CN105153048B - A kind of preparation method of 2,4 quinazoline diketone compound - Google Patents

Abstract

The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of 2,4-quinazolinedione compounds. The preparation method uses 2-aminobenzonitrile compounds and carbon dioxide as raw materials, preferably under the catalysis of amido divalent rare earth metal amides and DBU, at 50°C-150°C, normal pressure, in an aprotic polar solvent React 4-40h in middle, promptly can make 2,4-quinazolinedione compound with higher yield. The method not only has mild reaction conditions, less catalyst consumption, simple separation and purification, high yield, but also has a wide range of substrate applications.

Description

A kind of preparation method of 2,4-quinazoline diketone compound

technical field

The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of 2,4-quinazolinedione compounds.

Background technique

2,4-Quinazolinedione compounds are an important class of dominant structural skeletons with a wide range of biological activities, for example, they can be used as antibiotics, serum receptor antagonists, glutamate receptor antagonists, aldose reduction Enzyme inhibitors, calcium ion channel antagonists, acetylcholine receptor antagonists, etc.

At present, there are many methods for preparing 2,4-quinazolinedione compounds. Among them, an important one is prepared by using carbon dioxide and 2-aminobenzonitrile compounds as raw materials under the action of a catalyst. This reaction has attracted much attention due to its atom economy.

In 2002, Takumi Mizuno's research group disclosed a preparation method of 2,4-quinazolinedione compounds, that is, using 2-aminobenzonitrile compounds and carbon dioxide as raw materials, under the catalysis of 3 equivalents of DBU, to DMF is used as a solvent, and 2,4-quinazolinedione compounds can be prepared in a higher yield at 1 atmospheric pressure and 20°C for 24 hours; when the amount of DBU is 0.1 equivalent, it needs to Only at atmospheric pressure and 80°C can 2,4-quinazolinediones be produced (see Tetrahedron 2002, 58, 3155-3158). In 2007, the research group disclosed a method for preparing 2,4-quinazolinedione compounds, that is, using 2-aminobenzonitrile compounds and carbon dioxide as raw materials, under the catalysis of 0.2-1 equivalent DBU, The 2,4-quinazolinedione compounds can be prepared in a relatively high yield by reacting for 4 hours at 1 atmospheric pressure and 120-150°C (see Synthesis, 2007, 16, 2524-2428).

However, the above-mentioned preparation method has disadvantages such as large amount of catalyst used, limited types of catalyst, harsh reaction conditions, and narrow scope of substrate application.

Therefore, it is important to study the method for the preparation of 2,4-quinazolinediones compounds using 2-aminobenzonitrile compounds and carbon dioxide as raw materials with mild reaction conditions, low catalyst consumption and wide substrate application range. significance.

Contents of the invention

For this reason, what the present invention is to solve is that the existing method for preparing 2,4-quinazolinedione compounds with 2-aminobenzonitrile compounds and carbon dioxide as raw materials has harsh reaction conditions, a large amount of catalyst, and suitable substrates. Therefore, a kind of mild reaction conditions, less catalyst consumption and wide substrate application range are proposed to prepare 2,4-quinazolinedione with 2-aminobenzonitrile compounds and carbon dioxide as raw materials. method of compounds.

In order to solve the problems of the technologies described above, the present invention is achieved through the following technical solutions:

The present invention provides a kind of preparation method of 2,4-quinazoline diketone compound, and reaction equation is as follows,

The method comprises the following steps: using 2-aminobenzonitrile compounds and carbon dioxide as raw materials, reacting in an aprotic polar solvent under the catalysis of amido divalent rare earth metal amides and DBU;

Wherein, R is selected from (C ₁ -C ₁₀ )-alkyl, OR ₃ , CN, CF ₃ , NO ₂ , halogen, NR ₄ R ₅ , NHCOR ₆ , COOR ₇ ;

R ₃ is selected from H, (C ₁ -C ₁₀ )-alkyl, aryl;

R ₄ and R ₅ are independently selected from H, (C ₁ -C ₁₀ )-alkyl, aryl;

R ₆ and R ₇ are independently selected from (C ₁ -C ₁₀ )-alkyl, aryl;

x represents the number of substituents on the benzene ring, selected from 0, 1, 2, 3, 4;

The amido divalent rare earth metal amide has the chemical structural formula shown in formula (I):

Wherein, R ₁ and R ₂ are independently selected from hydrogen, methyl, isopropyl or tert-butyl;

m and n represent the number of substituents on the benzene ring, which are independently selected from 0, 1, 2, 3, 4 or 5;

Ln is Eu or Yb;

The aprotic polar solvent is at least one selected from amides, sulfoxides and ketones.

