KR100494058B1 - Novel 1-acyl(or aroyl)pyridazin-6-one derivatives, process for preparation of the same and its use as acylating agent - Google Patents

Abstract

The present invention provides a novel 1-acyl (or aroyl) pyridazin-6-one derivative represented by the following general formula (I), a preparation method thereof, and a carboxylic acid, activated methylene, amino acid, aminocarboxylic acid, alcohol and amine A method for use as an acylation reagent.

Wherein X, Y and Z represent the same or differently substituted halogen atom, hydrogen, nitro, cyano, C ₁ -C ₆ alkoxy, phenoxy (substituted phenoxy), heteroaryloxy and the like; R is independently at each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted Heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl and the like.

Description

Novel 1-acyl (or aroyl) pyridazin-6-one derivatives, process for preparation of the same and a novel 1-acyl (or aroyl) pyridazin-6-one derivative its use as acylating agent}

The present invention relates to a novel acylating agent and its use, and more particularly, 1-acyl (or aroyl) pyridazin-6-one derivative represented by the following general formula (I), a preparation method thereof and the following general formula (I) It relates to a method of acylating carboxylic acid, active methylene, amino acid, aminocarboxylic acid, alcohol and amine using a derivative.

In Formula (I), X, Y, and Z are the same or differently substituted halogen atom, hydrogen, nitro, cyano, C ₁ -C ₆ alkoxy, phenoxy (substituted phenoxy), heteroaryloxy, etc. Represent; R is independently at each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted Heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl and the like.

Among many organic reactions, reactions using acylation reagents are vast. Acylation usually uses carboxylic acid (RCOOH), carboxylic acid halide (RCOX), carboxylic anhydride [(RCO) ₂ O], and the like. However, the carboxylic acid has low reactivity, so it is necessary to use an acid or a base catalyst. Also, the carboxylic acid is affected by the water generated during the reaction and the acid used as a catalyst, thereby lowering the yield or causing decomposition of the product. To solve this problem, a highly reactive acid anhydride [(RCO) ₂ O] or acyl halide (RCOX) is used, which not only generates a lot of heat during the reaction, but also removes amines, such as hydrogen halides, to remove the reaction products. Additional steps using alkalis are required, and in some cases these acid removing materials can affect the final material, causing product modifications or making it difficult to separate and recover from the resulting acylation material. Cause. Thus, although acylation reagents have been developed that can be used to solve this problem, known acylation reagents partially contain problems such as 1) regeneration, 2) stability, and 3) restriction of the target reaction.

Therefore, there is a need for development of a new compound that can be recovered and recovered, is easy to manufacture and handle, has excellent safety, and can be used as an acylation reagent having excellent reactivity and selectivity.

For this reason, the present inventors have been able to solve or significantly improve the problems of the known acylating reagents, and at the same time, as a result of research on the development of a new class of compounds, 1-acyl (or aroyl) pyridazine-6 The method of synthesizing the -one series and found that these compounds have the ability to transfer acyl or aroyl groups to carboxylic acids, alcohols, amino acids, aminocarboxylic acids and amines.

That is, the 1-acyl (or aroyl) pyridinzin-6-one derivative prepared according to the present invention can be acylated with aliphatic, aromatic and heterocyclic amines in neutral conditions to prepare the corresponding amide in excellent yield. Rather, it reacts with the carboxylic acid under basic conditions, and the corresponding carboxylic anhydride in an excellent yield is reacted with alcohol, and the corresponding ester is reacted with diethyl malonate to form a beta-keto ester. It was confirmed that N-acylamino acid and the like can be easily synthesized by reacting with an amino acid, and completed the invention.

It is therefore an object of the present invention to provide novel 1-acyl (or aroyl) pyridazin-6-one derivatives which exhibit the ability of an acylation group as a delivery agent.

Another object of the present invention is to provide a method for preparing a 1-acyl (or aroyl) pyridazin-6-one derivative.

Another object of the present invention is to use 1-acyl (or aroyl) pyridazin-6-one derivatives as acylating reagents of carboxylic acids, active methylenes, amino acids, aminocarboxylic acids, alcohols (cyols) and amines. To provide a way.

Other advantages and uses of the present invention will be understood in more detail through the following examples. Hereinafter, the configuration of the present invention will be described in detail.

