KR20030061051A - Preparation of novel arene or alkane sulfonylpyridaznone derivatives and use in the organic reactions - Google Patents

Abstract

PURPOSE: Provided are arene(alkane)sulfonylpyridazinone derivatives represented by the formula(I) which are used as activators of carboxyl acid and sulfonylation reagents for alcohol or amine, making them utilizable in various synthetic reactions. The pyridazinone reagents are recoverable, easily handled, stable and very reactive. CONSTITUTION: A preparation method of pyridazinone derivatives of the formula (I) comprises reacting pyridazinone derivatives of the formula(II) with corresponding sulfonyl halides. In the formula (I) and (II) X, Y, Z are independently same or different substituted halogen atom, alkoxy, phenoxy, azido groups; R is independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl.

Description

Preparation of novel arene or alkane sulfonylpyridaznone derivatives and use in the organic reactions

The present invention relates to a novel arene (or alkane) sulfonylpyridazinone derivative and its use in organic chemical reactions, more specifically arene (or alkane) sulfonylpyri represented by the following general formula (I) The present invention relates to a derivative of arene (alkane) sulfonylpridazinone, a method for preparing the same, and a sulfonylation reaction of an alcohol (cyol) and an amine using the same.

In the general formula (I), X, Y and Z each represent the same or differently substituted halogen atom, hydrogen, alkoxy, aryloxy (phenoxy and substituted phenoxy), azido groups, 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.

Among many organic reactions, the reaction using carboxylic acid or its derivatives as a starting material is vast. However, the reactivity of the carboxylic acid (RCOOH) is relatively low, so the acid anhydride [(RCO) ₂ O] or acyl halide (RCOX) is used, which is more reactive than using the carboxylic acid. Therefore, there is a problem that the production cost increases due to the increase of the synthesis step, and cannot be used for the synthesis of an acid sensitive compound. Carboxylic acid activators have been developed that can be used to solve these problems, but known activators partially implicate problems such as: 1) difficulty in recovery of activator, 2) stability, and 3) limitation of the target reaction. Accordingly, the present inventors have attempted to develop a new compound that can be used as a sulfonylation reagent of alcohols and amines that can be recovered and regenerated, is easy to handle, has excellent stability, and has excellent reactivity, and a selectable carboxylic acid activator. It was.

For this reason, the present inventors have conducted research to develop new compounds that can solve or significantly improve the problems of carboxylic acid activators or sulfonylation reagents of amines or alcohols. It has been found that the ponylpyridazinone family has the ability to activate carboxylic acids and deliver sulfonyl groups to alcohols or amines. That is to say, without the catalyst from the carboxylic acid, the corresponding carboxylic anhydride cannot be made but basic conditions can be obtained from aliphatic, aromatic and heterocyclic carboxylic acids using the arene (or alkane) sulfonylpyridazinone derivatives prepared according to the invention. In addition to being able to prepare the corresponding carboxylic acid anhydride in excellent yield, it is easy to synthesize amide, ester, beta-ketoester and the like and alcohol and amine sulfone The invention was completed by confirming that it can be anecdotal.

It is therefore an object of the present invention to provide novel arene (or alkanes) sulfonylpyridazinone derivatives that exhibit the ability to activate novel carboxylic acids and deliver sulfonyl groups.

Another object of the present invention is to provide a method for preparing the arene (or alkanes) sulfonylpyridazinone derivatives.

Another object of the present invention is to provide the use of the arene (or alkanes) sulfonylpyridazinone derivatives as carboxylic acid activators and sulfonylation reagents of alcohols (cyols) and amines.

Hereinafter, the configuration and effect of the present invention will be described in detail. The construction and other advantages of the present invention will be more clearly understood by the following configuration.

The object of the present invention was achieved by providing a novel arene (or alkanes) sulfonylpyridazinone derivative which is a compound represented by the following general formula (I).

In the general formula (I), X, Y, and Z represent halogen atoms, hydrogen, alkoxy, aryloxy (phenoxy and substituted phenoxy), azido groups, etc., each substituted the same or differently; 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, preferably phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-bromophenyl, 2-chlorophenyl, 2-cyanophenyl, 4-methylphenyl, 4-chlorophenyl, 4-fulurophenyl, 2.5-dichlorophenyl, 2,4-dinitrophenyl, 2,4,6-trimethylphenyl, methyl, ethyl, isopropyl Qi, but not limited to this.

