JP3407040B2 - Method for producing quinazoline derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a quinazoline derivative. More specifically, it relates to a novel method for producing a quinazoline derivative by reacting an N-aryl-substituted ketene imine compound with an N, N-di-substituted cyanamide compound.

[0002]

BACKGROUND OF THE INVENTION Quinazoline derivatives are substances having various physiological activities, and are DHFR (dihydrofolate reductase) inhibitors [Chem. Rev., 84, 333 (1984); Int. J. Qu.
antnm. Chem., 17, 821 (1980)], a drug for pneumocystis carinii pneumonia that is common in AIDS patients [J. Exptl. Med, 16
5, 926 (1987)], insecticide and acaricide [JP-A-53-10]
3484], an antimalarial agent [J. Med. Chem., 24,
127 (1981)], etc., and is widely used as an agricultural chemical or an agricultural chemical or an intermediate thereof.

Conventionally, as a method for producing such a quinazoline derivative, for example, a method of reacting N-acyl-o-aminobenzophenone with ammonia (Bischler synthesis method),
Reductive cyclization of bisformamide derivatives of o-nitrobenzaldehyde (Reidel synthesis method), condensation of anthranilic acid and amide at high temperature (Neimentowski
Synthetic method), a method of reacting o-amidobenzonitrile with basic hydrogen peroxide, a method of reacting a diazonium salt with two equivalents of nitrile, and the like are known.

[0004]

An object of the present invention is to provide a method for efficiently producing a quinazoline derivative by using a novel reaction which is completely different from the above-mentioned conventional synthetic reaction of a quinazoline derivative.

[0005]

Means for Solving the Problems As a result of intensive studies to develop a novel method for producing a quinazoline derivative, the present inventors have found that a specific N-aryl-substituted ketene imine compound and N, N-di-substituted cyanamide It was found that a quinazoline derivative can be easily obtained by cyclizing and condensation with a compound, and completed the present invention.

That is, according to the present invention, the following general formula (a)

[Chemical 4] (In the formula, R ^{1 to} R ⁴ each represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group, or a halogen atom. R ⁵ and R ⁶ respectively represent A hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent), and an N-aryl-substituted ketene imine compound represented by the following general formula (II):

[Chemical 5] (In the formula, two R ^{7 s} are hydrocarbons, which may be the same as or different from each other, and may be bonded to each other to form a ring with the nitrogen atom to which each R ⁷ is bonded. And a N, N-disubstituted cyanamide compound represented by the formula (I) is subjected to a cyclization condensation reaction under pressure.

[Chemical 6] (In the formula, R ^{1 to} R ⁴ represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group, or a halogen atom. R ⁵ and R ⁶ are each hydrogen. An atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent, and two R ^{7 s} are hydrocarbons, which may be the same or different from each other. May be bonded to each other to form a ring together with the nitrogen atom to which each R ⁷ is bonded.). The cyclization condensation reaction is 100
It is preferable to carry out under a high pressure of at least MPa.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. Conventionally, various methods have been known as a method for producing a quinazoline derivative, but an N-aryl-substituted ketene imine compound and an N, N-di-substituted cyanamide compound are used as raw materials, and these are reacted under pressure. It has not been known at all so far that quinazoline derivative is produced by cyclization condensation with and is a new finding discovered by the present inventors for the first time. The synthetic reaction of the present invention can be represented by the following reaction formula.

[Chemical 7]

In the present invention, the N-aryl-substituted ketene imine compound used as one of the raw materials is a ketene imine compound which is an atomic group in which a carbon atom-carbon atom-nitrogen atom is bonded by a double bond. A compound having an aryl group attached to it is defined, and satisfies the definition,
Any compound having a group that does not participate in the reaction of the present invention can be used, but among them, the compound represented by the following general formula (a) is preferably used.

[0009]

[Chemical 8]

In the general formula (a), R ^{1 to} R ⁴ are each a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group or a halogen atom. Specific examples of the group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, hexyl group, cyclohexyl group, ethoxyethyl group, methoxy group, ethoxy group, propoxy group, butoxy group, cyclohexyloxy group, methoxycarbonyl. Group, ethoxycarbonyl group, dimethylamino group, diethylamino group, diisopropylamino group, chloro, bromo and the like.