The present inventors achieved the object of the present invention by providing a novel 1-acyl (or aroyl) pyridazin-6-one derivative compound represented by the following general formula (I).

In the general formula (I), X, Y, and Z are the same or differently substituted halogen atoms, hydrogen, nitro, cyano, C ₁ -C ₆ alkoxy, phenoxy (substituted phenoxy), heteroaryloxy, and the like. Represents; R is independently at each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted Heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl and the like.

In the terms used herein, "halogen" means fluoro, chloro, bromo and iodo.

"Alkoxy" means an alkyl moiety bonded through an oxygen bridge (ie -0-alkyl) such as methoxy, ethoxy and the like.

"Alkyl" means a straight or branched, acyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon having 1 to 20 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like; Saturated branched alkyl, on the other hand, includes isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and the like. Unsaturated alkyl, on the other hand, includes at least one double or triple bond (named "alkenyl" or "alkynyl", respectively) between neighboring carbon atoms. Representative straight and branched alkenyl compounds include ethylenyl, propyleneenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2-3-dimethyl-2-butenyl and the like; Typical straight and branched alkynyls, on the other hand, are acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl -1-butynyl and the like.

"Cycloalkyl" means a saturated or unsaturated (but not aromatic) ring having 3-8 carbon atoms, and representative saturated cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ Cyclopropyl, -CH ₂ cyclobutyl, -CH ₂ cyclopentyl, -CH ₂ cyclohexyl and the like; While unsaturated cyclic alkyls include cyclopentyl and cyclohexyl and the like.

"Aryl" refers to an aromatic hydrocarbon such as phenyl or naphthyl.

"Aryl alkyl (arylalkyl)" is a benzyl, -CH ₂ - in the aryl part, such as (CH _{2) 2} phenyl- (1 or 2-naphthyl), - (CH _{2) 3} phenyl, -CH (phenyl) _2, Alkyl having at least one alkyl hydrogen atom substituted.

"Heteroaryl" is a 5- to 10-membered member having at least one heteroatom selected from nitrogen, oxygen and sulfur and having at least one carbon atom, including mono- and -bicyclic ring systems Aromatic heterocycling means. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, pyrroyl, indolyl, isoindolyl, azaindolyl, azaindolyl, pyridyl (pyridyl), quinolinyl, isoquinolinyl, oxazolyl, oxazolyl, benzoxazolyl, pyrazolyl, pyridazinyl, pyrimidinyl ), Parazinyl, cinolinyl, cinazolinyl, phthalazinyl, imidazolyl, benzimidazolyl, thiazolyl, thiazolyl, benzothiazolyl, And isothiazolyl and the like.

"Heteroaryl-alkyl (heteroarylalkyl)" means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH ₂ pyridinyl, -CH ₂ pyrimidinyl.

A "heterocycle" is a 5- to 7-membered monocyclic, or 7- to 14-membered, saturated, unsaturated or aromatic, containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. It means polycyclic, heterocyclic ring of. Thus, heterocycles include heteroaryls as defined above, as well as the aromatic heteroaryls listed above, as well as the heterocycle compounds morpholinyl, pyrrolidinyl, piperidinyl, highdan Hydantoinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, and the like, but not limited thereto.

"Heterocyclealkyl" means alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH ₂ morpholinyl or the like.

The term "substituted" means any of the above groups in which at least one hydrogen atom is replaced with a substituent (eg, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, etc.) Means one. For example, in the case of keto substituents ("-C (= 0)-"), two hydrogen atoms are replaced. "Substituents" when substituted are halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl , Heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NR _a R _b , -NR _a C (= 0 ) R _b , -NR _a C (= 0) NR _a NR _b , -NR _a C (= 0) OR _b , -NR _a SO ₂ R _b , -OR _a , -C (= 0) R _a ,- C (= O) OR _a , -C (= O) NR _a R _b , -OC (= O) NR _a R _b , -SH, -SR _a , -SOR _a , -S (= O) R _a , -OS (= O) ₂ R _a , -S (= O) ₂ OR _a , and the like.

Thus, the invention "1-acyl (or aroyl) pyridazin-6-one derivative" is the same or differently substituted for X, Y, Z as defined above; R in each case is the desired acyl or aryl group to be acylated as defined above, ie independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted A compound that is arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.

