamide compounds and orthoesters to generate target quinazolinone compounds. The invention has the advantages of cheap and easy to obtain reaction system and a wide range of substrates, mild reaction conditions, high yield of target products, and broad application prospects. DETAILED DESCRIPTION

[0015] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0016] Example 1

[0017] The synthetic structure of quinazolinone is as follows:

[0018]

[0019] A mixture of 2-aminobenzamide (0.5mmol, 1.0 equivalent), trimethyl orthoformate (0.8mmol, 1.6 equivalent), Cp2TiCl2 (3.1mg, 2.5mol%) and ethanol (2mL) was added to a 10mL vial and reacted under magnetic stirring for 2 hours at room temperature. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (using petroleum ether and ethyl acetate as eluents) to obtain quinazolinone with a yield of 96%. The spectral data are: 1 H NMR (400MHz, DMSO) δ12.25(s,1H),8.18–8.01(m,2H),7.81(t,J=7.6Hz,1H),7.66(d,J=8.4Hz,1H),7.52(t,J=7.2Hz,1H); 13 C NMR (101MHz, DMSO) δ160.7,148.8,145.4,134.3,127.2,126.7,125.8,122.6.

[0020] Example 2

[0021] Synthesize 6-methylquinazolin-4(3H)-one with the following structural formula

[0022]

[0023] In this example, 2-amino-5-methylbenzamide was used to replace 2-aminobenzamide in Example 1 in equal moles, and the other steps were the same as in Example 1 to obtain 6-methylquinazolin-4(3H)-one with a yield of 99%. The spectral data were as follows: 1 HNMR (400MHz, DMSO) δ12.15(s,1H),8.03(s,1H),7.91(s,1H),7.61(dd,J=8.4,2.0Hz,1H),7.55(d,J=8.4Hz,1H),2.43(s,3H); 13 C NMR (101MHz, DMSO) δ160.7,146.7,144.5,136.4,135.5,127.0,125.2,122.4,20.8.

[0024] Example 3

[0025] Synthesize 6-fluoroquinazoline-4(3H)-one having the following structural formula

[0026]

[0027] In this example, 2-amino-5-fluorobenzamide was used to replace 2-aminobenzamide in Example 1 in equal moles, and the reaction was carried out under magnetic stirring at room temperature for 6 hours. The other steps were the same as in Example 1 to obtain 6-fluoroquinazolin-4(3H)-one with a yield of 91%. The spectral data were as follows: 1 H NMR (400MHz, DMSO) δ12.37(s,1H),8.08(s,1H),7.80–7.65(m,3H); 13 C NMR(101MHz,DMSO)δ160.2,158.8( 1 J=23.3Hz),145.7,144.8,130.1( 3 J=8.6Hz),123.8( 3 J=8.6Hz),122.6( 2 J=24.0Hz),110.3( 2 J = 23.3 Hz); 19 F NMR (376 MHz, DMSO) δ -113.4.

[0028] Example 4

[0029] Synthesize 6-chloroquinazoline-4(3H)-one with the following structural formula

[0030]

[0031] In this example, 2-amino-5-chlorobenzamide was used to replace 2-aminobenzamide in Example 1 in equal moles, and the reaction was carried out under magnetic stirring at room temperature for 6 hours. The other steps were the same as in Example 1 to obtain 6-chloroquinazoline-4(3H)-one with a yield of 99%. The spectral data were as follows: 1 H NMR (400MHz, DMSO) δ12.43(s,1H),8.12(s,1H),8.03(d,J=2.4Hz,1H),7.81(dd,J=8.8,2.4Hz,1H),7.67(d,J=8.8Hz,1H); 13 C NMR (101MHz, DMSO) δ159.8,147.5,145.9,134.4,131.0,129.5,124.8,123.9.

[0032] Example 5

[0033] Synthesize 6-bromoquinazoline-4(3H)-one with the following structural formula

[0034]

[0035] In this example, 2-amino-5-bromobenzamide was used to replace 2-aminobenzamide in Example 1 in equal moles, and the reaction was carried out under magnetic stirring at room temperature for 6 hours. The other steps were the same as in Example 1 to obtain 6-bromoquinazolin-4(3H)-one with a yield of 74%. The spectral data are: 1 H NMR (400MHz, DMSO) δ12.43(s,1H),8.18(d,J=2.4Hz,1H),8.13(s,1H),7.94(dd,J=8.8,2.4Hz,1H),7.60(d,J=8.8Hz,1H); 13 C NMR (101MHz, DMSO) δ159.6,147.8,146.0,137.1,129.7,127.9,124.2,119.2.

[0036] Example 6

[0037] Synthesize 3-cyclopropylquinazoline-4(3H)-one having the following structural formula

[0038]

[0039] In this example, 2-amino-N-cyclopropylbenzamide was used to replace the 2-aminobenzamide in Example 1. The other steps were the same as in Example 1 to obtain 3-cyclopropylquinazoline-4(3H)-one. The yield was 94%. The spectral data were as follows: 1 HNMR (400MHz, DMSO) δ8.27(s,1H),8.14(d,J=8.0Hz,1H),7.80(t,J=7.2Hz,1H),7.65(d,J= 8.4Hz,1H),7.53(t,J=7.6Hz,1H),3.28–3.19(m,1H),1.08–0.99(m,2H),0.98–0.91(m,2H); 13 C NMR (101MHz, DMSO) δ161.3,147.8,147.4,134.2,127.0,126.9,125.9,121.3,29.1,5.9.

