JP2023111473A - Production method of cyclization product formed by cyclization reaction involving dehydration condensation, and production method of 1,3,4-substituted pyrazole-5-carboxylic acid ester - Google Patents

Abstract

To provide a production method of a cyclization product in a cyclization reaction involving dehydration condensation in which no removal step of by-product water, such as an azeotropic dehydration operation or addition of an inorganic solid dehydrator requiring a filtration step after the reaction, is needed, and as an invention of the embodiment, to provide a simple and advantageous production method at an industrial scale in producing 1,3,4-substituted pyrazole-5-carboxylic acid esters useful as important intermediates in medical and agrochemical field and the like.SOLUTION: Invented is a reaction method which uses carbonic acid esters as a dehydrator in a cyclization reaction involving dehydration condensation. More concretely, invented is a production method at an industrial scale of 1,3,4-substituted pyrazole-5-carboxylic acid esters which uses carbonic acid esters as a dehydrator in a cyclization reaction of a hydrazino acetic acid ester derivative.SELECTED DRAWING: None

Description

The present invention provides a cyclic reaction such as 1,3,4-substituted-pyrazole-5-carboxylic acid esters by a novel reaction method that does not require removal of by-product water in a cyclization reaction involving dehydration condensation. Specifically, 1,3,4-substituted-pyrazole-5-carboxylic acids, which are useful as important intermediates in the fields of pharmaceuticals and agrochemicals, using the production method. The present invention relates to an industrial production method for esters.

Conventionally, 1,3,4-substituted-pyrazole-5-carboxylic acid esters are obtained after chloromethylating the 4-position of 1,3-dimethylpyrazole-5-carboxylic acid ester as seen in Patent Documents 1 and 2. , a method of introducing a methyl group by dechlorination under reducing conditions is known. However, this method has problems such as formation of toxic substance bis(chloromethyl)ether during the 4-chloromethylation reaction of 1,3-dimethylpyrazole-5-carboxylic acid ester. Further, in Patent Document 3, an intermediate synthesized using ethyl bromoacetate, dimethylsulfide and diacetyl is reacted with monomethylhydrazine to synthesize ethyl 1,3,4-trimethylpyrazole-5-carboxylate. However, it uses malodorous dimethyl sulfide with yields as low as 10% in four steps.

On the other hand, Patent Document 4 describes a method of obtaining 1,3,4-trimethylpyrazole-5-carboxylic acid esters by cyclizing a hydrazinoacetate derivative in the presence of a base. In this reaction, the hydrazinoacetate derivative is azeotropically dehydrated before the reaction. In addition, as a dehydration method other than azeotropic dehydration, the addition of inorganic solid dehydrating agents such as calcium chloride and molecular sieves is also described, but these dehydrating agents must be separated from the target product by filtration or the like after the completion of the reaction. necessary.

Patent Documents 5 and 6 use carbonate esters in pyrazole synthesis. However, in Patent Document 5, by using dimethyl carbonate as a solvent and a molecular sieve as a dehydrating agent, the yield is improved from 40% to 85% (comparison between Examples 1 and 2), and carbonate esters are There is no description that it is effective as a dehydrating agent. Patent Document 6 describes a method for producing 1,3-dialkylpyrazole-4-carboxylic acid in which the yield does not decrease even if the reaction temperature is raised by using a carbonate ester, and the yield increases due to the dehydration effect of the carbonate ester. No mention of improvement.

JP-A-2001-342178 JP 2008-007503 A WO2010/045764 JP 2008-208047 A JP-A-2001-58982 JP-A-2000-212166

As described above, currently known methods for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters include a dehydration step from the liquid phase by azeotropic dehydration and the use of an inorganic solid dehydrating agent. It cannot be said that the method is industrially satisfactory because a filtration step is required and the yield of the desired product is high. Therefore, a method for producing the compound using a dehydrating agent, which eliminates the need for complicated post-treatment, has been desired.

