JPH0477474A - Production of 6-amino-3-chloropyridazine - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the subject compound under a low reaction pressure at a low ammonia concentration by reacting 3,6- dichloropyridazine with ammonia in the presence of an ammonium salt. CONSTITUTION:3,6-Dichloropyridazine expressed by formula I is allowed so react in aqueous ammonia at ambient temperature to 150 deg.C, preferably at 50-130 deg.C temperature by adding an ammonium salt thereto to afford 6-amino-3- chloropyridazine expressed by formula II. The reaction pressure depends on the concentration of the aqueous ammonia and reaction temperature and, e.g. the initial pressure can be 2.0-4.0kg/cm<2> when the aqueous ammonia concentration is 5-20% and the reaction temperature is 100-120 deg.C. Imidazo[1,2-b]pyridazine, expressed by formula III and useful as a raw material for a substituent group at the 3position of cephalosporins having excellent antimicrobial action is obtained by reacting the compound expressed by formula II with monochloroacetaldehyde and then subjecting the resultant compound to dehalogenating reaction.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides a cephalosporin compound having an antibacterial effect,
For example, 7β-[(Z)-2-(5-amine 1.2.4-
As a raw material compound for the 3-position substituent of thiadiazol-3-yl)-2-methoxyiminoacetamide 3-(imidazo[1,2-b](pyridazinium)methyl-3-cephem 4-carboxylate, other pharmaceuticals and agricultural chemicals Imidazo [
The present invention relates to a method for producing 6-amino-3-chloropyridazine, which is useful as a raw material for 1,2-b]pyridazine.

(Prior Art and Problems to be Solved by the Invention) Conventionally, as a method for producing 6-amino-3-chloropyridazine, there has been a method in which 3,6-dichloropyridazine is reacted with concentrated aqueous ammonia (He1v, Chim.

Acta, 37, 121 (1954)), and the reaction method in ammonia/absolute ethanol (USP 29
27112, JAC8, 76, 3225 (1954)
) etc. are known. The former reaction is a high temperature (100°C) reaction in concentrated ammonia water, so the pressure is 7 kg/
am', and the latter reaction is also at a temperature of 130° C. and has an even higher pressure, so the high-pressure gas method is applied as an industrial production method. Furthermore, the yield is 80% for the former and 7 for the latter.
As low as 0%. Under such circumstances, a method that provides a high amination yield under lower pressure has been desired.

An object of the present invention is to provide an industrially advantageous and practical method for producing 6-amino-3-chloropyridazine by aminating 3,6-cyclopyritanine under milder conditions.

(Means for Solving the Problems) The present inventors have discovered an industrially advantageous 6-amino-3-chloropyridazine (hereinafter referred to as ACP) represented by -N
As a result of intensive research to find a method for producing 3,6-cyclobilitacin (sometimes abbreviated as DCP),
By reacting ammonium salt in ammonia water with the addition of an ammonium salt, ACP can be produced in an unexpectedly high yield and at lower pressure and lower ammonia concentration than conventional methods.
They found that the present invention can be obtained industrially advantageously, and after further studies, they completed the present invention.

A detailed explanation will be given below.

Ammonium salts to be used in the present invention include ammonium halides (e.g., ammonium chloride, ammonium bromide, etc.), ammonium sulfate, ammonium carbonate,
Ammonium acetate and the like can also be used. The amount of ammonium salt used is approximately ○ to 6 times the molar amount of DCP.
Preferably, about 0.2 to 5 times the molar amount is used.

The reaction is usually carried out at a high temperature of from room temperature to 150'C, preferably from 50°C to 130'C. The reaction time is the reaction temperature,
Although it can be set as appropriate in relation to the reaction conditions such as ammonia concentration, the time is usually in the range of 10 minutes to 40 hours, preferably 30 minutes to 40 hours.

The amount of ammonia used is approximately 1 to 2 times the mole of DCP.
It is preferably used in an amount of about 1 to 12 times the mole.