Preferably, in one embodiment of the present invention, the above-mentioned preparation method comprises the following steps:

Under the conditions of anhydrous, anaerobic and argon protection, with 100 molar parts of 2-aminobenzonitrile compound and excess carbon dioxide as raw materials, 1-15 molar parts of the amide group shown in the formula (I) are divalent Under the catalysis of rare earth metal amide and 3-10 mole parts of DBU, react in an aprotic polar solvent at 50°C-150°C and normal pressure for 4-40h.

Further preferably, in another embodiment of the present invention, the above-mentioned preparation method comprises the following steps:

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 mole parts of 2-aminobenzonitrile compound and excess carbon dioxide as raw materials, the amide group shown in 2-11 mole parts of formula (I) is divalent Under the catalysis of rare earth metal amide and 4-6 mole parts of DBU, react in an aprotic polar solvent at 70°C-130°C and normal pressure for 6-36h.

Further preferably, in another embodiment of the present invention, the above-mentioned preparation method comprises the following steps:

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 2.5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 100°C and normal pressure for 6-36h; or

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 80°C and normal pressure for 6-36h; or

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 100°C and normal pressure for 6-36h; or

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 120°C and normal pressure for 6-36h; or

Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 10 molar parts of formula (I) Under the catalysis of the aminate and 5 mole parts of DBU, react in an aprotic polar solvent at 100° C. under normal pressure for 6-36 hours.

Preferably, in one embodiment of the present invention, the above-mentioned preparation method,

R1 is isopropyl or methyl, m is ₂ , R2 is tert _- butyl or hydrogen, n is 1 or 5, Ln is Eu or Yb.

More preferably, in another embodiment of the present invention, the above-mentioned preparation method,

R ₁ is isopropyl, m is 2, R ₂ is tert-butyl, n is 1, Ln is Eu; or

R ₁ is isopropyl, m is 2, R ₂ is hydrogen, n is 5, Ln is Eu; or

R ₁ is isopropyl, m is 2, R ₂ is hydrogen, n is 5, Ln is Yb; or

R1 is methyl, m is ₂ , R2 is _hydrogen , n is 5, Ln is Yb.

Further preferably, in another embodiment of the present invention, the above-mentioned preparation method,

The amide group divalent rare earth metal amido compound shown in formula (I) is:

Preferably, in one embodiment of the present invention, the above-mentioned preparation method,

The aprotic polar solvent is at least one selected from N,N-dimethylformamide, dimethyl sulfoxide and acetone.

Further preferably, in another embodiment of the present invention, the above-mentioned preparation method comprises the following steps:

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 2.5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide at 100°C under normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 80°C and normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in N,N-dimethylformamide at 100°C and normal pressure for 6-36h; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 120°C under normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or

Under the condition of anhydrous, oxygen-free and adopting the protection of argon, take 100 molar parts of 2-aminobenzonitrile compounds and excessive carbon dioxide as raw materials, in 10 molar parts Under the catalysis of 5 mole parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C and normal pressure.

Preferably, in one embodiment of the present invention, the above-mentioned preparation method,

R is selected from (C ₁ -C ₄ )-alkyl, OR ₃ , F, Cl, Br, I, NR ₄ R ₅ , NHCOR ₆ , COOR ₇ ;

R ₃ is selected from (C ₁ -C ₄ )-alkyl;

R ₄ and R ₅ are independently selected from (C ₁ -C ₄ )-alkyl;

R ₆ and R ₇ are independently selected from (C ₁ -C ₄ )-alkyl groups.

