JP2003160569A - Method for producing quinazoline derivative using base catalyst - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial method for producing a quinazoline derivative from aminobenzonitriles and carbon dioxide gas. <P>SOLUTION: The method for producing a quinazoline derivative is characterized by that aminobenzonitriles and carbon dioxide gas are reacted in a medium in the presence of bicyclic amidine of 0.01-1 equivalent with respect to aminobenzonitriles. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a quinazoline derivative from aminobenzonitriles and carbon dioxide gas.

[0002]

As a method for synthesizing a 2,4-dihydroxyquinazoline derivative, for example, the following five methods have been proposed. 1) The anthranil derivative is heated with urea to ring-close 2,4-
Method for synthesizing dihydroxyquinazoline derivative (Bull.
Soc. Chim. Fr., 1331 (1975), Pharmazie, 37 , 115 (19
82)). 2) A method of reacting anthranilamide with phosgene or the like to insert a carbonyl group to obtain a 2,4-dihydroxyquinazoline derivative (JP-A-48-40789, Org. Prep. And Proce
d. Int., 10 , 13 (1978)). 3) A method of reacting anthranilic acid with an isocyanate and ring-closing the resulting phenylurea derivative to obtain a 2,4-dihydroxyquinazoline derivative (JP-B-42-11836, Eur.
J. Med. Chem., 9 , 263 (1974), Tetrahedron, 50 , 654
9 (1994)). 4) A method of reacting anthranilamide with carbon monoxide and sulfur and inserting a carbonyl group to obtain a 2,4-dihydroxyquinazoline derivative (Heteroatom Chem., 2 , 473 (199)
1)). 5) A method for obtaining a 2,4-dihydroxyquinazoline derivative by reacting aminobenzonitrile with carbon dioxide in the presence of a large excess of DBU (Tetrahedron Lett., 41 , 1051 (200
0), Heteroatom Chem., 11 , 428 (2000)).

However, in the above method 1),
Generally, a high temperature (150 ° C or higher) requires a pressure heating reaction condition in the above method 4), and a toxic reagent (phosgene, isocyanate, carbon monoxide) in the above methods 2) to 4). Is mandatory. Not only that, but above 1) ~
The method 4) has many industrial problems in terms of yield and operation. Further, in the above method 5), although the reaction proceeds under mild reaction conditions, a large excess of expensive DBU is required, so it cannot be said to be an industrially excellent method.

Quinazoline derivatives such as 2,4-dihydroxyquinazoline are useful as raw materials for pharmaceuticals (especially drugs for improving various symptoms of diabetes and erectile dysfunction), agricultural chemicals, and other raw materials for chemicals. It has been earnestly desired to develop a method for easily producing lactic acid on an industrial scale.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially advantageous method for producing a quinazoline derivative from aminobenzonitriles and carbon dioxide.

[0006]

The present inventor has conducted extensive studies to solve the problems of the prior art, and as a result,
It was found that the above object can be achieved by reacting 0.01 to 1 equivalent of aminobenzonitrile with carbon dioxide gas in the presence of a specific base, and completed the present invention.

That is, the present invention provides the invention according to the following items. Item 1. A process for producing a quinazoline derivative, which comprises reacting aminobenzonitriles with carbon dioxide in a solvent in the presence of 0.01 to 1 equivalent of a bicyclic amidine with respect to aminobenzonitriles. Item 2 Aminobenzonitriles are represented by the general formula (1)

[0008]

[Chemical 3]

(In the formula, X is a hydrogen atom, a halogen atom,
An alkyl group, an alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group or a nitro group, which may have a substituent, is shown. ) Are aminobenzonitriles represented by the general formula (2)

[0010]

[Chemical 4]

The method according to item 1, which is a quinazoline derivative represented by the formula (wherein X is the same as above). Item 3 Reaction of aminobenzonitriles with carbon dioxide gas
60 to 80 at 10 atm (0.5 to 1.0 MPa)
Item 3. The method according to Item 1 or 2, wherein the reaction is performed at ° C. Item 4 The solvent is at least one selected from the group consisting of amide solvents, sulfoxide solvents, ether solvents and halogen solvents, and the bicyclic amidine is DBU (1,8-
Diazabicyclo [5.4.0] undec-7-ene) and DBN (1,5-Diazabi
Item 4. The method according to any one of Items 1 to 3, which is at least one selected from the group consisting of cyclo [4.3.0] non-5-ene).

