JPH01316379A - Production of condensed heterocyclic rings - Google Patents

Abstract

PURPOSE:To obtain 2-chloroimidazo[1,2-a]pyridin-3-sulfonyl chloride, etc., by reacting 2-imino-1,2-dihydropyridine-1-acetic acid, etc., with a halogenating agent and then chlorosulfonic acid, etc. CONSTITUTION:A compound expressed by formula I (A is 6-membered heterocyclic ring which may be substituted; R is H or lower alkyl) or salt thereof is reacted with a halogenating agent (e.g., phosphorus oxychloride) at 70-180 deg.C to provide a compound expressed by formula II (X' is halogen), which is then reacted with a sulfonating agent and chlorinating agent at 60-90 deg.C to afford a compound expressed by formula III. The compound expressed by formula III useful as a raw material for herbicides, etc., can be readily obtained in high purity and yield by the above-mentioned method.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing fused heterocycles.

The compounds obtained by the method of the present invention are useful as raw material compounds for agricultural chemicals such as herbicides.

[Prior Art] As a method for producing the target compound of the method of the present invention, for example, 2-chloroimidazo[1,2
-a] A method for producing pyridazine is known.

This first step is carried out by Chemisier Berichte 57. 1:j8
1゜2092 (1924), the second step is Journal of Heterocyclic Chemistry 2.53
(1969).

Furthermore, European Published Patent Application No. 238070 describes that 2-chloroimidazo[1°2
-a1 pyridine is sulfonated to 2-chloroimidazo[
A method is described in which 1,2-a]pyridazine 3-sulfonic acid is produced, isolated, and then further reacted with a chlorinating agent to obtain 2-chloroimidazo[1,2-a]pyridazine 3-sulfonyl chloride. has been done.

[Problem to be solved by the invention] Chemisier Berichte mentioned above 57. 1381゜2
092 (1924) and Journal of Heterocyclic Chemistry λ, 53 (1969)
The method described in ) requires two reaction steps, is complicated to operate, has a low reaction yield, and is not satisfactory as an industrial production method.

In addition, in the method described in the above-mentioned European Published Patent Application No. 238070, the intermediate sulfonic acid compound easily absorbs moisture, is unstable to heat, and is difficult to handle, and requires two reaction steps, making the operation complicated. It has drawbacks such as low yield, and cannot be said to be a sufficient industrial production method.

[Means for Solving the Problems] The present invention provides (1) general formula [wherein, embedded is a 6-membered heterocycle which may be substituted, R
represents hydrogen or a lower alkyl group] or a salt thereof is reacted with a halogenating agent. A method for producing a compound represented by 1 or a salt thereof having a halogen content of 90 or less.

(2) General formula % Formula % [In the formula, the embedding represents an optionally substituted 6-membered heterocycle,
represents a halogen] or a salt thereof is reacted with a sulfonating agent, and then with a chlorinating agent. The present invention relates to a method for producing a compound or a salt thereof.

A 6-membered heterocycle indicated by embedding preferably contains 3 nitrogen atoms from 1 and further 2 oxygen atoms or/and 1 to 2 sulfur atoms from 1 (mono- or dioxidized). is a 61-element ring containing Specific examples of the six-membered heterocycle represented by embedding include pyridine, pyridazine, piperidine, pyrimidine, and triazine, preferably pyridine and pyridazine. The 6Fl heterocycle represented by ring A is, for example, a halogen or a compound of the formula -T-
Q [wherein, Q is a lower alkyl group, T is a bond, 0°S
, NH, or NR'(R' represents a lower alkyl group) may be substituted with 1 to 3 substituents.

Specifically, the group represented by the formula -T-Q is lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, mono-lower alkylamino, and di-lower alkylamino.

The lower alkyl group represented by Q, R and R' above preferably represents a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl.

5ec-butyl, tert-butyl, n-pentyl, 5
eC-pentyl, isopentyl, neopentyl, n-hexyl, etc. are used. More preferably, for example,
It is a straight chain or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, t'ert-butyl.

