Method for producing cyclized product by cyclization reaction involving dehydration condensation of carboxylic acid ester derivative, and method for producing 1,3,4-substituted-pyrazole-5-carboxylic acid ester

Abstract

The present invention relates to a reaction method in which a carbonic acid ester is used as a dehydrating agent in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative, and specifically relates to a method for producing an industrially applicable 1,3,4-substituted-pyrazole-5-carboxylic acid ester using a carbonic acid ester as a dehydrating agent in a reaction for cyclizing a hydrazinoacetic acid ester derivative.

Description

Method for producing cyclized products by cyclization reaction involving dehydration condensation of carboxylic acid ester derivatives, and method for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters

[0001] The present invention relates to a production method for producing cyclization products such as 1,3,4-substituted-pyrazole-5-carboxylic acid esters by a novel reaction method that can synthesize the target product in high yield without the need to remove by-produced water in a cyclization reaction accompanying dehydration condensation of a carboxylic acid ester derivative. Specifically, the present invention relates to an industrial production method using the production method for 1,3,4-substituted-pyrazole-5-carboxylic acid esters that are useful as important intermediates in the fields of medicine, agrochemicals, etc.

[0002] Conventionally, 1,3,4-substituted pyrazole-5-carboxylic acid esters have been known to be produced by chloromethylating the 4-position of 1,3-dimethylpyrazole-5-carboxylic acid ester, followed by dechlorination under reducing conditions to introduce a methyl group, as described in Patent Documents 1 and 2. However, this method has problems, such as the generation of toxic bis(chloromethyl) ether during the 4-chloromethylation reaction of 1,3-dimethylpyrazole-5-carboxylic acid ester. Furthermore, Patent Document 3 describes the synthesis of ethyl 1,3,4-trimethylpyrazole-5-carboxylate by reacting an intermediate synthesized using ethyl bromoacetate, dimethyl sulfide, and diacetyl with monomethylhydrazine. However, the process requires four steps, resulting in a low yield of 10%, and uses dimethyl sulfide, which has a foul odor.

[0003] On the other hand, Patent Document 4 describes a method for obtaining 1,3,4-trimethylpyrazole-5-carboxylic acid esters by subjecting a hydrazinoacetic acid ester derivative to a cyclization reaction in the presence of a base. In this reaction, the hydrazinoacetic acid ester derivative is subjected to azeotropic dehydration before the reaction. Furthermore, as a dehydration method other than azeotropic dehydration, the addition of an inorganic solid dehydrating agent such as calcium chloride or molecular sieves is also described. However, these dehydrating agents require a separation procedure, such as filtration, from the target product after completion of the reaction.

[0004] In Patent Documents 5 and 6, carbonate esters are used in pyrazole synthesis. However, the synthesis is carried out by a cyclization reaction of a cyanoalkene derivative or an alkoxymethylene compound with hydrazine, which is a reaction scheme different from the pyrazole synthesis of the present invention by a cyclization reaction of a hydrazinoacetic acid ester derivative, and there is no description that carbonate esters are effective as dehydrating agents.

[0005] JP 2001-342178 A JP 2008-007503 A WO 2010 / 045764 A JP 2008-208047 A JP 2001-58982 A JP 2000-212166 A

[0006] As described above, currently known methods for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters require a dehydration step from a liquid phase by azeotropic dehydration and a filtration step using an inorganic solid dehydrating agent, and are not necessarily industrially satisfactory in terms of the yield of the target product. Therefore, there has been a demand for a method for producing the compound using a dehydrating agent that does not require complicated post-treatment.

[0007] In view of the above circumstances, an object of the present invention is to provide a method for producing a cyclization product based on a new reaction with high yield, which does not require azeotropic dehydration or a filtration step using an inorganic solid dehydrating agent. One embodiment of this production method is to provide 1,3,4-substituted-pyrazole-5-carboxylic acid esters useful as pharmaceutical and agricultural intermediates by a cyclization reaction of a hydrazinocarboxylic acid ester derivative.