A method for preparing an arene (or alkane) sulfonylpyridazinone derivative for achieving another object of the present invention is to dissolve the pyridazinone derivative represented by the following general formula (II) in a solvent and to the corresponding sulfonyl chloride and It is made by adding a base and refluxing.

In Formula (II), X, Y and Z are as defined above.

In addition, the purpose of the carboxylic acid activation of the arene (or alkane) sulfonylpyridazinone derivative compound represented by the general formula (I) and the sulfonylation reagents of alcohols and amines and the aliphatic, aromatic and The heterocyclic carboxylic acid is reacted to prepare the corresponding carboxylic anhydride, amide, ester, thioester and beta-kedoester, and arene (or alkanes) sulfonylpyridazinone represented by the general formula (I). It was achieved by sulfonylating alcohols and amines (cyols) with derivatives.

Hereinafter, the present invention will be described in more detail.

The novel arene (or alkane) sulfonylpyridazinone derivatives according to the present invention are represented by the following general formula (I).

X, Y, Z in the general formula (I) represent the same or different groups selected from the group consisting of hydrogen, a halogen atom, alkoxy, aryloxy, and an azido group; 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, preferably phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-bromophenyl, 2-chlorophenyl, 2 -Cyanophenyl, 4-methylphenyl, 4-chlorophenyl, 4-fulurophenyl, 2.5-dichlorophenyl, 2,4-dinitrophenyl, 2,4,6-trimethylphenyl, methyl, ethyl, or isopropyl However, this is not limiting.

"Halogen" means fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

"Alkoxy" means an alkyl moiety bonded through an oxygen bridge (ie -0-alkyl) such as methoxy, ethoxy and the like. For example, alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Sec-butoxy, t-butoxy, n-penoxy, n-hexoxy, n-heptoxy, n- N-octyloxy, and their respective substituted compounds, cycloalkoxy such as cyclopentoxy and cyclohexoxy and their respective substituted compounds, but are not limited thereto now .

"Aryloxy" refers to phenoxy, p-methylphenoxy, m-methylphenoxy, o-methylphenoxy, 2,4 Dimethylphenoxy (2,4-dimethylphenoxy), 2,6-dimethylphenoxy (2,6-dimethylphenoxy), 2,4,6-trimethylphenoxy (2,4,6-trimethylphenoxy), 4-phenylphene Oxy (4-phenylphenoxy), and their respective substituted compounds.

"Azido" means an aprecursor-type protecting group which gives an amino group.

"Alkyl" means a straight or branched, cyclic 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 (referred to as "alkenyl" or "alkynyl", respectively) between adjacent carbon atoms. Alkenyl compounds are ethylenyl, propofenyl, 1-butenyl, 2-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl , 3-methyl-1butenyl, 2-methyl-2-butenyl, 2-3-dimethyl-2-butenyl, and the like; while representative straight and branched chain alkynyls are acetylenyl, propy Propylyl, 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.

"Aryl" means an aromatic hydrocarbon such as phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl or naphthyl.

"Aryl alkyl (arylalkyl)" is a benzyl, --CH ₂ - aryl, 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 with a moiety.

"Heteroaryl" is an aromatic, 5- to 10-membered member having at least one heteroatom selected from nitrogen, oxygen and sulfur, including mono- and -bicyclic ring systems and having at least one carbon atom Heterocyclic ring. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, pyrroyl, indolyl, pyridyl, quinolinyl, isoquinolin Isoquinolinyl, oxazolyl, benzooxazolyl, pyrazolyl, phthalazinyl, imidazolyl, thiazolyl, thiazolyl, benzothiazolyl And the like.

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

"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. Polycyclic, heterocyclic ring. The heterocycle thus comprises heteroaryls as defined above, and in addition to the aromatic heteroaryls listed above, the heterocycle compounds morpholinyl, pyrrolidinyl, piperidinyl, highdan Include, but are not limited to, hydantoinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyridinyl, and the like. .