Further preferably, in another embodiment of the present invention, the above-mentioned preparation method,

Described 2-aminobenzonitrile compound is selected from

Preferably, in one embodiment of the present invention, the above-mentioned preparation method further includes the step of quenching the reaction with an inorganic acid and the step of separating and purifying the 2,4-quinazolinedione compounds by using a separation and purification method .

Further preferably, in another embodiment of the present invention, in the above-mentioned preparation method, the acid is selected from at least one of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and the separation and purification method is selected from washing, filtration, extraction, and recrystallization. , distillation, column chromatography, thin layer chromatography, freeze-drying at least one.

The above technical solution of the present invention has the following advantages compared with the prior art:

The preparation method of 2,4-quinazolinedione compounds of the present invention uses 2-aminobenzonitrile compounds and carbon dioxide as raw materials, preferably under the catalysis of amido divalent rare earth metal amides and DBU, at 50°C- 150°C, normal pressure, react in an aprotic polar solvent for 4-40h, that is, 2,4-quinazolinedione compounds can be prepared in a relatively high yield. The method not only has mild reaction conditions (50 DEG C-150 DEG C, normal pressure, aprotic polar solvent), but also has a small amount of catalyst (the molar ratio of amido divalent rare earth metal amidide to 2-aminobenzonitrile compound is 2-11%, the molar ratio of DBU to 2-aminobenzonitrile compound is 4-6%), the separation and purification are simple and convenient, the yield is high (61-99%), and the substrate has a wide application range.

Description of drawings

In order to make the content of the present invention more easily understood, the present invention will be described in further detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

Fig. 1 is a single crystal structure diagram of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ in Example 1 of the present invention.

detailed description

1. Terminology description

DBU represents 1,8-diazabicyclo[5.4.0];

{L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ represents

{L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ represents

{L ² Yb[N(SiMe ₃ ) ₂ ]·THF} ₂ is expressed as

L ¹ H is expressed as

L ² H is expressed as

5mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ is expressed as: {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and the substrate 2-aminobenzonitrile compound The molar ratio is 5:100;

5mol% of DBU means: the molar ratio of DBU to the substrate 2-aminobenzonitrile compound is 5:100.

2. Reagent and instrument description

The reagents and solvents used in the following examples are commercially available, and the purity is chemically pure.

Rigaku Mercury four-circle diffractometer; Bruker AscendTM 400 NMR instrument.

3. Experimental operation instructions

Since amido rare earth metal amides are very sensitive to water vapor and air, all operations must be carried out under the protection of anhydrous, oxygen and inert gas using Schlenk technology. The high temperature is obtained by heating in an oil bath.

Comparative example 1 5mol% DBU catalyzes the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C under normal pressure to prepare 2,4-quinazolinedione compounds

Under the protection of anhydrous, oxygen and argon, 11.2 μL (7.5×10 ^-5 mol) DBU was added to the reaction flask, and under the protection of a carbon dioxide air bag, 2 mL of dimethyl sulfoxide was added, and then 0.1771 g (1.5 ×10 ^-3 mol) of 2-aminobenzonitrile, stirred and reacted in a constant temperature bath at 100°C. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 45%.

Comparative Example 2 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ catalyzes the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C under normal pressure to prepare 2,4-quinazolinedione compounds

Under the protection of anhydrous, oxygen and argon, add 0.0999 g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ into the reaction flask, and under the protection of carbon dioxide gas bag , add 2 mL of dimethyl sulfoxide, and then add 0.1771 g (1.5×10 ^-3 mol) of 2-aminobenzonitrile, and stir the reaction in a constant temperature bath at 100°C. After 24 hours, add 5 mL of 2 mol/L salt, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 12%.

Example 1 Preparation of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂

In an anhydrous, oxygen-free, argon-protected reaction flask, add Eu[N(SiMe ₃ ) ₂ ] ₂ , and dissolve it in tetrahydrofuran; in another anhydrous, oxygen-free, argon-protected reaction flask, weigh Ligand L ¹ H in an equimolar ratio to Eu[N(SiMe ₃ ) ₂ ] ₂ , add tetrahydrofuran, slowly add the ligand solution to the clear solution of Eu[N(SiMe ₃ ) ₂ ] ₂ ether solvent, and react 4h, and finally get the supernatant.