R ⁵ and R ⁶ are each a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a hexyl group, a cyclohexyl group and an ethoxyethyl group. further,
Examples of the substituent which may be substituted on these alkyl groups include a halogen atom, an alkoxyl group, a dialkylamino group, an acyl group and an alkoxycarbonyl group. Examples of the aryl group include a phenyl group, a tolyl group, a xylyl group, a naphthyl group and a biphenyl group. Further, as the substituent which may be substituted on these aryl groups, a halogen atom, an alkoxyl group,
Examples thereof include a dialkylamino group, an acyl group and an alkoxycarbonyl group. Further, R ⁵ and R ⁶ may be bonded to each other through one atom or atomic group to form a ring.

In the present invention, the N, N-disubstituted cyanamide compound used as another raw material is a cyanamide compound having an amino group and a cyano group bonded to each other and having two substituents at the nitrogen atom of the amino group. And any group having a group that does not participate in the reaction of the present invention can be used.
The compound represented by is preferably used.

[0013]

[Chemical 9]

The two R ^{7 s} in the general formula (b) are hydrocarbons, which may be the same or different, and are bonded to each other to form a ring together with the nitrogen atom to which each R ⁷ is bonded. May be formed. The hydrocarbon may be an alkyl group, a cycloalkyl group, an aralkyl group, or those having a substituent such as an alkoxyl group, and specific examples thereof include a methyl group, an ethyl group and a propyl group. , Isopropyl group, butyl group, hexyl group, cyclohexyl group, ethoxyethyl group, benzyl group and the like. Further, two R ^7's may be the same or different from each other, and may be bonded to each other to form a ring with the nitrogen atom to which R ⁷ is bonded. Specific examples of such N, N-disubstituted cyanamide compounds include dimethylcyanamide, diethylcyanamide, dipropylcyanamide, diisopropylcyanamide, 1-pyrrolidinecarbonitrile, 1-piperidinecarbonitrile, 1-morpholinecarbonitrile and the like. To be

In the method of the present invention, a quinazoline derivative is produced by causing a cyclization reaction involving condensation under pressure to the N-aryl-substituted ketene imine compound and the N, N-di-substituted cyanamide compound described above. When the reaction is performed under a high pressure of 100 MPa or more, the cyclocondensation reaction is promoted and the desired quinazoline derivative can be easily obtained. In this cyclization condensation reaction, the N, N-disubstituted cyanamide compound which is a reaction raw material is used as a solvent which also serves as a reaction reagent, but a nonpolar organic solvent such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, It may be used in combination with anisole or the like. Further, these solvents may be used alone or as a mixed solvent of two or more kinds.

The pressurization condition for the reaction is not particularly limited, but is preferably a pressure of 100 MPa or more, more preferably 100 to 1000 MPa, still more preferably 600 to 1000 MPa. . Further, the reaction temperature is not particularly limited, but if the temperature is too low, the reaction time will be delayed, and if it is too high, decomposition reactions and side reactions will increase, so that it is in the range of 50 to 150 ° C, preferably in the range of 80 to 120 ° C. Is suitable.
The reaction time cannot be unconditionally determined because it depends on the type of raw material, reaction pressure, reaction temperature, etc.
0 to 24 hours is sufficient.

In the method of the present invention, the desired N-aryl-substituted ketene imine compound and N, N-di-substituted cyanamide compound as raw materials are appropriately selected, and a desired quinazoline derivative is synthesized by a reaction in which they are combined and cyclized and condensed. be able to. At that time, as the N-aryl-substituted ketene imine compound, the compound represented by the general formula (A) is
By using the compound represented by the general formula (b) as the N, N-disubstituted cyanamide compound, a quinazoline derivative represented by the following general formula (c) can be obtained.

[0018]

[Chemical 10] (In the formula, each of R ^{1 to} R ⁷ has the same meaning as described above.)