"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 , -OR _a , -C (= 0) R _a , -C (= 0) OR _a , -C (= 0) NR _a R _b , -OC (= 0) NR _a R _b , -SH, -SR _a , -SOR _a , -S (= 0) R _a , -OS (= 0) ₂ R _a , -S (= 0) ₂ OR _a , and the like.

Accordingly, the present invention "arene or alkane sulfonylpyridaznone derivatives" as defined above X, Y, Z is the same or differently substituted halogen atoms, hydrogen, alkoxy, pen Oxy (substituted phenoxy), azido groups 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 By heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.

The preparation of the novel arene (or alkane) sulfonylpyridazinone of the present invention is prepared by dissolving a pyridazinone derivative represented by the following general formula (II) in a solvent and adding the corresponding sulfonyl halide and base to reflux. can do.

In Formula (II), X, Y and Z are as defined above.

Compounds of the general formula (II) are known compounds as described in Angew. Chem., Intl. Ed. Engl, 4, 292 (1965); Chem. Ber. 34, 1014 (1901); J. Heterocyclic Chem., 33 905 (1999); J. Heterocyclic Chem., 33, 1915 (1996), respectively.

In the present invention, R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted hetero Sulfonyl halides selected from the group consisting of arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl and the like can be prepared according to methods known in the art. For example, P-toluenesulfonyl chloride can be prepared industrially from toluene and chlorosulfonic acid, and benzenesulfonyl chloride can be prepared from benzene and chlorosulfonic acid.

As the solvent used in the sulfonylation reaction in the present invention, most organic solvents may be used. Examples of particularly preferred solvents include diethyl ether, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, acetone, toluene Methylene chloride and the like.

The solvent which can be used in the sulfonylation reaction of the present invention is not particularly limited as long as the solvent does not react with the derivative represented by the general formula (I), and examples of preferred bases include triethylamine, pyridine, piperidine, 4 Dimethylaminopyridine, potassium carbonate, cesium carbonate. Sodium hydride, potashumpulolide and the like.

In addition, when 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 may vary depending on the reactor quality and the solvent and generally a temperature between 0 and 110 ° C. is preferred but is not limited thereto. The reaction time may also vary depending on the reactor quality, the solvent and the reaction temperature, and generally the reaction takes place within 1 to 10 hours.

Furthermore, the present invention can be carried out in the presence of a base, and this method may promote the reaction rate and reduce the reaction temperature. Bases that can be used include triethylamine, tributylamine, pyridine, piperidine and the like.

When the sulfonylation reaction is completed, the product of the product of the product of aren (or alkane) sulfonylpyridazinone derivative is present in crystalline form, which is separated and purified by conventional methods such as crystallization or chromatography according to physical properties to identify the compound. Is carried out using an infrared spectrometer, nuclear magnetic resonance spectrometer or mass spectrometer.

Representative examples of the arene (or alkanes) sulfonylpyridazinone derivatives represented by Formula (I) prepared according to the present invention are shown in Table 1 below.

In order to achieve another object of the present invention, the carboxylic acid activator of the present invention and the sulfonylation reagent of alcohol and amine may include the arene (or alkanes) sulfonylpyridazinone derivatives of the general formula (I) and the carboxylic acid. From the corresponding carboxylic anhydrides, amides, esters and beta-ketoesters.

TABLE 1

Representative examples of the general formula (I) derivative of the present invention

