JPH05301874A - 3-nitrosonaphthylidine derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new compound having antiasthmatic activity similar to the case with theophylline, useful as an intermediate for bronchodilator, etc. CONSTITUTION:The objective compound of formula I [R<1> is H, lower alkyl, (substituted) aryl, or (substituted) aralkyl; X is O or S; Y is OH or NHR<2> (R<2> is H, lower alkyl, aryl, etc.)], e.g. 4-hydroxy-3-nitroso-1-phenyl-1,8-naphthylidin-2(1 H)-one. The compound of the formula I can be obtained, for example, by reaction of a compound of formula II with sodium sulfite.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to a 3-nitrosonaftyridine derivative and a process for producing the same. INDUSTRIAL APPLICABILITY The compound of the present invention has a theophylline-like anti-asthma action and is useful as an intermediate of an imidazolnaphthyridine derivative useful as a bronchodilator.

2. Description of the Related Art An imidazonaphthyridine derivative useful as a bronchodilator having an anti-asthma effect is disclosed in Japanese Patent Application No. 2-143.
Filed in 460. In the method according to the application, the following formula

[Chemical 6] (Wherein R ¹ has the same meaning as R ¹ described later) is reacted with trichloromethyl chloroformate to give a compound represented by the following formula:

[Chemical 7] (In the formula, R ¹ has the same meaning as described above) An acid anhydride type compound represented by
Heating to 00 to 150 ° C. to give a 4-hydroxy-3-nitro-1,8-naphthyridine derivative, amination at the 4-position and then reduction at the 3-position to give 3,4-diamino-1-phenyl-1,8. -A naphthyridine derivative was obtained, and finally an imidazole ring was formed to produce the intended imidazolnaphthyridine derivative. However, with this method,
In the step (1), trichloromethyl chloroformate, which is difficult to obtain in large quantities and generates highly toxic phosgene, is used. In the step (2), sodium hydride that explosively reacts with water as a base. In the step of (3) using the above, the reaction is carried out by heating to 100 to 150 ° C., but as a result of differential thermal analysis (DSC), the reaction product 4-hydroxy-3-nitro-1,8-naphthyridine is The derivative decomposes with a sharp exotherm at around 207 ° C,
Since the decomposition starts near 170 ° C, which is close to the reaction temperature, and it causes a decrease in yield and there is a risk of a runaway reaction. After that, ammonia is added, but since phosphorus oxychloride, which is a specific chemical substance, is used as a solvent in excess and is refluxed, there are problems in terms of safety and operation such as extremely difficult operation. And is not suitable for mass production.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a 3-nitrosonaphthyridine derivative useful as an intermediate for producing a large amount and safely of an imidazonaphthyridine derivative useful as a bronchodilator and a method for producing the same. Especially.

The present invention provides the following formula (I):

[Chemical 8] [Wherein R ¹ represents hydrogen, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, X represents O or S, and Y represents OH or NHR ²
(In the formula, R ² represents hydrogen, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl)], and a 3-nitrosonaphthyridine derivative [hereinafter referred to as compound (I)] and Regarding the manufacturing method. In the definition of formula (I), lower alkyl means linear or branched alkyl having 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl and the like are included. Aryl includes phenyl, naphthyl and the like, and aralkyl includes, for example, benzyl, benzhydryl, trityl, phenethyl, 1,2-diphenylethyl and the like having 7 to 20 carbon atoms. The substituents on the substituted aryl and the aryl moiety of the substituted aralkyl have the same or different number of substitutions of 1
To 3 include, for example, lower alkyl, lower alkoxy, lower alkoxycarbonyl, nitro, halogen, etc.,
The alkyl part of lower alkyl, lower alkoxy, and lower alkoxycarbonyl is the same as defined above, and halogen includes fluorine, chlorine, bromine, iodine and the like. In the definition of formula (I), a compound in which Y is OH [hereinafter referred to as compound (I) -1] is represented by the following formula (II)

[Chemical 9] It can be obtained by reacting a compound represented by the following formula (wherein R ¹ and X are as defined above) [hereinafter referred to as compound (II)] with sodium nitrite at room temperature.
The DSC pattern of compound (I) -1 is 4-hydroxy-
Almost the same as the 3-nitro-1,8-naphthyridine derivative, decomposition heat generation starts at around 180 ° C. However, in the presence of HNR ² , the compound has a 3rd position at a temperature much lower than the decomposition heat generation start temperature. It is rapidly enamined and Y is NHR ^{2 in} the definition of formula (I). The following compound [hereinafter referred to as compound (I) -2] can be obtained. This compound (I) -2 is easily reduced to give the result of Japanese Patent Application No. 2-1434.
The 3,4-diaminonaphthyridine derivative, which is an important intermediate of the imidazonaphthyridine derivative filed in No. 60, can be prepared. As described above, the method of using the compound (I) as an intermediate can safely produce a large amount of an imidazolnaphthyridine derivative useful as a bronchodilator without the problems associated with conventional methods. The present invention will be described in detail below. Compound (I) can be produced by the following steps.