In the method of the present invention, since the keteneimine group of the N-aryl-substituted keteneimine compound is reacted with the cyano group of the N, N-disubstituted cyanamide compound to cyclize,
A functional group that does not react with the ketene imine compound at the aryl position of the aryl-substituted ketene imine compound, such as an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group or a halogen atom, Whatever hydrocarbon group is directly attached to the nitrogen atom of the N, N-disubstituted cyanamide compound does not substantially affect the cyclization reaction itself. Therefore, according to the method of the present invention, for example,
The 2-substituted-4-disubstituted aminoquinazoline derivatives and the like shown as (1) to (8) in Table 1 can be easily produced.

[0020]

[Table 1]

[0021]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, but these Examples are representative ones for easily understanding the contents of the present invention. It is not limited. The quinazoline derivatives produced by the following examples are the known derivatives [quinazoline derivatives of the chemical structural formula (1) in Table 1] by comparison of various physical property values, and other compounds by various spectra and elemental analysis. Was identified as the main criterion. As the physical property values, melting point, nuclear magnetic resonance spectrum ( ¹ H-NMR or ¹³ C-NMR),
The results are shown in the order of infrared absorption spectrum (IR) and elemental analysis value.

Example 1 1 mmol of N-phenyldiphenylketeneimine was added to 1 m of dimethylcyanamide in a Teflon container having an internal volume of 2 ml.
It was dissolved in 1 and heated to 100 ° C. under a pressure of 800 MPa and reacted for 20 hours. After completion of the reaction, the reaction product was taken out of the container, and the crude product was purified by silica gel chromatography (elution solvent, methylene chloride: acetone: methanol = 100: 10: 2). Further, by recrystallization from benzene-hexane, a quinazoline derivative represented by the chemical structural formula (1) in Table 1 was obtained. Yield of the obtained quinazoline derivative (1) 71%; melting point 149-150 ° C; ¹ H-NMR (CDC
l ₃ ) 3.31 (6H, s), 5.62 (1H, s), 7.16-7.36 (7H,
m), 7.49 (4H, dd, J = 8.2, 1.0 Hz), 7.64 (1H, dd, J =
6.9, 1.4 Hz), 7.84 (1H, dt, J = 8.5, 0.6 Hz), 7.97 (1
H, dt, J = 8.5, 0.7 Hz); IR (KBr) 1566, 1532, 1491,
1381, 750, 702 cm ^-1 . Elementary analysis as _{C 23 H 21 N 3 (%} ) measurements: C, 80.98, H, 6.22 , N, 12.38 Calculated: C, 81.38, H, 6.24 N, 12.38

Example 2 The reaction was performed in the same manner as in Example 1 except that N- (p-methylphenyl) diphenylketeneimine was used in place of N-phenyldiphenylketeneimine, and the chemical structures are shown in Table 1. A quinazoline derivative represented by the formula (2) was obtained. Yield 66% of the obtained quinazoline derivative (2); melting point 104-1
05 ℃; ¹ H-NMR (CDCl ₃ ) 2.45 (3H, s), 3.27 (6H,
s), 5.61 (1H, s), 7.17-7.29 (6H, m), 7.46-7.50 (1H,
d, J = 0.8 Hz), 7.74 (1H, d, J = 8.5 Hz); ¹³ C-NMR (CD
Cl ₃ ) 21.8, 41.8, 60.7, 114.4, 124.4, 126.2, 127.9,
128.0, 129.4, 133.7, 143.0, 150.9, 163.4, 164.6;
IR (KBr) 1566, 1530, 1385, 1080, 833, 729, 698 cm
^-1 . Elemental analysis value (%) as C ₂₄ H ₂₃ N ₃ Measured value: C, 81.35, H, 6.75, N, 11.76 Calculated value: C, 81.55, H, 6.56 N, 11.89

Example 3 In a Teflon (registered trademark) container having an internal volume of 2 ml, N-
(P-Methoxyphenyl) diphenylketene imine 1mm
ol is dissolved in 1 ml of dimethyl cyanamide, and 800M
The mixture was heated to 100 ° C. under a pressure of Pa and reacted for 20 hours. After completion of the reaction, the reaction product was taken out of the container, and the crude product was purified by silica gel chromatography (elution solvent: methylene chloride: acetone: methanol = 100: 10: 2) to give the chemical structural formula (3) in Table 1. The quinazoline derivative shown by was obtained. Yield of the obtained quinazoline derivative (3) 47%; melting point 190-192.5 ° C. as picrate salt;
¹ H-NMR (CDCl ₃ ) 3.26 (6H, s), 3.88 (3H, s), 5.61
(1H, s), 7.18-7.29 (7H, m), 7.34 (1H, dd, J = 9.1, 2.
7 Hz), 7.47-7.50 (4H, m), 7.79 (1H, d, J = 9.1 Hz); I
R (KBr) 1570, 1530, 1399, 1225, 1032, 837, 700 cm
^{- 1.} Elemental analysis value (%) as picrate C ₃₀ H ₂₆ N ₆ O ₈ Measured value: C, 60.20, H, 4.32, N, 13.99 Calculated value: C, 60.20, H, 4.38, N, 14.04