An example of a halogen as a substituent on a ring is fluorine.

Chlorine, bromine, etc. are used.

Examples of the halogen represented by X include fluorine, chlorine, bromine, and iodine.

For example, chlorine, bromine, etc. are used as the halogen represented by X' having atoms of m30 to 90.

Compounds (+), (II), (III) and (
As the salt IV), addition salts with organic or inorganic acids are used.

Examples of inorganic acid addition salts of compounds (1) to (IV) include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acid addition salts of compounds (1) to (fV) include Toe I-! p-Toluenesulfonic acid, Hensensulfonic acid, methanesulfonic acid, ethanesulfonic acid, phosphoric acid.

Salts with trifluoroacetic acid and the like are used.

The first step of the present invention is a step of producing compound (II) or a salt thereof from compound (1) or a salt thereof.

Compound (Il) or a salt thereof is produced by reacting compound (+) or a salt thereof with a halogenating agent.

A preferred acid addition salt of compound ([) is hydrochloric acid.

Salts with hydrohalic acids such as hydrobromic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfone H, p-
Salts with organic sulfonic acids such as toluenesulfonic acid are used. Examples of halogenating agents include phosphorus chlorides such as phosphorus oxychloride and phosphorus pentachloride, chlorinating agents such as thionyl chloride and phosgene, and brominating agents such as phosphorus oxybromide, thionyl bromide, and phosphorus pentabromide. used.

Among these, phosphorus oxychloride is preferred. In the world of halogenating agents, the compound (1) or its salt usually has a
It can be used in twice the molar amount or in large excess, also serving as a solvent.

This reaction is carried out in a solvent.

Any solvent can be used as long as it does not adversely affect the reaction. For example, toluene.

Aromatic hydrocarbons such as xylene and chlorobenzene, chloroform, carbon tetrachloride, halogenated hydrocarbons such as l,2-dichloroethane and tetrachloroethane, nitriles such as acetonitrile and propionitrile, dioxane, and tetrahydrofuran. ethers etc. are used. Among these, better <badluene, xylene, 1
．． 2-dichloroethane.

The reaction temperature is about 50-200°C, preferably about 70-1
It is 80°C. The reaction is carried out under normal pressure or increased pressure.

The time required for the reaction is several tens of minutes to several tens of hours, usually about 1 hour to 10 hours.

In addition, in order to accelerate this reaction, pyridine, triethylamine, tri-propylamine, 7-methylaniline,
Tertiary amines such as diethylaniline may also be added.

The second step of the present invention is a step of preparing compound (IV) or a salt thereof from compound (1m) or a salt thereof.

Compound (IV) or a salt thereof is prepared by reacting compound (1) or a salt thereof with a sulfonating agent (first step reaction), and then reacting the reaction mixture with a chlorinating agent (second step reaction). Manufactured by In this reaction, the sulfonating agent is about 0.5 to
The chlorinating agent is used in an amount of about 0.5 to 20 times, preferably about 1 to 2 times the mole of the compound (In) or its salt.

Examples of the sulfonating agent used include chlorosulfonic acid, fuming sulfuric acid, and sulfuric anhydride. Chlorsulfonic acid is preferred.

As the chlorinating agent, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosgene, etc. are used. Among these, phosphorus soxychloride is preferred.

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

One such solvent is chloroform.

Examples include halogenated hydrocarbons such as carbon tetrachloride, 1.2-chloroethane, trichloroethylene, and tetrachloroethane, and nitriles such as acetonitrile and propionitrile. Among these, chloroform is preferred; 1.
2-dichloroethane.

The second stage reaction is accelerated by the presence of the tertiary amine. Tertiary amines include triethylamine, trilopropylamine, and dimethylaniline.

Examples include diethylaniline. Among these, triethylamine is preferred.