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

The method for producing a quinazoline derivative in the present invention is characterized in that aminobenzonitriles and carbon dioxide gas are reacted in a solvent in the presence of 0.01 to 1 equivalent of a bicyclic amidine with respect to aminobenzonitriles. And

As the aminobenzonitriles, the compound represented by the general formula (1) is preferably used, and it is preferable to obtain the corresponding compound represented by the general formula (2).

In the general formulas (1) and (2), X is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group or a nitro group. Shows those which may have a substituent.

Examples of the halogen atom include F, Cl, B
r, I, etc.

Examples of the alkyl group include a methyl group,
Examples thereof include an alkyl group having 1 to 10 carbon atoms such as ethyl group, propyl group, isopropyl group and butyl group.

Examples of the alkoxy group include alkoxy groups having 1 to 10 carbon atoms such as methoxy group, ethoxy group, propoxy group, isopropoxy group and butoxy group.

The aryl group includes, for example, a phenyl group, a tolyl group, a naphthyl group, a biphenyl group and the like having 6 carbon atoms.
~ 12 aryl groups.

Examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms such as ethylene group.

Examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 1 to 10 carbon atoms in the alkoxy group such as a methyloxycarbonyl group and an ethyloxycarbonyl group.

As the substituent, an alkyl group (for example, an alkyl group having 1 to 10 carbon atoms as exemplified above) and an aryl group (for example, 6 to 12 carbon atoms as exemplified above)
And an alkenyl group (for example, an alkenyl group having 2 to 10 carbon atoms as exemplified above) and the like are preferable.

Examples of the group having a substituent include an aminocarbonyl group substituted with an alkyl group or an aryl group, a carbonylamino group substituted with an alkyl group or an aryl group, and the like. Specifically, an aminocarbonyl group which is 1 or 2 substituted with an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 12 carbon atoms such as a methylaminocarbonyl group, an ethylaminocarbonyl group and a phenylaminocarbonyl group; A methylcarbonylamino group,
An alkyl group having 1 to 10 carbon atoms such as an ethylcarbonylamino group or a phenylcarbonylamino group or a carbon number of 6 to 1
Examples thereof include a carbonylamino group which is 1 or 2 substituted with 2 aryl groups.

In addition to the above groups, examples of the group having a substituent include an alkyl group substituted with an aryl group and an alkenyl group substituted with an aryl group.
Specific examples thereof include a benzyl group; a styryl group and a cinnamyl group.

In the present invention, x is a hydrogen atom,
A halogen atom, an alkoxy group, a nitro group and the like are preferable.

As the carbon dioxide gas, gas in a commercially available cylinder or dry ice can be used. It is generally preferable to use carbon dioxide having a purity of 90% or more, preferably 99% or more.

The reaction conditions can be appropriately changed depending on the type of aminobenzonitriles used, etc., but the reaction pressure is usually about 1 to 50 atm (0.1 to 5.1 MPa), preferably
It should be 5-10 atm (0.5-1.0 MPa). The reaction temperature is usually about 0 to 200 ° C, preferably 60 to 80 ° C.

It is preferable to carry out the reaction under pressure and heating, because the reaction easily proceeds in a short time.

As the reaction solvent, it is preferable to use a polar solvent such as an amide-based solvent, a sulfoxide-based solvent, an ether-based solvent, or a known solvent such as a halogen-based solvent. These can be used alone or in combination of two or more.