[0040] Example 7

[0041] Synthesize 3-(prop-2-yn-1-yl)quinazolin-4(3H)-one having the following structural formula

[0042]

[0043] In this example, 2-amino-N-(prop-2-yn-1-yl)benzamide was used to replace the 2-aminobenzamide in Example 1. The other steps were the same as in Example 1 to obtain 3-(prop-2-yn-1-yl)quinazolin-4(3H)-one with a yield of 94%. The spectral data were as follows: 1 H NMR (400MHz, DMSO) δ8.46(s,1H),8.17(d,J=8.0Hz,1H),7.84(t,J=7.2Hz,1H),7.69( d,J=8.0Hz,1H),7.57(t,J=7.6Hz,1H),4.83(d,J=2.4Hz,2H),3.42(t,J=2.4Hz,1H); 13 C NMR (101MHz, DMSO) δ159.5,147.7,147.0,134.6,127.3,127.3,126.0,121.4,78.5,75.6,35.1.

[0044] Example 8

[0045] Synthesize 2-methylquinazolin-4(3H)-one with the following structural formula

[0046]

[0047] In this example, trimethyl orthoformate in Example 1 was replaced by an equal molar amount of triethyl orthoformate, and the other steps were the same as in Example 1 to obtain 2-methylquinazoline-4(3H)-one with a yield of 93%. The spectral data were as follows: 1 H NMR (400MHz, DMSO) δ12.19(s,1H),8.06(d,J=7.6Hz,1H),7.75(t,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.44(t,J=7.2Hz,1H),2.34(s,3H); 13 CNMR(101MHz,DMSO)δ161.7,154.2,149.0,134.3,126.6,125.8,125.7,120.6,21.4.

[0048] Example 9

[0049] Synthesize 2-ethylquinazoline-4(3H)-one with the following structural formula

[0050]

[0051] In this example, trimethyl orthoformate in Example 1 was replaced with an equal molar amount of triethyl orthopropionate, and the other steps were the same as in Example 1 to obtain 2-ethylquinazoline-4(3H)-one with a yield of 95%. The spectral data were as follows: 1 H NMR (400MHz, DMSO) δ12.16(s,1H),8.07(d,J=7.2Hz,1H),7.76(t,J=8.0Hz,1H),7.59 (d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),2.62(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H); 13 C NMR (101MHz, DMSO) δ161.8,158.3,149.0,134.2,126.8,125.9,125.7,120.8,27.8,11.3.

[0052] Example 10

[0053] Synthesize 2-methyl-3-(o-tolyl)quinazolin-4(3H)-one having the following structural formula

[0054]

[0055] In this example, 2-amino-N-(o-tolyl)benzamide was used to replace 2-aminobenzamide in Example 1, and triethyl orthoformate was used to replace trimethyl orthoformate in Example 1. The reaction was stirred under magnetic stirring at room temperature for 6 hours. The other steps were the same as those in Example 1 to obtain 2-methyl-3-(o-tolyl)quinazolin-4(3H)-one with a yield of 55%. The spectral data are as follows: 1 H NMR (400MHz, DMSO) δ8.13(d,J=8.0Hz,1H),7.85(t,J=7.6Hz,1H),7.68(d,J=8 .0Hz,1H),7.52(t,J=7.6Hz,1H),7.47–7.35(m,4H),2.09(s,3H),2.03(s,3H); 13 C NMR (101MHz, DMSO) δ160.7,154.2,147.4,136.8,135.0,134.7,131.0,129.3,128.4,127.4,126.7,126.5,126.3,120.3,23.5,16.8.

Claims

1. A method for synthesizing quinazolinone compounds by catalytic cyclization of titanocene dichloride, characterized in that: Adding a 2-aminobenzamide compound of formula I, an orthoester of formula II, and titanocene dichloride into an organic solvent, stirring and reacting at room temperature, and separating and purifying after the reaction is completed to obtain a quinazolinone compound of formula III; In the formula, R 1 represents any one of H, C1-C4 alkyl, halogen, and nitro; R 2 represents any one of H, C1-C4 alkyl, and phenyl; R 3 represents any one of H, cyclopropyl, propargyl, phenyl, C1-C4 alkyl substituted phenyl, and halogenated phenyl; The organic solvent is methanol or ethanol.

2. The method for synthesizing quinazolinone compounds by titanocene dichloride catalysis cyclization according to claim 1, characterized in that: R 1 represents any one of H, methyl, F, Cl, and Br; R 2 represents any one of H, methyl, ethyl, and phenyl; R 3 represents any one of H, cyclopropyl and propargyl.

3. The method for synthesizing quinazolinone compounds by titanocene dichloride catalysis cyclization according to claim 1 or 2, characterized in that: The reaction is carried out at room temperature for 2 to 6 hours.

4. The method for synthesizing quinazolinone compounds by titanocene dichloride catalysis cyclization according to claim 1 or 2, characterized in that: The added amount of the dichlorotitanocene is 2.5% to 5.0% of the molar amount of the 2-aminobenzamide compound.

5. The method for synthesizing quinazolinone compounds by titanocene dichloride catalysis cyclization according to claim 1 or 2, characterized in that: The molar ratio of the 2-aminobenzamide to the orthoester is 1:1.2-1.6.

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