Carboxylic acids of the present invention include, for example, formic acid, acetic acid, phenylacetic acid, diphenylacetic acid, acetoacetic acid, propionic acid acid, phenylpropionic acid, butanoic acid, isobutanoic acid, pentanoic acid, 3-methylbutanoic acid, pivalic acid, Hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, myristic acid, palmitic acid , Stearic acid, cinnamic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, chloropropionic acid, alpha-bromoacetic acid (alpha-bromoacetic acid), dibromoacetic acid (di bromoacetic acid) and other aliphatic monocarboxylic acids; Oxalic acid, malonic acid, succinic acid, methylsuccinic acid, glutaric acid, adipic acid, 1,1-dimethyl-1, 3-dicarboxypropane (1,1-dimethyl-1,3-di-carboxypropane), 1,5-pentanedicarboxylic acid, 1,6-hexanedicarboxylic acid (1 6-hexanedicarboxylic acid, 1,7-heptane -dicarboxylic acid, 1,8-octanedicarboxylic acid and other aliphatic dicarboxylic acids Acids (aliphatic dicarboxylic acids); Benzoic acid, toluic acid, 4-isopropylbenzoic acid, 4-tert-butylbenzoic acid, methoxybenzoic acid, dimethoxy Benzoic acid 3,4,5-trimethoxybenzoic acid, o-chlorobenzoic acid, 2,6-dichlorobenzoic acid, 3,4 3,4-dichlorobenzoic acid, 2,3,6-trichlorobenzoic acid, 4-bromobenzoic acid, and other aromatic monocarboxylics Acids (aromatic monocarboxylic acids); Phthalic acid, isophthalic acid, terephthalic acid, 2-chloroterephthalic acid, 2,5-dibromo-terephthalic acid (2,5-dibromo-tere-phthalic acid ), And other aromatic dicarboxylic acids; Lactic acid, butyric acid, 3-hydroxy-2,2-dimethylpropionic acid and other aliphatic carboxylic acids with a second hydroxyl group in the molecule ; Salicylic acid, 5-methoxy-salicylic acid, 2-oxy-m-toluic acid, 3,5-di-tert-butylsalicylic acid ( Aromatic carboxylic acids having hydroxyl groups in 3,5-di-tert-butylsalicylic acid), p-hydroxybenzoic acid and other molecules; Aliphatic carboxylic acids having amino groups in beta-alanine and other molecules; 4-aminobenzoic acid, 3-aminobenzoic acid, N-methylamino-benzoic acid, m-dimethylaminobenzoic acid, 5- 5-amino-2,4,6-triiodoisophthalic acid and aromatic carboxylic acids having amino groups in other molecules; And 3-mercapto-propionic acid, o-mercaptobenzoic acid, and other carboxylic acids with mercapto groups in the molecule. However, the carboxylic acid is not limited to these compounds.

In order to prepare a suitable carboxylic anhydride, as shown in the following Scheme 1, the corresponding carboxylic acid and the derivative of the general formula (I) are dissolved in a solvent and reacted with a base to react the corresponding acid anhydride. Can be obtained.

(Scheme 1) Scheme of carboxylic anhydride.

In this case, the molar ratio of the starting material is preferably 2: 1: 1, and the molar ratio of any one reagent may be somewhat excessive. The reaction can proceed in most organic solvents, and particularly preferred solvents include diethyl ester, tetrahydrofuran, acetonitrile, acetone, toluene, methylene chloride and the like. Bases that can be used in the acid anhydride production reaction of the present invention are triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate. Sodium hydride, potassium fullolide 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.

The preparation of the amide (Scheme 2), the ester (Scheme 3) and the beta-keto ester (Scheme 4) of the present invention dissolves the corresponding carboxylic acid, the derivative of the general formula (I) of the present invention in a solvent and adds a base for a certain time. After stirring, the corresponding amine, alcohol or diethylmalonate anion is added to the reaction to prepare the corresponding amide, ester or beta-keto ester.

Scheme 2 Preparation of Amide Scheme.

(Scheme 3) Scheme of preparation of ester.

Scheme 4 Preparation of beta-ketoesters.

In the above reactions, the molar ratio of each starting material is preferably in a ratio of 2: 1: 1: 1, and any one or two reagents may be somewhat excessive. Diethylmaronate anion can be prepared by conventional methods of treating diethylmaronate with sodium hydride. The solvents and bases that can be used in the reaction for preparing amides, esters and beta-keto esters from the carboxylic acid of the present invention are preferably the above solvents and bases. The reaction temperature is preferably between -10 ° C and 100 ° C and the reaction time is preferably between 0.5 and 10 hours.

The sulfonylation reaction of alcohols and amines of the present invention can be prepared by reacting an arene (or alkanes) sulfonylpyridazinone derivative of the general formula (I) with an alcohol or an amine in a solvent.