Example 4 In Example 3, N- (p-methylphenyl) diphenylketeneimine was used instead of N- (p-methoxyphenyl) diphenylketeneimine, and diethylcyanamide was used instead of dimethylcyanamide. Other than that, it reacted similarly and obtained the quinazoline derivative shown by chemical structural formula (4) in Table 1. Obtained quinazoline derivative (4)
Yield 65%; melting point as picrate 176-177.5
℃; ¹ H-NMR (CDCl ₃ ) 1.23 (6H, t, J = 7.0 Hz), 2.46
(3H, s), 3.62 (4H, q, J = 7.0 Hz), 5.63 (1H, s), 7.14
-7.28 (6H, m), 7.38-7.42 (4H, m), 7.47 (1H, dd, J =
8.5, 1.8 Hz), 7.62 (1H, s), 7.74 (1H, d, J = 8.5 H
z); IR (KBr) 1562, 1524, 1348, 1086, 833, 698 cm
^-1 . Elemental analysis value (%) as picrate C ₃₂ H ₃₀ N ₆ O ₇ Measured value: C, 62.87, H, 4.93, N, 13.72 Calculated value: C, 62.94, H, 4.95, N, 13.72

Example 5 In Example 3, N- (p-methylphenyl) diphenylketeneimine was used instead of N- (p-methoxyphenyl) diphenylketeneimine, and diisopropylcyanamide was used instead of dimethylcyanamide. Except for the above, the reaction was performed in the same manner to obtain the quinazoline derivative represented by the chemical structural formula (5) in Table 1. Yield 44% of the obtained quinazoline derivative (5); melting point 205 as picrate.
-208 ℃; ¹ H-NMR (CDCl ₃ ) 1.30 (12H, d, J = 6.6 Hz),
2.45 (3H, s), 4.09 (2H, hep, J = 6.6 Hz), 5.71 (1H,
s), 7.15-7.32 (10H, m), 7.45 (1H, dd, J = 8.5, 1.9 H
z), 7.54 (1H, s), 7.71 (1H, d, J = 8.5 Hz); IR (KBr)
1559, 1526, 1379, 1152, 831, 698 cm ^-1 . Elemental analysis value (%) as picrate C ₃₄ H ₃₄ N ₆ O ₇ Measured value: C, 63.77, H, 5.33, N, 13.15 Calculated value: C, 63.94, H, 5.37, N, 13.16

Example 6 Except that in Example 1, N- (p-methylphenyl) diphenylketeneimine was used in place of N-phenyldiphenylketeneimine and 1-pyrrolidinecarbonitrile was used in place of dimethylcyanamide. Then, the reaction was carried out in the same manner to obtain a quinazoline derivative represented by the chemical structural formula (6) in Table 1. Yield of the obtained quinazoline derivative (6) 60%; melting point 154.6-155.5 ° C; ¹ H-NMR (CDCl ₃ ) 1.97
-2.02 (4H, m), 2.45 (3H, s), 3.85-3.90 (4H, m), 5.
57 (1H, s), 7.15-7.29 (6H, m), 7.45-7.51 (5H, m),
7.72 (1H, d, J = 8.5 Hz), 7.88 (1H, s); IR (KBr) 156
2, 1514, 1391, 1333, 835, 718, 698 cm ^-1 . Elemental analysis value (%) as C ₂₆ H ₂₅ N ₃ Measured value: C, 82.29, H, 6.73, N, 11.04 Calculated value: C, 82.29, H, 6.64, N, 11.07

