JP3018185B1 - Method for producing quinazoline derivative or salt thereof - Google Patents

Abstract

The present invention provides a method for efficiently producing a quinazoline derivative or a salt thereof useful as an intermediate material for medicines, agricultural chemicals and the like by a simple operation. SOLUTION: General formula: (R ¹ is an inert substituent, and two adjacent R ^1s may be bonded to each other to form a ring, and R ² may be directly or a carbon atom via an oxygen atom, a sulfur atom or a nitrogen atom. bonded to that hydrocarbon radical, n and is 0 or an integer of 1 to 4) N- arylthiocarbamoyl compound represented by the general formula _{^{NC-N- (R 3) 2}} (R3 is a hydrocarbon group, the two R ³ may be bonded to form a ring) with an N, N-disubstituted cyanamide represented by the following general formula: (Wherein R ^{1 to} R ³ and n have the same meanings as described above) or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a quinazoline derivative or a salt thereof, and more particularly, to a method for producing a quinazoline derivative or a salt thereof useful as an intermediate material for fine chemical products such as pharmaceuticals and agricultural chemicals by a simple operation. And a method for efficiently producing the same.

[0002]

2. Description of the Related Art Quinazoline derivatives are known as DHFR (dihydrofolate reductase) inhibitors [Chemical Review (Ch.
em. Rev .. ) ", Vol. 84, pp. 333 (19
1984), "International Journal of
Quantum Chemistry (Int. J. Quantn)
m. Chem. ) ", Vol. 17, pp. 821 (19
1980)], a drug for treating pneumocystis carinii pneumonia common in AIDS patients [Journal of Experimental Medication (J. Exptl. Me.)
d. ), Vol. 165, pp. 926 (1987
)], Insecticides, acaricides (JP-A-53-103484), antimalarial agents [Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 24, p. 127 ( 1981)], etc., and are widely used as pharmaceuticals, agricultural chemicals or intermediates thereof.

[0003] As a method for producing quinazoline or a derivative thereof, a method of reacting o-nitrobenzaldehyde with formaldehyde to form o-nitrobenzylidene diformamide and reducing the same with zinc and acetic acid has been proposed. Quinazoline in the presence of alkali,
A method of oxidizing with potassium ferricyanide, a method of reacting o-acylamidobenzaldehyde or phenyl ketones with ammonia, a method of reducing o-nitrobenzylamide derivative with hydrogen in the presence of nickel, N-arylacyl imido chloride and nitrile A method of reacting a diazonium salt with a nitrile is known, and a method for producing a 2,4-diaminoquinazoline derivative includes reacting an alkyl mercaptan sodium salt with 2,4-dichloroquinazoline. A method is known in which 2-chloro-4-alkylthioquinazoline is produced, further reacted with an alkylamine in the presence of a trialkylamine, and then the reaction mixture is desulfurized with Raney-nickel.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a method for producing 2-quinazoline derivatives by a reaction completely different from that of a conventional method for producing quinazoline derivatives, using easily available starting compounds, and performing a simple operation efficiently.
The purpose of the present invention is to provide a new method for producing a substituted-4-disubstituted aminoquinazoline derivative.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to develop a novel method for producing a quinazoline derivative. As a result, the thiocarbonyl compound is desulfurized by a metal ion such as silver, and They have found that they react with substituted cyanamides to cyclize and form 2-substituted-4-disubstituted aminoquinazoline derivatives in high yields, and have completed the present invention based on this finding.

