A method for synthesizing quinazolinone compounds by catalytic cyclization of titanocene dichloride

Abstract

The invention discloses a method for synthesizing quinazolinone compounds by catalytic cyclization of dichlorotitanocene. The method uses a 2-aminobenzamide compound and an orthoester as reaction substrates, dichlorotitanocene as a catalyst, and methanol or ethanol as a solvent. The dichlorotitanocene generates a Lewis acid (Cp2Ti(OCH3)Cl or Cp2Ti(OEt)Cl) and an acid (HCl) with high catalytic activity in situ under the action of the 2-aminobenzamide compound and the methanol or ethanol. The two acids work together to efficiently catalyze the synthesis of the quinazolinone compound. The method has the advantages of a cheap and readily available reaction system and a wide range of substrates, mild reaction conditions, and a high yield of the target product, thus having broad application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of quinazolinone compound synthesis, and particularly relates to a method for efficiently catalyzing quinazolinone compounds using titanocene dichloride. 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 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 possible to achieve a 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 milder 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 the current quinazolinone compounds, it is very necessary to develop a milder and more efficient catalytic system. Summary of the Invention

[0004] The present invention aims 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 provides a method for synthesizing quinazolinone compounds by catalyzing the cyclization of dichlorotitanocenes.

[0005] 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 dichlorotitanocene (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] Where 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 1:1.2-1.6.

[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 dichlorotitacenes as catalyst. Under the action of 2-aminobenzamide compounds and methanol or ethanol, dichlorotitacenes in situ generate bis-acid Lewis acid (Cp2Ti(OCH3)Cl or Cp2Ti(OEt)Cl) with high catalytic activity and Acid (HCl) catalysts and dual acid catalysts work together to catalyze the reaction of 2-aminobenzamide compounds with orthoesters to produce target quinazolinone compounds. This invention has the advantages of a cheap and readily available reaction system, a wide range of substrates, mild reaction conditions, and a high yield of the target product, thus possessing broad application prospects. DETAILED DESCRIPTION

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

[0016] Example 1

[0017] Synthesize quinazolinone with the following structural formula

[0018]

[0019] A mixture of 2-aminobenzamide (0.5 mmol, 1.0 equivalent), trimethyl orthoformate (0.8 mmol, 1.6 equivalent), Cp2TiCl2 (3.1 mg, 2.5 mol%) and ethanol (2 mL) was added to a 10 mL vial and reacted under magnetic stirring at room temperature for 2 hours. 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 in a yield of 96%. The spectral data are as follows: 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-aminobenzamide in Example 1 was replaced with an equal mole of 2-amino-5-methylbenzamide. 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-fluoroquinazolin-4(3H)-one with the following structural formula

[0026]

[0027] In this example, 2-amino-5-fluorobenzamide was used in place of 2-aminobenzamide in Example 1 at an equal molar ratio, 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 in place of 2-aminobenzamide in Example 1 at an equal molar ratio, 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-bromoquinazolin-4(3H)-one with the following structural formula

[0034]

[0035] In this example, 2-aminobenzamide in Example 1 was replaced with an equal mole of 2-amino-5-bromobenzamide. 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 in a yield of 74%. The spectral data were: 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 with the following structural formula

[0038]

[0039] In this example, 2-aminobenzamide in Example 1 was replaced with an equal mole of 2-amino-N-cyclopropylbenzamide. The other steps were the same as in Example 1 to obtain 3-cyclopropylquinazolin-4(3H)-one in a yield of 94%. The spectral data were as follows: 1 H NMR (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] Synthesis of 3-(prop-2-yn-1-yl)quinazolin-4(3H)-one with the following structural formula

[0042]

[0043] In this example, 2-aminobenzamide in Example 1 was replaced with an equal mole of 2-amino-N-(prop-2-yn-1-yl)benzamide. The other steps were the same as in Example 1 to obtain 3-(prop-2-yn-1-yl)quinazolin-4(3H)-one in 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. The other steps were the same as in Example 1 to obtain 2-methylquinazolin-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-ethylquinazolin-4(3H)-one with the following structural formula

[0050]

[0051] In this example, 2-ethylquinazolin-4(3H)-one was obtained by replacing the trimethyl orthoformate in Example 1 with an equal molar amount of triethyl orthopropionate. The other steps were the same as in Example 1. The yield was 95%, and 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] Synthesis of 2-methyl-3-(o-tolyl)quinazolin-4(3H)-one with the following structural formula

[0054]

[0055] In this example, 2-aminobenzamide in Example 1 was replaced with an equal mole of 2-amino-N-(o-tolyl)benzamide, and trimethyl orthoformate in Example 1 was replaced with an equal mole of triethyl orthoformate. 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 2-methyl-3-(o-tolyl)quinazolin-4(3H)-one in a yield of 55%. The spectral data were: 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 to an organic solvent, stirring and reacting at room temperature, and separating and purifying after completion of the reaction to obtain a quinazolinone compound of formula III; Where 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 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 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 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 according to claim 1 or 2, characterized in that: The molar ratio of the 2-aminobenzamide compound to the orthoester is 1:1.2-1.6.

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