The reaction pressure is determined by the amount of ammonia water used and the reaction temperature. For example, in a reaction with 10% ammonia water at 100°C, the initial pressure is about 2 kg/cm2, and in a reaction with 15% ammonia water at 100°C, the initial pressure is about 3 kg/cm'. The concentration of ammonia water is 5% to 20%, preferably 10%.
By selecting the reaction temperature to be 10.5% to 10.5% and preferably 100 to 10.5°C, the initial pressure can be suppressed to below about 20 to 4.0 kg/cm'.

ACP and DCP may be salts, including inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, e.g. Examples include organic acid addition salts such as fluoroacetate, methanesulfonate, and p-toluenesulfonate.

If ACP is obtained free by the above reaction,
It can be converted into a salt, or if it is obtained as a salt, it can be converted into a free form by a known method.

The ACP thus produced i.e. 6-amino-3
-Chloropyridazine or a salt thereof can be isolated and purified by means known per se, such as concentration, vacuum concentration, extraction, dissolution, crystallization, recrystallization, and chromatography.

In particular, the produced 6-amino-3-chloropyridazine is advantageously separated after the completion of the reaction by cooling the reaction solution to crystallize it, and in this way it can be obtained as highly pure crystals.

Furthermore, the ACP obtained by the method of the present invention can be obtained from public TazoCl.
2-b]pyritanne (hereinafter sometimes abbreviated as CIP).

As a method for this purpose, it is convenient to obtain it by reacting with monochloroacetaldehyde as described in, for example, JP-A-2-40387.

Furthermore, the obtained 6-chloroimidazoN, 2bEpyridazine is subjected to dehalogenation reaction 2, such as reductive de...
N'7 dazoF1,2-b]pyritazine (hereinafter sometimes abbreviated as IP) or a salt thereof.

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

DCP ACP IP These preferred implementation methods are detailed below.

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

This reaction is carried out in a solvent that does not inhibit the reaction.

Examples of such solvents include water, alcohols such as methanol, ethanol, n-propanol, isopronochloro, n-butanol, and tert-butanol;
Ethers such as oxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, sulfoxides such as /methylsulfoquinde, and fluoric acid.

Aliphatic carboxylic acids such as acetic acid and propionic acid are used. If necessary, two or more of these solvents may be mixed in any ratio, for example, in a ratio of 1:1 to 1:10. Of the above, water, alcohols, and mixed solvents of water and alcohol are particularly preferred.

The reaction is normally carried out at a temperature of about 30 to 110°C, preferably about 50 to 100°C. The reaction time can be set as appropriate depending on the reaction conditions such as reaction temperature, and is usually in the range of about 10 minutes to 20 hours, preferably about 30 minutes to 10 hours.

6-chloroimidazolo 2-b thus obtained]
Piritanne hydrochloride can be prepared by means known per se, such as concentration, vacuum concentration, extraction, dissolution, crystallization, and recrystallization.

It can be isolated and purified by chromatography or the like. For example, after the completion of the reaction, the desired 6-chloroimidazo[1,2b]pyridazine hydrochloride may be precipitated by cooling the reaction solution, and this may be filtered off, or the reaction solution may be concentrated under normal pressure or reduced pressure. The desired 6-chloroimidazo[1,2-b]pyridazine hydrochloride is precipitated by adding an organic solvent, such as the above-mentioned alcohols, to the resulting residue, and is removed by conventional means such as filtration. It can also be collected. The water in the reaction solution is preferably distilled off azeotropically by adding ethanol or the like. Also, 6-chloroimidazo [
The reaction solution may be directly subjected to the next dehalogenation reaction (preferably reductive halogenation reaction) without separating the crystals of 1,2-bl pyrimidine hydrochloride.

Furthermore, 6-chloroimidazo[1,2-bll pyrimidine hydrochloride may be converted into a free base by a known method and then subjected to a dehalogenation reaction.

As a method for reductive membrane halogenation, a catalytic reduction method can be used. That is, 6-chloroimitan E
The reaction is carried out by shaking or stirring 1,2-bIl pyritazine or its hydrochloride in a suitable solvent in the presence of a catalyst for catalytic reduction in a hydrogen stream. As the catalyst for catalytic reduction, for example, Pararum-Hon, Paraum-Kuro, Ufu-Ninoker, etc. are used. Preferred is palladium carphone. Examples of the reaction solvent include water, alcohols such as methanol and ethanol, and dioxane.

