JP3012993B2 - Method for producing 6-amino-3-chloropyridazine - Google Patents

Description

The present invention relates to a cephalosporin compound having an antibacterial activity, for example, 7β-[(Z) -2- (5-amino-1,2,4,4).
-Thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (imidazo- [1,2-b] (pyridazinium) methyl-3-cephem-4-carboxylate as a starting compound for the 3-position substituent The present invention also relates to a method for producing 6-amino-3-chloropyridazine, which is useful as a raw material for imidazo [1,2-b] pyridazine, which is useful as a starting compound for compounds useful as pharmaceuticals and agricultural chemicals.

(Problems to be Solved by the Related Art and the Invention) Conventionally, as a method for producing 6-amino-3-chloropyridazine, a method of reacting 3,6-dichloropyridazine with concentrated aqueous ammonia (Helv. Chim. Acta, 37,121 (1954)),
And a method of reacting in ammonia / absolute ethanol (US Pat. No. 2,927,112, JACS., 76, 3225 (1954)). The former reaction is a high-temperature (100 ° C) reaction in concentrated ammonia water, so the pressure is as high as 7 kg / cm ² , and the latter reaction is a reaction at a temperature of 130 ° C, which is even higher. Subject to the Gas Act. Furthermore, the yields are as low as 80% for the former and 70% for the latter. Under such circumstances, a method for providing a high amination yield under a lower pressure has been desired.

It is an object of the present invention to provide an industrially advantageous and practical process for preparing 6-amino-3-chloropyridazine by amination of 3,6-dichloropyridazine under milder conditions.

(Means for Solving the Problems) The present inventors have found that an industrially advantageous formula As a result of intensive studies to find a method for producing 6-amino-3-chloropyridazine (hereinafter sometimes abbreviated as ACP) represented by the following formula, 3,6-dichloropyridazine (hereinafter D)
By adding an ammonium salt in aqueous ammonia to react with ACP at an unexpectedly high yield and a lower pressure and lower ammonia concentration than the conventional method.
Have been found to be industrially advantageous, and have been further studied to complete the present invention.

 A detailed description is given below.

As the ammonium salt to be used in the present invention, ammonium halide (for example, ammonium chloride, ammonium bromide, etc.), ammonium sulfate, ammonium carbonate, ammonium acetate and the like can be used. The amount of ammonium salt used is about 0.1 to 6 times the molar amount of DCP,
Preferably, it is used in a molar amount of about 0.2 to 5 times.

The reaction is usually performed at room temperature to 150 ° C, preferably at 50 ° C to 130 ° C.
Performed at high temperatures. The reaction time can be appropriately set in relation to the reaction conditions such as the reaction temperature and the ammonia concentration.
Usually it ranges from 10 minutes to 40 hours, preferably from 30 minutes to 40 hours.

The amount of ammonia used is about 1 to 20 times mol, preferably about 1 to 12 times mol of DCP.

The reaction pressure is determined by the concentration of the aqueous ammonia used and the reaction temperature. For example, the initial pressure is about 2 kg / cm ² for a reaction of 10% aqueous ammonia at 100 ° C., and about 3 kg / cm ² for a reaction of 15% aqueous ammonia at 100 ° C. Ammonia water concentration 5% ~ 2
0%, preferably 10% to 15%, and the reaction temperature is 100 ° C to 120 ° C
Preferably, the initial pressure can be suppressed to about 2.0 to 4.0 kg / cm ² or less by selecting from 100 ° C. to 105 ° C.

ACP and DCP may be salts, and such salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, for example, formate, acetate, trifluoroacetate. Organic acid addition salts such as acetate, methanesulfonate, p-toluenesulfonate and the like can be mentioned.

If ACP is obtained free by the above reaction,
Each of them can be converted into a salt or, when obtained with a salt, into a free form by a known method.

The ACP thus produced, namely 6-amino-3
-Chloropyridazine or a salt thereof can be isolated and purified by a means known per se, for example, concentration, concentration under reduced pressure, extraction, phase transfer, crystallization, recrystallization, or chromatography.

Particularly, the formed 6-amino-3-chloropyridazine is advantageously cooled after the completion of the reaction, crystallized by cooling, and separated, and thus can be obtained as high-purity crystals.