[Chemical 10] (In the formula, R ¹ , R ² and X have the same meanings as described above.) (Step 1) The starting compound (II) is Jounal of Medicinal
It can be produced from 2-chloronicotinic acid according to the method shown in Chemistry 31 , 2108 (1990) or Reference Example 1. Compound (I) -1 can be obtained by adding an aqueous sodium nitrite solution to compound (II) in the presence of a solvent. As the solvent, for example, carboxylic acids such as formic acid, acetic acid, propionic acid and the like are used alone or in combination. The reaction is carried out at 5 to 100 ° C., preferably room temperature, and is completed in 5 minutes to 24 hours, preferably 30 minutes to 3 hours. (Step 2) Compound (I) -1, ammonium acetate, R ²
Compound (I) -2 can be obtained by reacting NH ₂ (in the formula, R ² has the same meaning as defined above) or an acid addition salt thereof in the presence or absence of a solvent. Examples of the acid addition salt include carboxylic acids such as formic acid and acetic acid, sulfonic acids such as methanesulfonic acid, and salts of inorganic acids such as hydrochloric acid and sulfuric acid. As the solvent, amides such as N, N-dimethylformamide and carboxylic acids such as acetic acid may be used alone or as a mixture. Ammonium acetate or the like is used in an amount of 2 to 100 times (weight ratio) the substrate, preferably 5 to 20.
The solvent is used in an amount of 0.1 to 10 times (weight ratio), preferably 0.2 to 5 times, the amount of the substrate. The reaction is
80-200 ° C. in the absence of solvent, preferably 100-200 ° C.
It is performed at 120 ° C., in the presence of a solvent at 0 to 100 ° C., and is completed in 5 minutes to 48 hours. Compound (I) -2 is
A 3,4-diaminonaphthyridine derivative which is easily reduced and is represented by the following formula (III) [hereinafter referred to as compound (III)]
Compound (III) can be obtained, for example, from Japanese Patent Application No.
The following formula which is useful as a bronchodilator described in 143460
The compound (I) -2 is useful as an intermediate for the compound (IV) and the like because an imidazonaphthyridine derivative represented by (IV) [hereinafter referred to as compound (IV)] can be produced.

[Chemical 11] (In the formula, R ¹ , R ² and X have the same meanings as described above.) Examples and reference examples of the present invention will be shown below.