After the reaction, drain the solvent, wash with n-hexane, then add tetrahydrofuran until completely dissolved, centrifuge, take the supernatant liquid into a crystallization bottle, drain the solvent, dissolve with an appropriate amount of tetrahydrofuran-n-hexane, and stand at room temperature until crystals precipitate , that is, amido divalent rare earth amides {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ , with a yield of 75%.

The detailed crystallographic parameters of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ are shown in Table 1, the main bond length and bond angle data are shown in Table 2, and the single crystal structure is shown in Figure 1.

Table 1 Crystal structure parameters of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂

Table 2 Main bond lengths and bond angles of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂

Example 2 Preparation of {L ² Yb[N(SiMe ₃ ) ₂ ]·THF} ₂

In an anhydrous, oxygen-free, argon-protected reaction flask, add Yb[N(SiMe ₃ ) ₂ ] ₂ , and dissolve it in THF; in another anhydrous, oxygen-free, argon-protected reaction flask, weigh and Yb[N(SiMe ₃ ) ₂ ] ₂ Ligand L ² H in equimolar ratio, add tetrahydrofuran, slowly add the ligand solution into the clear liquid of Yb[N(SiMe ₃ ) ₂ ] ₂ ether solvent, react for 4h , and finally a supernatant was obtained.

After the reaction, drain the solvent, wash with n-hexane, then add tetrahydrofuran until completely dissolved, centrifuge, take the supernatant liquid into a crystallization bottle, drain the solvent, dissolve with an appropriate amount of tetrahydrofuran-n-hexane, and stand at room temperature until crystals precipitate , that is, amido divalent rare earth amides {L ² Yb[N(SiMe ₃ ) ₂ ]·THF} ₂ , with a yield of 82%.

Implementation·3 Preparation of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂

Add Eu[N(SiMe ₃ ) ₂ ] ₂ to an anhydrous, oxygen-free, argon-protected reaction flask, and dissolve it in tetrahydrofuran; weigh and Eu[N(SiMe ₃ ) ₂ ] ₂ ligand L ² H in equimolar ratio, add tetrahydrofuran, slowly add the ligand solution into the clear solution of Eu[N(SiMe ₃ ) ₂ ] ₂ ether solvent, react for 4h Finally a clear solution was obtained.

After the reaction, drain the solvent, wash with n-hexane, then add tetrahydrofuran until completely dissolved, centrifuge, take the supernatant liquid into a crystallization bottle, drain the solvent, dissolve with an appropriate amount of tetrahydrofuran-n-hexane, and stand at room temperature until crystals precipitate , that is, amido divalent rare earth amides {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ , with a yield of 78%.

Example 4 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C to prepare 2,4-quinazole Phenyldione Compounds

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 24 hours, 5 mL of 2 mol/L hydrochloric acid was added to quench the reaction, and then suction filtered. The solid was washed successively with 3×5 mL of hydrochloric acid, toluene and ether, the residual solvent was removed, and the solid was dried to obtain the product with a yield of 91%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.29(s, 1H, NH), 11.14(s, 1H, NH), 7.89-7.91(d, 1H, ArH), 7.62-7.66(t, 1H, ArH) , 7.17-7.20 (t, 2H, ArH).

Example 5 5mol% of {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% of DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C to prepare 2,4-quinazole Phenyldione Compounds

Under the protection of anhydrous, anaerobic and argon, add 0.1083g (7.5×10 ^-5 mol) {L ¹ Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 83%.

Example 6 5mol% {L ² Yb[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C to prepare 2,4-quinazole Phenyldione Compounds

Under the protection of anhydrous, oxygen and argon, add 0.1030g (7.5×10 ^-5 mol) {L ² Yb[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, and then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 24 hours, 5 mL of 2 mol/L hydrochloric acid was added to quench the reaction, and then suction filtered. The solid was washed successively with 3×5 mL of hydrochloric acid, toluene and ether, the residual solvent was removed, and the solid was dried to obtain the product with a yield of 61%.

Example 7 2.5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C to prepare 2,4-quinone oxazolinediones

Under anhydrous, oxygen-free and argon protection, add 0.0499g (3.75×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, and then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 78%.