Ethers such as tetrahydrofuran, dimethylformamide, etc. are used. Two or more types of these may be used in combination.

The reaction can also be carried out under alkaline conditions by adding an organic base, for example, a tertiary amine such as triethylamine or tri-n-butylamine.

The reaction is usually carried out at about 10°C to 70°C, preferably 20°C.
The temperature is between 50°C and 50°C. The reaction is usually carried out under normal pressure to increased pressure. The reaction time is usually about 10 minutes to 18 hours.

Further, a method of reaction with sodium or lithium in liquid ammonia, a method of reductive membrane halokenization with zinc and hydrochloric acid or acetic acid, and a method of reductive membrane halokenization by electrolytic reduction reaction can also be used.

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

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

Compound (1) or a salt thereof obtained in this way can be purified by isolation and purification means known per se, such as concentration, vacuum concentration, vacuum distillation, liquid conversion, dissolution, solvent extraction, crystallization recrystallization, chromatography, etc. It can be isolated and purified.

(Example) Examples of the present invention are shown below.

Examples 1 to 4 According to the conditions listed in Table 1 below, 36.8 g of 3,6-cyclopyridazine and 20 g of ammonia water at each concentration were added.
0m was placed in an autoclave and reacted at different temperatures for different times. After the reaction was completed, the mixture was cooled to below 10'C and stirred for 1 hour, and the precipitated crystals were filtered and washed with 30 d of water.

The crystals and washing solution were analyzed by high performance liquid chromatography to determine the production rate of 6-amino-3-riOOpynodazine. The analysis conditions are as follows.

Column YMCA-312 Detector: UV254nm Mobile phase: 0.005M tetra-n-butylammonium solution 't& (pH 5,5), acetonitrile (93N) Flow rate: 1. Om/min The results are shown in Table-1.

(Left below) Example 5 21.0 g of 6-ami7-3-chloropyridazine obtained by the method of Example 3 (purity 100%), 40% (W/W)
663.0 g (twice the molar amount) of an aqueous monochloroacetaldehyde solution and 105 d of water were mixed at 70'C for 7 hours.

After cooling, 1.5 g of activated carbon was added to the reaction solution, stirred at room temperature for 1 hour, and then filtered and washed with water. This activated carbon treatment solution contains
6-chloroimidazo[l,2-b]pyritazine is 30.
2g'' (yield 98.1%).

The yield marked 9 was measured by high performance liquid chromatography under the following conditions.

Column: YMCA-312 Detector'UV 254nm Mobile phase 0. IM! Aqueous solution of potassium phosphoric acid/acetonitrile/triethylamine (85:15:0.5) Flow rate: IOㆆ/n+in Example 6 Liquid containing 30.2 g of 6-chloroimidazoE1.2b]pyridazine obtained in Example 5 of water 60d and 10% (w
/v) Palladium on carbon [50% (w/w) wet] 2°2g
Put it in a 500d capacity autoclave with hydrogen pressure of 5kg.
/cm'' at room temperature for 5 hours. After the reaction was completed, one catalyst was removed and the reaction solution was concentrated under reduced pressure.

1001 dl of isobutanol was added to the concentrate, and a Dean-Stark type dehydrator was equipped to perform azeotropically dehydrated liquid reflux under reduced pressure. Distillation was stopped when the aqueous layer of the distillate reached 34 m, and the mixture was stirred at 15°C for 1 hour to crystallize. After filtering the precipitated crystals and washing them with 60 ml of isobutanol, the crystals were dried under reduced pressure to obtain 22.8 g of white imidazo[1,2-b]pyritacin hydrochloride (purity, 100% as hydrochloride, yield 92
．． 3%).

Note that the purity marked with ' was measured by high performance liquid chromatography as described in Examples.

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

This makes imidazo Jl useful as a raw material for the 3-position substituent of cephalosporin, which has excellent antibacterial activity.
, 2-bl biritanne or a salt thereof can be provided.

Claims (2)

[Claims] (1) A method 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) 6-chloroimidazo[1,2
-b] A method for producing imidazo[1,2-b]pyridazine or a salt thereof, which comprises subjecting pyridazine or a salt thereof to a dehalogenation reaction.