That is, the present invention provides a compound represented by the general formula

Embedded image (R ¹ in the formula is an inert substituent, when R ¹ are a plurality, even each R ¹ mutually identical, may be different, binding two adjacent R ¹ are each other And R ² may be a hydrocarbon group bonded to a carbon atom directly or via an oxygen atom, a sulfur atom or a nitrogen atom, and n is 0 or an integer of 1-4. An N-arylthiocarbamoyl compound represented by the formula: NC-N- (R ³ ) ₂ (II) (wherein each R ³ is a hydrocarbon group, and two R ^{3 s} are the same as each other) Or a N, N-disubstituted cyanamide represented by the formula (I) which may form a ring together with the nitrogen atom to which each R ³ is bonded: General formula characterized by performing a desulfurization reaction in the presence of a metal salt

Embedded image (Wherein R ¹ , R ² , R ³ and n have the same meanings as described above) or a method for producing a quinazoline derivative or a salt thereof.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, one of raw materials
For example, an N-arylthiocarbamoyl compound represented by the general formula (I) is used. In the general formula (I), R ¹ is, for example, a hydrocarbon group such as an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a hydrocarbyloxy group such as an alkoxyl group, a cycloalkoxyl group, an aryloxy group, an aralkyloxy group. Substituents which are inert to the reaction of a carbamoyl group such as a group, a heterocyclic group, a halogen atom, a nitro group and a cyano group can be exemplified. n is 0 or an integer of 1 to 4, and when there are a plurality of R ¹ , each R ¹ may be the same or different, and two adjacent R ¹ may be different from each other. They may combine to form a ring.

On the other hand, examples of the hydrocarbon group directly bonded to a carbon atom in R ² include an alkyl group, a cycloalkyl group, an aryl group and an aralkyl group. Examples of the hydrocarbon group bonded through an atom or a nitrogen atom include an alkoxyl group, a cycloalkoxyl group, an aryloxy group, an aralkyloxy group, an alkylthio group, a cycloalkylthio group, an arylthio group, an aralkylthio group, Dialkylamino group, mono- or dicycloalkylamino group,
A mono or diarylamino group, a mono or diaralkylamino group and the like can be mentioned. In addition, the above-mentioned inert substituent may be further introduced into these groups. The N-arylthiocarbamoyl compound represented by the general formula (I) can be easily obtained by replacing oxygen of the carbonyl group of the corresponding carbamoyl compound with sulfur.

In the method of the present invention, a disubstituted cyanamide represented by the above general formula (II) is used as another raw material. In the general formula (II), examples of the hydrocarbon group represented by R ³ include an alkyl group, a cycloalkyl group, an aryl group, and an aralkyl group. These groups may be introduced inert substituents, examples of the inert substituent may include the same as those exemplified in the description of the R ^1. Furthermore, two R ³ may be identical to each other;
R ³ may be different from each other and may form a ring together with the nitrogen atom to which each R ³ is bonded.
No.

In the method of the present invention, examples of the metal salt used as a desulfurizing agent include a silver salt, a mercury salt, and a copper salt of a strong acid such as perchloric acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and fluoroboric acid. I) and lead salts (II), among which silver salts are preferred.
These metal salts may be used alone or in combination of two or more.

In the method of the present invention, the above-mentioned general formula (I)
An N-arylthiocarbamoyl compound represented by
The disubstituted cyanamide represented by the general formula (II) is reacted in the presence of a metal salt. This reaction is preferably performed in an organic solvent. Examples of the organic solvent include acetonitrile, dioxane, benzene, toluene, N, N-dimethylformamide, chloroform, methylene chloride, and the like. These may be used alone or as a mixture of two or more. Is also good.

Next, a preferred embodiment of the present invention will be described. First, in an appropriate organic solvent, the N-arylthiocarbamoyl compound represented by the general formula (I) and 2 or more equivalents thereof are added. After dissolving the di-substituted cyanamide represented by the general formula (II)
A metal salt such as a silver salt is added in an amount of at least an equivalent, preferably 2.2 to 2.5 equivalents, and the mixture is stirred at room temperature and, if necessary, heated to accelerate and complete the reaction.