Example 8 10mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% of DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 100°C to prepare 2,4-quinazole Phenyldione Compounds

Under anhydrous, oxygen-free and argon protection, add 0.1998g (1.5×10 ^-4 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, and then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 73%.

Example 9 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 80°C to prepare 2,4-quinazole Phenyldione Compounds

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 80°C reaction. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 63%.

Example 10 5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU catalyzed the reaction of 2-aminobenzonitrile and carbon dioxide at 120°C under normal pressure to prepare 2,4-quinazole Phenyldione Compounds

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 120°C reaction. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 68%.

Example 11 5mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% of DBU catalyzed the reaction of anthranilonitrile and carbon dioxide at 100°C under normal pressure to prepare 2,4-quinazoline Diketones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.1771g (1.5×10 ^-3 mol) 2-aminobenzonitrile, stir in a constant temperature bath at 100°C reaction. After 36 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 92%.

Example 12 5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU catalyzed 2-amino-4,5-dimethoxybenzonitrile and Preparation of 2,4-quinazolinediones by Reaction of Carbon Dioxide

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of a carbon dioxide bag, add 2mL dimethyl sulfoxide, then add 0.3333g (1.5×10 ^-3 mol) 2-amino-4,5-dimethoxybenzonitrile , Stir the reaction in a constant temperature bath at 100 °C. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 99%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.13(s, 1H, NH), 10.95(s, 1H, NH), 7.29(s, 1H, ArH), 6.71(s, 1H, ArH), 3.81-3.86 (d, 6H, _CH3 ).

Example 13 5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU catalyzed the reaction of 2-amino-5-methylbenzonitrile and carbon dioxide at 100°C under normal pressure to prepare 2 ,4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.2643g (1.5×10 ^-3 mol) 2-amino-5-methylbenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 97%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.21 (s, 1H, NH), 11.04 (s, 1H, NH), 7.69 (s, 1H, ArH), 7.45-7.47 (d, 1H, ArH), 7.06 -7.08 (d, 1H, ArH), 2.32 (s, 3H, _CH3 ).

Example 14 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-amino-5-nitrobenzonitrile and carbon dioxide at 100°C under normal pressure to prepare 2 ,4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.3107g (1.5×10 ^-3 mol) 2-amino-5-nitrobenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, 5 mL of 2 mol/L hydrochloric acid was added to quench the reaction, then suction filtered, the solid was washed successively with 3×5 mL of hydrochloric acid, toluene and ether, the residual solvent was removed, and the solid was dried to obtain the product with a yield of 81%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.73 (s, 1H, NH), 11.78 (s, 1H, NH), 8.59 (d, 1H, ArH), 8.44-8.47 (m, 1H, ArH), 7.32 -7.34 (d, 1H, ArH).

Example 15 5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU catalyzed the reaction of 2-amino-5-trifluoromethylbenzonitrile and carbon dioxide at 100°C under normal pressure Preparation of 2,4-quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.3452g (1.5×10 ^-3 mol) 2-amino-5-trifluoromethylbenzonitrile, in The reaction was stirred in a constant temperature bath at 100°C. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 80%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.55-11.60 (d, 2H, NH), 8.13 (d, 1H, ArH), 7.98-8.01 (m, 1H, ArH), 7.35-7.37 (d, 1H, ArH).

Example 16 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-amino-5-fluorobenzonitrile and carbon dioxide at 100°C to prepare 2, 4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.2702g (1.5×10 ^-3 mol) 2-amino-5-fluorobenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 97%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.44(s, 1H, NH), 11.23(s, 1H, NH), 7.55-7.63(m, 2H, ArH), 7.21-7.25(m, 1H, ArH) .

Example 17 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-amino-5-chlorobenzonitrile and carbon dioxide at 100°C to prepare 2, 4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.2949g (1.5×10 ^-3 mol) 2-amino-5-chlorobenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, 5 mL of 2 mol/L hydrochloric acid was added to quench the reaction, and then suction filtered. The solid was washed successively with 3×5 mL of hydrochloric acid, toluene and ether, the residual solvent was removed, and the solid was dried to obtain the product with a yield of 91%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.47(s, 1H, NH), 11.31(s, 1HNH), 7.84(d, 1H, ArH), 7.70-7.73(m, 1H, ArH), 7.70-7.72 (d, 1H, ArH).