Examples of the amide solvent include N, N-dimethylformamide, N, N-dimethylacetamide and the like.
As the sulfoxide-based solvent, dimethyl sulfoxide,
Examples thereof include sulfolane. As an ether solvent,
Tetrahydrofuran, dioxane, dimethoxyethane and the like can be mentioned. Examples of the halogen-based solvent include methylene chloride and chloroform.

Examples of the bicyclic amidine include DBU (1,
8-Diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-Diazabi
cyclo [4.3.0] non-5-ene), (1,5-Diazabicyclo [4.4.0] de
c-5-ene) can be used, especially DBU (1,8-Diazab
icyclo [5.4.0] undec-7-ene) or DBN (1,5-Diazabicyclo
[4.3.0] non-5-ene) is preferred.

The amount of the bicyclic amidine used can be appropriately set according to the type of aminobenzonitriles used, etc., and is usually 0.1% of the aminobenzonitriles of the general formula (1).
The amount may be about 01 to 1 equivalent, preferably about 0.05 to 0.1 equivalent, and more preferably about 0.05 equivalent.

Since the bicyclic amidine is an expensive reagent,
The method of the present invention, which uses only 1 equivalent or less with respect to the bicyclic amidine, is suitable as an industrial production method. It is preferable that the amount of the bicyclic amidine used is small because it is difficult to damage the reaction device, the amount of the bicyclic amidine mixed in the target compound is small, and the purification is easy.

The reaction time can be appropriately set depending on the reaction pressure, reaction temperature, etc., and is usually about 6 to 48 hours, preferably about 20 to 24 hours.

In general, a decrease in carbon dioxide gas pressure in the reaction vessel is recognized by the above reaction, and the degree of progress of the reaction can be inferred from the decrease in pressure. In addition, by performing TLC analysis on a sampled portion, it is possible to confirm the disappearance of the raw materials and to ask the extent of the reaction.

After completion of the reaction, the reaction solution is acidified with an acidic aqueous solution such as an aqueous hydrochloric acid solution, and then washed with toluene, diethyl ether, methyl tert-butyl ether, ethyl acetate or the like according to a known washing method to obtain the compound represented by the general formula (2). The quinazoline derivative represented by can be obtained.

The compounds of the general formula (2) thus obtained are quinazoline derivatives such as the above 2,4-dihydroxyquinazoline, which are medicinal products (especially drugs for improving various symptoms of diabetes and erectile dysfunction), pesticides, It is also useful as a raw material for other chemicals, and by subjecting it to substitution reactions, elimination reactions, alkylation reactions, etc., various target products can be designed and
It can be manufactured.

[0038]

According to the production method of the present invention, 2,4-dihydroxyquinazolines can be produced easily, efficiently, economically and industrially by utilizing carbon dioxide gas. That is, 1) the reaction can be carried out using a catalytic amount (small amount) of the bicyclic amidine, 2) relatively mild reaction conditions that can be industrially easily performed can be adopted, and a highly toxic reagent is required. Therefore, it can greatly contribute to industrial scale production.