Method for producing the 1-acyl (or aroyl) pyridazin-6-one derivative to achieve another object of the present invention is to dissolve the pyridazinone derivative represented by the general formula (II) It is prepared by adding acyl (or aroyl) chloride and a base and then refluxing.

In the general formula (II), X, Y and Z are as defined above.

In addition, the purpose for use as an acylation reagent of the carboxylic acid, alcohol, amino acid, aminocarboxylic acid and amine of the 1-acyl (or aroyl) pyridazin-6-one derivative compound represented by the general formula (I) By reacting the compound with carboxylic acid to synthesize carboxylic anhydride, react with amine to synthesize amide, react with amino acid to synthesize N-acylamino acid, react with alcohol to synthesize ester and react with active methylene to synthesize beta-ketoester Was achieved.

The novel dicylation reagent 1-acyl (or aroyl) pyridazin-6-one derivatives according to the present invention are represented by the following general formula (I).

X, Y, Z in the general formula (I); And R is as defined above.

In the preparation of the novel 1-acyl (or aroyl) pyridazin-6-one, a pyridazinone derivative represented by the following general formula (II) is dissolved in a solvent, and the corresponding acyl chloride and base are added to reflux. Can be prepared.

In Formula (II), X, Y, and Z are the same or differently substituted halogen atom, hydrogen, nitro, cyano, C ₁ -C ₆ alkoxy, phenoxy (substituted phenoxy), heteroaryloxy, or the like. to be. Compounds of the general formula (II) are known in the art as Angew. Chem., Intl. Ed. Engl, 4, 292 (1965); Chem. Ber. 34, 1014 (1901), respectively.

However, the 1-acyl (or aroyl) pyridazin-6-one derivatives having the general formula (I), ie, compounds in which R is optionally substituted with a preferred acyl group, are novel substances first synthesized by the inventors with acylating reagents. For example, the corresponding pyridazin-6-one, acyl (or aroyl) chloride, and the base are dissolved in a solvent and the starting materials are all at a suitable reaction temperature such as -30 ° C-100 ° C depending on the type of solvent used. After the reaction, the reaction is completed and the reaction is completed by conventional methods and separated by recrystallization or chromatography to obtain the corresponding 1-acyl (or aroyl) pyridazin-6-one derivative.

In the present invention, the solvent used for the pyridazone acylation reaction may use most organic solvents. Examples of particularly preferred solvents include diethyl ether, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, and acetone. , Toluene, methylene chloride and the like.

Examples of bases that can be used in the pyridazinone acylation reaction of the present invention include triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, sodium hydride, potassium fluoride, and the like. .

In addition, looking at the preferred conditions for the reaction according to the present invention, the molar ratio between the reactants is preferably a stoichiometric amount, but one of the reagents is somewhat excessive, that is, 1-10% excess. The reaction temperature is preferably between -20 ° C and 50 ° C. And the reaction time is preferably within 2 hours.

When the acylation reaction is completed, the product 1-acyl (or aroyl) pyridazin-6-one derivative is present in the crystalline form, which is separated and purified by conventional methods such as crystallization or chromatography depending on the physical properties The structure of the compound is identified using an infrared spectrometer, nuclear magnetic resonance spectrometer or mass spectrometer.

R of the 1-acyl (or aroyl) pyridazin-6-one derivative represented by the general formula (I) produced by the present invention is preferably a C ₁ to C ₂₀ alkyl, C ₃ to C ₆ cyclo Acyl, phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, benzyl, furan-2-yl and heterocyclic groups, etc., wherein R is methyl, ethyl, pentyl, cyclo Examples of representative compounds that are hexyl, phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, benzyl and furan-2-yl are shown in Table 1 below.

Acylation reagents of the present invention for achieving another object of the present invention is an amide from the corresponding carboxylic anhydride, amine from the carboxylic acid to the 1-acyl (or aroyl) pyridazin-6-one derivative of formula (I) , N-acylamino acids from amino acids, esters from alcohols and beta-keto esters from active methylene.

As illustrated in Scheme 1 below, the carboxylic acid and the derivative of formula (I) can be dissolved in a solvent and reacted with a base to yield the corresponding acid anhydride.