[0008] As a result of intensive investigations to solve the above-mentioned problems, the present inventors have found that, in a cyclization reaction involving dehydration condensation, such as obtaining a 1,3,4-substituted-pyrazole-5-carboxylic acid ester by cyclization of a hydrazinoacetate ester derivative, by using a carbonate ester in the presence of a base, the carbonate ester functions as a dehydrating agent, thereby providing a reaction method that does not require azeotropic dehydration for removing by-product water generated in the dehydration condensation reaction and increasing the yield, or a step for filtering the inorganic solid dehydrating agent used.In fact, it has been found that, when obtaining a 1,3,4-substituted-pyrazole-5-carboxylic acid ester by dehydration cyclization of a hydrazinoacetate ester derivative, by using a carbonate ester as if it were a solvent, the 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be obtained in high yield even in a state where by-product water is present in the reaction system.

[0009] In short, the present inventors have found that carbonates function as dehydrating agents when used in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative, and have also found that 1,3,4-substituted-pyrazole-5-carboxylic acid esters, which are cyclization products obtained from, for example, hydrazinoacetic acid ester derivatives, can be easily produced on an industrial scale without the need for complicated post-treatment, thereby completing the present invention.

[0010] That is, the present invention relates to a method for producing a cyclized product by using a carbonate ester as a dehydrating agent in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative, and also relates to a method for producing a pyrazole carboxylic acid ester by using a hydrazinocarboxylic acid derivative as the carboxylic acid ester derivative and forming a pyrazole ring by a cyclization reaction involving dehydration condensation. (In the formula, R １ From R ３ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ４ represents an alkyl group having 1 to 4 carbon atoms, and a carbonate ester is reacted with the hydrazinoacetic acid ester derivative represented by the general formula (2): (In the formula, R１ From R ４ has the same meaning as above.)

[0011] By using a carbonate ester in the cyclization reaction accompanying dehydration condensation of a carboxylic acid ester derivative of the present invention, it is possible to eliminate the need for azeotropic dehydration or the use of an inorganic solid dehydrating agent and a filtration step therefor in order to increase the yield, and thus provide an industrial method for producing a cyclized product that can produce the cyclized product in high yield.In addition, in the method for producing a 1,3,4-substituted-pyrazole-5-carboxylic acid ester from a hydrazinoacetic acid ester derivative of the present invention by a cyclization reaction accompanying dehydration condensation, the use of a carbonate ester as a dehydrating agent serves as an effective dehydrating agent for water that is by-produced in the reaction, thereby eliminating the need for the azeotropic dehydration step or the filtration step for the inorganic solid dehydrating agent, and providing a simple and convenient method that enables the cyclized compound to be produced industrially and more advantageously.

[0012] The production method of the present invention will be described in more detail below. The present invention relates to a method for producing a cyclization product, in which a carbonate ester is used as a dehydrating agent in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative. The cyclization reaction of the present invention involves dehydration condensation, and is, for example, a reaction as shown in Reaction Formula (A) below, in which a hydrazinoacetic acid ester derivative (1), a carboxylic acid ester derivative, is used as a starting material. In the presence of a base, the hydrogen at the α-position of the acetate ester is abstracted to form an enolate, which then attacks the carbon of the carbonyl group, resulting in intramolecular cyclization with water as a by-product. Examples of such intramolecular cyclization reactions include intramolecular aldol reactions. The "cyclization product" referred to in the present invention is a compound obtained by a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative, in which intramolecular cyclization has occurred to form a ring, and the carboxylic acid ester from the starting material remains, and is a compound having a carboxylic acid ester and a ring structure, and is usually the compound to be produced.

[0013] Examples of carbonate esters that can be used as dehydrating agents include dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, and di-t-butyl dicarbonate. These carbonate esters can be used either alone or in combination of two or more.

[0014] As for the reaction method, the carbonate ester can be used as if it were a solvent. When a solvent is used, the carbonate ester can be added together with the starting materials to the reaction system, or when no solvent is used, the carbonate ester can be added alone to the reaction system, and the starting materials can be reacted as is. This simple reaction method does not require a dehydration operation such as azeotropic dehydration or an operation for removing by-product water generated by dehydration condensation, such as the use and removal of an inorganic solid dehydrating agent, and allows the cyclization product to be produced.