The reaction temperature is approximately 30 to 15% for both the first and second stage reactions.
0°C1 is preferably about 60-90°C. The reaction time is about 1 to 15 hours for the first stage, preferably about 3 to 7 hours, and about 1 to IO hours, preferably about 2 to 5 hours for the second stage reaction.

Compounds (u), (1'ir
) or their salts can be isolated and purified by methods known per se, such as concentration, vacuum concentration, water injection, extraction, dissolution, crystallization, recrystallization, and chromatography.

Compound (IV) or a salt thereof prepared by the method of the present invention is further reacted with ammonia without being isolated to form a compound represented by the general formula (V) (the symbols in formula 1 have the same meanings as above). Or you can lead to the salt.

In the reaction of compound (IV) or a salt thereof with ammonia, ammonia is usually used in an amount of about 0.8 to 10 mol per mol of compound (IV) or a salt thereof. This reaction is usually carried out in an inert solvent such as ethers such as water-ether and tetrahydrofuran, nitriles such as acetonitrile, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as dichloromethane, chloroform, and l,2-dichloroethane. It takes place inside. The reaction temperature is about -6
0 to 100°C. The reaction time is about 30 minutes to 8 hours.

Compound (II), (R') or a salt thereof is a known herbicide (EP-Δ238070. JP-A-64-38091).
It is useful as an intermediate for the sulfonylurea compounds described in .

For example, a sulfonylurea compound (■) having herbicidal activity or a salt thereof can be derived from compound (U), (IV) or a salt thereof by the route of the following formula.

(Left below) (Vr) [In the formula, embedding and It shows excellent selective weeding effect against weeds, has low toxicity to mammals, fish and shellfish, and does not pollute the environment, and can be used for weeding rice fields, fields, orchards, and non-agricultural land. It can be used extremely safely as a drug.

The raw material compounds ([), (II) or salts thereof for the method of the present invention can be prepared by known methods (for example, EP-A 238070.
It can be produced by a method described in JP-A No. 64-38091) or a method similar thereto.

Next, the present invention will be explained more specifically using reference examples and examples.

Reference Example 1 2-Imino-1,2-dihydropyridine-1=acetic acid Dissolve 50.2 g of monochloroacetic acid in 20 d of ethanol. Under cooling and stirring, dissolve 75 d of triethylamine.
at 10-15°C, then 2-aminopyridine 50°C.
．． Add Og. After heating the reaction solution to 75-80°C for 5 hours, 100 d of ethanol is added and then cooled with ice water. The precipitated crystals are collected by filtration, washed with ethanol, and dried to obtain 64.6 g (yield: 80.0%) of the title compound.

mp 250°C (dec, ) Reference example 2 6-chloro-3-imino-2,3-dihydropyridazine-2-acetic acid 56.0 g of monochloroacetic acid was mixed with 80 M of water and 4 ml of ethanol.
60.7 g of triethylamine dissolved in 0d and stirred while cooling.
dropwise at 5-10°C. 3-amino-6- in the reaction solution
Chloro-pyridazine 52.0g [Journal of American Chemical Society (J, Δ, C9S,)
76 3225 (1954)] and 9
Heat at 0'C for 7 hours. After cooling, add 40 m (l) of ethanol.
Add and leave overnight. The precipitated crystals were collected by filtration and dried with ethanol for 15 minutes to obtain 36.0 g (yield: 47.8%) of the title compound.

mp 1899C (dec, ) NMR (D, 0) δ: 4.90 (s, 211), 7
．． 63 (d, 1ll), 7°84 (d, 111) Reference example 3 2-imino-1,2-dihydropyridine-1-acetic acid ethyl ester hydrobromide 19.0 g of 2-aminopyridine and ethyl bromoacetate 33
, 0 g was dissolved in 20 liters of acetone and heated under reflux for 1 hour. The precipitated crystals were collected by filtration, washed with acetone and dried to obtain 43.2 g (yield: 81.9%) of the title compound.