(Scheme 5) The sulfonation scheme of alcohol.

(Scheme 6) The sulfonation scheme of amines.

At this time, the molar ratio of the starting material to be used is 1: 1, and may be a little excessive amine or alcohol. Depending on the reaction, it is preferable to use 1 mole of base. The solvent and base used in this reaction are preferably the above solvent and base. The reaction temperature is preferably between -10 ° C and 100 ° C, and the reaction time is preferably between 0.5 and 10 hours.

On the other hand, in the activation or sulfonyl group transfer reaction of the carboxylic acid using the general formula (I) derivative of the present invention, the degree and reactivity of steric hindrance of the reactive carboxyl group, amino group, hydroxy group, etc., the amount of use of the reagent of the present invention, reaction time, or reaction It will be apparent to those skilled in the art that temperature and the like may affect the selectivity of the reaction, so that these reaction conditions can be varied depending on the reaction compound and the purpose of activation or sulfonylation. The reaction using the carboxylic acid activator and the sulfonylation 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.

The present invention also provides a method for preparing the corresponding beta-keto ester from carboxylic acid and diethyl malonate metal salt using the derivative represented by the general formula (I), alcohol using the derivative represented by the general formula (I). To prepare a corresponding alkyl (or aryl) arene (or alkane) sulfonate under basic conditions, using a derivative represented by the general formula (I) from an amine with a corresponding N-alkyl (or under normal or basic conditions) Aryl) arene (or alkane) sulfonamide process for the preparation of the compound, the formula (I) using a derivative of the corresponding process for preparing the corresponding lactam in neutral or basic conditions, and the formula (I) It provides a method for producing the corresponding lactone in basic conditions from carboxylic acid using a derivative.

To prepare the carboxylic anhydride, as shown in Scheme 1 below, the corresponding 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. have.

(Scheme 1) carboxylic anhydride reaction scheme

In this case, the molar ratio of the starting material is preferably 2: 1: 1, and the molar ratio of any one reagent may be somewhat excessive. The reaction can proceed in most organic solvents, and particularly preferred solvents include diethyl ester, tetrahydrofuran, acetonitrile, acetone, toluene, methylene chloride and the like. Bases that can be used in the acid anhydride production reaction of the present invention are triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate. Sodium hydride, potassium fullolide 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.

The preparation of the amide (Scheme 2), the ester (Scheme 3) and the beta-keto ester (Scheme 4) of the present invention dissolves the corresponding carboxylic acid, the derivative of the general formula (I) of the present invention in a solvent and adds a base for a certain time. After stirring, the corresponding amine, alcohol or diethylmalonate anion is added to the reaction to prepare the corresponding amide, ester or beta-keto ester.

Scheme 2 Preparation of Amide

Scheme 3 Preparation of Ester Scheme

Scheme 4 Preparation of Beta-Ketoesters

In the above reactions, the molar ratio of each starting material is preferably in a ratio of 2: 1: 1: 1, and any one or two reagents may be somewhat excessive. Diethylmaronate anion can be prepared by conventional methods of treating diethylmaronate with sodium hydride. The solvents and bases that can be used in the reaction for preparing amides, esters and beta-keto esters from the carboxylic acid of the present invention are preferably the above solvents and bases. The reaction temperature is preferably between -10 ° C and 100 ° C and the reaction time is preferably between 0.5 and 10 hours.

The sulfonation reaction of alcohols (Scheme 5) and amines (Scheme 6) of the present invention may be prepared by reacting an arene (or alkanes) sulfonylpyridazinone derivative of the general formula (I) with an alcohol or an amine in a solvent. Can be.

(Scheme 5) Alcohol sulfonation reaction scheme

Scheme 6

At this time, the molar ratio of the starting material to be used is 1: 1, and may be a little excessive amine or alcohol. Depending on the reaction, it is preferable to use 1 mole of base. The solvent and base used in this reaction are preferably the above solvent and base. The reaction temperature is preferably between -10 ° C and 100 ° C, and the reaction time is preferably between 0.5 and 10 hours.

Hereinafter, the configuration and effect of the present invention will be described in more detail through the following examples. 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. Therefore, the present invention is not limited by the following examples.