After completion of the reaction, the precipitated metal sulfide is removed by means such as filtration, the solvent is distilled off under reduced pressure, and the resulting target product is recrystallized, if necessary, by a method such as column chromatography. Purify. The compound thus obtained is usually a compound represented by the general formula (III).
In the form of a salt of a -substituted-4-disubstituted aminoquinazoline derivative. This salt is a salt derived from the anion of the metal salt used, and thus includes perchlorate, trifluoromethanesulfonate, trifluoroacetate, fluoroborate and the like. When a free 2-substituted-4-disubstituted aminoquinazoline derivative is desired, it may be neutralized by adding an alkali before or after filtration of the metal sulfide. When a salt other than the salt derived from the anion of the metal salt used is desired, a desired inorganic acid or organic acid is added to the free quinazoline derivative obtained as described above to derive the salt. Good.

The reaction mechanism in this reaction is based on the use of thiobenzanilide, dimethyl cyanamide and silver perchlorate.
An example of the production of -phenyl-4-dimethylaminoquinazolinium perchlorate is as follows.

[0015]

Embedded image

As can be seen from this reaction formula, in the method of the present invention, the carbamoyl group bonded to the benzene nucleus of the N-arylthiocarbamoyl compound reacts with the metal of the metal salt to form a carbamoyl metal salt. Furthermore, since the cyano group of the N, N-disubstituted cyanamide reacts and cyclizes, even if an inert substituent other than the carbamoyl group is present in the benzene nucleus of the N-arylthiocarbamoyl compound, the N, N-di-substituted No matter what hydrocarbon group the N, N-substituent of the substituted cyanamide is, the reaction itself is substantially unaffected. Therefore, according to the method of the present invention, the following 2-substituted-4-disubstituted aminoquinazoline derivatives can be produced.

[0017]

Embedded image

Since the obtained compound is a known substance for the compound (B), its melting point was measured and compared with literature values. Other compounds (A),
Regarding (C) to (I), melting point (mp), nuclear magnetic resonance spectrum of proton and isotope carbon ( ¹ H-NMR,
¹³ C-NMR), infrared absorption spectrum (IR), and elemental analysis.

[0019]

According to the present invention, an N-arylthiocarbamoyl compound and a disubstituted cyanamide, which are easily available, are used as raw materials, and are treated under mild conditions with a metal salt such as a silver salt. Thus, various 2-substituted-4-disubstituted aminoquinazoline derivatives or salts thereof can be produced simply and in good yield in a novel reaction format. The 2,4-diaminoquinazoline derivative or its salt obtained by the method of the present invention is useful as an intermediate material for fine chemical products such as medicines and agricultural chemicals.

[0020]

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

Example 1 213 m of thiobenzanilide in 4 ml of acetonitrile
g (1.0 mmol) and dimethyl cyanamide 210 mg
(3 mmol) was stirred at room temperature, and 500 mg (2.4 mmol) of silver perchlorate was added thereto.
The reaction solution was heated to reflux on a water bath for 5 hours. After completion of the reaction, the precipitated silver sulfide was filtered off with heating, and the crude product obtained by evaporating the solvent of the filtrate under reduced pressure was recrystallized and purified with methanol to obtain 297 mg (yield: 85%) of 2-phenyl. -4-Dimethylquinazolinium perchlorate [Compound (A)] was obtained. Melting point (mp), ¹ H-NMR and
^{The 13} C-NMR spectrum, IR spectrum, and elemental analysis results are as follows. mp 218 ° C; ¹ H-NMR δ = 3.69 (s, 6
H), 7.68-7.80 (m, 4H), 7.98-
8.07 (m, 2H), 8.25-8.43 (m, 3
H); ¹³ C-NMR δ = 42.51, 111.84,11
9.40, 126.85, 28.06, 129.11,
129.27, 131.28, 133.55, 135.
50, 141.14, 154.81, 161.33; IR 3260, 1620, 1606, 1566, 13
75,1111,769 cm- ¹ . Elemental _{analysis: C 16 H 16 N 3 O} 4 calculated for Cl: C, 54.94; H, 4.61; N, 12.0
1%. Found: C, 55.12; H, 4.65; N, 11.9.
1%.