At this time, the molar ratio of the acylation reagent, the carboxylic acid and the base is preferably in a ratio of 1: 1: 2, and the molar ratio of either reagent may be somewhat excessive. The reaction can proceed in most organic solvents. Examples of particularly preferred solvents include diethyl ether, tetrahydrofuran, acetonitrile, acetone, toluene, methylene chloride and the like.

Examples of bases that can be used in the acid anhydride preparation reaction of the present invention include triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, sodium hydride, potassium fluoride and the like. The reaction temperature is preferably between -10 ° C and 100 ° C and the reaction time is preferably between 0.5 and 10 hours.

In the preparation of the amide and ester of the present invention, the derivative and the amine or alcohol of the general formula (I) may be dissolved in a solvent, and a corresponding amide or ester may be prepared by adding a base or stirring for a predetermined time without a base. The molar ratio of each starting material is preferably in a ratio of 1: 1: 1 (or 0), and any one or two reagents may be somewhat excessive. Synthesis process of amide and ester by the method of the present invention is shown in the following schemes 2 and 3.

R 'and R "in Scheme 2 are each independently H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkynyl, aryl, heterocycle and the like.

R ′ and R ″ in Scheme 3 are each independently H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkynyl, aryl, heterocycle, and the like.

Production of the beta-keto ester of the present invention can be prepared by dissolving the derivative of formula (I) in a solvent and stirring for a certain time by adding a carbon anion species. Carbon anion species, such as ethylmaronate anion, can be prepared by conventional methods for treating activated methylene, such as diethylmalonate, with sodium hydride or alkyl lithium (Scheme 4).

The preparation of N-acylamino acid of the present invention can be prepared by dissolving the derivative of formula (I) in a solvent and stirring the solution for a certain time by adding amino acids (Scheme 5).

As in Scheme 5, an amino acid or amino carboxylic acid is acylated with a derivative compound having the general formula (I) of claim 1 under neutral conditions to prepare a chemically corresponding N-acylated amino acid or carboxylic acid. In addition, in neutral conditions, a mixture of primary and secondary or sterically hindered amines and small sterically hindered compounds may be acylated with a derivative compound having the general formula (I) of the present invention to selectively convert the corresponding primary or secondary amide. It can also manufacture.

As described above, the acylation reagent of the general formula (I) of the present invention is characterized by chemical selective and stereoselective acylation reactions, and has good reactivity and stability even under neutral conditions, and it can be used to recover the starting materials. Has the advantage.

The solvent and base that can be used in the reaction for preparing the carboxylic anhydride, amide, ester, N-acylamino acid and beta-keto ester using the acylating reagent of the general formula (I) of the present invention are preferably the solvents and bases described above. The reaction temperature is preferably between -10 ° C and 100 ° C and the reaction time is between 0.5-10 hours.

On the other hand, in the acylation reaction of the present invention, the degree of steric hindrance and reactivity of the carboxyl group, amino group, hydroxy group and the like of the compound to be acylated, the amount of use of the acylation reagent of the present invention, reaction time, reaction temperature, etc. The reaction conditions may be varied depending on the reaction compound and the acylation purpose. The acylation reaction using the acylation reagent of the present invention has an advantage that it can be widely used in agrochemicals, pharmaceuticals, protein synthesis, solid phase synthesis, and other fine chemical fields that require such a reaction.

Hereinafter, the configuration and operation of the present invention through the examples will be described in more detail. Although specific embodiments of the present invention have been disclosed for purposes of illustration, it is believed that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited by the following examples.

Example

Example 1: Preparation of 1-acyl (or aroyl) pyridazin-6-one

The corresponding pyridazin-6-one (3.03 mmole), acyl (or aroyl) chloride (0.67 mmole), and base (7.27 mmole) are dissolved in solvent (40 ml) and the reaction temperature is between -30 ° C and 100 ° C. The reactants were reacted until all of the starting materials were reacted, and when the reaction was completed, they were treated by conventional methods and separated by recrystallization or chromatography to obtain corresponding 1-acyl (or aroyl) pyridazin-6-one derivatives. .