[0039]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 A stirrer was put into a 100 ml three-necked flask, and the inside of the flask was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 1.50 ml (1.0
(Equivalent weight) DBU, 20 ml of N, N-dimethylformamide (DMF) was added using a syringe, and the inside of the flask was replaced with carbon dioxide, and the reaction solution was vigorously stirred at 1 atm 20 ° C. for 24 hours for reaction. . The obtained solution was poured into 200 ml of a 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. 100m
By washing with 1 toluene and 100 ml methyl tert-butyl ether, 1.56 g (96% yield) of 2,4-dihydroxyquinazoline was obtained. Melting point 300 ° C or higher (350 ° C or higher (Beilstein, 24 , 373)) IR spectrum (KBr) 3255, 3055, 1705 cm ^{-1 1} H-NMR spectrum (300 MHz, d ₆ -DMSO) δ7.13-7.18
(m, 2H), 7.61 (t, J = 8Hz, 1H), 7.86 (d, J = 8Hz, 1H), 1
1.11 (s, 1H), 11.25 (s, 1H) ¹³ C-NHR spectrum (75 MHz, d ₆ -DMSO) δ114.3, 115.
3, 122.3, 126.9, 134.9,140.8, 150.3, 162.8 MS spectrum (m / z,%) 162 (M ⁺ , 100), 119 (48), 92
(17) Exact MS spectrum theoretical value 162.0429, measured value 162.04
08 Example 2 A stirrer was put into a 100 ml three-necked flask, and the inside of the flask was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.75 ml (0.5
(Equivalent weight) DBU and 20 ml of DMF were added using a syringe, the inside of the flask was replaced with carbon dioxide, and the reaction solution was vigorously stirred and reacted at 1 atm 20 ° C. for 48 hours. 20 solution obtained
It was poured into 0 ml of a 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 100 ml methyl te
By washing with rt-butyl ether, 1.25 g (yield 77%) of 2,4-dihydroxyquinazoline was obtained.

Example 3 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.
Add 15 ml (0.1 equivalent) of DBU and 20 ml of DMF using a syringe, and autoclave with a carbon dioxide cylinder at 20 ° C, 10 ° C.
The atmosphere was replaced with atmospheric pressure (1.0 MPa) three times, the pressure was increased to 10 atm, and the reaction was carried out by stirring at 80 ° C. for 24 hours. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. 200m of the obtained reaction solution
It was poured into 1N aqueous hydrochloric acid solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 100 ml methyl tert
-1.52 g (yield by washing with butyl ether
94%) of 2,4-dihydroxyquinazoline was obtained.

Example 4 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.
Add 075 ml (0.05 eq) DBU and 20 ml DMF using a syringe, and autoclave with a carbon dioxide cylinder at 20 ° C.
The atmosphere was replaced with 10 atm (1.0 MPa) three times, then the pressure was increased to 10 atm, and the mixture was stirred at 80 ° C. for 24 hours for reaction. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. 200m of the obtained reaction solution
It was poured into 1N aqueous hydrochloric acid solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 100 ml methyl tert
-By washing with butyl ether, 1.48 g (yield
91%) of 2,4-dihydroxyquinazoline was obtained.

Example 5 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.
062 ml (0.05 equivalent) of DBN and 20 ml of DMF were added using a syringe, and the autoclave was heated with a carbon dioxide cylinder at 20 ° C.
The atmosphere was replaced with 10 atm (1.0 MPa) three times, then the pressure was increased to 10 atm, and the mixture was stirred at 80 ° C. for 24 hours for reaction. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. 200m of the obtained reaction solution
It was poured into 1N aqueous hydrochloric acid solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 100 ml methyl tert
-By washing with butyl ether, 1.23 g (yield
76%) of 2,4-dihydroxyquinazoline was obtained.

Example 6 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.
075ml (0.05eq) DBU, 20ml dimethylsulfoxide
(DMSO) was added using a syringe, and the autoclave was replaced with a carbon dioxide cylinder at 20 ° C and 10 atm (1.0 MPa) three times, then pressurized to 10 atm and stirred at 80 ° C for 24 hours to react. It was After the reaction, cool the autoclave to room temperature,
After purging with carbon dioxide, the autoclave was opened.
The obtained reaction solution was poured into 200 ml of 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. By washing with 100 ml of toluene and 100 ml of methyl tert-butyl ether, 1.50 g (yield 93%) of 2,4-dihydroxyquinazoline was obtained.

Example 7 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.18 g of 2-aminobenzonitrile and 0.
075m (0.05eq) DBU, 20ml tetrahydrofuran (TH
(F) was added using a syringe, and the autoclave was replaced with a carbon dioxide cylinder at 20 ° C. and 10 atm (1.0 MPa) three times, then pressurized to 10 atm, and stirred at 80 ° C. for 24 hours to react. . After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. The obtained reaction solution was poured into 200 ml of 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 1
Washing with 00 ml of methyl tert-butyl ether gave 1.16 g (71% yield) of 2,4-dihydroxyquinazoline.