EXAMPLE 2 Thiobenzanilide 213 m in 4 ml of acetonitrile
g (1.0 mmol) and dimethyl cyanamide 210 mg
(3 mmol) dissolved therein was stirred at room temperature, and 500 mg (2.4 mmol) of silver perchlorate was added.
The reaction solution was heated to reflux on a water bath for 5 hours. After the completion of the reaction, the precipitated silver sulfide was filtered off with heating, the solvent of the obtained filtrate was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution and chloroform were added, and the mixture was vigorously stirred to neutralize the chloroform layer. Separation was performed to extract a crude product. Further, chloroform was distilled off from this and purified by recrystallization with hexane to give a melting point (mp) of 70 ° C [literature value: 69 to 70].
C; "Chem. Chemiker-Zeitun.
g ", Vol. 335, p. 711 (1993)], and 202 mg (yield 78%) of 2-phenyl-4-dimethylaminoquinazoline [compound (B)] was obtained.

Example 3 In Example 1, thiobenzanilide was replaced by 1,
Except that 3-diphenylthiourea was used, the same treatment as in Example 1 was carried out to give 250 mg (yield 68%) of 2-anilino-4-dimethylaminoquinazolinium perchlorate [compound (C) ]was gotten. Mp, ¹ H-
The NMR, ¹³ C-NMR spectrum, IR spectrum, and elemental analysis results are as follows. mp 194 ° C. (methanol); ¹ H-NMR δ = 3.
49 (s, 6H), 7.21-7.26 (m, 1H),
7.42-7.64 (m, 6H), 7.81-7.87
(M, 1H), 8.22-8.25 (m, 1H), 1
0.02 (s, 1H), 12.09 (brs, 1H); ¹³ C-NMR δ = 35.46, 42.29, 11
0.63, 117.75, 122.62, 124.0
2,125.15,128.06,129.19,13
4.94, 137.09, 141.14, 149.6
4,162.05; IR 3325,1635,1593,1564,13
86,1105,756 cm- ¹ . Elemental _{analysis: C 16 H 17 N 4 O} 4 calculated for Cl: C, 52.68; H, 4.70; N, 15.3
6%. Found: C, 52.69; H, 4.69; N, 15.7.
0%.

Example 4 In Example 1, thiobenzanilide was replaced by 1,
Using exactly 3-diphenylthiourea and N-cyanomorpholine in place of dimethylcyanamide, exactly as in Example 1, 354 mg (87% yield) of 2-anilino-4-morpholinoquinazolinium peroxide Chlorate [compound (D)] was obtained. Mp, ¹ H-NMR of this product
And the ¹³ C-NMR spectrum, IR spectrum, and elemental analysis results are as follows. mp 281 ° C (ethanol); ¹ H-NMR δ = 3.
77-3.80 (m, 4H), 4.03-4.06
(M, 4H), 7.22-7.30 (m, 1H);
41-8.03 (m, 8H), 10.18 (s, 1
H), 12.28 (brs, 1H); ¹³ C-NMR δ = 49.43, 65.88, 11
0.32, 118.29, 122.97, 124.1
7, 125.43, 127.22, 128.91, 12
9.26,135.21,136.91,150.4
4,162.85; IR 3339,1631,1593,1541,13
58,1114,758 cm < ^-1 >. Elemental _{analysis: C 18 H 19 N 4 O} 5 calculated for Cl: C, 53.14; H, 4.71; N, 13.7
7%. Found: C, 53.31; H, 4.68; N, 13.7.
5%.