Example 1: Preparation of 2- (para-nitrobenzene tanfonyl) -4,5-dichloropyridazin-3-one

Dissolve 4,5-dichloropyridazin-3-one (6.06 mmole), 2-nitrophenyl chloride (7.27 mmole), potassium carbonate (7.27 mmole) in tetrahydrofuran (40 ml), and all the starting materials react at 40 ° C. After 4 hours of reaction, the mixture was recrystallized to obtain 2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one.

Example 2: Preparation of Benzoic Acid Anhydride

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.1 g) prepared in Example 1, benzoic acid (0.765 g), potassium carbonate (0.433 g) and tetrahydro The mixture of furan (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 (959 mg, 95%) and 4,5-dichloropyridazin-3-one (50 mg, 96%).

Example 3: Preparation of 4-methoxyphenyl benzoate

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.1 g), benzoic acid (0.77 g), 4-methoxyphenol (0.039 g) prepared in Example 1 , A mixture of potassium carbonate (0.087 g) and tetrahydrofuran (6 ml) was reacted at 40 ° C. for 10 hours and filtered. The filtrate was evaporated and separated by silica gel column (methylene chloride / normal hexane = 1: 1, v / v) to 4-methoxyphenyl benzoate (61 mg, 95%) and 4,5-dichloropyridazine-3 -On (48 mg, 92%) was obtained.

Example 4 Preparation of N-benzylbenzamide

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.2 g), benzoic acid (0.154 g), potassium carbonate (0.173 g) and tetrahydro prepared in Example 1 The mixture of furan (10 ml) was stirred at 40 ° C. for 3 hours, then benzylamine (74 μl) was added, reacted for 10 minutes and filtered. The filtrate was evaporated and separated by silica gel column to give N-benzylbenzamide (118 mg, 89%) and 4,5-dichloropyridazin-3-one (93 mg, 96%).

Example 5: Preparation of Diethyl Benzoylmalonate

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.2 g), benzoic acid (0.153 g) potassium carbonate (0.173 g) and tetrahydrofuran prepared in Example 1 (6 ml) of the mixture was reacted at 40 ° C. for 3 hours, and the diethyl maronate sodium salt (diethyl malonate, 0.12 ml, previously prepared) was dissolved in 5 ml of tetrahydrofuran, followed by sodium hydride (50 mg). Is added) and stirred for 10 minutes. The reaction was terminated by addition of water, the solvent was evaporated under reduced pressure, extracted with ethyl acetate in slightly acidic condition with 5% hydrochloric acid solution, the solvent was evaporated and separated by silica gel column (ethyl acetate / normal hexane = 1: 5, v / v). This gave diethyl benzoylmalonate (92 mg, 74%) and 4,5-dichloropyridazin-3-one (96 mg, 96%).

Diethyl benzoylmalonate; mp 65 ° C. IR (NaCl) 1760 (C = 0), 1740 (C = 0), 1700 (C = 0)

Example 6: Preparation of N-cyclonuclear chamber para-nitrobenzenesulfonamide

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (1.76 g), cyclohexanamine (0.5 g) and tetrahydrofuran (30 ml) prepared in Example 1 The mixture was stirred at rt for 12 h and filtered. The filtrate was evaporated and separated by silica gel column (ethyl acetate / normal hexane = 1: 3, v / v) to N-cyclohexylpara-nitrobenzenesulfonamide (0.9 g, 63%) and 4,5-dichloro Pyridazin-3-one (85 mg, 96%) was obtained.

N-cyclohexyl para-nitrobenzenesulfonamide; mp 135-137 ° C.

Example 7 Preparation of Cyclohexyl Para-Nitebenzenesulfonate

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (1 g), cyclohexanol (0.43 g), 4-dimethylaminopyridine (0.53) prepared in Example 1 g), and a mixture of tetrahydrofuran (40 ml) was refluxed for 3 hours and filtered. The filtrate was evaporated and separated by silica gel column to give cyclohexyl para-nitrobenzenesulfonate (0.504 g, 63%) and 4,5-dichloropyridazin-3-one (0.46 g, 96%).

Cyclohexyl para-nitrobenzenesulfonate; mp 76-77 ° C.