Example 18 5mol% {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5mol% DBU catalyzed the reaction of 2-amino-5-bromobenzonitrile and carbon dioxide at 100°C under normal pressure to prepare 2, 4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.3616g (1.5×10 ^-3 mol) 2-amino-5-bromobenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, 5 mL of 2 mol/L hydrochloric acid was added to quench the reaction, and then suction filtered. The solid was washed with 3×5 mL of hydrochloric acid, toluene and ether successively, the residual solvent was removed, and the solid was dried to obtain the product with a yield of 64%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.44 (s, 1H, NH), 11.28 (s, 1H, NH), 7.94 (d, 1H, ArH), 7.78-7.81 (m, 1H, ArH), 7.11 -7.13 (d, 1H, ArH).

Example 19 5 mol% of {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ and 5 mol% of DBU were catalyzed at 100°C under normal pressure to react 2-amino-4-chlorobenzonitrile with carbon dioxide to prepare 2, 4-Quinazolinediones

Under the protection of anhydrous, anaerobic and argon, add 0.0999g (7.5×10 ^-5 mol) {L ² Eu[N(SiMe ₃ ) ₂ ]·THF} ₂ to the reaction flask, then add 11.2μL (7.5 ×10 ^-5 mol) DBU, under the protection of carbon dioxide gas bag, add 2mL dimethyl sulfoxide, then add 0.2949g (1.5×10 ^-3 mol) 2-amino-4-chlorobenzonitrile, at 100℃ The reaction was stirred in a constant temperature bath. After 24 hours, add 5 mL of 2 mol/L hydrochloric acid to quench the reaction, then filter with suction, wash the solid with 3×5 mL of hydrochloric acid, toluene and ether successively, remove the residual solvent, and dry the solid to obtain the product with a yield of 62%. ¹ HNMR (400MHz, DMSO-d ₆ ): 11.39 (s, 1H, NH), 11.23 (s, 1H, NH); 7.87-7.89 (d, 1H, ArH); 7.17-7.22 (m, 2H, ArH) .

The reaction substrate, reaction conditions and productive rate of above each embodiment are as shown in table 3.

Reaction substrate, reaction conditions and productive rate of each embodiment of table 3

As can be seen from Table 3, 2-aminobenzonitrile compounds and carbon dioxide are used as raw materials, preferably under the catalysis of amido divalent rare earth metal amides and DBU, at 50°C-150°C, normal pressure, under aprotic polarity After reacting in a solvent for 4-40 hours, 2,4-quinazolinedione compounds can be prepared in a relatively high yield. The method not only has mild reaction conditions (50 DEG C-150 DEG C, normal pressure, aprotic polar solvent), but also has a small amount of catalyst (the molar ratio of amido divalent rare earth metal amidide to 2-aminobenzonitrile compound is 2-11%, the molar ratio of DBU to 2-aminobenzonitrile compound is 4-6%), the separation and purification are simple and convenient, the yield is high (61-99%), and the substrate has a wide application range.

Apparently, the above-mentioned embodiments are only examples for clear description, rather than limiting the implementation. For those of ordinary skill in the art, other changes or changes in different forms can be made on the basis of the above description. It is not necessary and impossible to exhaustively list all the implementation manners here. And the obvious changes or changes derived therefrom are still within the scope of protection of the present invention.

Claims (10)