[0015] In addition, a solvent and a catalyst can be used in the reaction as needed, but the reaction conditions, including the amounts of the starting materials and carbonate esters charged, as well as the reaction temperature, reaction pressure, and reaction time, are appropriately selected depending on the type of cyclization product to be obtained by the reaction. Typically, the reaction can be carried out using 0.5 to 10.0 equivalents of carbonate esters per equivalent of the starting materials, at a reaction temperature of −10 to 130° C. for a reaction time of about 1 to 15 hours.

[0016] The reason why the use of carbonate esters allows for the production of cyclized products in high yields without the need for dehydration of the by-product water is presumably because, compared to the starting materials and the cyclized products, the hydrolysis of carbonate esters proceeds very rapidly, and the by-product water reacts preferentially with the carbonate esters, consuming the water and promoting the reaction while preventing hydrolysis of the carboxylic acid ester. Furthermore, in the presence of a base, carbonate esters reacting with water form stable carbonates, which presumably prevents side reactions such as hydrolysis of the starting materials and the cyclized products. This is also observed in the reaction described below in which a hydrazinoacetic acid ester derivative undergoes intramolecular cyclization to obtain a 1,3,4-substituted-pyrazole-5-carboxylic acid ester. It has also been observed that the same is true for other reactions to produce cyclized products by intramolecular cyclization reactions that generate by-product water by dehydration condensation of a carboxylic acid ester derivative, which have a similar reaction mechanism. Among the methods for producing cyclized products using such carboxylic acid ester derivatives, examples of methods for producing cyclized products by intramolecular cyclization reactions using different starting materials include the following: Here, R is an alkyl group having 1 to 4 carbon atoms.

[0017] Next, a specific method for producing a 1,3,4-substituted-pyrazole-5-carboxylic acid ester according to the present invention will be described. This method produces a 1,3,4-substituted-pyrazole-5-carboxylic acid ester represented by general formula (2) by using a carbonate ester as a dehydrating agent in the cyclization reaction of a hydrazinoacetate ester derivative (1). This reaction process is shown in the following reaction formula (A). Here, in the compounds of formula (1) and (2), the substituent R １ From R ３ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ４ represents an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a s-butyl group, and a t-butyl group.

[0018] The production method of the present invention can be carried out by reacting a hydrazinoacetic acid ester derivative in the presence of a base and a carbonate ester as a dehydrating agent for a predetermined time at a predetermined temperature and under a predetermined pressure.

[0019] Carbonate esters that can be used as dehydrating agents include dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, and di-t-butyl dicarbonate. These can be used alone or in combination of two or more. Among these, carbonate esters are preferred, with dimethyl carbonate and diethyl carbonate being particularly preferred. The amount of dehydrating agent used is preferably 0.5 to 10.0 equivalents, and particularly preferably 1 to 3 equivalents, relative to the substrate hydrazinoacetic acid ester derivative (1).

[0020] Examples of bases that can be used in the reaction and serve as catalysts include alkali metal carbonates such as potassium carbonate and sodium carbonate, metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide, and organic bases such as pyridine, morpholine, and triethylamine. These bases can be used alone or in combination of two or more. Among these, metal alkoxides are preferred, with sodium methoxide and sodium ethoxide being particularly preferred. These metal alkoxides may be used in the form of alcohol solutions or simple powders. The amount of base used is preferably 0.5 to 5 equivalents, and particularly preferably 1.0 to 1.5 equivalents, relative to the substrate hydrazinoacetic acid ester derivative (1).

[0021] The reaction temperature is preferably −10 to 130° C., more preferably 30 to 50° C. The reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours. Within these conditions, a 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be obtained in a high yield of 80% or more. Furthermore, with regard to the reaction pressure, it is preferable to carry out the reaction at normal pressure from the viewpoint of operability, but in view of the vapor pressure of the reaction system and the reaction temperature, it is also acceptable to carry out the reaction under reduced or increased pressure.