Example 8: Preparation of N-ethyl para-nitrobenzenesulfonamide

2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.5 g) prepared in Example 1, cyclohexane (20 ml) and ethylamine (1.64 ml, 2M THF Solution) was stirred at room temperature for 3 hours and filtered. The filtrate was evaporated and separated by silica gel column to give N-ethyl para-nitrobenzenesulfonamide (97%) and 4,5-dichloropyridazin-3-one (96%).

N-ethyl para-nitrobenzenesulfonamide; mp 102-103 ° C.

Example 9: Preparation of N-benzyl para-nitrobenzenesulfonamide

A mixture of 2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (1.65 mmole), cyclohexane (20 ml) and benzylamine (1.65 mmole) prepared in Example 1 above Was stirred at room temperature for 48 hours and filtered. The filtrate was evaporated and separated by silica gel column to give N-benzyl para-nitrobenzenesulfonamide (95%) and 4,5-dichloropyridazin-3-one (95%).

N-benzyl para-nitrobenzenesulfonamide; mp 124-125 ° C.

Example 10 Preparation of N-cyclohexyl para-nitrobenzenesulfonamide

Preparation of 2- (para-nitrobenzenesulfonyl) -4,5-dichloropyridazin-3-one (0.5 g), cyclohexane (20 ml) and cyclohexaneamine (3.44 mmoles) prepared in Example 1 above The mixture was refluxed for 3 hours and filtered. The filtrate was evaporated and separated by silica gel column to give N-cyclohexyl para-nitrobenzenesulamide (95%) and 4,5 dichloropyridazin-3-one (96%).

N-cyclohexyl para-nitrobenzenesulfonamide; mp 135-137 ° C.

As described above, the present invention, aren (or alkanes) sulfonylpyridazinone, which is recyclable, easy to handle, excellent in stability and excellent in reactivity, is not only a novel carboxylic acid activator, but also a sulfonylation reaction of an alcohol or an amine. It has a very good effect that can be used as a reagent, and can be widely used in pesticides, pharmaceuticals, protein synthesis, solid phase synthesis and other fine chemicals using carboxylic acid, amine or alcohol.

Claims (11)

Sulfonylpyridazinone derivative represented by the following general formula (I). In the general formula (I), X, Y, and Z represent halogen atoms, alkoxy, phenoxy, azido groups, etc., each substituted with the same or different values; 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. The compound of claim 1, wherein R is phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-bromophenyl, 2-chlorophenyl, 2-cyanophenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluor Derivatives selected from the group consisting of rophenyl, 2,5-dichlorophenyl, 2,4-dinitrophenyl, 2,4,6-trimethylphenyl, methyl, ethyl, propyl, and isopropyl groups. A method of preparing a sulfonylpyridazinone derivative represented by the following general formula (I) by reacting a pyridazinone derivative of the following general formula (II) with a corresponding sulfonyl halide. X, Y, Z and R in the general formulas (I, II) are as defined in claim 1. A method for producing the corresponding carboxylic anhydride under basic conditions from carboxylic acid using the derivative represented by the general formula (I) of claim 1. A method for producing a corresponding carboxylic acid ester or thioester under basic conditions from a carboxylic acid, an alcohol or a siol using the derivative represented by the general formula (I) of claim 1. Method for preparing the amide corresponding to the basic conditions from the carboxylic acid and the amine using the derivative represented by the general formula (I) of claim 1 A method for producing the corresponding beta-keto ester from carboxylic acid and diethylmalonate metal salt using the derivative represented by the general formula (I) of claim 1. A method for preparing a corresponding alkyl (or aryl) arene (or alkane) sulfonate under basic conditions from an alcohol using a derivative represented by the general formula (I) of claim 1. A method for preparing a corresponding N-alkyl (or aryl) arene (or alkane) sulfonamide under neutral or basic conditions from an amine using a derivative represented by the general formula (I) of claim 1. A method for producing a lactam in neutral or basic conditions from an amide by using the derivative represented by the general formula (I) of claim 1. A method for producing a lactone corresponding to the basic conditions from carboxylic acid using a derivative represented by the general formula (I) of claim 1.