In view of such circumstances, the present invention first provides a method for producing a cyclized product based on a new reaction with a high yield without requiring azeotropic dehydration or a filtration step of an inorganic solid dehydrating agent. It is intended for As one embodiment of this production method, 1,3,4-substituted-pyrazole-5-carboxylic acid esters useful as pharmaceutical and agricultural intermediates are provided by cyclization reaction of hydrazinocarboxylic acid ester derivatives. to do.

As a result of intensive studies to solve the above problems, the present inventors have found that cyclization of a hydrazinoacetate derivative accompanies dehydration condensation such that a 1,3,4-substituted-pyrazole-5-carboxylic acid ester is obtained. By using carbonate esters in the cyclization reaction, the carbonate esters function as a dehydrating agent, and azeotropic dehydration for removing the by-product water generated in the dehydration condensation reaction and increasing the yield, and the inorganic The inventors have found that this reaction method eliminates the need for a filtration step for a solid dehydrating agent in the system, and actually produced a 1,3,4-substituted-pyrazole-5-carboxylic acid ester by cyclodehydration of a hydrazinoacetate derivative. When obtaining 1,3,4-substituted-pyrazole-5 in a high yield, even in a state where by-product water is mixed in the reaction system, by using the carbonate ester as if it were a solvent. - carboxylic acid esters are obtained.

In short, the present invention finds that the use of carbonate esters acts as a dehydrating agent in a cyclization reaction involving dehydration condensation. The inventors have found that 1,3,4-substituted-pyrazole-5-carboxylic acid esters, which are products, can be easily produced on an industrial scale, and have completed the present invention.

That is, the present invention is a method for producing a cyclized product using a carbonate ester as a dehydrating agent in a cyclization reaction involving dehydration condensation.
Also, specifically, the present invention provides
General formula (1)

(Wherein, R ₁ to R ₃ represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₄ represents an alkyl group having 1 to 4 carbon atoms.) characterized by reacting a carbonate ester as a dehydrating agent in the presence of a base,
general formula (2)

(wherein R ₁ to R ₄ have the same meanings as above).

By using carbonate esters in the cyclization reaction accompanied by dehydration condensation of the present invention, the equilibrium is shifted and the use of azeotropic dehydration or inorganic solid dehydrating agent for increasing the yield and the filtration process thereof become unnecessary. , provides an industrial production method for the cyclized product that can obtain the cyclized product in high yield, and also provides a 1,3,4-substituted-pyrazole-5 from the hydrazinoacetic ester derivative of the present invention. -In the production method of producing a carboxylic acid ester by a cyclization reaction accompanied by dehydration condensation, the use of a carbonate ester as a dehydrating agent makes it an effective dehydrating agent for water produced as a by-product of the reaction. As a result, the azeotropic dehydration step and the filtration step of the inorganic solid dehydrating agent are not required, and a simple production method is provided that makes it possible to industrially produce the cyclized compound more advantageously.

The manufacturing method of the present invention will be described in more detail below.
INDUSTRIAL APPLICABILITY The present invention relates to a method for producing a cyclized product using a carbonate ester as a dehydrating agent in a cyclization reaction involving dehydration condensation.
The cyclization reaction targeted by the present invention is accompanied by dehydration condensation. In the presence of the enolate, the hydrogen at the α-position of the acetate ester is abstracted, and the enolate formed attacks the carbon of the carbonyl group, cyclizes in the molecule, and produces water as a by-product. Examples of intramolecular cyclization reactions include, for example, intramolecular aldol reactions.
In the present invention, the "cyclization product" is a compound obtained by a cyclization reaction accompanied by dehydration condensation, in which intramolecular cyclization occurs to form a ring. It is a compound for manufacturing purposes.

Examples of carbonate esters that can be used as a dehydrating agent include dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, and di-t-butyl dicarbonate. Two or more types can be used in combination.