(1) Experimental Example 1: Preparation of 1-acetyl-4,5-dichloropyridazin-6-one

4,5-Diclopyridazin-6-one (0.5 g) and triethylamine (0.84 mL) were dissolved in methylene chloride (15 mL) and acetyl chloride (0.67 mL) was added dropwise at room temperature. The reaction was carried out at the same temperature for 10 minutes, and when the reaction was completed, the solvent was evaporated under reduced pressure, filtered by adding diethyl ether, and the filtrate was evaporated under reduced pressure to yield 1-acetyl-4,5-dichloropyridazin-6-one in 97% yield. Obtained. mp 109-110 ℃

(2) Experimental Example 2: Preparation of 1-benzoyl-4,5-dichloropyridazin-6-one

4,5-Diclopyridazin-6-one (1 g) and triethylamine (1.68 mL) were dissolved in methylene chloride (30 mL) and benzoyl chloride (0.7 mL) at a temperature between -13 and -15 ° C. Added dropwise. After 30 minutes of reaction at the same temperature, the solvent was evaporated under reduced pressure, filtered by adding diethyl ether, the solvent of the filtrate was evaporated under reduced pressure, the residue was dissolved in chloroform, the organic layer was washed with water, and the solvent was evaporated under reduced pressure. Yield 1-benzoyl-4,5-dichloropyridazin-6-one in% yield. mp 84-86 ° C.

(3) Experimental Example 3: Preparation of 1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one

4,5-Diclopyridazin-6-one (0.5 g) and triethylamine (0.84 mL) were dissolved in methylene chloride (10 mL) and paramethoxybenzoyl chloride (0.62 g) was added dropwise at room temperature. After 10 minutes of reaction at the same temperature, the solvent was evaporated under reduced pressure, the residue was washed with diethyl ether, the solvent of the obtained ether solution was evaporated under reduced pressure, and the residue was recrystallized, yielding 1- (para-meth) in 74% yield. Oxybenzoyl) -4,5-dichloropyridazin-6-one was obtained. mp 184-185 ° C.

Example 2: Preparation of Benzoic Acid Anhydride

A mixture of 1- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-6-one (0.1 g), benzoic acid (0.765 g), potassium carbonate (0.433 g) and tetrahydrofuran (6 ml) Was reacted at 40 ° C. for 3 hours and filtered. The filtrate was evaporated and separated by silica gel column to give benzoic anhydride (59 mg, 95%) and 4,5-dichloropyridazin-6-one (50 mg, 96%).

Example 3: Preparation of N-phenyl Benzamide

A mixture of 1-benzoyl-4,5-dichloropyridazin-6-one (0.2 g), aniline (0.68 mL) and tetrahydrofuran (7 ml) was reacted at room temperature for 24 hours and the solvent was evaporated. Separation was performed by silica gel column (methylene chloride) to recover N-phenyl benzamide (145 mg, 98%; mp 164-166 ° C.) and 4,5-dichloropyridazin-6-one (110 mg, 9%). .

Example 4: Preparation of Phenyl Benzoate

A mixture of 1-benzoyl-4,5-dichloropyridazin-6-one (0.2 g), phenol (0.07 g), potassium carbonate (0.11 g) and tetrahydrofuran (10 ml) was refluxed for 24 hours and filtered. . The filtrate was evaporated and separated by silica gel column to give phenyl benzoate in quantitative yield. In addition, 4,5-dichloropyridazin-6-one (93 mg, 96%) was recovered.

Example 5: Preparation of Diethyl Benzoylmalonate

1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one (0.2 g) was dissolved in tetrahydrofuran (6 ml) and prepared in advance diethyl malonate sodium salt (0.11 ml diethyl malonate) Was dissolved in 5ml tetrahydrofuran and prepared by treating 45mg sodium hydride) and stirred at room temperature for 3 hours. The reaction solution was filtered and dried to give diethyl benzoylmalonate (74%) and 4,5-dichloropyridazin-6-one (96%); Diethyl benzoylmalonate; mp 65 ° C. IR (NaCl) 1760 (C═O), 1740 (C═O), 1700 cm ⁻¹ (C═O).

Example 6: Preparation of N- (para-hydroxyphenyl) para-methoxybenzamide

Dissolve 1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one (0.2 g) in tetrahydrofuran (10 mL) and add para-aminophenol (0.075 g) at room temperature for 5 hours. Reaction to remove the solvent. The residue was washed with methylene chloride (30 mL) and n-hexane (20 mL) and dried to give N- (para-hydroxyphenyl) benzamide in 98% yield. mp 223-224 ° C.