[0022] Furthermore, a solvent can be used as needed from the viewpoint of the solubility and reactivity of the starting materials and the cyclization product. The solvent to be used will vary depending on the types of starting materials and the cyclization product, but generally, aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic solvents, alcohol solvents, ester solvents, etc. are preferably used, and these solvents can be used alone or in combination of two or more. Specifically, methanol, ethanol, etc. are preferably used from the viewpoint of dissolving the base. The amount of solvent to be used is preferably 50 to 100 parts by mass, and more preferably about 80 parts by mass, per 100 parts by mass of the hydrazinoacetic acid ester derivative (1).

[0023] After completion of the reaction, the reaction solution can be treated by commonly known methods such as neutralization and washing and separation, and then the 1,3,4-substituted-pyrazole-5-carboxylic acid esters can be isolated by known separation methods such as distillation and crystallization. Here, during neutralization, washing and separation, a solvent can be added to the reaction solution. Examples of solvents that can be used include the solvents described above that can be used in the reaction. Taking into consideration the efficiency of washing and separation, a solvent that separates from water is preferred, and the amount of solvent is preferably about 150 parts by mass per 100 parts by mass of the resulting 1,3,4-substituted-pyrazole-5-carboxylic acid esters. Distillation and crystallization can be carried out by commonly known methods. For example, in the case of distillation, the conditions may be selected depending on the physical properties of the target product and are not particularly limited. However, in an apparatus equipped with a distillation column, the heating temperature is preferably 30 to 300°C, more preferably 50 to 180°C. Furthermore, the pressure is preferably from atmospheric pressure of 760 torr to high vacuum of 0.1 torr, more preferably 500 torr to 1 torr. The number of plates in the distillation column is preferably 5 to 40, more preferably 10 to 30. The reflux ratio is preferably 1 to 40, more preferably 2 to 20. Furthermore, if crystals precipitate due to cooling or concentration of the reaction solution, the precipitated crystals can be separated and isolated using a centrifuge or the like. The separation temperature is preferably 40 to −10°C, more preferably 30 to −5°C. The heating temperature for concentration is preferably 30 to 300°C, and the pressure is preferably atmospheric pressure of 760 torr to 10 torr. The 1,3,4-substituted-pyrazole-5-carboxylic acid ester of this embodiment can generally be distilled at about 40 to 3 torr and 80 to 140°C, although this varies depending on the type of ester. In addition, in the treatment after completion of the above reaction, by performing a concentration step prior to washing, i.e., neutralization followed by concentration and subsequent washing, the product yield can be improved by 3 to 5%. It has also been found that incorporating a concentration step is one of the preferred production methods for obtaining valuable cyclized products.

[0024] The hydrazinoacetic acid ester derivative of general formula (1) can be synthesized in accordance with the method described in JP-A-2008-208047 by reacting a hydrazine with a halogenoacetic acid ester such as a bromoacetic acid ester, a chloroacetic acid ester, or an iodoacetic acid ester, followed by reaction with diacetyl.

[0025] The present invention and its embodiments will be described in detail below with reference to examples, but the scope of the present invention is not limited to these examples. In the following examples and comparative examples, high performance liquid chromatography (HPLC) was used to calculate yields.

[0026] Reference Example 1 Synthesis of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate 149.7 g (3.25 mol) of monomethylhydrazine, 520.7 g (16.25 mol) of methanol, and 296.0 g (2.93 mol) of triethylamine were charged into a 2 L four-neck flask and cooled to 5°C with stirring. To this was added 497.2 g (3.25 mol) of methyl bromoacetate dropwise over 2 hours. The reaction was continued for 1 hour, and then 265.8 g (3.09 mol) of diacetyl was added dropwise over 1.5 hours, followed by a reaction 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 separation, and 147.2 g of water was added to the toluene layer, followed by washing. The aqueous layer was removed by separation, and the toluene layer was concentrated under reduced pressure to give 541.2 g of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. The yield based on the methyl bromoacetate used was 74.7%.