As a reaction method, a carbonate ester can be used as if it were a solvent. When a solvent is used, the carbonate ester is added together with the solvent, and when no solvent is used, the carbonate ester is added to the reaction system together with the starting materials. The cyclization product can be obtained by a simple reaction method that does not require an operation for removing the by-product water generated by the dehydration condensation such as a dehydration operation such as azeotropic dehydration during the reaction. can be manufactured.

In the reaction, a solvent and a catalyst can be used as necessary. Including these solvents and catalysts, the amount of starting materials and carbonates charged, reaction temperature, reaction pressure, reaction time, etc. The reaction is carried out under conditions appropriately selected according to the kind of cyclized product to be obtained in the reaction to be produced. Usually, the carbonate is used in an amount of 1.0 to 10.0 equivalents relative to 1 equivalent of the starting material, and the reaction is carried out under the conditions of a reaction temperature of 10 to 70° C. and a reaction time of about 15 hours. be able to.

In addition, the reason why the cyclization product can be obtained in good yield without dehydration of the by-product water by carbonate esters is that the by-product water, the starting material, the cyclization product and the carbonate Based on the interaction of the esters, it is believed that the by-produced water reacts with the carbonate esters to remove the water and prevent hydrolysis of the esters. Then, the hydrazinoacetic ester derivative described below undergoes dehydration condensation to cause intramolecular cyclization to obtain a 1,3,4-substituted-pyrazole-5-carboxylic acid ester. Similar effects have been observed in other intramolecular cyclization reactions that produce cyclization products such as by-product water.
Examples of methods for producing cyclized products using intramolecular cyclization using such different starting materials include the following.

However, R is an alkyl group having 1 to 4 carbon atoms.

Next, a specific method for producing a 1,3,4-substituted-pyrazole-5-carboxylic acid ester in the present invention will be described. In the production method, a 1,3,4-substituted-pyrazole-5-carboxylic acid represented by the general formula (2) is obtained by using a carbonate ester as a dehydrating agent in the cyclization reaction of the hydrazinoacetate derivative (1). It manufactures esters. This reaction step is represented by the following reaction formula (A).

Reaction formula (A)

Here, in the compounds of formulas (1) and (2), substituents _R1 to _R3 represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and _R4 represents an alkyl group having 1 to 4 carbon atoms. represent. Examples of alkyl groups having 1 to 4 carbon atoms usually include methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, s-butyl group and t-butyl group.

The production method of the present invention can be carried out by reacting a hydrazinoacetate derivative in the presence of a base and a carbonic acid ester as a dehydrating agent at a predetermined time, at a predetermined temperature, and at a predetermined pressure.

Dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, di-t-butyl dicarbonate and the like can be used as carbonate esters that can be used as a dehydrating agent. These can be used alone or in combination of two or more. Among these, carbonate esters are preferred, and dimethyl carbonate and diethyl carbonate are particularly preferred. The amount of the dehydrating agent to be used is preferably 0.5 to 10.0 equivalents, particularly preferably 1 to 3 equivalents, relative to the substrate hydrazinoacetate derivative (1).

Bases that can be used in the reaction and serve as a so-called catalyst include alkali metal carbonates such as potassium carbonate and sodium carbonate, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium-t-butoxide, or pyridine and morpholine. , triethylamine and the like can be used. These bases can be used alone or in combination of two or more. Among these, metal alkoxides are preferred, and sodium methoxide and sodium ethoxide are particularly preferred. These metal alkoxides may be used in the form of alcohol solutions or single powders thereof. The amount of the base to be used is preferably 0.5 to 5 equivalents, particularly preferably 1.0 to 1.5 equivalents, relative to the substrate hydrazinoacetate derivative (1).

The reaction temperature is preferably 10 to 70°C, more preferably 30 to 50°C.
The reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours. Within this range of conditions, a 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be obtained with a high yield of 80% or more.
Further, as for the reaction pressure, normal pressure is preferable from the viewpoint of operability, but from the viewpoint of the vapor pressure and reaction temperature of the reaction system, it may be carried out under reduced pressure or increased pressure.