Further, ACP obtained by the method of the present invention can be prepared by a known method or the like. 6-chloroimidazo [1,2-b] pyridazine represented by the following formula (hereinafter sometimes abbreviated as CIP).

This method is conveniently obtained by reacting with monochloroacetaldehyde, for example, as described in JP-A-2-40387.

Further, the obtained 6-chloroimidazo [1,2-b] pyridazine is subjected to a dehalogenation reaction, for example, a reductive dehalogenation reaction to give a compound of the formula Imidazo [1,2-b] pyridazine represented by the following formula (hereinafter I)
P) or a salt thereof.

 These series of steps can be represented by the following formula.

These preferred embodiments are described in detail below.

In the reaction from ACP to CIP, monochloroacetaldehyde is used in an amount of about 1 to 6 times, preferably about 1 to 5 times, the molar amount of 6-amino-3-chloropyridazine. Monochloroacetaldehyde is in the form of solid or aqueous solution, usually about 55 to 1% (W / W), preferably 55 to 1% (W / W).
A content of about 20% (W / W) is used.

This reaction is performed in a solvent that does not inhibit the reaction. Examples of such a solvent include water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dioxane,
Ethers such as tetrahydrofuran, acetonitrile,
Nitriles such as propionitrile, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, and aliphatic carboxylic acids such as formic acid, acetic acid and propionic acid are used. If necessary, two or more of these solvents may be mixed at an arbitrary ratio, for example, at a ratio of 1: 1 to 1:10. Among them, water or alcohols, and a mixed solvent of water and alcohol are particularly preferable.

The reaction is usually about 30 to 110 ° C, preferably about 50 to 100 ° C
At a temperature of The reaction time can be appropriately set depending on the reaction conditions such as the reaction temperature, but is usually from about 10 minutes.
20 hours, preferably in the range of about 30 minutes to 10 hours.

The 6-chloroimidazo [1,2-
b] Pyridazine hydrochloride can be isolated and purified by a means known per se, for example, concentration, concentration under reduced pressure, extraction, phase transfer, crystallization, recrystallization, chromatography and the like. For example, after the reaction is completed, the reaction solution is cooled to obtain the desired 6
-Chloroimidazo [1,2-b] pyridazine hydrochloride may be precipitated and collected by filtration, or the reaction solution may be concentrated under normal pressure or reduced pressure, and the resulting residue may be added with an organic solvent such as those described above. The desired 6-chloroimidazo [1,2-b] pyridazine hydrochloride can be precipitated by adding an alcohol or the like, and can be collected by conventional means such as filtration. The water in the reaction solution is preferably distilled off azeotropically by adding ethanol or the like. In addition, 6-chloroimidazo [1,2-
b] The reaction solution may be directly subjected to the next dehalogenation reaction (preferably reductive halogenation reaction) without separating the pyrimidine hydrochloride crystals.

Further, 6-chloroimidazo [1,2-b] pyrimidine hydrochloride may be converted to a free base by a method known per se and then subjected to a dehalogenation reaction.

As a method for reductive dehalogenation, a catalytic reduction method can be used. That is, the reaction is carried out by shaking or stirring 6-chloroimidazo [1,2-b] pyridazine or a hydrochloride thereof in a suitable solvent in the presence of a catalyst for catalytic reduction in a stream of hydrogen. As the catalyst for catalytic reduction, for example, palladium carbon, palladium black, Raney nickel or the like is used. Preferably, it is palladium carbon. Examples of the reaction solvent include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and dimethylformamide. These may be used as a mixture of two or more.

The reaction is carried out with an organic base such as triethylamine, tri-n-
The reaction can be performed under alkaline conditions by adding a tertiary amine such as butylamine.

The reaction is usually performed at about 10 ° C to 70 ° C, preferably at 20 ° C to 50 ° C. The reaction is usually performed under normal pressure to pressurization. The reaction time is usually about 10 minutes to 18 hours.

Further, a method of reacting sodium or lithium in liquid ammonia, a method of reductive dehalogenation with zinc and hydrochloric acid or acetic acid, a method of reductive dehalogenation by an electrolytic reduction reaction, and the like can also be used.

When IP is obtained as a free base, salts which may be converted to salts by known means include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, for example, formic acid Organic acid addition salts such as salts, acetates, trifluoroacetates, methanesulfonates, and p-toluenesulfonates.