[0027] Reference Example 2 Synthesis of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate A 3 L four-neck flask was charged with 149.7 g (3.25 mol) of monomethylhydrazine, 748.6 g (16.25 mol) of ethanol, and 296.0 g (2.93 mol) of triethylamine, and the mixture was cooled to 5°C with stirring. To this was added dropwise 542.8 g (3.25 mol) of ethyl bromoacetate over 2 hours. The reaction was continued for 1 hour, and then 265.8 g (3.09 mol) of diacetyl was added dropwise over 1.5 hours, followed by a reaction 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 the mixture was stirred. The aqueous layer was removed by separation, and 147.2 g of water was added to the toluene layer, followed by washing. The aqueous layer was removed by separation, and the toluene layer was concentrated under reduced pressure to give 551.2 g of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. The yield based on the ethyl bromoacetate used was 72.0%.

[0028] 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 a 28% sodium methoxide methanol solution and 192.8 g (2.15 mol) of dimethyl carbonate were charged into a 2 L four-neck flask and heated to 40°C with stirring. 229.4 g (1.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.0 hours. The reaction was continued 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 the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 88.2%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 5.3%. When the mixture was neutralized with hydrochloric acid and washed without concentration, the yield was 84.9%, demonstrating that the addition of the concentration step improved the yield.

[0029] 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 a 20% sodium ethoxide ethanol solution and 472.5 g (4.00 mol) of diethyl carbonate were charged into a 3 L four-neck flask and heated to 40°C with stirring. 479.3 g (2.00 mol) of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.5 hours. The reaction was continued 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. 654.0 g of toluene and 504.3 g of water were added to the mixture 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 the ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 85.3%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 6.9%.

[0030] Comparative Example 1 Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester without using a dehydrating agent 247.7 g (1.28 mol) of 28% sodium methoxide methanol solution was charged into a 2 L four-neck flask and heated to 40°C with stirring. 229.4 g (1.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.0 hours. The reaction was continued 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. 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 wash water, the toluene layer contained 11.5 wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 25.8%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 42.8%.

[0031] Comparative Example 2: Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester by dehydration prior to reaction. 32.2 g (0.15 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate, 10.0 g (0.11 mol) of toluene, and 300.0 g (9.36 mol) of methanol were charged into a 500 ml four-neck flask and heated under atmospheric pressure. 31.3 g of a distillate was collected and the water in the system was removed. After ice cooling, 20.7 g (0.15 mol) of potassium carbonate was added and the mixture was heated under reflux for 4 hours. After ice cooling, the methanol was recovered under reduced pressure, and 100 g of water and 100 g of normal hexane were added to extract the organic matter. The aqueous layer was further extracted with 30 g of normal hexane, and the organic layer was mixed. The organic layer contained 1.4 wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 7.1%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 70.1%.

[0032] Comparative Example 3: A 2-L four-neck flask was charged with 247.7 g (1.28 mol) of a 28% sodium methoxide methanol solution and 227.1 g (2.14 mol) of methyl orthoformate, and the temperature was raised to 40°C with stirring. To this was added 229.4 g (1.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate dropwise over 2.0 hours. The reaction was then carried out at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 107.4 g (1.03 mol) of hydrochloric acid. 345.1 g of toluene and 264.8 g of water were added to this and stirred. The aqueous layer was removed, and the toluene layer was washed with water. After removing the wash water, the toluene layer contained 11.7 wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 25.5%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 45.3%.

[0033] Comparative Example 4: A 500 ml four-neck flask was charged with 93.4 g (0.48 mol) of a 28% sodium methoxide methanol solution and 35.2 g of methanol (MeOH), and 24.4 g (0.22 mol) of calcium chloride was added with stirring. The temperature was then raised to 40°C, and 51.4 g (0.22 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 4.0 hours. The reaction was then continued at 40°C for 5 hours. After the reaction, the yield of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester based on methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was 61.4%. Furthermore, the production of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was very small (0.1% or less), but 5.2% of the raw material methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate remained, possibly because the reaction did not proceed due to the influence of calcium chloride used as a dehydrating agent.

[0034] Comparative Example 5: A 300 ml four-neck flask was charged with 14.0 g (0.07 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate and 44.9 g of methanol, and with stirring, 16.2 g (0.08 mol) of sodium methoxide and 9.9 g (0.07 mol) of sodium sulfate were added. The temperature was then raised to 40°C, and the reaction was continued at 40°C for 4 hours. After the reaction, the yield of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester based on methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was 54.3%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 23.0%.