Furthermore, from the viewpoint of the solubility and reactivity of the starting materials and cyclization products, a solvent can be used as necessary. However, in general, aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic solvents, alcohol solvents, ester solvents, etc. are preferably used. More than one species can be used in combination. Specifically, methanol, ethanol and the like are preferably used in terms of dissolving the base. The amount of the solvent to be blended is preferably 50 to 100 parts by mass, more preferably about 80 parts by mass, per 100 parts by mass of the hydrazinoacetate derivative (1).

After the completion of the reaction, the reaction solution is treated by commonly known methods such as neutralization and washing and separation, and then the 1,3,4-substituted-pyrazole-5-carboxylic acid esters are isolated by distillation or other methods. can do.
Here, neutralization, washing and separation can be carried out by adding a solvent to the reaction solution, and usable solvents include the above-mentioned solvents that can be used in the reaction. In consideration of the efficiency of washing and separation, a solvent that separates from water is preferable. Therefore, it is preferable to set the amount to about 150 parts by mass.
In addition, in the treatment after the completion of the above reaction, by providing a concentration step prior to washing, that is, concentration after neutralization and then washing, the product yield can be improved by 3 to 5%, which is a valuable cyclization Incorporating a concentration step is also one of the preferred manufacturing methods to obtain the product.

The hydrazinoacetate derivative of general formula (1) can be obtained by combining hydrazines with a halogenoacetate such as bromoacetate, chloroacetate or iodoacetate according to the method described in JP-A-2008-208047. can be synthesized by reacting diacetyl after the reaction of

EXAMPLES The present invention and its embodiments will be specifically described below with reference to Examples, but the scope of the present invention is not limited by these Examples. Also, in the following examples and comparative examples, high performance liquid chromatography (HPLC) was used to calculate yields.

Reference example 1
Synthesis of 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]methyl acetate 149.7 g (3.25 mol) of monomethyl hydrazine, 520.7 g (16 .25 mol) and 296.0 g (2.93 mol) of triethylamine were added and cooled to 5° C. while stirring. 497.2 g (3.25 mol) of methyl bromoacetate was added dropwise thereto over 2 hours. The reaction was continued for 1 hour, 265.8 g (3.09 mol) of diacetyl was added dropwise over 1.5 hours, and the reaction was carried out at 10° C. for 19 hours. The resulting reaction solution was concentrated under reduced pressure, and 900.0 g of toluene and 404.8 g of water were added and stirred. The aqueous layer was removed by liquid separation, and 147.2 g of water was added to the toluene layer for washing. After removing the aqueous layer by liquid separation, the toluene layer was concentrated under reduced pressure to obtain 541.2 g of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. Yield based on methyl bromoacetate used was 74.7%.

Reference example 2
Synthesis of 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]ethyl acetate 149.7 g (3.25 mol) of monomethyl hydrazine, 748.6 g (16 .25 mol) and 296.0 g (2.93 mol) of triethylamine were added and cooled to 5° C. while stirring. 542.8 g (3.25 mol) of ethyl bromoacetate was added dropwise thereto over 2 hours. The reaction was continued for 1 hour, 265.8 g (3.09 mol) of diacetyl was added dropwise over 1.5 hours, and the reaction was carried out at 10° C. for 19 hours. The resulting reaction solution was concentrated under reduced pressure, and 900.0 g of toluene and 404.8 g of water were added and stirred. The aqueous layer was removed by liquid separation, and 147.2 g of water was added to the toluene layer for washing. After removing the aqueous layer by liquid separation, the toluene layer was concentrated under reduced pressure to obtain 551.2 g of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. Yield based on ethyl bromoacetate used was 72.0%.