Examples Example 1: 4-Hydroxy-3-nitroso-1-phenyl-1,8-naphthyridin-2 (1H) -one (Compound 1) 4-Hydroxy-1-phenyl obtained in Reference Example 1 −
1,8-Naphthyridin-2 (1H) -one 10.7 g (4
(5 mmol) was suspended in a mixed solution of 22.5 ml of acetic acid and 67.5 ml of water, and 10 ml of an aqueous solution containing 4.35 g (63 mmol) of sodium nitrite was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours and further cooled with ice for 1 hour, and the crystals were collected by filtration.
Dried to obtain 11.5 g (96%) of compound 1 as yellow crystals. The physicochemical properties of Compound 1 are as follows. IR (KBr) νmax (cm ^-1 ): 1678, 1585, 1437, 1402, 134
0, 1057, 783 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 8.44 (1H, br), 8.37 (1H, br),
7.46 to 7.58 (3H, m), 7.28 to 7.44 (3H, m) MS (m / e): 266 (M ⁺ ), 249 Example 2: 4-amino-3-nitroso-1-phenyl-1,8 -Naphthyridin-2 (1H) -one (Compound 2) 5 g of compound 1 obtained in Example 1 (18.7 mmol)
10 ml of acetic acid and 50 g of ammonium acetate were added to
Heated at 70 ° C. for 3 hours. After completion of the reaction, 50 ml of water was added, and the mixture was stirred under ice cooling for 2 hours, then the precipitated crystals were collected by filtration and dried to obtain 4.6 g (92%) of yellow crystals of compound 2. The physicochemical properties of Compound 2 are as follows. IR (KBr) νmax (cm ^-1 ): 1657, 1630, 1597, 1445, 134
8, 1300, 1215, 785 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 12.88 (2H, br), 8.95 (1H, d, J
= 7.2Hz), 8.51 (1H, d, J = Hz), 7.46 ~ 7.59 (3H, m), 7.32
~ 7.39 (3H, m) MS (m / e): 266 (M ⁺ ), 249 Reference Example 1: 4-hydroxy-1-phenyl-1,8-
Naphthyridin-2 (1H) -one (Compound a) 115 g (0.73 mol) of 2-chloronicotinic acid in water 38
The suspension was suspended in 0 ml, 82.8 g (0.88 mol) of aniline was added at 50 ° C., and the mixture was refluxed for 2 hours. 760m of water in the reaction solution
l was added, the mixture was cooled to room temperature, the pH was adjusted to 4 with 10N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration,
212.3 g (91%) of 2-aniliniconicotinic acid were obtained as white crystals. 212.3 g (0.99 mol) of these crystals were
227.2 g (1.09 mol) of phosphorus pentachloride was added to 5 parts of methylene chloride.
The solution suspended in 00 ml was gradually added at room temperature. After stirring for 30 minutes at room temperature, 500 ml of methanol was added at room temperature. After stirring for another 30 minutes, the reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in 1000 ml of methylene chloride, 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, and then 1 part of water.
It was washed with 000 ml. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 24-anilinonicotinic acid methyl ester as an oily substance in an amount of 241.3 g (99.7%). This was dissolved in 1500 ml of acetic anhydride, refluxed for 4 hours, and then the reaction solution was cooled. The reaction mixture was concentrated to 450 ml under reduced pressure, water (1600 ml) was added, the mixture was stirred under ice cooling for 2 hours, and the precipitated crystals were collected by filtration and dried, and N-acetyl-2-
224.3 g of anilinonicotinic acid methyl ester (83
%) Obtained as white crystals. 224.3 g (0.83) of this crystal
Was dissolved in 2000 ml of p-xylene, 186.3 g (1.66 mol) of potassium t-butoxide was added, and the mixture was refluxed for 6 hours. After cooling, 1000 ml of water was added to separate the aqueous layer, and the pH was adjusted to 6 with acetic acid. The precipitated crystals were collected by filtration under ice-cooling and dried to obtain 189.8 g (96%) of white crystals of compound a. The physicochemical properties of compound a are as follows. Mp 310 to 313 ° C. Elemental analysis C ₁₄ H ₁₀ N ₂ O ₂ theory (%) C70.58 H4.23 N11.76 Found (%) C70.32 H4.30 N11.81 IR ( KBr) νmax (cm ^-1 ): 1641, 1560, 1452, 1331, 125
2, 781 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 11.89 (1H, br), 8.42 (1H, d, J
= 7.8Hz), 7.41 ~ 7.54 (3H, m), 7.21 ~ 7.30 (3H, m), 5.90
(1H, s) Reference example 2: 5-phenyl-3H-imidazo [4,5-
c] [1,8] naphthyridin-4 (5H) -one (compound b) 4.5 g (16.9 mmol) of the compound 2 obtained in Example 2 was suspended in 90 ml of water to give sodium hydrosulfite. 9 g was added at room temperature. After reacting for 4 hours at room temperature, the crystals were collected by filtration to obtain 3,4-diamino-1-phenyl-1,8-naphthyridin-2 (1H) -one.
After drying the obtained crystals, 75 ml of ethyl orthoformate
(0.454 mol) was added, and the mixture was stirred at 120 ° C. for 2 hours.
After cooling the reaction solution, diisopropyl ether 200 m
1 was added and the crystals were collected by filtration. Compound b was recrystallized from dimethylformamide-water to give compound b as 3.
Obtained as 6 g (82%) colorless crystals. The physicochemical properties of compound b are as follows. Mp> 300 ° C. Elemental analysis _{C 15 H 10 N 4 O ·} 0.2H 2 O Theoretical value (%) C67.76 H3.94 N21.07 Found (%) C67.90 H3.70 N21.10 IR ( KBr ) νmax (cm ^-1 ): 1668, 1583, 1423 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 13.84 (1H, br), 8.50 (1H, d
d, J = 8.2Hz), 8.33 ~ 8.36 (2H, m), 7.42 ~ 7.58 (3H, m),
7.22 ~ 7.38 (3H, m)

INDUSTRIAL APPLICABILITY The present invention provides a 3-nitrosonaftyridine derivative useful as an intermediate for producing an imidazonaphthyridine derivative useful as a bronchodilator.
By using this intermediate, the imidazolnaphthyridine derivative can be produced safely and in large quantities.

Claims (3)

[Claims] 1. The formula: [Wherein R ¹ represents hydrogen, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, X represents O or S, and Y represents OH or NHR ²
(In the formula, R ² represents hydrogen, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl). 2. The formula: (Wherein R ¹ and X have the same meanings as defined above) and sodium nitrite are reacted with each other. (Wherein R ¹ and X have the same meanings as described above). 3. The formula: (Wherein R ¹ and X have the same meanings as described above) or a salt thereof and a formula R ² NH ₂ (wherein R ² has the same meanings as described above) are reacted. Formula to (Wherein R ¹ , R ² and X are as defined above).