Example 7: Preparation of N- (1-hydroxynaphthal-5-yl) para-methoxybenzamide

Dissolve 1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one (0.2 g) in tetrahydrofuran (10 mL) and add 5-amino-1-naphthol (0.11 g) for 14 hours. The solvent is removed by reaction at reflux condition. The residue was washed with methylene chloride (20 mL) and recrystallized to yield N- (1-hydroxynaphthyl-5-yl) para-methoxybenzamide in 87% yield. mp 248-249 ° C.

Example 8: Preparation of N-benzoylglycine

Dissolve 1- (benzoyl) -4,5-dichloropyridazin-6-one (0.5 g) in tetrahydrofuran (10 mL), add glycine (0.133 g), and react under reflux for 24 hours to obtain silica gel (1 g) is added and the solvent is removed. The residue was adsorbed on the column and eluted with n-hexane / ethyl acetate (2: 1, v / v) to give N-benzoylglycine quantitatively. mp 186-l87 ° C.

Example 9 Preparation of N-cyclohexyl Para-methoxybenzamide Selective in Mixed Amine

Dissolve cyclohexylamine (0.077 mL) and dicyclohexylamine (0.134 mL) in methylene chloride (10 mL), and dissolve 1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one (0.2 g). The reaction mixture was added and reacted at room temperature for 10 minutes to add silica gel (1 g), and the solvent was removed. The residue was adsorbed on the column and eluted with chloroform / ethyl acetate (2: 1, v / v) to give only N-cyclohexyl para-methoxybenzamide in 97% yield. mp 163-164 ° C.

Example 10 Preparation of N- (para-mercaptophenyl) paramethoxybenzamide

Dissolve para-mercaptoaniline (0.093 g) in tetrahydrofuran (10 mL) and add 1- (para-methoxybenzoyl) -4,5-dichloropyridazin-6-one (0.2 g) to obtain 15 at room temperature. N-hexane (20 mL) was added by reaction, and the produced crystal | crystallization was filtered. The obtained crystals were recrystallized from tetrahydrofuran / n-hexane (1: 2, v / v) to give N- (para-mercaptophenyl) para-methoxybenzamide in a yield of 51%. mp 194-196 ° C.

Example 11: Preparation of N- (N-propylaminopropyl) para-methoxybenzamide

N-propyl-1,3-propanediamine (0.094 mL) was dissolved in tetrahydrofuran (10 mL) and 1- (para-methoxybenzoyl) -4,5-dichloropyridazine-6-one (0.2 g) The reaction was carried out at room temperature for 0.5 hours to remove the solvent, and the residue was adsorbed on a silica gel column and eluted with ethyl acetate / n-hexane (1: 2, v / v) to N- (propylaminopropyl) para-methoxy. Benzamide was obtained. mp 55-57 ° C.

As described above, the 1-acyl (or aroyl) pyridazin-6-one-based compound of the present invention is a novel acylating reagent, and is chemically selective to various R compounds having a carboxyl group, an amine group, or a hydroxyl group as a target R group. It is possible to stereoselective acylation, excellent reactivity in neutral conditions, can be used to re-start the starting material, easy product recovery, high reaction yield, pesticides, pharmaceuticals, protein synthesis, solid phase synthesis and There is a very excellent effect that can be used extensively in other fine chemical fields.

Claims (10)

1-acyl (or aroyl) pyridazin-6-one derivatives as acylating reagents having the general formula (I) Wherein X, Y and Z represent the same or differently substituted halogen atom, hydrogen, nitro, cyano, C ₁ -C ₆ alkoxy, phenoxy or substituted phenoxy, heteroaryloxy and the like; R in each occurrence is independently C ₁ -C ₂₀ alkyl, C ₃ -C ₆ cycloacyl, phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, benzyl, furan-2yl -2-yl) or a heterocyclic group. delete The 1-acyl (or aryl) pyridazine of claim 1 having the general formula (1) by reacting a pyridazinone derivative of formula (II) with an R-halide compound having the target R group to be acylated in claim 1 How to prepare 6-one derivatives: Wherein X, Y, Z; And R is as defined in claim 1 above. delete delete delete delete delete delete A method of using the 1-acyl (or aroyl) pyridazin-6-one derivative of claim 1 in an acylation reaction.