[0035] The above examples and comparative examples reveal the following. Specifically, Comparative Example 1 shows that in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative, the cyclization product contains a carboxylic acid ester, and the water by-produced by dehydration hydrolyzes this carboxylic acid ester to form a carboxylic acid, resulting in a reduced yield of the desired carboxylic acid ester. In contrast, when a carbonate ester is used as a dehydrating agent in the reaction as in Examples 1 and 2, the carbonate ester consumes the by-produced water and is hydrolyzed, so that the carboxylic acid ester of the cyclization product remains as a carboxylic acid ester without being hydrolyzed, thereby producing the desired cyclization product in high yield. It can be seen from the results that, compared to Examples 1 and 2, a significantly larger amount of the carboxylic acid ester in the cyclization product of Comparative Example 1 is converted to a hydrolyzed carboxylic acid; conversely, the yield of the desired cyclization product is significantly lower.

[0036] On the other hand, even if water was removed from the system before the cyclization reaction as in Comparative Example 2, there was no dehydration effect, and in the obtained cyclization product, many of the carboxylic acid esters were hydrolyzed into carboxylic acids, and it was found that the yield of the cyclization product having the desired carboxylic acid ester was low. Furthermore, even if an organic dehydrating agent or an inorganic solid dehydrating agent other than carbonate esters was used in the cyclization reaction as in Comparative Examples 3, 4, and 5, a significant improvement in yield was not achieved, and the yield was low and the dehydration effect was insufficient, resulting in many of the cyclization products in which the carboxylic acid esters were hydrolyzed into carboxylic acids.

[0037] These findings demonstrate that the use of a carbonate ester as a dehydrating agent allows the cyclization reaction to proceed sufficiently, and also prevents the ester group in the resulting cyclization product from being hydrolyzed to a carboxylic acid, allowing the production of a cyclized compound having an ester (an ester of 1,3,4-trimethylpyrazole-3-carboxylic acid) in high yield.

[0038] According to the present invention, in the production of 1,3,4-substituted-pyrazole-5-carboxylic acid esters used as pharmaceutical and agrochemical intermediates, removing water generated as a by-product during the reaction is important for completing the reaction and obtaining the target product in high yield. The use of carbonate esters as dehydrating agents enables a simple dehydration procedure, allowing the target product to be obtained in high yield. Furthermore, when an inorganic solid dehydrating agent is used to remove the water generated as a by-product during the reaction, a step of separating the dehydrating agent by filtration or the like is required after the reaction is completed, which requires a great deal of labor and time for mass production. On the other hand, the method of the present invention does not require the problematic complicated operations, making it possible to provide a simple and economical industrial production method, and the present invention is of great significance in the pharmaceutical and agrochemical fields.

Claims

1. A method for producing a cyclization product of a carboxylic acid ester derivative, characterized in that a carbonate ester is used as a dehydrating agent in a cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative.

2. A method for producing pyrazole carboxylates, comprising using a carbonate as a dehydrating agent in a pyrazole ring-forming reaction by cyclization accompanied by dehydration condensation of a hydrazinocarboxylate derivative.

3. General formula (1) (In the formula, R １ From R ３ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ４ represents an alkyl group having 1 to 4 carbon atoms. In the cyclization reaction of a hydrazinoacetate derivative represented by the general formula (2), a carbonate ester is used as a dehydrating agent. (In the formula, R １ From R ４ has the same meaning as above.

4. The method for producing a cyclization product according to claim 1, wherein the amount of carbonate ester used in the cyclization reaction involving dehydration condensation of a carboxylate derivative is 0.5 to 10 equivalents.

5. A method for producing the cyclization product according to claim 1, characterized in that a carbonate ester is used in the presence of a base in the cyclization reaction involving dehydration condensation of a carboxylate derivative.

6. The method for producing a cyclization product according to claim 5, wherein the amount of base used in the cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative is 0.5 to 5 equivalents.

7. The method for producing the cyclization product according to claim 1, wherein the reaction temperature in the cyclization reaction involving dehydration condensation of a carboxylic acid ester derivative is -10 to 130°C.

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