1. a kind of preparation method of 2,4-quinazoline diketone compound, it is characterized in that, reaction equation is as follows, The method comprises the following steps: under the conditions of anhydrous, oxygen-free and argon protection, using 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, in 1-15 molar parts of the formula (I) Under the catalysis of amide divalent rare earth metal amides and 3-10 mole parts of DBU, react in an aprotic polar solvent at 50°C-150°C and normal pressure for 4-40h; Wherein, R is selected from (C ₁ -C ₁₀ )-alkyl, OR ₃ , CF ₃ , NO ₂ , halogen, NR ₄ R ₅ ; R ₃ is selected from H, (C ₁ -C ₁₀ )-alkyl; R ₄ and R ₅ are independently selected from H, (C ₁ -C ₁₀ )-alkyl; x represents the number of substituents on the benzene ring, selected from 0, 1, 2, 3, 4; The amido divalent rare earth metal amide has the chemical structural formula shown in formula (I): Wherein, R ₁ and R ₂ are independently selected from hydrogen, methyl, isopropyl or tert-butyl; m and n represent the number of substituents on the benzene ring, which are independently selected from 0, 1, 2, 3, 4 or 5; Ln is Eu or Yb; The aprotic polar solvent is at least one selected from amides, sulfoxides and ketones. 2. preparation method according to claim 1, is characterized in that, comprises the following steps: Under the conditions of anhydrous, oxygen-free and argon protection, with 100 mole parts of 2-aminobenzonitrile compound and excess carbon dioxide as raw materials, the amide group shown in 2-11 mole parts of formula (I) is divalent Under the catalysis of rare earth metal amide and 4-6 mole parts of DBU, react in an aprotic polar solvent at 70°C-130°C and normal pressure for 6-36h. 3. the preparation method according to claim 1 or 2, is characterized in that, comprises the following steps: Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 2.5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 100°C and normal pressure for 6-36h; or Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 80°C and normal pressure for 6-36h; or Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 100°C and normal pressure for 6-36h; or Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 5 molar parts of formula (I) Under the catalysis of amine compound and 5 molar parts of DBU, react in an aprotic polar solvent at 120°C and normal pressure for 6-36h; or Under the conditions of anhydrous, oxygen-free and argon protection, with 100 molar parts of 2-aminobenzonitrile compounds and excess carbon dioxide as raw materials, the amido divalent rare earth metal shown in 10 molar parts of formula (I) Under the catalysis of the aminate and 5 mole parts of DBU, react in an aprotic polar solvent at 100° C. under normal pressure for 6-36 hours. 4. the preparation method according to claim 1 or 2, is characterized in that, R1 is isopropyl or methyl, m is ₂ , R2 is tert _- butyl or hydrogen, n is 1 or 5, Ln is Eu or Yb. 5. the preparation method according to claim 1 or 2, is characterized in that, R ₁ is isopropyl, m is 2, R ₂ is tert-butyl, n is 1, Ln is Eu; or R ₁ is isopropyl, m is 2, R ₂ is hydrogen, n is 5, Ln is Eu; or R ₁ is isopropyl, m is 2, R ₂ is hydrogen, n is 5, Ln is Yb; or R1 is methyl, m is ₂ , R2 is _hydrogen , n is 5, Ln is Yb. 6. the preparation method according to claim 1 or 2, is characterized in that, The amide group divalent rare earth metal amido compound shown in formula (I) is: 7. The preparation method according to claim 1 or 2, characterized in that, The aprotic polar solvent is at least one selected from N,N-dimethylformamide, dimethyl sulfoxide and acetone. 8. The preparation method according to claim 1 or 2, characterized in that, comprising the following steps: Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 2.5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide at 100°C under normal pressure; or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 80°C and normal pressure; or or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in N,N-dimethylformamide at 100°C and normal pressure for 6-36h; or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 120°C under normal pressure; or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or Under the condition of anhydrous, oxygen-free and adopting argon protection, take 100 mole parts of 2-aminobenzonitrile compound and excessive carbon dioxide as raw material, in 5 mole parts Under the catalysis of 5 molar parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C under normal pressure; or Under the condition of anhydrous, oxygen-free and adopting the protection of argon, take 100 molar parts of 2-aminobenzonitrile compounds and excessive carbon dioxide as raw materials, in 10 molar parts Under the catalysis of 5 mole parts of DBU, react in dimethyl sulfoxide for 6-36h at 100°C and normal pressure. 9. The preparation method according to claim 1 or 2, characterized in that, R is selected from (C ₁ -C ₄ )-alkyl, OR ₃ , F, Cl, Br, I, NR ₄ R ₅ ; R ₃ is selected from (C ₁ -C ₄ )-alkyl; R ₄ and R ₅ are independently selected from (C ₁ -C ₄ )-alkyl groups. 10. The preparation method according to claim 1 or 2, characterized in that, Described 2-aminobenzonitrile compound is selected from