Example 7 In Example 3, instead of N- (p-methoxyphenyl) diphenylketeneimine, N- (p-methylphenyl) diphenylketeneimine was used, and instead of dimethylcyanamide.
The reaction was carried out in the same manner except that 1-piperidinecarbonitrile was used to obtain a quinazoline derivative represented by the chemical structural formula (7) in Table 1. Yield 67% of the obtained quinazoline derivative (7); melting point as picrate 199
-120.5 ℃; ¹ H-NMR (CDCl ₃ ) 1.64 (6H, m), 2.47 (3
H, s), 3.64 (4H, brs), 5.63 (1H, s), 7.15-7.29 (6
H, m), 7.45-7.51 (5H, s), 7.58 (1H, s), 7.76 (1H,
d, J = 8.5 Hz); IR (KBr) 1562, 1539, 1508, 1447, 136
0, 833, 698 cm ^{- 1} . Elemental analysis value (%) as picrate C ₃₃ H ₃₀ N ₆ O ₇ Measured value: C, 63.49, H, 4.82, N, 13.54 Calculated value: C, 63.66, H, 4.86, N, 13.50

Example 8 In Example 3, N- (p-methylphenyl) diphenylketeneimine was used instead of N- (p-methoxyphenyl) diphenylketeneimine, and dimethylcyanamide was used instead.
The reaction was performed in the same manner except that 1-morpholinecarbonitrile was used, and the chemical structural formula (8) is shown in Table 1.
The quinazoline derivative shown by was obtained. Yield of the obtained quinazoline derivative (8) 43%; melting point as picrate 190-192.5 ° C; ¹ H-NMR (CDCl ₃ ).
2.48 (3H, s), 3.69-3.45 (4H, m), 3.78-3.81 (4H, m),
5.67 (1H, s), 7.16-7.29 (6H, m), 7.41-7.44 (4H,
m), 7.53 (1H, dd, J = 8.5, 1.9 Hz), 7.58 (1H, s), 7.8
0 (1H, d, J = 8.5 Hz); IR (KBr) 1562,1505, 1433, 135
8, 1115, 700 cm ^-1 . Elemental analysis value (%) as picrate C ₃₂ H ₂₈ N ₆ O ₈ Measured value: C, 61.36, H, 4.36, N, 13.47 Calculated value: C, 61.53, H, 4.52, N, 13.46

Comparative Example 1 The reaction in Example 2 was heated in a sealed tube at 100 ° C. for 10 hours, but no quinazoline derivative was obtained.

[0031]

INDUSTRIAL APPLICABILITY According to the method of the present invention, various quinazoline derivatives can be specifically treated by a cyclization reaction of an N-aryl-substituted ketene imine compound and an N, N-di-substituted cyanamide compound, which is a novel reaction which has never been known. It can be produced in a high yield in one step without adding various additives.

─────────────────────────────────────────────────── ─── Continuation of front page (72) Yoichi Taguchi Yoichi Taguchi, 1-1, Higashi, Tsukuba-shi, Ibaraki Institute of Industrial Science and Technology (58) Field of research (Int.Cl. ⁷ , DB name) C07D 239 / 94 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The following general formula (a): (In the formula, R ^{1 to} R ⁴ each represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group, or a halogen atom. R ⁵ and R ⁶ respectively represent A hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent), and an N-aryl-substituted ketene imine compound represented by the following general formula (II): Chemical 2] (In the formula, two R ^{7 s} are hydrocarbons, which may be the same as or different from each other, and may be bonded to each other to form a ring with the nitrogen atom to which each R ⁷ is bonded. A N, N-disubstituted cyanamide compound represented by the formula (I) is subjected to a cyclization condensation reaction under pressure. (In the formula, R ^{1 to} R ⁴ represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyl group, a dialkylamino group, an acyl group, an alkoxycarbonyl group, or a halogen atom. R ⁵ and R ⁶ are each hydrogen. An atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent, and two R ^{7 s} are hydrocarbons, which may be the same or different from each other. Or may be bonded to each other to form a ring with the nitrogen atom to which each R ⁷ is bonded.). 2. The method for producing a quinazoline derivative according to claim 1, wherein the cyclization condensation reaction is carried out under a high pressure of 100 MPa or more.