Reference example 4 2-chloroimidazo[1,2-a]pyridazine a) 2-
Imino-1,2-dihydropyridine-1-acetic acid 10.0
g is dissolved in 200 d of a 30 w/w % aqueous sodium hydroxide solution and heated under reflux for 30 minutes. The reaction solution was cooled with water. The precipitated colorless scaly crystals were collected by filtration and dried to yield 7.0 g of 2-hydroxyimidazo[1,2-a]pyridazine sodium salt.
(Yield 68.2%) is obtained.

(b) Add 25d of phosphorus oxychloride to 2-hydroxy-
imidazo[1,2-a]pyridazine sodium salt 7°O
Slowly add g (vigorous exotherm). After adding the entire amount, heat and reflux for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was poured into ice water. After extraction with chloroform, separate the chloroform layer. The aqueous layer is neutralized with sodium hydroxide solution and further extracted with chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, and the chloroform was distilled off under reduced pressure to obtain 5.8 g of crude crystals of the title compound (yield: 82.
5%) is obtained. The crude crystals are purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 4.0 g (yield 58.0%) of the title compound as colorless needle-like crystals.

mp 73-75°C Reference example 5 2-chloroimidazo[1,2-b]virida/n 2.6-
3.0 g of dichloroimidazo[1,2-b]pyridazine is dissolved in 100 d of tetrahydrofuran and 50 d of ethanol, and 0.30 g of 10% palladium on carbon and 1.6 g of triethylamine are added and hydrogenated. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: chloroform) to obtain 1.6 g (yield: 65.3%) of the title compound as colorless crystals.

NMR (CDC&j) δ: 7.06 (dd, 1ll
), 7.87 (d, II+), 7.91 (s, 1
ll), 8.33(d, 1tl) Reference Example 6 2-chloro-6-methylimidazo[1,2-b]pyritazine 2.6-dichloroimidazo[1,2-bl pyritazine 5
0 g was dissolved in 100 d of tetrahydrofuran, and 30 d of an ether solution of methylmagnesium bromide (3 mol/l2) was added dropwise over 5 minutes while stirring at room temperature.

After continued stirring for 20 hours, 5M ethyl acetate was added to decompose the supercharge methylmagnesium bromide.

The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After separating the chloroform layer and distilling off the chloroform under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 0.71 g (yield 16.9%) of the title compound as colorless crystals. It will be done.

NMR (CDC,) δ: 2.57 (s, 311)
, 6.95(d, III).

77s (d, l11), 7. go(d, nD[
Examples] Example 1 45.7 g of 2-chloroimidazo[1,2-a]pyridine 2-imino-1,2-dihydropyridine-1-acetic acid is suspended in 120 d of toluene. 93.1 g of phosphorus oxychloride was heated and stirred at 105-110° C. over 1 hour, and the mixture was refluxed for 5 hours. After cooling, pour the reaction solution into ice water and separate the liquid. The aqueous layer was dissolved in sodium hydroxide solution 3001t1 (N
ao (containing 883.7 g) at 30-45°C, and the precipitated crystals are collected by filtration, washed with water (100 dX 2'), and dried to obtain 42.0 g (yield 91.7%) of the title compound as colorless crystals. .

mp 72-73°C Example 2 2-chloroimidazo[1,2-a]pyridine 2-im/
10.4 g of -1,2-dihydropyridine-1-acetic acid ethyl ester hydrobromide is heated under reflux for 6 hours in 30 d of phosphorus oxychloride. After cooling, pour the reaction solution into ice water and neutralize with aqueous ammonia. Extract with chloroform, wash with water, and dry over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure to obtain 5.6 g (yield: 91.8 g) of the title compound.

mp 71-73°C Example 3 2.6-dichloroimidazo[1,2-b]pyridazine 6-chloro-3 in a 100d pressure-resistant reaction tube (stainless steel)
-Imino-2,3-dihydropyridazine-2-acetic acid6.
Add 7 g and 50 d of phosphorus oxychloride and heat to 180°C after sealing.
Heat for 7 hours. After cooling, pour the reaction solution into ice water.
Neutralize with w% aqueous sodium hydroxide solution and extract with chloroform. After decolorizing the chloroform layer with preparative silica gel, the chloroform is distilled off to obtain 5.3 g (yield 78.9%) of the title compound as colorless crystals.

mp 175-176°C NMR (CDCf23) δ: 7.12 (d, III
), 7.83(d, III).