Example 1
Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester using dimethyl carbonate as a dehydrating agent 247.7 g (1.28 mol) of 28% sodium methoxide methanol solution in a 2 L four-neck flask, dimethyl carbonate 192.8 g (2.15 mol) was charged, and the temperature was raised to 40° C. while stirring. 229.4 g (1.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise thereto over 2.0 hours. Subsequently, the reaction was carried out at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 129.3 g (1.24 mol) of hydrochloric acid. The neutralized solution was concentrated under reduced pressure of 10 kPa, and 345.1 g of toluene and 264.8 g of water were added and stirred. The aqueous layer was removed and the toluene layer was washed with water. After removing the washing water, the toluene layer contained 29.9% by weight of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used so far was 88.2%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 5.3%. The yield was 84.9% when the product was washed without concentration after neutralization with hydrochloric acid, and it was found that the addition of the concentration step improved the yield.

Example 2
Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid ethyl ester using diethyl carbonate as a dehydrating agent 816.6 g (2.40 mol) of 20% sodium ethoxide ethanol solution in a 3 L four-neck flask, diethyl carbonate 472.5 g (4.00 mol) was charged, and the temperature was raised to 40° C. while stirring. 479.3 g (2.00 mol) of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise thereto over 2.5 hours. Subsequently, the reaction was carried out at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 233.7 g (2.24 mol) of hydrochloric acid. To this, 654.0 g of toluene and 504.3 g of water were added and stirred. The aqueous layer was removed and the toluene layer was washed with water. After removing the washing water, the toluene layer contained 17.4% by weight of 1,3,4-trimethylpyrazole-5-carboxylic acid ethyl ester. The yield based on ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used so far was 85.3%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 6.9%.

Comparative example 1
Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester without dehydrating agent 247.7 g (1.28 mol) of 28% sodium methoxide methanol solution was charged in a 2 L four-necked flask, and stirred for 40 minutes. °C. 229.4 g (1.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise thereto over 2.0 hours. Subsequently, the reaction was carried out at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 129.3 g (1.24 mol) of hydrochloric acid. To this, 345.1 g of toluene and 264.8 g of water were added and stirred. The aqueous layer was removed and the toluene layer was washed with water. After removing the washing water, the toluene layer contained 11.5% by weight of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used so far was 25.8%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 42.8%.

Comparative example 2
Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester, the reaction is carried out after pre-dehydration 2-[(1-aza-2-methyl-3-oxobut-1-enyl ) Methylamino]methyl acetate 32.2 g (0.15 mol), toluene 10.0 g (0.11 mol) and methanol 300.0 g (9.36 mol) were charged and heated under normal pressure. A fraction of 31.3 g was collected and the water in the system was removed. After cooling with ice, 20.7 g (0.15 mol) of potassium carbonate was added and heated under reflux for 4 hours. After cooling with ice, methanol was recovered under reduced pressure, and 100 g of water and 100 g of normal hexane were added to extract organic substances. The aqueous layer was further extracted with 30 g of normal hexane, and the organic layer was mixed. The organic layer contained 1.4% by weight of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used so far was 7.1%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 70.1%.

According to the present invention, in the production of 1,3,4-substituted-pyrazole-5-carboxylic acid esters used as pharmaceutical and agrochemical intermediates, removal of water produced as a by-product during the reaction completes the reaction. It is important for obtaining the desired product in high yield by The use of carbonate esters as a dehydrating agent enables a simple dehydration operation, and the desired product can be obtained in a high yield. In addition, when an inorganic solid dehydrating agent is used to remove the water produced as a by-product during the reaction, a step of separating the dehydrating agent by filtration or the like is required after the completion of the reaction. need. On the other hand, according to the method of the present invention, it is possible to provide a simple and economical industrial production method because the troublesome complicated operations are not required. big.

Claims (2)

A method for producing a cyclized product, which comprises using a carbonate ester as a dehydrating agent in a cyclization reaction involving dehydration condensation. General formula (1)

(Wherein, R ₁ to R ₃ represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₄ represents an alkyl group having 1 to 4 carbon atoms.) General formula (2) characterized by using a carbonate ester as a dehydrating agent in the cyclization reaction

(wherein R ₁ to R ₄ have the same meanings as above).