Example 8 A stirrer was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. While maintaining the argon gas atmosphere, 1.53 g of 2-amino-5-chlorobenzonitrile, 0.075 ml (0.05 equivalent) of DBU, and 20 ml of DMF were added using a syringe, and the autoclave was heated with a carbon dioxide cylinder at 20 ° C. , 3 atmospheres at 10 bar (1.0 MPa), then 10
The pressure was increased to atmospheric pressure, and the mixture was reacted at 80 ° C. for 24 hours with stirring. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. The obtained reaction solution was poured into 200 ml of 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. By washing with 100 ml toluene and 100 ml methyl tert-butyl ether,
1.90 g (97% yield) of 6-chloro-2,4-dihydroxyquinazoline was obtained. Melting point 300 ° C or higher IR spectrum (KBr) 3200, 3060, 1745, 1715 cm ^{-1 1} H-NMR spectrum (300 MHz, d ₆ -DMSO) δ 7.16 (d, J = 9H
z, 1H), 7.64 (d, J = 9Hz, 1H), 7.78 (s, 1H), 11.24
(s, 1H), 11.41 (s, 1H) ¹³ C-NHR spectrum (75 MHz, d ₆ -DMSO) δ 115.7, 117.
5, 125.9, 126.2, 134.7, 139.7, 150.0, 161.8 MS spectrum (m / z,%) 196 (M ⁺ , 100), 153 (73), 125
(26) Exact MS spectrum theoretical value 196.040, measured value 196.003
7 Example 9 A stir bar was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. While maintaining the argon gas atmosphere, 1.53 g of 2-amino-4-chlorobenzonitrile, 0.075 ml (0.05 equivalent) of DBU, and 20 ml of DMF were added using a syringe, and the autoclave was heated with a carbon dioxide cylinder at 20 ° C. , 3 atmospheres at 10 bar (1.0 MPa), then 10
The pressure was increased to atmospheric pressure, and the mixture was reacted at 80 ° C. for 24 hours with stirring. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. The obtained reaction solution is poured into 200 ml of a 1N hydrochloric acid aqueous solution, and the precipitated solid is collected on a glass filter. By washing with 100 ml toluene and 100 ml methyl tert-butyl ether,
1.77 g (yield 90%) of 7-chloro-2,4-dihydroxyquinazoline was obtained. Melting point 300 ° C or higher IR spectrum (KBr) 3305, 3055, 1745, 1685 cm ^{-1 1} H-NMR spectrum (300 MHz, d ₆ -DMSO) δ 7.17-7.19 (m,
2H), 7.85 (d, J = 9Hz, 1H), 11.24 (s, 1H), 11.36 (s,
1H) ¹³ C-NHR spectrum (75 MHz, d ₆ -DMSO) δ 113.3, 114.
7, 122.4, 129.0, 139.3, 141.9, 150.1, 162.0 MS spectrum (m / z,%) 196 (M ⁺ , 100), 153 (91), 126
(49) Exact MS spectrum theoretical 196.0040, measured 196.00
36 Example 10 A stir bar was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.78 g of 2-amino-4,5-dimethoxybenzonitrile, 0.075 ml (0.05 equivalent) of DBU, and 20 ml of DMF.
Was added using a syringe, and the autoclave was replaced with a carbon dioxide cylinder at 20 ° C. and 10 atm (1.0 MPa) three times, then pressurized to 10 atm, and stirred at 80 ° C. for 24 hours for reaction. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. The obtained reaction solution was poured into 200 ml of 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. 100 ml toluene and 1
By washing with 00 ml of methyl tert-butyl ether, 2.04 g (yield 92%) of 2,4-dihydroxy-6,7-dimethoxyquinazoline was obtained. Mp 300 ° C. or higher IR spectrum ^{(KBr) 3470, 1710 cm -1} 1 H-NMR spectrum _{(300 MHz, d 6 -DMSO)} δ3.77 (s, 3H),
3.81 (s, 3H), 6.67 (s, 1H), 7.24 (s, 1H), 10.91
(s, 1H), 11.08 (s, 1H) ¹³ C-NHR spectrum (75 MHz, d ₆ -DMSO) δ55.7, 55.8,
97.8, 106.2, 107.2, 136.5, 145.0, 150.4, 154.9, 16
2.4 MS spectrum (m / z,%) 222 (M ⁺ , 100), 207 (38), 164
(22) Exact MS spectrum theoretical value 222.0641, measured value 222.06
42 Example 11 A stir bar was put into a 100 ml autoclave, and the inside of the autoclave was replaced with argon gas. With the argon gas atmosphere maintained, 1.63 g of 2-amino-5-nitrobenzonitrile, 0.75 ml (0.5 equivalent) of DBU, and 20 ml of DMF were added using a syringe, and the autoclave was heated with a carbon dioxide cylinder at 20 ° C. The atmosphere was replaced three times with 10 atm (1.0 MPa), then the pressure was increased to 10 atm, and the mixture was reacted at 80 ° C. for 24 hours with stirring. After the reaction, the autoclave was cooled to room temperature, carbon dioxide was purged, and then the autoclave was opened. The obtained reaction solution was poured into 200 ml of 1N hydrochloric acid aqueous solution, and the precipitated solid was collected on a glass filter. By washing with 100 ml of toluene and 100 ml of methyl tert-butyl ether, 1.7
1 g (yield 82%) of 2,4-dihydroxy-6-nitroquinazoline was obtained. Melting point 300 ° C or higher IR spectrum (KBr) 3455, 1680 cm ^{-1 1} H-NMR spectrum (300 MHz, d ₆ -DMSO) δ 7.26 (dd, J =
2,9Hz, 1H), 8.38 (td, J = 2,9Hz, 1H), 8.50 (d, J = 2H
z, 1H), 11.65 (s, 1H), 11.71 (s, 1H) ¹³ C-NHR spectrum (75 MHz, d ₆ -DMSO) δ 114.4, 116.
6, 123.0, 129.5, 141.8, 145.6, 149.9, 161.5 MS spectrum (m / z,%) 207 (M ⁺ , 100), 164 (27) Exact MS spectrum theoretical 207.0280, measured 207.02
71