7,87 (s, III) Example 4 2-chloroimidazo[1,2-alpyridine-3-sulfonyl chloride (compound "A No, l) 2-chloroimidazo[1,2-a]pyridine 15.3 g was dissolved in 75d of dichloroethane. Under stirring, chlorosulfonic acid (
144 g (content: 9 g, 5 w/w%) was added dropwise over 10 minutes (exothermic heat was generated and the temperature of the reaction solution rose to 45-50°C).

After heating under reflux for 5 hours, the mixture was cooled to 20°C, 12.1 g of triethylamine was added, and the mixture was heated under reflux for 10 minutes. After adding 16.9 g of phosphorus oxychloride over 30 minutes under reflux, heating and refluxing was continued for an additional 3 hours. After cooling, the mixture was poured into 200H of ice water, stirred for 30 minutes, and then the dichloroethane layer was separated.

Dichloroethane was distilled off under reduced pressure and the residue was dried to obtain 24.7 g (yield 97.6%) of the title compound as pale yellow crystals.

NMR(CDC(!z)δ: 7.2-7.4(m,I
II), 7.6-7゜9 (m, 211), 8.8
7(d, l1l) Example 5 2-chloroimidazo[1,2-a]pyridine-3-sulfonyl chloride (compound No. 1) 15.3 g of 2-chloroimidazo[1,2-a]pyridine was dissolved in chloroform 7
Dissolves in 5d. Chlorosulfonic acid (including ffi:
98.5v/w%) was added dropwise over 5 minutes (the temperature of the reaction solution rose to 59°C), and the mixture was heated under reflux for 5 hours. After cooling, 13.0 g of triethylamine was added, and then 23.2 g of phosphorus oxychloride was added dropwise over 10 minutes, followed by heating under reflux for 3 hours. After cooling, pour into 200H of ice water and stir for 20 minutes. Separate the chloroform layer and distill off the chloroform under reduced pressure. After washing the solid residue with water, it is dissolved in dichloromethane and dried over anhydrous sodium sulfate. When dichloromethane was distilled off under reduced pressure, 23.3 g of the title compound (yield 92.7%) was obtained.
) or as pale yellow crystals.

NMR was completely consistent with that obtained in Example 4.

Example 6 Compounds obtained in the same manner as Examples 4 and 5 are shown in Table 1.

Table 1 *Used in the next reaction without isolation Compounds Nos. 2 to 5 obtained in the secondary reaction were reacted with ammonia by the method shown below to form compound (Va), and the structure of each was recognized as r6. (Table 2) (Method) Compounds Nos. 2 to 5 (0.01 mol) were dissolved in 10 M1 of acetonitrile, and 5 d of aqueous ammonia was added under water cooling, followed by stirring at room temperature for 15 hours. Acetonitrile is distilled off under reduced pressure, water is added to the residue, and the precipitate is filtered, washed with water, and dried to obtain crystals of the corresponding sulfonamide.

[Effect of the Invention 1] The method of the present invention allows obtaining the target compounds (II) and (IV) with good yield (high purity) through short steps and simple operations.

Agent Patent Attorney Iwa 1) Hiroshi

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, ring A is an optionally substituted 6-membered heterocycle, R
represents hydrogen or a lower alkyl group] or its salt is reacted with a halogenating agent ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Symbol A in the formula is the same as above] Same meaning, X' represents a halogen having an atomic weight of 30 or more and 90 or less] or a method for producing a salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, ring A is an optionally substituted 6-membered heterocycle,
represents a halogen] or its salt is reacted with a sulfonating agent and then a chlorinating agent ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Symbols in the formula has the same meaning as above] or a method for producing a salt thereof.