Example 5 The procedure of Example 1 was repeated, except that dimethylthiocarbamoylanilide was used instead of thiobenzanilide, to give 215 mg (68% yield) of 2,4- Bis (dimethylamino) quinazolinium perchlorate [Compound (E)] was obtained. Mp of this thing, ¹
1 H-NMR, ¹³ C-NMR spectrum, IR spectrum and the results of elemental analysis are as follows. mp 293 ° C (methanol); ¹ H-NMR δ = 3.
26 (s, 6H), 3.47 (s, 6H), 7.38-
7.42 (m, 1H), 8.16-8.19 (m, 1
H), 11.52 (s, 1H); ¹³ C-NMR δ = 37.86, 42.30, 11.
1.00, 117.69, 123.99, 128.0
8, 134.87, 141.69, 151.12, 16
1.07; IR 3298, 1637, 1601, 1556, 13
83,1109,761 cm- ¹ . Elemental _{analysis: C 12 H 17 N 4 O} 4 calculated for Cl: C, 45.50; H, 5.41; N, 17.6
9%. Found: C, 45.26; H, 5.25; N, 17.9.
2%.

Example 6 In Example 1, thiobenzanilide was replaced with N-
Except that phenyl-N'-cyclohexylthiourea was used, the same treatment as in Example 1 was carried out to obtain 341 mg (yield 92%) of 2-cyclohexylamino-4-dimethylaminoquinazolinium perchlorate [ Compound (F)] was obtained. Mp, ¹ H-NMR and ¹³ C-NM
The R spectrum, IR spectrum, and elemental analysis results are as follows. mp 190 ° C. (methanol); ¹ H-NMR δ = 1.
30-1.93 (m, 10H), 3.47 (s, 6
H), 3.87 (brs, 1H), 7.35-7.81.
(M, 3H), 8.16-8.18 (m, 1H), 8.
44 (brs, 1H), 11.59 (brs, 1H); ¹³ C-NMR δ = 24.38, 24.93, 31.
92, 42.01, 49.18, 50.10, 117.
25, 123.49, 128.02, 134.71, 1
41.16, 150.65, 161.83; IR 3337, 2932, 1637, 1599, 15
62, 1394, 1113, 760 cm- ¹ . Elemental _{analysis: C 16 H 23 N 4 O} 4 calculated for Cl: C, 51.82; H, 6.25; N, 15.1
1%. Found: C, 51.89; H, 6.28; N, 15.0.
7%.

Example 7 The same procedure as in Example 1 was repeated, except that diphenylthioacetyl-p-toluid was used in place of thiobenzanilide, and N-cyanopyrrolidine was used in place of dimethyl cyanamide. (75% yield) 2
-Diphenylmethyl-4-pyrrolidino-6-methylquinazolinium perchlorate [Compound (G)] was obtained. The mp, ¹ H-NMR and ¹³ C-NMR spectra, IR spectrum, and elemental analysis results of this product are as follows. mp 223 ° C. (ethanol); ¹ H-NMR δ = 1.
97-2.01 (m, 4H), 2.50 (s, 3H),
3.95 (brs, 4H), 5.63 (s, 1H),
7.25-7.47 (m, 11H), 7.65-7.7
7 (m, 2H), 8.16 (s, 1H); ¹³ C-NMR δ = 21.09, 24.72, 51.
75, 56.79, 113.01, 121.22, 12
6.12, 127.22, 128.51, 129.1
1,136.07,136.39,140.45,15
8.14, 161.51; IR 3256, 1612, 1582, 1554, 13
36,1113,739 cm- ¹ . Elemental _{analysis: C 26 H 26 N 3 O} 4 calculated for Cl: C, 65.06; H, 5.46; N, 8.76
%. Found: C, 65.25; H, 5.22; N, 8.75.
%.