General methods for synthesizing DCP and its salts are known, and can be easily produced by a known method described in the literature or a method analogous thereto.

The compound (I) or a salt thereof thus obtained can be isolated and purified by a means known per se, for example, concentration, concentration under reduced pressure, distillation under reduced pressure, liquid conversion, liquid transfer, solvent extraction, crystallization, recrystallization, chromatography and the like. Can be isolated and purified.

(Examples) Examples of the present invention will be described below.

Examples 1 to 3 According to the conditions described in Table 1 below, 36.8 g of 3,6-dichloropyridazine and 200 ml of aqueous ammonia at each concentration were placed in an autoclave and reacted at each temperature for each time. After completion of the reaction, the mixture was cooled to 10 ° C. or lower and stirred for 1 hour, and the precipitated crystals were collected and washed with 30 ml of water.

The crystals and the washings were analyzed by high performance liquid chromatography to determine the yield of 6-amino-3-chloropyridazine. The analysis conditions are as follows.

Column: YMC A-312 Detector: UV254 nm Mobile phase: 0.005 M tetra-n-butylammonium solution (pH 5.5) / acetonitrile (93: 7) Flow rate: 1.0 ml / min The results are shown in Table 1.

Example 5 21.0 g (purity 100%) of 6-amino-3-chloropyridazine obtained by the method of Example 3, 63.0 g (2 times molar amount) of a 40% (w / w) aqueous solution of monochloroacetaldehyde and 105 ml of water
Was stirred at 70 ° C. for 7 hours. After cooling, add activated carbon to the reaction mixture.
After adding 5 g and stirring at room temperature for 1 hour, the mixture was washed with water. 6-chloroimidazo [1,2-b] is contained in the activated carbon treated liquid.
Pyridazine was contained in 30.2 g ^* (yield 98.1%).

The yields marked with ^* were measured by high performance liquid chromatography under the following conditions.

Column: YMC A-312 Detector: UV 254 nm Mobile phase: 0.1 M aqueous solution of potassium phosphate / acetonitrile / triethylamine (85: 15: 0.5) Flow rate: 1.0 ml / min Example 6 6 obtained in Example 5 -Chloroimidazo [1,2-b]
A solution containing 30.2 g of pyridazine is placed in a 500 ml autoclave together with 60 ml of water and 2.2 g of 10% (w / w) palladium carbon [50% (w / w) wet] and stirred at room temperature under a hydrogen pressure of 5 kg / cm ² for 5 hours. Was. After completion of the reaction, the catalyst was removed, and the reaction solution was concentrated under reduced pressure. Add 100 ml of isobutanol to the concentrate and add
Equipped with a Stark type dehydrator, azeotropic dehydration and separation were performed under reduced pressure. When the aqueous layer of the distillate reached 34 ml, the distillation was stopped, and the mixture was stirred at 15 ° C. for 1 hour for crystallization. The precipitated crystals are collected, washed with 60 ml of isobutanol, and dried under reduced pressure to give 22.8 g of white imidazo [1,2-b] pyridazine hydrochloride (purity: 100% ^* as hydrochloride, 92.3% yield). Obtained.

The purity of the mark ^* was measured by the high performance liquid chromatography described in the examples.

(Effect of the Invention) The present invention provides an industrially suitable method for producing 6-amino-3-chloropyridazine, which has a low reaction pressure and uses a small amount of ammonia.

This can provide an efficient process for producing imidazo [1,2-b] pyridazine or a salt thereof, which is useful as a raw material for the 3-position substituent of cephalosporin having excellent antibacterial activity.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 237/20 C07D 487/04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A process for producing 6-amino-3-chloropyridazine or a salt thereof, which comprises reacting 3,6-dichloropyridazine or a salt thereof with ammonia in the presence of an ammonium salt. 2. A reaction of 3,6-dichloropyridazine or a salt thereof with ammonia in the presence of an ammonium salt, and a reaction of 6-amino-3-chloropyridazine with monochloroacetaldehyde to obtain 6-chloroimidazo [1] , 2-b] pyridazine or a salt thereof is subjected to a dehalogenation reaction, a process for producing imidazo [1,2-b] pyridazine or a salt thereof.