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Takumi Mizuno             6171, Andoji Town, Itami City, Hyogo Prefecture F-term (reference) 4H039 CA42 CA60 CF30 CH40

Claims (4)

[Claims] 1. Aminobenzonitriles and carbon dioxide gas,
A method for producing a quinazoline derivative, which comprises reacting in a solvent in the presence of 0.01 to 1 equivalent of a bicyclic amidine with respect to aminobenzonitriles. 2. Aminobenzonitriles are represented by the general formula (1): (In the formula, X is a hydrogen atom, a halogen atom, an alkyl group,
An alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group or a nitro group, which may have a substituent, is shown. ), And a quinazoline derivative represented by the general formula (2): It is a quinazoline derivative represented by (In formula, X is the same as the above.) The manufacturing method of Claim 1 characterized by the above-mentioned. 3. The reaction of aminobenzonitriles and carbon dioxide gas at 6 to 10 atm (0.5 to 1.0 MPa).
The method according to claim 1 or 2, wherein the reaction is performed at 0 to 80 ° C. 4. The solvent is at least one selected from the group consisting of an amide solvent, a sulfoxide solvent, an ether solvent and a halogen solvent, and the bicyclic amidine is
DBU (1,8-Diazabicyclo [5.4.0] undec-7-ene) and DBN (1,5
-Diazabicyclo [4.3.0] non-5-ene), at least one selected from the group consisting of:
The manufacturing method according to any one of 1.