Example 8 In Example 1, thiobenzanilide was replaced with N-
Except that (dimethylthiocarbamoyl) -1-naphthylamine was used, the same treatment as in Example 1 was carried out to give 150
mg (41% yield) of 2,4-bis (dimethylamino)
-7,8-Benzoquinazolinium perchlorate [Compound (H)] was obtained. Its mp, ¹ H-NMR and ¹³ C-NMR spectra, IR spectrum and elemental analysis results are as follows. mp 286 ° C. (ethanol); ¹ H-NMR δ = 3.
35 (s, 6H), 3.46 (s, 6H), 7.77-
7.88 (m, 3H), 8.01-8.11 (m, 2
H), 8.75-8.78 (m, 1H); ¹³ C-NMR δ = 35.91, 37.98, 41.
84, 106.43, 122.57, 123.13, 1
23.76, 127.15, 128.46, 130.2
1,134.96, 152.19, 162.20; IR 3398, 2935, 1637, 1593, 15
62,1379,1091,769 cm- ¹ . Elemental _{analysis: C 16 H 19 N 4 O} 4 calculated for Cl: C, 52.54; H, 4.96; N, 15.3
2%. Found: C, 52.77; H, 4.93; N, 15.1.
1%.

Example 9 230 mg (1.0 mmol) of N- (dimethylthiocarbamoyl) -1-naphthylamine and 600 mg of silver trifluoromethanesulfonate in 3 ml of dimethyl cyanamide
(2.33 mmol) was stirred at room temperature, and then heated to 140 ° C. for 5 hours on an oil bath. After the reaction,
A 2N aqueous solution of sodium hydroxide and chloroform were added to the reaction solution, and the mixture was vigorously stirred. The insolubles were filtered off, the chloroform layer was separated, and a crude product was extracted. Further, chloroform was distilled off from the extract and purified by recrystallization with hexane to obtain 149 mg (yield 56%) of 2,4.
-Bis (dimethylamino) -7,8-benzoquinazoline [compound (I)] was obtained. The melting point (m
p), ¹ H-NMR and ¹³ C-NMR spectra, I
The results of the R spectrum and elemental analysis are as follows. mp 95 ° C; ¹ H-NMR δ = 3.24 (s, 6
H), 3.33 (s, 6H), 7.24-7.32.
(M, 1H), 7.53-7.63 (m, 2H), 7.
69-7.77 (m, 2H), 9.06-9.09
(M, 1H); ¹³ C-NMR δ = 36.96, 41.83,10
6.70, 119.28, 122.87, 125.3
4,125.75,127.35,128.64,13
0.46, 135.29, 154.01, 159.5
0, 165.63; IR 3046, 2941, 1556, 1504, 13
98, 1371, 1035, 968, 765 cm- ¹ . Elemental _analysis: calculated for _{C 16 H 18 N 4: C} , 72.23; H, 6.81; N, 21.0
3%. Found: C, 72.23; H, 7.06; N, 21.0.
2%.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Akihiro Oishi 1-1-1, Higashi, Tsukuba, Ibaraki Pref., National Institute of Advanced Industrial Science and Technology (56) References JP-B-47-7708 (JP, B1) Chem. Soc. Chem. Commun. , 1984 (No. 16) p1105-1107 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 239/94 C07D 239/95 C07D 239/70 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (R ¹ in the formula is an inert substituent, when R ¹ are a plurality, even each R ¹ mutually identical, may be different, binding two adjacent R ¹ are each other And R ² may be a hydrocarbon group bonded to a carbon atom directly or via an oxygen atom, a sulfur atom or a nitrogen atom, and n is 0 or an integer of 1-4. And an N-arylthiocarbamoyl compound represented by the formula: NC-N- (R ³ ) ₂ (wherein each R ³ is a hydrocarbon group, and two R ^{3 s} are the same as each other) Or a N, N-disubstituted cyanamide represented by the following formula: may be different from each other, or may be bonded to each other to form a ring together with the nitrogen atom to which each R ³ is bonded. General formula characterized by a desulfurization reaction in the presence of (Wherein R ¹ , R ² , R ³ and n have the same meanings as described above) or a method for producing a quinazoline derivative or a salt thereof. 2. The method according to claim 1, wherein the metal salt is a silver salt.